CZ20003113A3 - Phospholipase inhibitors - Google Patents

Abstract

The phospholipase inhibitors described in the application are chemical inhibitors of the activity of various phospholipases, especially type A2 enzymes. The substances can be used in the form of pharmaceutical compositions, which also form part of the solution, for the treatment of conditions that can be beneficially affected by phospholipase inhibition, in particular various inflammatory conditions.

Description

Technical area

The invention relates to chemical inhibitors of various phospholipases, especially from the group of phospholipases A ₂ .

State of the art

Leukotrienes and prostaglandins are important mediators of inflammation, and each contributes to the development of the inflammatory response in a different way. Leukotrienes attract inflammatory cells, such as neutrophils, to the site of inflammation, promote the egress of these cells from the blood vessels, and also release superoxide and proteases, which destroy tissue. Leukotrienes also play a pathophysiological role in hypersensitivity in asthmatics, according to B. Samuelson et al., Science, 237: 117176, 1987. Prostaglandins promote inflammatory responses by increasing blood flow, which then leads to infiltration of white blood cells into the site of inflammation. Prostaglandins also increase the pain of the site of inflammation.

Prostaglandins and leukotrienes are unstable and are not stored in cells, but are synthesized from arachidonic acid in response to various stimuli according to W. L. Smith, Biochem. J., 259, 315-324, 1989. Prostaglandins are produced from arachidonic acid by the action of the enzymes COX-1 and COX-2. Arachidonic acid is also a substrate for the enzymatic reaction that leads to leukotriene production.

Arachidonic acid, which is fed into these different inflammatory reactions, is released from the sn-2 position in the phospholipid membrane by the action of phospholipase A ₂ enzymes, which will be referred to as PLA ₂ hereinafter. The reaction catalyzed by PLA ₂ enzymes is probably the rate-limiting step in lipid-mediated biosynthesis and thus the rate-limiting step in the production of prostaglandins and leukotrienes, which promote inflammation. In the case where the phospholipid substrate of PLA ₂ is a phosphatidylcholine group with an ether bond in the sn-1 position, the resulting lysophospholipid is the immediate precursor of platelet-activating factor, PAF, which is another effective mediator of inflammatory reactions according to the publication SI Wasserman, Hospital Practice, 15: 49-58, 1988.

Most anti-inflammatory therapies have been directed at preventing the production of prostaglandins or leukotrienes by these metabolic pathways, but not all of them simultaneously. For example, commonly prescribed agents such as ibuprofen, aspirin, and indomethacin are NSAIDs that inhibit prostaglandin production by COX-1 and COX-2, but have no effect on the production of leukotrienes from arachidonic acid by other pathways. On the other hand, zileuton only inhibits the conversion of arachidonic acid to leukotrienes without affecting prostaglandin production. None of these widely used anti-inflammatory agents affect PAF production.

Direct inhibition of PLA ₂ activity was considered a suitable mechanism of action for drug substances, as it interferes with the inflammatory response according to

publication J. Chang et al., Biochem. Pharmacol., 36, 2429-2436, 1987.

The PLA ₂ group of enzymes, characterized by the presence of a signal sequence for secretion and secreted from cells, has been studied in detail and structurally defined including the entire sequence. This type of PLA ₂ had a molecular weight of approximately 14,000 and contained several disulfide bonds, necessary for the activity of the enzymes. The enzymes are found in large quantities in the pancreas of mammals, in bee venom and in various snake venoms, as shown, for example, in literature citations 13 to 15 of the above-mentioned publication by Chang et al. and also in the publication by EA Dennis, Drug Devel. Res., 10, 205-220, 1987. However, the pancreatic enzyme probably has a digestive function and for this reason does not participate in the inflammatory reaction.

The primary structure of the first non-pancreatic enzyme PLA ₂ in humans has also been determined. This non-pancreatic enzyme is found in platelets, synovial fluid and spleen and is also secreted. It is an enzyme from the above-mentioned group of enzymes according to the publications of JJ Seilhamer et al., J. Biol. Chem., 264, 5335-5338, 1989, RM Kramer et al., J. Biol. Chem., 264, 57685775, 1989 and A. Kando et al., Biochem. Biophys. Res. Comm. 163, 42-48, 1989. However, it is doubtful whether this enzyme is important for the synthesis of prostaglandins, leukotrienes and PAF, since this non-pancreatic type of PLA ₂ is an extracellular protein that would be difficult to control and the other enzymes involved in the biosynthesis of these compounds are intracellular proteins. In addition, evidence has already been presented that PLA ₂ enzymes are controlled by protein kinase C and G proteins according to the publication R. Burch and J. Axelrod, Proc.

·* ·· ··

Natl. Acad. Sci, USA, 84, 6374-6378, 1989, are cytosolic proteins that must act on intracellular proteins. For the non-pancreatic enzyme PLA ₂ , it is impossible to act in the cytosol because the high reduction potential would reduce disulfide bonds while inactivating the enzyme.

The mouse PLA ₂ enzyme was identified from a mouse macrophage cell line, designated RAW 264.7. A specific activity of 2 mol/min/mg was associated with molecules of approximately 60,000 molecular weight, and the enzyme was resistant to reducing conditions. However, this enzyme has not been purified to homogeneity, as reported in CC Leslie et al., Biochem. Biophys. Acta, 963, 476-492, 1988. The above references are provided for background information on the function of phospholipases, particularly PLA ₂ .

Cytosolic phospholipase A ₂ , hereinafter referred to as cPLA ₂ , has also been identified and the enzyme has been cloned as described in US 5,322,776 and US 5,354,677 . The enzymes of these patents are intracellular PLA ₂ enzymes, purified from their natural sources or otherwise obtained in purified form, the enzymes act inside cells and promote the production of arachidonic acid in response to inflammatory stimuli.

Several types of phospholipases have now been identified, and it would be desirable to identify chemical inhibitors of the activity of these enzymes that could be used to treat inflammatory conditions, particularly where inhibition of the production of prostaglandins, leukotrienes and PAF is desired. There remains a need in the art to identify

• · · · for medicinal use in disease.

other anti-inflammatory agents at various stages of inflammation

The essence of the invention

The invention consists of phospholipase inhibitors of the general formula

Rs where

Ri and Rv independently represent a hydrogen atom, a halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, -S-Cl-ClOalkyl, preferably -S-Cl-C6alkyl, Cl-ClOalkoxy, preferably Cl-C6alkoxy, -CN, -NO ₂ , -NH ₂ , -HN(Cl-C6alkyl), -N(Cl-C6alkyl) 2 , phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or any of the groups

• · ·· 44 • · 4 • 4

R6 represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, _-NO2 , _-NH2 ,

-CN, -CF ₃ or -OH,

R7 represents -OH, -CF3, C1-C6alkyl, C1-C6alkoxy,

-NH-(Cl-C6alkyl), -N-(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl Cl-C6alkoxy group, -N0 ₂ , -NH ₂ ,

-CN, -CF ₃ or -OH,

R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy, preferably Cl-C6alkoxy, -CHO, -CN, -NO ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -SO ₂ -Cl-C6alkyl,

R ₃ is selected from the group of hydrogen atom, -CF ₃ , C 1-C 6 alkyl, C 1-C 6 alkoxy group, C 3-C 10 cycloalkyl, C 1-C 6 alkylC 3-Cl 0 cycloalkyl, -CHO, halogen atom or L ² -M ² group,

L ² represents a linking or bridging group of the formula -(CH ₂ ) n -, -S-, -0-, -C(0)-, - (CH ₂ ) _n -C (0)-, -(CH ₂ ) _n -C(O)-(CH ₂ ) _n - or - (CH ₂ ) „-S- (CH ₂ ) _n -, -C(O)C(O)X, where X represents an oxygen or nitrogen atom, • · · ·

M ² is selected from the group C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, phenyl or benzyl, wherein the phenyl, benzyl and cycloalkyl rings are optionally substituted with 1 to 3 substituents from the group halogen atom, C1-ClOalkyl, preferably C1-C6alkyl,

C1-C10 alkoxy, preferably C1-C6 alkoxy, -N0 ₂ , -NH ₂ , -CN or -CF 3 or means

a) a 5-membered heterocyclic ring, containing in the ring 1 or 2 heteroatoms from the group N, S or O, for example furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolidinyl or tetrazolyl, the 5-membered heterocyclic ring is optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-ClOalkyl, preferably Cl-C6alkyl Cl-ClOalkoxy group, preferably Cl-C6alkoxy group, _-NO2 , _-NH2 , -CN or -CF3 or means

b) a 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms from the group N, S or O in the ring, for example pyridinyl, pyrimidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 3 substituents from the group halogen atom, C1-C10alkyl, preferably C1-C6alkyl, C1-C10alkoxy, preferably C1-C6alkoxy, _-N02 , _-NH2 , -CN, -CHO, -OH or _-CF3 or means

c) a bicyclic ring group containing 8 to 10 atoms in the rings and optionally 1 to 3 heteroatoms from the group N, S or O, for example benzofuranyl, indolyl, indolinyl, naphthalenyl, purinyl or quinolinyl, wherein the bicyclic ring group is optionally substituted with 1 to 3 substituents from the group halogen atom, C1-C10alkyl, preferably C1-C6alkyl, C1-C10alkoxy group, preferably C1-C6alkoxy group, _-NO2 , _-NH2 , -CN, -CHO, -OH or -CF3, n represents an integer from 0 to 3,

R ₄ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) _n ^- C3-C6cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C5cycloalkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -C3-C5cycloalkyl or any of the groups

a) - (CH ₂ ) η-phenyl-O-phenyl, - (CH ₂ ) n ^_ phenyl-CH ₂ -phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) ₂ , -CH ₂ ~ -phenyl-C(0)-benzothiazolyl or groups of the formula:

(CH ₂ ),r.

(CH ₂ )^ where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2,

Y represents C3-C5cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy, _-NH2 , _-N02 or

5-membered heterocyclic ring, containing 1 heteroatom from the group N, S or O, preferably S or O or

b) groups of the formula -(CH ₂ ) _n -A, -(CH ₂ ) _n -SA, or - (CH ₂ ) n ^- 0-A, where A means a group

Dc where • ·

D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or -CF3,

B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2, substituents from the group of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy or -NO 2 or

c) formula groups

where

Z is O or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group consisting of halogen, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy, _-NH2 or _-NO2 ,

R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) n-COOH, -CH=CH-COOH, - (CH ₂ ) _n -tetrazolyl, '(C _r C ₆ •(C _r C ₆ haloalkyl) alkyl)

N'

O

—P—OH 11 O

S-OH

II or a group of the formula -L ¹ -M ¹ , where L ¹ is a bridging or connecting group from the group of single chemical bonds -(CH ₂ ) _n -S~, -0-, -C(0)-, -(CH ₂ )nC(0)-, - (CH ₂ ) _n -C (0)~(CH ₂ ) _n -, -(CH ₂ )nO-(CH ₂ ) _n -, -(CH ₂ ) _n -S-(CH ₂ ) _n -, -C(Z)-N(R ₆ )-, -C(Z)-N(R ₆ )-(CH ₂ ) _n -,

-C (0)-C (Z)-N (R ₆ )-, -C(O)-C(Zj-N(R ₆ )-(CH ₂ ) _n -, -C(Z)-NH-SO ₂ or -C(Z)-NH-SO ₂ -(CH ₂ ) _n -,

M ¹ is selected from the group -COOH, - (CH ₂ ) _n ~COOH, - (CH ₂ ) _n -C (0) -COOH, tetrazolyl or one of the groups

* «

where Rg, Rg or Rio can be attached at any point of the cyclic or bicyclic system,

Rg is independently selected from the group consisting of hydrogen, -COOH,

- (CH ₂ ) n-COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazolyl,

OH

Rg is selected from the group of hydrogen or halogen, _-CF3 , -OH, -COOH, -( _CH2 ) _n- COOH, -( _CH2 ) _n -C(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ ,

R 10 is selected from the group consisting of hydrogen or halogen, -CF 3 , -OH, - (CH ₂ ) n -COOH, - (CH ₂ ) _n -C (0) -COOH, Cl-C 6 alkyl, -0-C 1 -C 6 alkyl, -NH(Cl-C 6 alkyl or -N(Cl-C 6 alkyl) ₂ , ♦ tt tt ·· ·· ·· · ··· · · · · · · · · · · · · · · • tt ·· tttttt • tt··· ···· · · · · · • ••tt ··· ·· ttttttt ··

• · ♦ · hydrogen, Cl-C6alkyl, Cl- (CH ₂ ) _n -COOH, -(CH ₂ )nC(O) • · • fr • ••fr fr • fr fr···

Rn is selected from the group consisting of -C6cycloalkyl, -CF3, -COOH, -COOH,

provided that the complete group at position 1 of the indole or indoline group, formed by any combination of groups R ₅ , Rs, Rg, R10 and/or Rn, will contain at least one group of acidic nature selected from the group of carboxyl, tetrazolyl or a group of the formula

n represents an integer from 0 to 3, as well as pharmacologically acceptable salts thereof.

It is clear that the substituents R3 and _R4 are attached to the indole or indoline rings at positions 2 or 3 and the groups Ri, Rp and _R2 are attached to said rings at positions 4, 5, 6 or 7 on the carbon atoms.

• ·

One group of compounds according to the invention consists of those substances in which R1 and R3 represent hydrogen atoms and the other symbols have the meanings given above.

Another group of compounds according to the invention consists of those substances in which Rv and R3 represent hydrogen atoms and the groups Ri, _R4 and R5 have the above-mentioned meaning. These substances can be further divided into two preferred groups, in the first of which the group Ri is bound in the 5-position and in the second the group Ri is bound in the 6-position of the indole or indoline ring.

Another preferred group of compounds according to the invention consists of those substances in which R _x is located in the 5-position of the indole or indoline ring and represents a benzyloxy group, R ₂ and R ₄ represent hydrogen atoms and R 3 and R 5 have the above-mentioned meaning.

In another preferred group of compounds according to the invention, R _x represents a cyclopentylcarboxamide group or a cyclopentyloxycarbonylamino group in position 5 or 6 of the indole or indoline ring, R ₂ and R ₄ represent hydrogen atoms and R 3 and R 5 have the above-mentioned meaning.

Another preferred group of compounds according to the invention consists of those substances in which the symbols R1 and _R2 are bonded in position 5 or 6 of the indole or indoline ring and represent a C1-C6 alkoxy group, a cyano group, a sulfonyl group or a halogen atom, _R2 and _R4 represent hydrogen atoms and R3 and R5 have the above-mentioned meaning.

• · ¹⁵ ..·.. .:.

Within each of these preferred groups, there is a preferred subgroup in which the core molecule is an indole group, which is more preferred than an indoline group.

Preferred compounds according to the invention are compounds of the general formulae

where

R1 represents a hydrogen or halogen atom, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy, _-NO2 , _-NH2 , -HN(C1-C6alkyl), -N(C1-C6alkyl) ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl or any of the groups

Re means a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, a phenyl, -O-phenyl, a benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, _-NO2 , _-NH2 , _-CF3 or -OH,

R ₇ represents - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) ₂ , -(CH ₂ ) _n -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy group, -NH ₂ , -N0 ₂ , -CF ₃ or -OH,

R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy, preferably Cl-C6alkoxy, -CHO, -CN, -NO ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -SO ₂ -Cl-C6alkyl,

R ₃ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) _n -C3-C6cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C6cycloalkyl or one of the groups

a) - (CH ₂ ) η-phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) ₂ , -CH ₂ -phenyl-C(O)benzothiazolyl or any of the groups

(CH ₂ ) n\

Ť • · • · • ·

···· where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2,

Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-NO2 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or

b) groups of the formula -(CH ₂ ) _n -A, -(CH ₂ ) _n ^_ SA, or - (CH ₂ ) _η ~θ ^-Α Λ where A means group 1

Where?

D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or -CF3,

B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2, substituents from the group of hydrogen or halogen, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy or _-NO2 or

c) formula groups

•About ·» «· ► » · «

wherein the phenyl and pyrimidinyl rings in each group are optionally and independently substituted with 1 to 3 substituents selected from the group consisting of halogen, -CF ₃ , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -N0 ₂ ,

R ₄ is selected from the group consisting of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl,

-C(O)-benzyl, -CH ₂ -(C3-C6cycloalkyl), -C(O)-OH, -CH=O,

-C (0)-Cl-C6 alkyl, -C (O)-O-Cl-C6 alkyl, -C(O)-CF ₃ , -(CH ₂ ) _n —S—CH ₂ —(C3-C6 cycloalkyl),

wherein the phenyl and benzyl rings of the respective R ₃ groups are optionally substituted with 1 to 3 groups from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ ,

-CF ₃ , -C(O)-OH or -OH, n is an integer from 0 to 3,

R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n -C(0)-COOH, -(CH ₂ ) _n -COOH, -CH=CH-COOH,

00 • 00 00 00 0 • 0 00 0 • 0 0 0 • 00 • 0 0 0 0 • 0 • • • 0 0 0 0 0 0 • ···· 000 00 00*0 ·· 000

l

Rg is H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O)-COOH, tetrazolyl, y>-p-oH ' o

Oh

Rg represents a hydrogen or halogen atom, -CF₃, -OH, -(CH₂)_n -COOH, -(CH₂)_n-C (O)-COOH, Cl-C6alkyl, -O-Cl-C6alkyl,

-NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ ,

R10 represents a hydrogen or halogen atom, _-CF3 , -OH, -( _CH2 ) _n -COOH, -( _CH2 ) _n -C(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl,

-NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ ,

alkyl).

Ru represents a hydrogen atom, C1-C6alkyl, _-CF3 , -COOH, -(CH2) _n ~-COOH, -( _CH2 ) _n -C(0)-COOH or a group

provided that the complete group at position 1 of the indole or indoline ring, formed by any combination of groups R ₅ , R 5 , R 9 , R 10 and/or R n , will contain at least one acidic group selected from a carboxylic acid residue, a tetrazolyl group or a group of the formula

as well as pharmaceutically acceptable salts thereof.

• * · · • · ···· ·

Another group of compounds according to the invention consists of compounds of the general formulas

where

R1 represents a hydrogen or halogen atom, _-CF3 , -OH, C1-C6alkyl, C1-C6alkoxy, _-N02 , _-NH2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a group of the formula

R6 represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group atom • 0

-CF ₃ or

- (CH ₂ ) _n 23 - :

••«0 00 halogen, Cl-C6 alkyl, Cl-C6 alkoxy group, -N0 ₂ ,

-OH,

R ₇ means - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N-(C 1 -C 6 alkyl) ₂ ,

-NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -N0 ₂ , -CF ₃ or -OH,

R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy, preferably Cl-C6alkoxy, -CHO, -CN, -NO ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -S0 ₂ -Cl-C6alkyl,

R ₃ is selected from the group of hydrogen or halogen, -CF ₃ ,

-OH, Cl-C6alkyl, Cl-C6Alkoxy, Benzyl, Benzyloxy, Phenyl, Phenyloxy, -C(O)-phenyl,

-C(O)-benzyl, -CH ₂ -(C3-C6cycloalkyl), -C(O)-OH, -CH=O, -C(0)-Cl-CSalkyl, -C (0)-O-Cl-C6alkyl, -C(O)-CF ₃ , - (CH ₂ ) _n -S-CH ₂ -(C3-C6cycloalkyl),

wherein the phenyl and benzyl rings of the respective R ₃ groups are optionally substituted with 1 to 3 groups from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ ,

-CF ₃ , -C(O)-OH or -OH, • · • · ··»· ·9 η means an integer from 0 to 3,

R ₄ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) _n -C3-C5cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C5cycloalkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -C3-C5cycloalkyl or one of the groups

a) - (CH ₂ ) η-phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) ₂ , -CH ₂ -phenyl-C(0)benzothiazolyl or any of the groups

(CHS)

Y

(CH2) _n \

Y

J (CH ₂ u γ 0^

(0Η ₂ )^ _γ

(CH ₂ )^ _y where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2,

Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-N02 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or

b) groups of the formula -(CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or -(CH ₂ )n ^- 0-A, where A means a group

B • · · <

• * I ···· ·· where

D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or _-CF3 ,

B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2, substituents from the group of hydrogen or halogen, -CF ₃ , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ or

c) formula groups

FROM

• ·

Z is O or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group consisting of a halogen atom, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy, _-NH2 or _-N02 ,

R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n -C (Q) -COOH, - (CH ₂ ) _n -COOH, -CH=CH-COOH,

N

O

• · * · φ φ · * · · φ φ « φφφ φ φ • · «φφφ · φ

R ₈ represents H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (0)-COOH, tetrazolyl,

lf —P—OH II O

OH

Rg represents a hydrogen or halogen atom, _-CF3 , -OH, -( _CH2 ) _n- COOH, -( _CH2 )nC(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl,

-NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ ,

R10 represents a hydrogen or halogen atom, _-CF3 , -OH, -( _CH2 ) _n -COOH, -( _CH2 )nC(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl,

-NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ ,

N alkyl 'N (C _r C ₆ haloalkyl) φ · φ φ

alkyl).

• · φ φ • < φ · · • · φ φ •φφφ ·· «

R_atmeans hydrogen atom, C1-C6alkyl, -CF₃, -COOH, - (CH?) n -COOH, - (CH₂)_n-C(0)-COOH or group

provided that the complete group at position 1 of the indole or indoline ring, formed by any combination of groups R5, Rs, R9, R10 and/or Ru, will contain at least one acidic group selected from a carboxylic acid residue, a tetrazolyl group or a group of the formula

as well as pharmaceutically acceptable salts thereof.

One group of compounds according to the invention consists of those substances in which the 3-position of the indole or indoline ring (R3) is substituted only by a hydrogen atom and the substituents in other positions have the meanings given above.

Another group of compounds according to the invention consists of those substances in which R ₂ represents a hydrogen atom and R 1 , R 3 and R 5 have the meanings given above. There are two more preferred groups in this group. In the first of them, R 1 is located in the 5-position of the indole or indoline ring and in the second, R 1 is located in the 6-position of these rings.

In another preferred group of compounds, R 1 is located in the 5-position of the indole or indoline ring and represents a benzyloxy group, R ₂ and R ₄ represent a hydrogen atom and R 3 and R ₅ have the meanings given above.

Another preferred subgroup in each of the above groups consists of those substances in which the basic molecule is an indoline ring.

Other compounds of the subgroup of compounds according to the invention are of the general formulae

• · • · where

Rx represents a hydrogen or halogen atom, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy group, -N0 ₂ , -NH ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl or a group of the formula

R6 represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, -N0 ₂ , -CF ₃ or -OH,

R ₇ represents - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) 2, -(CH ₂ ) _n -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -N0 ₂ , -CF ₃ or -OH,

R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl 4

4 • 4 • 4 4444

4

4·

-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy, preferably Cl-C6alkoxy, -CHO, -CN, -NO2, _-NH2 , _-NH -Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N- _SO2- Cl-C6alkyl or -SO2 _- Cl-C6alkyl,

R3 represents a C1-C6alkyl, a C1-C6alkoxy group, -( _CH2 ) _{n_C3} - ^C6cycloalkyl , -( _CH2 ) _n -S-( _CH2 ) _n- C3-C6cycloalkyl or any of the groups

a) - (CH ₂ ) η-phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) 2, -CH ₂ -phenyl-C(0)benzothiazolyl or any of the groups

(CH ₂ )n\ /(CH ₂ )^ γ ^X Y ' S

Y

(CH ₂ )nx. (CH ₂ ) _n \

S ^Y

(CH ₂ ) rr\ where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2,

Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-N02 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or

b) groups of the formula -(CH ₂ ) _n -A, -(CH ₂ ) _n -SA, or -(CH ₂ ) _n -O-A, where A means a group

9

where

D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or _-CF3 ,

B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2 substituents from the group of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy or -NO ₂ or

c) formula groups

* φ

Φ · ¹ φφφφ where Z is Ο or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group halogen atom, -CF ₃ , -OH, Cl-C6alkyl, Cl-C6alkoxy group, -NH ₂ or -N0 ₂ ,

R ₄ is selected from the group consisting of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl,

-C(O)-benzyl, -CH ₂ -(C3-C6 cycloalkyl) , -C(O)-OH, -CH=O,

-C (0)-Cl-C6 alkyl, -C (0)-O-Cl-C6 alkyl, -C{O)-CF ₃ , -(CH ₂ ) _n -S-CH ₂ -(C3-C6 cycloalkyl) ,

wherein the phenyl and benzyl rings of the respective R ₃ groups are optionally substituted with 1 to 3 groups from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ ,

-CF ₃ , -C(O)-OH or -OH, n is an integer from 0 to 3,

R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n -C(0)-COOH, - (CH ₂ ) _n -COOH, -CH=CH-COOH,

• · ·Μ· ·· ·

Rg is independently selected from the group consisting of hydrogen, -COOH, -( _CH2 )n-COOH, -( _CH2 )nC(O)-COOH, tetrazolyl, z ⁰ o

AND)

-P—OH

II

O

R ₉ is selected from the group of hydrogen or halogen atom, -CF3, -OH, -COOH, - (CH ₂ ) n -COOH, - (CH ₂ ) _n -C (0) -COOH, C1-C6alkyl, « 9

9 • 9 • 999 •99 99 9999

-O-Cl-C6alkyl, -NH(Cl-C6alkyl or -N (Cl-C6alkyl) ₂ ,

R10 is selected from the group consisting of hydrogen or halogen, _-CF3 , -OH, -( _CH2 )n-COOH, -( _CH2 ) _n -C(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl)2,

R11 is selected from the group of hydrogen atom, C1-C6alkyl, C1-C6cycloalkyl, _-CF3 , -COOH, -( _CH2 ) _n- COOH, -( _CH2 ) _n- C(O)-COOH,

provided that the complete group at position 1 of the indole or indoline group formed by any combination of R ₅ , Rg , R9 , R10 and/or Rn groups contains at least one ···· ·♦ · · • · · ·

a group of acidic nature, which is selected from a carboxyl group, a tetrazolyl group or a group of the formula

as well as pharmacologically acceptable salts of these substances.

Another preferred group of compounds according to the invention are compounds of the general formulae

where

R _x represents -NH ₂ , -O-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl or a group of the general formula

About ··*« 4

R ₆ represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, -NO ₂ , -NH ₂ , -CF 3 or -OH,

R ₇ represents - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) ₂ , ~(CH ₂ ) _n -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ of pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -NH ₂ , -N0 ₂ , -CF ₃ or -OH, n represents an integer from 0 to 3,

R ₃ is selected from the group of halogen atom, C1-C6 alkyl, C1-C6 alkoxy group, -CF ₃ , -CH=O, -C(0)Cl-C6 alkyl, -C(0)-0-Cl-C6 alkyl, -C(O)-OH, -C(O)-CF ₃ , -C(0)-phenyl, -C(0)-benzyl, -C(0)-pyrrolyl, -C(0)-thienyl, -C(0)-furanyl or -C(0)-morpholinyl, • · »» ·« ·· • ·

R ₄ is selected from the group - (CH ₂ ) _n -C3-C6 cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C6 cycloalkyl, - (CH ₂ ) _n -O-(CH ₂ ) _n ^- C3-C6 cycloalkyl,

- (CH ₂ ) _n ~S-Cl-C6alkyl or any of the groups

a) -C (O)-O-(CH ₂ ) _n -C3-C5cycloalkyl, - (CH ₂ ) ""phenyl, -(CH ₂ ) _n -O-phenyl, - (CH ₂ ) _n -S-phenyl, - (CH ₂ ) "-S-(CH ₂ ) "-phenyl, -(CH ₂ )"-phenyl-O-phenyl, - (CH ₂ ) "-phenyl-(CH ₂ ) „-phenyl, -(CH ₂ )„-O-phenyl-CH ₂ -phenyl, - (CH ₂ ) „-phenyl-(O-CH ₂ -phenyl) ₂ , -C(O)-O~ -phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, -C(O)-O-naphthyl, - (CH ₂ )„-S-naphthyl, - (CH ₂ ) _n -S-pyridinyl, -(CH ₂ )„-pyridinyl or - (CH ₂ ) „-naphthyl, - (CH ₂ ) „-O-naphthyl, wherein phenyl pyridinyl and naphthyl in these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF ₃ , -OH, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ or a 5-membered heterocyclic ring, containing one heteroatom from the group of N, S or O, preferably S or O or

b) a group of the general formula -(CH ₂ )“-A, - (CH ₂ )“-SA or -(CH ₂ )“-OA, where A means a group

where

D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or _CF3 ,

R ₅ is selected from the group -COOH, -C(O)-COOH, -(CH ₂ ) "-C(0)-COOH, -(CH ₂ ) "-COOH, -CH=CH-C00H,

»1··

·· · · • 4

4 S

4 »

R ₈ is independently selected from the group consisting of hydrogen, -COOH, ^_ (CH ₂ ) _n -COOH, -(CH ₂ ) n -C(0) -COOH, tetrazolyl, o °W°

O—p—OH / II /

P O ,

Oh;

• 4

Φ · •

4444

44 4 4

4 4 • 4 · 4 •44

4444 • 44

4

4 4

4

4

Rg is selected from the group of hydrogen or halogen, -CF3, -OH, -COOH, -( _CH2 )n-COOH, -( _CH2 ) _n -C(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ ,

R10 is selected from the group consisting of hydrogen or halogen, -CF3, -OH, - ( _CH2 ) _n -COOH, - ( _CH2 ) _n -C(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ ,

alkyl).

Ru is selected from the group of hydrogen atom, C1-C6alkyl, C1-C6cycloalkyl, _-CF3 , -COOH, -( _CH2 ) _n- COOH, -( _CH2 ) _n- C(O)-COOH,

provided that the complete group at position 1 of the indole or indoline group, formed by any combination of groups R ₅ , R 5 , H 9 , R 10 and/or R _{n ,} will contain at least one group of acidic nature selected from the group of carboxyl, tetrazolyl or a group of the formula • ·

9999 · ,s

About

p—OH II

as well as pharmaceutically acceptable salts thereof.

Aryl and substituted aryl throughout the application mean monocyclic, especially 5- and 6-membered monocyclic aromatic or heteroaromatic rings, as well as bicyclic aromatic or heteroaromatic groups, especially those containing 9 to 10 atoms in the ring. Among these aryl groups, phenyl, phenoxy, benzyl, benzyloxy, biphenyl and similar molecules can be mentioned. Aryl and heteroaryl groups also include the following groups:

a) a 5-membered heterocyclic ring containing 1 or 2 heteroatoms from the group N, S or O, for example furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolyl, 1 pyrazolinyl, imidazolyl, tetrazolyl or oxathiazolyl or

b) a 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms in the ring, selected from the group N, S or O, it can therefore be, for example, pyronyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, tetrazinyl, thiazinyl, thiadizinyl, oxazinyl or morpholinyl or • 9

c) a bicyclic ring group, optionally containing 1 to 3 heteroatoms from the group N, S or O in the ring, may therefore be, for example, benzofuranyl, chromenyl, indolyl, isoindolyl, indolinyl, isoindolinyl, naphthalenyl, purinyl, indolizinyl, indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl or naphthyridinyl.

Substituted aryl groups according to the invention include the above groups, optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-C10 alkyl, preferably a C1-C6 alkyl, a C1-C10 alkoxy group, preferably a C1-C6 alkoxy group, -CHO, -COOH, or esters of these groups, -NO ₂ , -NH ₂ , -CN, -CF ₃ or -OH or combinations of these groups, such as -CH ₂ CF ₃ ,

-NH(CH ₃ ) and the like.

A preferred subgroup of these groups are benzene, pyridine, naphthylene or quinoline rings. Other preferred groups are furan, pyrrole, thiophene, pyrimidine and morpholine rings. A preferred group of bicyclic aromatic rings are benzofuran, indole, naphthalene and quinoline rings.

Alkyl, alkenyl and alkynyl groups may contain 1 to 10, preferably 1 to 6 carbon atoms and may be straight, branched or cyclic. Unless otherwise specified, these groups are preferably straight or branched. Halogen atoms may be fluorine, chlorine, bromine or iodine atoms.

The term "phospholipase activity" refers to positive activity in a phospholipid metabolism assay, preferably the assay described further in Example 86. With regard to inhibitory activity on the enzyme phospholipase, preferably cPLA ₂ in various assays, preferably the assays of Example 86 or 87. In preferred embodiments, the compounds of the invention have (1) an IC50 value of less than 25, preferably less than 6 microM in the LysoPC assay, (2) an IC50 value of less than 50 microM in the vesicle assay, (3) an IC50 value of less than 1 microM in the PMN assay, (4) an IC50 value of less than 15 microM in the coumarin assay, and/or (5) measurable activity in a carrageenan-induced rat paw edema assay, preferably at least a 5% reduction in edema, preferably at least 10 to 15% reduction and especially 20 to 30% reduction in swelling.

The compounds of the invention are effective inhibitors of the enzyme phospholipase, preferably cPLA ₂ , and can therefore be used to treat inflammatory conditions or inflammatory responses to various stimuli, such as rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease and other diseases mediated by the action of prostaglandins, leukotrienes and PAF, as well as other diseases such as osteoporosis, colitis, myelogenous leukemia, diabetes, atherosclerosis and cachexia.

Part of the essence of the invention also includes pharmaceutical compositions containing active ingredients according to the invention, intended for the treatment of the above-mentioned diseases.

In the manufacture of pharmaceutical compositions according to the invention, the active ingredients are processed together with a pharmaceutical carrier. In addition, these compositions may contain other excipients, such as diluents, fillers, buffers, stabilizers, co-solvents and other substances commonly known and used in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the biological activity of the active ingredient used. The nature of the carrier will depend on the chosen route of administration. The pharmaceutical compositions may also contain other anti-inflammatory substances. These other factors and/or other active ingredients can be incorporated into the pharmaceutical composition to achieve a synergistic effect with the compounds according to the invention or to minimize the side effects caused by the compound according to the invention.

The pharmaceutical composition according to the invention may be in the form of liposomes, in which the compounds according to the invention are combined, in addition to carriers, with amphipathic substances, for example with lipids that form various types of aggregates, such as micelles, insoluble monolayers, liquid crystals or lamellar layers in aqueous solutions. Suitable lipids for the formation of liposomes are, for example, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponins, bile acids and the like. The preparation of liposomes is known and has been described, for example, in US 4235871, US 4501728, US 4837028 and US 4737323.

The term "therapeutically effective amount" means the total amount of active ingredient in a pharmaceutical composition that is capable of producing the desired effect, that is, improving, preventing or curing an inflammatory response or inflammatory condition, or is capable of accelerating treatment or healing. In the case of a combination of active ingredients, this term means the combined amounts of the active ingredients that result in a therapeutic effect, whereby

the individual substances can be administered in combination, simultaneously or sequentially.

Mammals suffering from any of the above-mentioned disease states are therefore administered an effective amount of the compounds of the invention. These substances can be administered alone or together with other active substances, as already mentioned above, in particular other anti-inflammatory substances, cytokines, lymphokines or other blood factors. When administered together with other anti-inflammatory substances, cytokines, lymphokines or other blood factors, the compounds of the invention can be administered with these substances simultaneously or sequentially. Suitable doses and suitable intervals between the administration of the individual substances must always be determined by the attending physician.

The pharmaceutical compositions of the invention may be intended for various routes of administration, for example orally, by inhalation, transdermally, subcutaneously or intravenously.

When an effective amount of the compounds of the invention is administered orally, the pharmaceutical compositions of the invention will usually be in the form of tablets, capsules, powders, solutions or elixirs. In the case of tablets, the pharmaceutical composition will usually contain a solid carrier such as gelatin or other excipients. Tablets, capsules and powders will usually contain 5 to 95, preferably 25 to 90% by weight of the compounds of the invention. In the case of liquid form, a liquid carrier such as water, oils of animal or vegetable origin such as peanut oil, mineral oil, soybean oil or sesame oil is used, in addition, synthetic oils can be used. Liquid forms of pharmaceutical compositions may further contain saline, dextrose or other saccharide or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. In the case of liquid form, the pharmaceutical composition will contain 0.5 to 90, preferably 1 to 50% by weight of the compounds of the invention.

When the compounds of the invention are to be administered intravenously or by cutaneous or subcutaneous injection, they will contain a non-pyrogenic, parenterally acceptable carrier. Preferably, the carrier will be an aqueous carrier. Preparation of parenterally acceptable solutions is carried out with consideration of pH, osmotic pressure, stability and the like. Preferred pharmaceutical compositions for injection should contain, in addition to the compounds of the invention, an isotonic carrier medium, for example, sodium chloride solution, Ringer's solution, dextrose solution, dextrose solution with sodium chloride, lactated Ringer's solution or other known carrier medium. These compositions may also contain stabilizers, preservatives, buffers, antioxidants or other conventional additives.

The amount of compounds of the invention in the pharmaceutical composition will depend on the nature and severity of the condition being treated and also on the nature of the previous treatment of the patient. The total amount of active ingredients must always be determined by the attending physician. Usually, higher doses are administered at the beginning of treatment until the optimal therapeutic effect is achieved, after which the dose used is not increased. Usually, the pharmaceutical compositions will contain 0.1 micrograms to 100 mg of active ingredient, preferably 0.1 to 50 and especially 1 to 2 mg of active ingredient per kg of body weight.

• · · · ·

The duration of intravenous treatment with the active ingredient of the invention will vary depending on the severity of the condition being treated and the general condition of the patient. It is anticipated that the duration of each application will be in the range of 12 to 24 hours of continuous intravenous administration. The duration of this treatment will again be determined by the attending physician.

The compounds of the invention can be prepared by the processes set forth below. The preparation of preferred active ingredients of the invention will then be described in the examples section of the application.

Method A

The procedure is that ethyl-5-nitro-2-carboxylateindole is chlorinated at the 3-position by the action of N-chlorosuccinamide in a solvent such as DMF or DMSO at an elevated temperature of 40 to 80 °C. The ester is then reduced in three steps. First, the ester is hydrolyzed under alkaline conditions by the action of a base such as sodium or potassium hydroxide in a solvent system such as a mixture of water, methanol and THF. The acid is then activated by the addition of carbonyldiimidazole in THF and the reduction is carried out by the action of a reducing agent such as sodium hydroborate or sodium triacetoxyhydroborate in an alcohol such as methanol or ethanol. The resulting alcohol is protected as the TBDMS ether with TBDMSC1 in a solvent such as DMF, methylene chloride or THF by the action of a base such as triethylamine or imidazole. The nitrogen atom of the indole group is then alkylated by treatment of methyl 4-bromomethylbenzoate in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, n-butyllithium or bis(trimethylsilyl)amide • ·

9··· potassium. The nitro group at position 5 is then reduced with hydrogen in the presence of a catalyst such as platinum or palladium on charcoal in a solvent such as ethyl acetate, methanol or THF or any mixture of these solvents. The amine is then acylated with cyclopentylcarbonyl chloride in a two-phase system of saturated sodium bicarbonate and methylene chloride. R1 is then introduced in two steps, the TBDMS ether being converted to the bromide by treatment with dibromotriphenylphosphorane in methylene chloride, after which the crude bromide is treated with thiols or phenols in a solvent such as THF, methylene chloride or DMF in the presence of a base such as potassium or cesium carbonate. The ester products are then prepared by hydrolysis under alkaline conditions using sodium hydroxide in a solvent mixture such as water, methanol and THF.

Method B

Acylation at the 3-position of the indole of formula I with an acylating agent, for example naphthoyl chloride, can be carried out using ethylmagnesium bromide in a solvent, for example THF, to give the compound of formula II. Alkylation of the nitrogen atom of the indole group can be carried out with a suitable base, for example sodium hydride.

Removal of the protecting group on the hydroxy group can be carried out with tetrabutylammonium fluoride, oxidation with an oxidizing agent then gives the compound of formula IV. The Horner-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent, for example tetrahydrofuran, gives the unsaturated ester of formula V, from which the protecting groups in the 1-position of the indole ring can be removed using a suitable system, for example hydrofluoric acid in acetonitrile. Saponification of the remaining acidic group gives the compound of formula VI.

Method C

The indole of formula I can be converted to the compound of formula II in two steps: (1) reduction with LAH in a solvent, for example THF, and (2) silylation with tert-butyldimethylsilyl chloride, TBDMSC1 in a solvent, such as dichloromethane or DMF in the presence of a base, for example imidazole. Treatment of the compound of formula II with a Grignard reagent, for example ethylmagnesium bromide in a solvent, such as THF at -60°C gives an intermediate which is acylated with a suitable acyl chloride, for example acetyl chloride in ether, and finally alkylated on the nitrogen atom with an alkyl halide, for example methyl (4-bromomethyl)benzoate in the presence of a strong base, such as NaH in DMF, to give the ketone of formula III. The silyl group of the ketone of formula III is removed by treatment with tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is converted to the bromide using tetrabromomethane and bis(diphenylphosphine)ethane in a solvent such as dichloromethane to give the bromide of formula IV. This bromide is treated with a thiol compound in the presence of a base such as cesium carbonate or with an alcohol in the presence of a strong base such as NaH in DMF to give the product of formula V as a sulfide or ether.

Method D

4444 • · 4 · · · »· · 4 4 ·» · · · · *

The protected alcohol is deprotected in a suitable solvent such as THF and the resulting alcohol is converted to the halide by treatment with carbon tetrabromomethane or methanesulfonyl chloride, followed by reaction with the nucleophilic oxygen bound by previous deprotonation with a strong base, such as sodium hydride, or with a sulfur nucleophile in the presence of cesium carbonate in DMF or THF. The nitro group can then be reduced to the amine by hydrogenation using platinum on activated carbon or by treatment with sodium hydroborate in the presence of cuprous acetate. The resulting amine is hydrolyzed in the conventional manner with sodium hydroxide in a mixture of methanol and THF or using an acylating reagent such as acid chlorides, chloroformates and isocyanates and the reactions are carried out in the presence of a base in a solvent such as THF or dichloromethane. The amine can also be acylated by treatment with EDCI and various acids. The starting amine can also be alkylated by reductive amination using various aldehydes and sodium triacetoxyhydroborate as a reducing agent. The resulting amine derivatives can be hydrolyzed to give the desired acids, which can also be converted to acylsulfonamides using EDCI and sulfonamide. The amine derivatives can also be further alkylated by reaction with a strong base and an alkyl halide and then hydrolyzed in a conventional manner to give the desired final product.

Method E

The starting indole is derivatized at C3 without or with substitution at C2 using a mixture of DMF and phosphorus oxychloride or by the action of a magnesium salt with various acid chlorides to form ketones. These ···♦ · •· φφφφ φφ φ products are then subjected to N-alkylation in the presence of a strong base and various alkylhalogenesters or arylhalogenesters. In the case where R' represents a nitro group, in this step the nitro group is reduced with hydrogen in the presence of platinum on activated carbon or with sodium hydroborate and copper acetate to an amine, which is then acylated with various acid chlorides, isocyanates, chloroformates or reductive alkylation with amines or coupling with acids is carried out. The resulting esters are hydrolyzed to the desired acids, which can be further converted to acylsulfonamides.

Way

alkyl ether £

• · ·

9 9

9

9 9

9999

Method B

• 4 * 44 ·· 44 ·

4 44 · 4· 4 4 4 44 • 4 4 4 4 4 4 φ • 4444 444 4 4 • · 444 444 •444 444 44 4444 44 444

Method C

IZ

R'SH, CsCO ₃ \ R'OH, NaH or K ₂ CO ₃ v

X—R'

R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO ₂ , alkyl, aryl R' = alkyl, aryl

R= alkyl acid, benzyl acid, alkenyl, R' = alkyl, aryl X = O,S

Y = haiogen, alkyne mesylate • · · · • 9 9 9

9

9 9

9 9999

Cu(OAc)2./NaBH4

X · 9 ··

9999

9 9 9

9

9 9

9

Way

0009

9 9 9

999 99 9999

9 9

999

at.

• · · frfr frfr * » • · frfr · · · fr · · · • · · · · · • · · · · · · fr ••frfr ··· frfr frfr·· ·· ··· ___Ρ_ϊ_2_Υ_θ_^_θ_2_ί___vjy_n_á_l_e_z_u

Example 1)

Preparation of 4-(3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-(phenethylsulfanyl)-methyl]-1H-indol-1-ylmethyl)-benzoic acidStep® 1)

Preparation of the intermediate product "ethyl ester"

To a solution prepared by dissolving 21.10 g of ethyl 5-nitroindole-2-carboxylate in 500.0 ml of N,N-dimethylformamide (obtained as a brown solution), a solution prepared by dissolving 12.0 g of N-chlorosuccinamide in 125.0 ml of N,N-dimethylformamide was added over 5 minutes.

After the resulting reaction mixture was heated at 50.0 °C for 1.50 hours, the completion of the reaction was checked by thin layer chromatography (TLC). The reaction mixture was then cooled to room temperature, and after dilution with 2.0 liters of water, it was extracted 3 times, each time with 1.0 liter of ethyl acetate. After separation of the organic and aqueous phases, the organic layers were combined, and after drying with magnesium sulfate, they were filtered and concentrated.

96.0 g of the desired intermediate, the ethyl ester, was obtained as a wet substance with N,N-dimethylformamide, which was used in the following Step 2) without any further purification.

·· * ·« ·· • · ·· · «· · » · · • · · « · · 8 φ ···· ··· «Φ ···· ·« ···

Grade. 2)

Preparation of the intermediate “carboxylic acid”

To a solution prepared by dissolving the intermediate "ethyl ester" obtained in the previous, above-described Step 1) in 400.0 ml of methanol and 800.0 ml of tetrahydrofuran (in the form of a clear, brown-colored solution), 450.0 ml of 2N sodium hydroxide solution was added.

The resulting black colored reaction mixture was checked by TLC after being stirred at room temperature overnight, and since the reaction was not complete, 7.20 g of sodium hydroxide in the form of pellets was added to the mixture. After 7.0 hours, the reaction was found to be complete, and about 2.0 liters of solvent were removed from the reaction mixture by rotary evaporation.

The residue was dissolved in ethyl acetate and water, and after acidification with 2N hydrochloric acid to pH 2.0, the mixture was extracted 3 times with 1.0 liter of ethyl acetate each time. After separation of the organic and aqueous phases, the combined organic layers were dried with magnesium sulfate, filtered and concentrated.

24.30 g of the desired title intermediate was obtained as a brown solid in a yield of 100.0%.

S: level 3)

Preparation of the intermediate “alcohol”

To the solution, prepared by dissolving 24.0 g of the carboxylic acid intermediate, obtained in the previous, above-described Step 2), in 700.0) ml of tetrahydrofuran,

• 4 4 4 • • 9 44 4 9 • 4 * · 4 9 • 4 4 4 4 • 4 • 4 • 4 · • 4444 444 «4 • 44· 44 44 4

(in the form of a clear, amber-colored solution), 16.20) g of carbonyldiimidazole were added, and the resulting reaction mixture was stirred at room temperature for 1.50 hours, during which time a slightly brown-colored suspension was formed.

After the reaction mixture was cooled in an ice-cold bath, 10.80 g of sodium borohydride was slowly added to the reaction mixture, and 140.0 ml of ethanol was added, while gas evolution was observed. After 2.0 hours, the reaction was found to be complete by TLC. After adjusting the mixture to pH 2.20 with 2N hydrochloric acid solution, the mixture was extracted 3 times with 600.0 ml of ethyl acetate each time. After separating the organic and aqueous phases, the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated.

28.50 g of the desired intermediate alcohol was obtained as a brown solid.

Level 4.)

Preparation of the intermediate "tert-butyldimethylsilyl-protected alcohol" A solution prepared by dissolving 25.40 g of the intermediate "alcohol" obtained in the previous, above-described Step 3), 18.60 g of imidazole, and 13.30 g of tert-butyldimethylsilyl chloride in 350.0 ml of N,N-dimethylformamide was stirred overnight.

Since it was found that the reaction did not proceed completely, 18.70 g of imidazole and 18.60 g of tert-butyldimethylsilyl chloride were added to the reaction mixture. After 1.0) hour, the reaction was completed, and after the subsequent addition of 1.50 liters of water, the mixture was extracted 3 times with 500.0 ml of ethyl acetate each time. After separation of the organic and aqueous phases, they were combined

φφ

ΦΦ • ·

φφ φφ ·· φφφφ

9 9 9

9 Φ

ΦΦΦΦ • Φ Φ

The organic layers were evaporated to dryness, and the crude, and the target, -butyldimethylallyl-protected alcohol, was obtained, which was dissolved in ethyl acetate.

After absorption onto silica gel _, the resulting solution was evaporated to dryness, and after application to a silica gel column and elution with a mixture of 15% ethyl acetate in hexanes, 18.50 g of the desired title intermediate was obtained as a bright yellow _crystalline solid in a yield of 69% (based on the syntheau from the first stage).

Step » 5)

Preparation of the intermediate, N-alkyl-indole

To a solution prepared by dissolving 1.0 g of the intermediate "tert-butyldimethylsilyl-protected alcohol", obtained in the previous, above-described Step 4), in 10.0 ml of N,N-dimethylformamide (in the form of a yellow-colored solution), cooled in an ice-cooled bath _, was added 147.0 mg of sodium hydride.

After 15.0 minutes, 807.0 mg of 4-(bromomethyl)-benzoate was added to the dark red reaction mixture. After another 15.0 minutes, TLC analysis showed that the reaction was complete, and the reaction mixture was poured into a cooled 1 NT hydrochloric acid solution. After adding 800.0 ml of water, the mixture was extracted with ethyl acetate. After separating the organic and aqueous phases, the combined organic extracts were evaporated to dryness to give the crude intermediate, i.e., N-alkylated indole, as an orange solid.

The crude product was absorbed onto silica gel and applied to a silica gel column, and after elution with a mixture of 15% ethyl acetate in hexanes, 1.05 g of the desired intermediate product mentioned in the specification was obtained as a yellow-colored substance in a yield of 73.0%.

Level 6)

Addition of the "amine" intermediate

To a solution prepared by dissolving 3.80 g of the intermediate "Ν-alkyl indole" obtained in the previous, above-described Step 5) in 50.0 ml of tetrahydrofuran*, 1.60 g of 5% platinum on activated carbon was added, and the resulting reaction mixture was bubbled with hydrogen and stirred at room temperature overnight.

The reaction mixture was then filtered (silica) and concentrated. After column chromatography of the residue using 35% ethyl acetate in hexane as eluent, 1.70 g of the desired title product was obtained as an off-white solid.

Level 7)

Preparation of the intermediate amide

To a solution prepared by dissolving 1.60 g* (3.50 mmol) of the intermediate "amine" obtained in the previous, above-described Step 6) in 10.0 ml of dichloromethane and 10.0 ml of saturated aqueous sodium bicarbonate solution, 1.10 equivalents, i.e. 0.467 ml, of cyclopentylcarbonyl chloride were added, and the resulting reaction mixture was stirred for 45 minutes.

• · ··· 0 · · 0··· ··· 00 0000 ·· 0··

Then, after taking up in 100.0 ml of ethyl acetate, the ethyl acetate extract was washed 3 times, each time with 20.0 ml of brine, and after drying with magnesium sulfate, it was filtered and concentrated.

After chromatography of the residue, using a mixture of 20% ethyl acetate in hexanes as eluent, 1.55 g of the desired title intermediate was obtained as a pale yellow oily substance in a yield of 82.0%.

Grade 8)

Preparation of the intermediate product, “crude bromide”

To a solution prepared by dissolving 0.60 g (1.10 mmol) of the intermediate "amide" obtained in the previous, above-described Step 7) in 3.0 ml of dichloromethane, 0.50 g (1.10 equivalent) of dibromotriphenylphosphorane was added at 0.0 °C, and the resulting reaction mixture was stirred at room temperature for 2.0 hours.

Then, after taking up in 50.0 ml of ethyl acetate, the ethyl acetate extract was washed 3 times with 10.0 ml of brine each time, and after drying with magnesium sulfate and concentration, the desired intermediate product was obtained, which was used as such in the following Step 9).

Grade 9)

Preparation of the intermediate “ester” ·· · · · · · · · • · · · · · · · · · · • i · · · ·* · J · /1/) · ···· · ·

................

To a solution prepared by dissolving (ca. 0.54 mmol) of the intermediate crude bromide obtained in the previous Step 8 above in 2.0 ml of degassed N,N-dimethylformamide was added first 0.08 g (1.10 equivalents) of phenethyl mercaptan and then 0.21 g (1.20 equivalents) of cesium carbonate. The resulting reaction mixture was then stirred for 1.0 h, and after being taken up in 20.0 ml of ethyl acetate, the ethyl acetate extract was washed 3 times with 5.0 ml of brine each time, and after drying with magnesium sulfate and filtering, it was concentrated.

Chromatography of the residue, using a mixture of 25% ethyl acetate in hexanes as eluent, afforded 0.17 g of the desired title intermediate as a colorless oily substance in a yield of 56.0%»

Grade 10))

Preparation of 4-(£3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-[(phenethylsulfanyl)-methyl]-1H-indol-1-yl-methyl)-benzoic acid

To a solution prepared by dissolving the intermediate "ester" obtained in the previous, above-described Step 9) in 1.0 ml, tetrahydrofuran, and 0.550 ml of methanol, was added 0.28 ml, (5.0 equivalents), of a 5M sodium hydroxide solution, and the resulting reaction mixture was stirred for 4.0 hours, then acidified with sodium hydrogen phosphate, poured into ethyl acetate, and after washing with brine, dried with magnesium sulfate.

After subsequent mechanical work-up and extraction of the residue with ethyl acetate, 0.157 g of the desired title compound was obtained in a yield of 98.0%.

Each of the compounds listed below in the following Examples 2) to 11) was prepared in Step 1) by an analogous procedure described above in Example 1), Step 9) using the appropriate thiol, and subsequently in Step 2) by an analogous procedure described above in Example 1), Step 10)

Example 2)

Preparation of 4-((3-chloro-5-(cyclopentylcarbonyl)amino)-[(2-furylmethyl)sulfanyl]-methyl]-1H-indol-1-yl)methyl]-benzoic acid

Example. 3)

Preparation of 4'-(3)-chloro-5-[(cyclopentylcarbonyl)-amino]-2-[(4-hydroxy-6-phenyl-2-pyrimidinyl)-sulfanyl]-methyl]-1H-indol-1yl)-methyl]-benzoic acid

Example 44)

Preparation of 4-[3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-([4(2-thienyl)-2-pyrimidinyl]-methyl]-benzoic acid (methyl)-1H-indol-1-yl]

Example 5)

Preparation of 4-(£3-chloro-5-[(cyclopentylcarbonyl)amino]-2-(2,4-dibromophenoxy)methyl]-1H-indol-1-yl{-methyl)benzoic acid

Example 6)

Preparation of 4-({3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-[(cyclopentylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Example 7)

Preparation of 4-({3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-[(propylsulfamyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Example 8)

Preparation of 4-((2-[(4-(tert-butyl)phenoxy)methyl]-3-chloro-5-(cyclopentylcarbonyl)amino)-1H-indol-1-ylmethyl)benzoic acid

Example. 9)

Preparation of 4-(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-(2-quinolinylsulfanyl)methyl]-1H-indol-1-yl)-methylbenzoic acid

6£

· · · · 4 4 4 • 444 ··· 44 ···· 44 444

Example 8 4 10))

Preparation of 4-((3-chloro-5-(cyclopentylcarbonyl)amino)-2-((2cyclopropylmethyl)sulfanyl)methyl)-1H-indol-1-yl)methylbenzoic acid

Example 11)

Preparation of 4-(£2-[(. benzhydrylsulfanyl)-methyl]-3-chloro-5-[(cyclopentylcarbonyl)-amino]-1H-indol-1-yl]-methyl)-benzoic acid

The compounds listed below in Examples 12) to 14) were prepared as follows:

Level 1)

The material prepared in Example 1, Step 6, was acylated at the 5-amino position using the documentation provided in Example 1, Step 7, and the appropriate cyclizing agent.

Level 2)

The title compound was prepared using the intermediate obtained in Step 1), 8 subsequently

according to the procedures described in Example 1), Steps 8), to 10), using the appropriate thiol.

Example; 12)

Preparation of 4-({5-/(3-carboxypropanoyl)-amino/-3-chloro-2-/(phenethylsulfanyl)-methyl/-1H-indol-1-yl-methyl)-benzoic acid

Example 13)

Preparation of 4-((5-[(1-carboxypropanoyl)-amino]-3-chloro-2-((3-methylbenzyl)-sulfanyl)-methyl)-1H-indol-1-yl)-methyl)-benzoic acid

Example 14)

Preparation of 4-([2-([4-(tert-butyl)benzyl]sulfanylmethyl)5-[(3-carboxypropanoyl)-8amino]-3-chloro-1H-indol-1-yl]methyl]benzoic acid

Example 15)

Preparation of 4-(|3-chloro-5-(3-furoylamino)-2-[(2-naphthylsulfenyl)methyl]-1H-indol-1-yl]-methyl)-benzoic acid

The title compound was prepared by an analogous procedure described below in Example 43) using the appropriate acylating agent.

··

The following Examples 17) to 21) were carried out according to the procedure described below in Example 43) using the appropriate acylating agent.

Example 17)

Preparation of 4-({3-chloro-5-[3-(diethylamino-1-propanoyl]-amino]-2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Example 18)

Preparation of 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3thienylcarbonyl)amino]-1H-indol-1-yl]-methyl)benzoic acid

Example 19)

Preparation of 4-(^5-{ /(benzylamino)-carbonyl/-aminoj-3-chloro-2/(2-naphthylsulfanyl)-methyl/-iH-indol-1-ylj-methyl)-benzoic acid / • 9 * 9 9 · · 9

9999 999 99 ···· 9· 99«

Appendix 203

Preparation of 4?-(£5-£(butylamino)-carbonyl)-amino)-3-chloro-2/(2-naphthylsulfanyl)-methyl)-1H-indol-1-yl-methyl)-benzoic acid

Example 21)

Preparation of 3-[({1-(4-carboxybenzyl)-3-chloro-2-(2-naphthylsulfenyl)methyl]-1H-indol-2-yl-amino)carbonyl]-benzoic acid

Example 22)

Preparation of 4-{[5-(benzyloxy)-2-[(E)-2-carboxyethenyl]-2-(2-naphthoyl) 1H-indol-1-yl]-methyl}-benzoic acid

S t e g e 1)

To the solution prepared by dissolving 2.0 g*. ( 5.40 mmol ),

2-(tert-butyldimethylsilyloxymethyl)-5-benzyloxyindole, in 10.0 ml of anhydrous ether, and cooled to minus 78.0 °C, were added dropwise 4.00 ml* (12.0 mmol) of a 3.0M solution of ethylmagnesium bromide in ether, and the resulting reaction mixture was stirred in the temperature range of minus 0.0 °C to minus 65.0 °C for 2.0 hours.

During this operation, a slurry was formed from the homogeneous solution, to which a solution obtained by dissolving

2.28 g, (12.0 mmol), of naphthoyl chloride, in 8.0 mL of ether.

After stirring the mixture at a temperature range of minus 60.0°C to minus 40.0°C for 2.0 hours, the reaction mixture was carefully stirred with saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate. The separated combined organic layers were washed with brine, dried, and concentrated.

The residue was flash chromatographed using hexane:acetone (6.0:1.0) as eluent.

2.20 g of the intermediate product (see Example 17) was obtained in the form of a yellow-colored substance of foamy character, in a yield of 78.0%.

S t e g e 2)

To a solution prepared by dissolving 1.0 g (1.90 mmol) of the intermediate obtained in the previous, above-described Step 1) in 10.0 ml of N,N-dimethylformamide and cooled in an ice-cooled bath to 0.0 °C was added 0.12 g (2.10 mmol) of sodium hydride. After removing the ice-cooled bath after 10.0 minutes, the reaction mixture was stirred at room temperature for 30.0 minutes. During this time, 0.50 ml (2.80 mmol) of bromomethyl-SEM-ether was added dropwise to the mixture.

The resulting reaction mixture was then stirred at room temperature for 4.0 hours, and after adding water, it was extracted with ethyl acetate. After separating the organic and aqueous phases, the organic layer was washed with brine, and after drying with magnesium sulfate, it was concentrated.

After processing the residue by flash chromatography, using a mixture of hexane:acetone (6.0:1.0), as eluent, 1.22 g of the desired intermediate was obtained in the form of a white-colored substance, foamy in nature, in a yield of 81.0%.

φφφ Φ· φφ ·« · • φφφ φ φφφ * φφφ φ φ φφφ φφφ φφφφ φφφ φφ φφφφ φφ φφφ

Level 3)

To a solution prepared by dissolving 6.60 g (8.40 mmol) _of the intermediate obtained in the previous, above-described Step 2) in 80.0 ml of tetrahydrofuran was added 21.0 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran.

The resulting reaction mixture was then stirred at room temperature for 2.0 hours, and after adding water, it was extracted with ethyl acetate. After separating the organic and aqueous phases, the combined organic layers were washed successively with water and brine, and after drying, they were concentrated.

After processing the residue by flash chromatography, using a mixture of hexane::ethyl acetate, (4.0:1.0), as eluent, 3.80 g of the desired intermediate was obtained, in the form of a thick, colorless substance of oily consistency, in a yield of 67.0%.

The intermediate prepared in the previous operation was dissolved in 50.0 ml of tetrahydrofuran, and 5.50 g (63.20 mmol) of manganese dioxide was added to the resulting solution. After the reaction mixture was stirred for 22.0 hours, it was filtered through a pad of silica, and the filtrate was concentrated.

3.70 g _of the desired intermediate product _were obtained in the form of a slightly yellow colored substance, foamy in nature, in a yield of 96.0%.

Level 4)

To a solution prepared by dissolving 0.12 ml (0.70 mmol) of trimethylphosphonoacetate in 5.0 ml of N,N-dimethylformaldehyde and cooled in an ice bath to 0.0 °C was added 0.027 g (0.80 mmol) of sodium hydride.

After 30.0 minutes, a solution obtained by dissolving 0.50 g of the intermediate prepared in the previous, above-described Step 3) (0.7 mmol) in 5.0 ml of N,N-dimethylformamide was added to the resulting reaction mixture, and after subsequent removal of the ice-cooled bath, this mixture was stirred overnight.

After adding water, the mixture was extracted with ethyl acetate, and after separating the organic and aqueous phases, the combined organic layers were washed with brine, and after drying with magnesium sulfate, they were concentrated.

After processing the residue by flash chromatography, using a mixture of hexane:ethyl acetate, (3.0:2.0), as eluent, 0.20 g of the desired intermediate was obtained, in the form of a white foamy substance, in a yield of 37.0%»

Level 5) ·»

Preparation of 4-[5-(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2naphthoyl)-1H-indol-1-yl]-methyl]-benzoic acid

To a solution prepared by dissolving 0.50 g (0.70 mmol) of the intermediate obtained in the previous Step 4) in 10.0 ml of acetonitrile was added 5.0 ml of a 48% aqueous solution of hydrofluoric acid. After 2.0 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After separating the organic and aqueous phases, the organic layer was washed successively with water, and brine, and after drying with magnesium sulfate, it was concentrated.

The obtained crude material was dissolved in 2.0 ml of tetrahydrofuran, 1.0 ml of methanol, and 2.0 ml of 1N sodium hydroxide solution. After the thus prepared solution was stirred at room temperature overnight, the mixture was acidified with 1N hydrochloric acid solution to pH 3.0, and then extracted with ethyl acetate.

The residue was flash chromatographed using dichloromethane:methanol (10.0:1.0) as eluent to afford 0.20 g of the desired title compound as a white solid in 50.0% yield.

• 0

0000

Example 23)

Preparation of 4-[3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl(-methyl)-benzoic acid

Level 1)

Preparation of the intermediate product "crude indole alcohol"

To a solution prepared by dissolving 30.0 g (102.0 mmol) of ethyl 5-benzyloxy-2-indolecarboxylate in 250.0 ml of tetrahydrofuran and cooled to 0°C, a 1M solution of lithium tetrahydroaluminate (255.0 ml) in tetrahydrofuran was added over 40.0 minutes using an addition funnel.

The resulting reaction mixture was then stirred at 0.0 °C for 2.0 hours and then worked up by adding 190.0 mL of 4N sodium hydroxide solution. The resulting salts were filtered and washed 3 times with 400.0 mL of ethyl acetate. The combined filtrates were dried over magnesium sulfate and concentrated.

24.80 g of the desired title intermediate was obtained.

»· φ ·· *» * · · · · « · · φ φ φ * φ ···· ··· ·· Φ···

S u r e n 2)

Preparation of the intermediate,>tert-butyldimethylsilyl-protected indole

To a solution prepared by dissolving 8.30 g (32.6 mmol) of the crude indole alcohol intermediate obtained in the previous, above-described Step 1) in 10.50 ml of N,N-dimethylformamide, 5.50 g (81.50 mmol) of imidazole and 5.40 g (35.8 mmol) of tert-butyldimethylsilyl chloride were added, and the resulting reaction mixture was stirred at room temperature overnight.

The mixture was then poured into water, and extracted 3 times with ethyl acetate. After separating the organic and aqueous phases, the organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified on a silica gel column using hexane:ethyl acetate (19:1) as the eluent.

11.90 g (31.0 mmol) of the desired title intermediate was obtained in a yield of 94.0 _% (pure product).

Thin layer chromatography (TLC):

Rg, = 0.80, in a mixture of toluene : ethyl acetate, ( 2.0 : 1.0 )J

S t e r g e 33)

Preparation of the intermediate product "indole"

To a solution prepared by dissolving 2.0 g (6.56 mmol) of the intermediate "tert-butyldimethylsilyl-protected indole" obtained in the previous, above-described Step 2) in 20.0 ml of ether was added dropwise 2.40 ml of 3M ...

of a solution of ethylmagnesium bromide (7.20 mmol), in ether, in 10.0 ml, of ether, which was cooled to a temperature of minus 78.0°C,

The resulting reaction mixture was then stirred at minus 60.0 °C for 2.0 hours. Then, 0.51 ml, (7.20 mmol), of acetyl chloride in 4.0 ml, of ether was slowly added to the mixture, and the reaction mixture was maintained at a temperature range of minus 50.0 °C to minus 60.0 °C for an additional 2.0 hours. Then, the mixture was mixed with saturated aqueous sodium bicarbonate solution, and extracted 3 times with ethyl acetate.

After separation of the organic and aqueous phases, the organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified on a silica gel column using hexane:ethyl acetate (19.0:1.0) as eluent.

1.20 g of the title intermediate was obtained in a yield of 50.0%.

S t e g e 4)

Preparation of the “Sily1-protected indole intermediate”

To a solution prepared by dissolving 1.20 g (2.90 mmol) of the intermediate "indole" obtained in the previous, above-described Step 3) in 10.50 ml of N,N-dimethylformamide was added at room temperature 0.13 g (3.23 mmol) of sodium hydride in the form of a 60% oil dispersion.

To the reaction mixture, 0.81 g (3.53 mmol) of methyl (4-bromomethyl) benzoate was added during 30 minutes of stirring, and the reaction mixture was then stirred overnight. After completion of the reaction (checked by TLC), the mixture was mixed with water, and extracted 3 times with ethyl acetate. After separation of the organic and aqueous phases, the organic layers were dried over magnesium sulfate, and

• · • fr· • fr • · · • fr • · fr · • fr • · · · • • • • · • • frfr ···· • frfr • fr fr··· • · frfr ·

concentrated, 8 used in the following Stage 5).

Level 5)

Preparation of the intermediate product "indole alcohol"

A mixture, prepared by mixing 0.65 g, (1.20 mmol), of the silyl protected indole intermediate obtained in the previous, above-described Step 4), and 2.90 ml, (2.90 mmol),

A 1M solution of tetra-butylammonium fluoride in tetrahydrofuran in 6.0 ml of tetrahydrofuran was stirred at room temperature for 1.0 hour.

The reaction mixture was then diluted with ethyl acetate and water, and extracted 3 times with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and concentrated. The crude residue was purified on silica gel using hexane:ethyl acetate (1.0:1.0) as eluent to afford 0.47 g of the desired title intermediate as pure material in a yield of 91.0;4%."

Level 6)

Preparation of the intermediate product "indole bromide"

A mixture prepared by mixing 0.30 g (0.68 mmol) of the intermediate indole alcohol obtained in the previous, above-described Step 5), 0.27 g (0.01 mmol) of tetrabromomethane, and 0.21 g (0.51 mmol) _of 1,3-bis-(diphenylphosphine)-propane in 8.40 ml of dichloromethane was stirred for 16.0 h.

• 4 ·· ·· 4 4 4 • 4 4 • 4 · 4 • 4 4 4 • • 4 4 4 4 4 ·· ··· 44 *444 44 44 ·

then diluted with dichloromethane, and half-saturated ammonium chloride solution. The aqueous layer was extracted 3 times with ethyl acetate, and after drying, the ethyl acetate extracts were concentrated.

The residue, as crude material, was purified on silica gel using hexane:ethyl acetate (2.0:1.0) as eluent.

0.27 g of the desired title intermediate was obtained as pure substance, in a yield of 78.0%.

Step 7) Preparation of the intermediate ester

To a solution prepared by dissolving 0.10 g (0.20 mmol) _of the intermediate "indole bromide" obtained in the previous, above-described Step 6) in 0.40 ml of N,N-dimethylformamide (degassing of the solvent is strongly recommended), 0.20 g (0.60 mmol) of cesium carbonate was added, followed by 0.034 g (0.22 mmol) of ethyl-2-naphthalenethiol, and the resulting reaction mixture was stirred for 1 day.

The reaction mixture was then poured into half a saturated ammonium chloride solution, and extracted 3 times with ethyl acetate. The ethyl acetate extracts were then dried and concentrated, and after chromatography of the residue, using a mixture of hexane:ethyl acetate (3.0; 1.0), as eluent, 0.05 g of the desired intermediate mentioned in the title was obtained as a pure substance, in a yield of 57.0%.

9 9 9 9 9 9 • 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9 9

9999 999 99 9999 99 999

Grade 8)

Preparation of 4-(3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl)-benzoic acid

To a solution prepared by dissolving 0.20 g (0.34 mmol) of the intermediate "ester" obtained in the previous, above-described Step 7) in 4.0 mL of a mixture of tetrahydrofuran::methanol (1.0::1.0) was added 2.50 mL of 1N sodium hydroxide solution, and the resulting reaction mixture was stirred at room temperature for 16.0 hours.

The resulting crude product was purified by chromatography using a mixture of hexane:ethyl acetate (1.0:1.0) with 1% acetic acid as eluent.

CD, 17 g, _of the desired title compound was obtained as a solid in 85.0% yield.

Example 1 (24)

4-[(5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-3(2,2,,2-trifluoroacetyl)-1H-indol-1-yl]-methyl]-benzoic acid

Level 1)

Preparation of the intermediate “indole derivative”

The desired title intermediate was prepared by an analogous procedure to that described above in the previous Example 233), Step 3), from the intermediate tert-butyldimethylsilyl-protected indole obtained in the previous Example 23), Step 2), and trifluoroacetic anhydrides.

Step 2)

Preparation of the intermediate product "indole alcohol"

The desired title intermediate was prepared by an analogous procedure to that described above in the previous Example 23) Step 4U using the intermediate indole derivative obtained in the previous Step 1) and methyl (4-bromomethyl) benzoate.

Step by step})

Preparation of the intermediate, ester

To a solution prepared by dissolving 0.10 g (0.20 mmol) of the indole-alcohol intermediate obtained in the previous, above-described Step 2) and 0.04 ml (0.3 mmol) of triethylamine in 0.40 ml of dichloromethane was added dropwise at 0.00°C; 0.02 ml (0.24 mmol) of methanesulfonyl chloride, and the resulting reaction mixture was stirred for 1.50 hours.

Then, the dichloromethane was removed from the mixture, and to the residue, dissolved in 0.40 ml of N,N-dimethylformamide, was added at 0.0°C 0.034 g (0.22 mmol) of 2-naphthalenethiol. After subsequent addition of 0.96 g (0.30 mmol) of cesium carbonate, the reaction mixture was stirred at room temperature overnight, and

* · ♦ 4 4 4 · • 4 4 4 4 «

4444 «« 444 was then poured into brine, and extracted 3 times with ethyl acetate. The ethyl acetate extract was dried, concentrated, and the residue was _{chromatographed} using hexane:ethyl acetate (3.0:1) as eluent.

0.064 g _of the desired title intermediate was obtained as a pure substance in a yield of 50 _± 0%.

Level 4!)

Preparation of 4-(£/5-(benzyloxy)-2-/(2-naphthylsulfanyl)-methyl/3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)-methyl)-benzoic acid

The title compound was prepared by an analogous procedure to that described above in Example 23), Step 8), using the intermediate ester obtained in Step 4), above.

Example 25)

Preparation of 4-([5-[(4-(-aminobutanoyl)-amino]-3-chloro-2-(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Step 1)

Preparation of the intermediate product "alcohol" ·· ··

9 9 ·

9 ·

♦ ··

To a solution prepared by dissolving 25.0 g _of the intermediate "t-butylsilyl-protected alcohol" obtained in Example 1), Step 6), described above, in 200.0 ml of tetrahydrofuran, 125.0 ml of a 1M tetrabutylammonium fluoride solution was added, and the resulting reaction mixture was stirred at room temperature for 10.0 minutes, and then, after dilution with water, the tetrahydrofuran was concentrated, and after addition of ethyl acetate, the organic and aqueous layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate.

The combined ethyl acetate extracts were dried and concentrated to give 21.50 g of the desired title intermediate.

D e g e r e s t? 2)

Preparation of the intermediate "chloride"

To a suspension prepared by suspending 13.1 g of the intermediate alcohol obtained in the previous, above-described Step 1) in 450.0 ml of dichloromethane and cooled to 0.0 °C, 10.0 ml of triethylamine and 4.0 ml of methanesulfonyl chloride were added, and the resulting reaction mixture was allowed to warm to room temperature overnight.

The reaction mixture was then diluted with saturated aqueous sodium bicarbonate solution, and after dilution with dichloromethane, the aqueous and organic phases were separated, and the aqueous layer was then extracted 3 times with dichloromethane. The combined organic extracts were dried, and concentrated.

13.50 g of the desired intermediate chloride were obtained.

S t e g e 3)

Preparation of the intermediate , ,-disulfide

To a solution* prepared by dissolving 13.50 g* of the intermediate "chloride" obtained in the previous* above-described Step 2) and 33.50 g* of cesium carbonate in 150.0 ml of N, controlled thiol formamide* and degassed by bubbling argon for 20.0 minutes, 2-naphthalenethiol was added, and the reaction mixture was stirred at room temperature for 20.0 minutes.

Then, after addition of water, and ethyl acetate*, the organic and aqueous phases were separated, and the combined organic extracts were concentrated to a slurry, which was stirred overnight* and then filtered.

The resulting solids were mechanically worked up and extracted with a mixture of 40% ethyl acetate in hexane to afford 12.20 g of the desired title intermediate in 69.0% yield.

By step Φ)

Preparation of the intermediate amine

To a solution prepared by dissolving 11.25 g* of the intermediate "disulfide", obtained in the previous, above-described Step 3), in 500.0 ml, tetrahydrofuran, was added 500.0 ml* of methanol, and then a suspension obtained by suspending 19.20 g, copper acetate in 300.0 ml* of water, and then another 100.0 ml, tetrahydrofuran, and in portions 11.20 g, sodium borohydride.

After the reaction mixture was stirred at room temperature for 2.50 hours, the resulting black-colored solution, foamy in nature, was diluted with saturated aqueous sodium hydrogen carbonate solution, and after separating the organic and aqueous phases, the aqueous layer was extracted 3 times with ethyl acetate, the combined organic extracts were dried, and chromatographed.

9.0 g of the desired intermediate "amine" was obtained in a yield of 85.0%.

Grade. 5)

Preparation of the intermediate _r ,amide”

The intermediate "amine", obtained in the previous, above-described Step 4), was coupled with protected 4-aminobutyric acid, (4-aminobutanoic acid), and then was processed by an analogous procedure, described below in Example 43), Step 1), and after trituration with dichloromethane, the desired intermediate "amide", was obtained in a yield of 43.0%.

Level 6)

Preparation of the intermediate “aminoester”

A solution prepared by dissolving 1.0 equivalent of the intermediate "amide" obtained in the previous,- above-described Step 5?), in methanol, (5.0 mg/ ml), and piperidine^ (0.024 ml/mg), was stirred at room temperature for 2.0 hours. Then the reaction mixture was concentrated, and the residue was chromatographed', and the desired intermediate, "aminoester", was obtained in quantitative yield* ·· • · • tt tt * ttttt tt tt tt ···· tt·· ···· ··· ··· section mixture undiluted with dichloromethane, and with water.

After separation of the aqueous and organic phases, the aqueous phase was

Extracted 3x with dichloromethane, and the combined organic extracts were then dried, concentrated and chromatographed, or the desired intermediate, amide, was used crude. Yield 50.0%.

Step 2) Preparation of 4-(£3-chloro-5-[(cyclopentylcarbonyl)-amino]-2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

To a solution prepared by dissolving the intermediate amide obtained in the previous, above-described Step 1) in a mixture of tetrahydrofuran::methanol,/3.0:1.0), 3.0 equivalents of 1N sodium hydroxide solution were added, and the resulting reaction mixture was stirred until analysis with TLG showed that the reaction was complete.

The reaction mixture was then concentrated, diluted with water, and after acidification with concentrated hydrochloric acid to pH 2.0, it was extracted 3x with ethyl acetate. After separation of the organic and aqueous phases, the organic extracts were dried with magnesium sulfate, concentrated and purified by chromatography.

The desired title acid was obtained in a yield of 69.0%.

Example 27)

Preparation of 4-({3-chloro-2-(2-naphthylsulfanyl)methyl)-5-(2-quinoxalinylcarbonyl)amino)-1H-indol-1-yl)methyl)benzoic acid

Level 1)

Preparation of the intermediate amide

By an analogous procedure, described below in the general procedure in Step 1), Example 71), the intermediate amine obtained in the above-described Example 25), Step 4), was treated with the appropriate acid chloride, and the desired intermediate _? ,amide was prepared in a yield of 76.0

Level 2)

Preparation of 4-(£3-chloro-2-[(2-naphthylsulfanyl)-methyl]-5-[(2-quinoxalinylcarbonyl)-amino]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure described above in the previous Example 26) ₍ Step 2), the intermediate "amide" obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title acid in a yield of 53.0 • 4 ·♦ ♦♦ 44 4 • · · 4 4 44 4 444 ·· · · ·444 • · 444 444 • 444 ·44 4444 4444 4444

Example 28)

Preparation of 4-(3-chloro-5-[(2,2-dimethylpropanoyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]-methyl)benzoic acid

Level 1)

Preparation of the intermediate “amide”

By an analogous general procedure described above in Example 71), Step 1), the intermediate "amine" obtained in the above-described Example 25) "Step 4") was treated with the appropriate acid chloride, and the desired intermediate "amide" was obtained in a yield of 100.0%.

Level 2)

Preparation of 4-({3-chloro-5-[(2,2-dimethylpropanoyl)-amino]-2-[(2naphthylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure described above in Example 26) ₍ Step 2), the intermediate "amide", obtained in the previous, above-described Step 1), was hydrolyzed to give the desired, title acid, in a yield of 79.0%, <F7

Example 29)

[(2-naphthylsulfanyl)-methyl/-1H-indol-1-yl]-methyl)-benzoic acid

Level 1)

Preparation of the intermediate amide

By an analogous, simple procedure, described below in Example 71), Step 1), the intermediate "amine _" obtained in the above-described Example 25), Step 4), was treated with the appropriate acid chloride, and the desired intermediate "amide" was obtained in a yield of 96.0

Grade) 2)

acids

By an analogous procedure described above in Example 26),

Step 2), the intermediate "amide" obtained in the previous, above-described Step 1) was hydrolyzed to yield the desired title acid.

Example) 3®)

Preparation of 4-({3-chloro-5-[[cyclopentyloxy)-carbonyl]-amino]2-[(2-naphthylsulfenyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Level 1)

Preparation of the intermediate amide

By an analogous/general procedure, described below in Example 71), Step 1), the intermediate "amine", obtained in the above-described Example 25), Step 4), was treated with acetic anhydride _T , and the desired, title intermediate "amide", was obtained in a yield of 92.0

8'; level 2)

Preparation of 4-({3-chloro-5-[(cyclopentyloxy)carbonyl]-amino] 2-((2-naphthylsulfanyl)methyl]-1H-indol-1-yl-methyl)-benzoic acid

By an analogous procedure described above in Example 26)

Step 2) The intermediate amide obtained in the previous, above-described Step 1) was hydrolyzed to obtain the desired title acid 4ο • · · ·

Example 31)

Preparation of 4-(5-acetylamino)-3-chloro-2-(2-naphthylsulfanyl)methyl)-1H-indol-1-ylmethyl)benzoic acid

Level 1)

Preparation of the intermediate amide

By an analogous general procedure, described below in Example 71), Step 1), the intermediate "amine", obtained in the above-described Example 25), Step 4), was treated with acetic anhydride, and the desired intermediate "amide" was obtained, in a yield of 77.0%, in the title.

Level 2)

Preparation of 4-(5-raceylamino)-3-chloro-2-(2-naphthylsulfanyl)methyl)-1H-indol-1-ylmethyl)benzoic acid

By an analogous procedure described above in Example 26),

Step 2), the intermediate amide obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title acid in a yield of 29.0

Example 1 8 (32)

Preparation of 4-((5-[(butylamino)carbonyl]-amino]-3-chloro-2[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]-methyl)-benzoic acid

(With a sigh)

Preparation of the intermediate product "urea"

A 0.12 M tetrahydrofuran solution, prepared using 1.0 equivalent of the intermediate "amine" obtained in Step 4), was cooled to 0.0 °C, and then, after adding 1.10 equivalents of butyl isocyanate, the resulting reaction mixture was warmed to room temperature overnight, and then diluted by half with saturated ammonium chloride solution.

After separation of the aqueous and organic phases, the aqueous layer was extracted 3 times with ethyl acetate, and then the combined organic extracts were dried, concentrated, and the residue was purified by chromatography.

The desired intermediate, "urea", was obtained in a yield of 57.0%.

Step 2) Preparation of 4-((5-[(butylamino)carbonyl]-amino]-3-chloro-2[(2-naphthylsulfanyl)methyl]-1H-indol-1-ylmethyl)benzoic acid

By an analogous procedure described above in Example 26),

Step 2), the intermediate "urea", obtained in the previous, above-described Step 1), was hydrolyzed, and the desired title acid was obtained in a yield of 41.0%.

• · · β

Example 1 β « 33)

Preparation of 4-(1H-[(butylamino)carbonyl]-amino]-3-chloro-2-(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

Level 1)

Preparation of the intermediate "ester"

By an analogous procedure to that described above in the previous Example 32), Step 1), the intermediate “amine” was treated with benzyl isocyanate to give the desired title intermediate in 16.0% yield.

Level 2)

Preparation of 4-(£5-£(butylamino)carbonyl)amino)-3-chloro-2-(2-naphthylsulfanyl)methyl)-1H-indol-1-yl-methyl)benzoic acid

By an analogous procedure described above in Example 26),

Step 2), the intermediate "ester" obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title acid in a yield of 100.0%· • 9

9991

Example 34)

Preparation of 4-(3-chloro-5-[(morpholinecarbonyl)-amino ^] -2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl-methyl)-benzoic acid

Step 1)

Preparation of the intermediate product "urea"

To a mixture prepared by mixing 1.0 equivalent of the intermediate "amine" obtained in Step 4 above, and introduced into a reaction flask together with 1.50 equivalents of 4-dimethylaminopyridine, in dichloromethane, (0.08 M solution), was added 1.50 equivalents of 4-morpholinocarbonyl chloride, and the resulting reaction mixture was stirred at room temperature overnight. Then, after further heating at 40.0 °C for 4.0 hours, ethyl acetate and half-saturated ammonium chloride solution were added to the mixture.

After separation of the organic and aqueous phases*, the aqueous layer was extracted 3 times with ethyl acetate, and the combined organic extracts were concentrated after drying, and the residue was purified by chromatography.

The desired intermediate product, urea, was obtained in a yield of 100.0%.

Level 2)

Preparation of 4-(3-chloro-5-[(morpholinecarbonyl)-amino]-2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl-methyl)-benzoic acid

By an analogous procedure described above in Example 26),

Step 2), the intermediate "urea", obtained in the previous, above-described Step 1), was hydrolyzed, and the desired title acid was obtained in a yield of 79.0%,

Example 1 and dl 3 5)

Preparation of 4-(£5-(benzylamino)-3-chloro-2-[(2-naphthylsulfonyl)methyl]-1H-indol-1-yl-methyl)-benzoic acid

S t e g e s 1 )

Preparation of the intermediate product “urea”

To a solution prepared by dissolving 1.0 equivalent of the intermediate "amine" obtained in Step 1) above in dichloromethane, 1.0 equivalent of benzaldehyde was added first, followed by 2.0 mL/1.0 mmol of acetic acid, and the resulting reaction mixture was stirred for 20.0 minutes.

Then, 1.30 equivalents of sodium triscetoxyborohydride were added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. Then, after mixing with an aqueous solution of diethanolamine and dichloromethane, the aqueous and organic phases were separated, and the aqueous layer was extracted 3 times with dichloromethane.

The combined organic extracts were dried and concentrated, and after chromatographic purification of the residue, the desired intermediate, urea, was obtained in a yield of 74.0%.

r • ·· ·

Level 2)

Preparation of 4-({5-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure, described above in Example 26), Step 2), the intermediate "^urea", obtained in the previous, above-described Step 1), was hydrolyzed, and the desired title acid was obtained in a yield of 49.0%.

Example 36)

Preparation of 4-(3-chloro-2-[(2-naphthylsulfanyl)-methyl]-5-[(3-phenoxybenzyl)-amino]-1H-indol-1-yl]-methyl)-benzoic acid (step 2)

Step 1)

Preparation of the intermediate "secondary amine"

By an analogous procedure described above in the previous Example 35), Step .1), the intermediate "amine" obtained in the above-described Example 25), Step 4), was treated with the appropriate aldehyde, and the desired title intermediate was obtained in a yield of 38.0%, » ·· 9 ·· ·

Preparation of 4-( ⁽ £3-chloro-2-[(2-naphthylsulfanyl)-methyl]-5-[(3'•, phe j phenoxybenzyl)-amino]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure described above in Example 26), Step 2), the intermediate, secondary amine, obtained in the previous, above-described Step 1), was hydrolyzed to give the desired title acid in 87.0% yield.

Example 1; 37)

Preparation of 4-(£3-chloro-5-[(cyclopentylcarbonyl)(methyl)-amino]2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl-methyl)-benzoic acid

Level 1)

Preparation of the intermediate, methylated amide

To a mixture prepared by mixing the intermediate "ester" obtained in Example 27, Step 1, above, with N,N-dimethylformamide (0.05 M), cooled to 0.0°C, was added 10.0 equivalents of sodium hydride, and the resulting reaction mixture was stirred for 30.0 minutes.

Then, after adding 10.0 equivalents of methyl iodide to the resulting reaction mixture, the mixture was stirred at room temperature overnight, and then diluted with ethyl acetate, and half a saturated ammonium chloride solution.

' After separation of the aqueous and organic phases, the aqueous layer was 3x <7?

The mixture was extracted with ethyl acetate, and the combined organic extracts were concentrated after drying, and the residue was purified by chromatography.

The desired title intermediate was obtained in a yield of 56.0

S t e g e 2)

Preparation of 4-(£3-chloro-5-[(cyclopentylcarbonyl)(methyl)-amino]2-[(2-naphthylsulfenyl)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure described above in Example 26), Step 2), the intermediate, methylated amide, obtained in the previous, above-described Step 1), was hydrolyzed to give the desired, title acid in a yield of 57.0

(Appendix 1 and 38)

Preparation of 4-(£5-/acetyl-(benzyl)-amino/-3-chloro-2-/(2-naphthylsulfanyl)-methyl/-1H-indol-1-yl?-methyl)-benzoic acid

Level 1)

Preparation of the intermediate "tertiary amide"

By an analogous procedure, described above in Example 37),

Step 1), the intermediate "amide" obtained in the above-described Example 31), Step 1), was benzylated, and the desired* title intermediate* was prepared in a yield of 90.0

Level 2)

Preparation of 4-({5-/acetyl-(benzyl)-amino/-3-chloro-2-(2-naphthylsulfanyl)-methyl/-1H-indol-1-yl-methyl)-benzoic acid

By an analogous procedure described above in Example 26), Step 2), the intermediate "tertiary amide", obtained in the previous, above-described Step 1), was hydrolyzed to give the desired title acid, in a yield of 41.0%.

Example 59)

Preparation of 4-({3-chloro-2-(2-naphthylsulfanyl)methyl}-5-((tetrahydro-3-furanylcarbonyl)amino)-1H-indol-1-yl)methyl)benzoic acid

Grade T)

Preparation of the intermediate "ester"

To 1.0 equivalent of the intermediate, indole-amine, was added dimethylaminopyridine acid, (1.20 equivalent; 10.0 mol%), followed by 1.50 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride, and N,N-dimethylformamide, (0.3M), and the reaction mixture was stirred under nitrogen at room temperature for 24.0 hours, then poured into half a saturated solution of ammonium chloride and ethyl acetate.

After separation of the aqueous and organic phases, the aqueous layer was extracted 3 times, and the combined organic extracts were washed with water (2 times), and then concentrated after drying. The residue was chromatographed to give the title compound, i.e., the intermediate ester, in 55.0% yield.

S t e g e 2)

Preparation of 4-(3-chloro-2-[(2-naphthylsulfenyl)methyl]-5-[(tetrahydro-3-furanylcarbonyl)amino]-1H-indol-1-yl]-methyl)benzoic acid

By an analogous procedure to that described above in Example 26), Step 2) _, the desired title acid was prepared using the intermediate ,,-ester obtained in the previous, Step 1), described above, in a yield of 55.0%.

example 40)

Preparation of 4-(3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3 ^; “thienylcarbonyl)amino]-1H-indol-1-yl]-methyl)benzoic acid

J00 ···

With a smile)

Preparation of the intermediate “amide”

By an analogous procedure to that described above in Example 39), Step 1), using the intermediate "amine" obtained in Example 25), Step 4), reacted with the appropriate acid, the desired intermediate "amide" specified in the title was prepared in 100.0% yield.

Level 2)

Preparation of 4-([3-chloro-2-[(2- ^{naphthylsulfanyl} )methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure described above in Example 26), Step 2), the intermediate "amide" obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title compound in 21.0% yield.

Example 41)

Preparation of 4-[3-chloro-2-(2-naphthylsulfanyl)methyl]-5-[(18-damantylcarbonyl)amino]-1H-indol-1-ylmethyl]-benzoic acid • · • · ·· » · · * • · · « · ·«·· · • · ··· * « » ··· ··· ·· *.·* ·. ...

S5 t u ρ β B 1 )

Preparation of the intermediate “amide”

By an analogous procedure, described above in Example 39), Step 1), using the intermediate "amine", obtained in the above-described Example 25), Step 4), reacted with the appropriate acid, the desired intermediate "amide", mentioned in the title, was prepared in a yield of 100.0%»

Level 2)

Preparation of 4-(£3-chloro-2-[(2-naphthylsulfonyl)-methyl]-5-[(1adamentylcarbonyl)-amino]-1H-indol-1-yl^-methyl)-benzoic acid

By an analogous procedure described above in Example 26), Step 2), the intermediate "amide" obtained in the previous, Step 1) described above was hydrolyzed to give the desired title acid in 35.0% yield.

Example 42)

Preparation of 3-/({ ¹ -( 4-carboxybenzyl)-3-chloro-2-/( 2-naphthylsulfanyl)-methyl/-1H-indol-5-yl^ -amino)-carbonyl/-benzoic acid • ·· ♦ · · · · · · ··· ··· 99 9 99 9 fr··

Step* 1)

Preparation of the intermediate “amide”

By an analogous procedure described above in Example 39), Step 1), using the intermediate "amine**" obtained in Example 26), Step 4), reacted with the appropriate acid, the desired intermediate "amide" mentioned in the title was prepared in 100.0% yield.

S t e g e 2)

Preparation of 3-[({1-(4-carboxybenzyl)-3-chloro-2-(2-naphthylsulfanyl)methyl]-1H-indol-5-yl-amino)carbonyl]-benzoic acid

By an analogous procedure to that described above in Example 26), Step 2), the intermediate "amide**" obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title compound in 20.0% yield.

(43)

Preparation of 4-(^3-chloro-2-/(2-naphthylsulfanyl)-methyl/-5-/(3-phenylpropanoyl)-amino/-1H-indol-1-yl-methyl)-benzoic acid

Level 1)

4444

4 4

484

Preparation of the intermediate “amide”

By an analogous procedure described above in Example 39), Step 1), using the intermediate "amine", obtained in Example 25), Step 4), reacted with the appropriate acid, the desired intermediate "amide ^M" mentioned in the title was prepared in a yield of 100.0¾%.

Level 2)

Preparation of 4-({3-chloro-2-[(?-[(2-naphthylsulfanyl)-methyl]-5[(3-phenylpropanoyl)-8amino]-1H-indol-1-yl}-methyl)-benzoic acid

By an analogous procedure to that described above in Example 26), Step 2), the intermediate "amide" obtained in the previous, above-described Step 1) was hydrolyzed to give the desired title compound in 32.0% yield.

Example 44)

Preparation of 4-((5-amino-3-chloro-2-[1,2-naphthylsulfonyl)-methyl)-1H-indol-1-yl-methyl)-benzoic acid

Level 1)

Sieves ···· ·

By an analogous procedure, described above in Example 26),

Step 2), the intermediate "amine", obtained in the above-described Step 4), was hydrolyzed to give the desired title compound in a yield of 79.0

Example 45)

Preparation of N-[3-chloro-1-(4-[(methylsulfonyl)-amino]-carbonyl]-benzyl)-2-[('2-naphthylsulfanyl)-methyl]-1H-indol-5-yl]-cyclopentanecarboxamide

Level 1)

Preparation of the title compound

A mixture prepared by mixing the compound obtained in Example 26, described above ₍ 10 equivalents), N-ethylN-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.50 equivalents), 4-dimethylaminopyridine (1.0 equivalents), and methanesulfonamide (1.0 equivalents) in a reaction flask under nitrogen with N,N-dimethylformamide (0.08 M) was stirred at room temperature overnight, and then worked up by adding half a saturated aqueous solution of ammonium chloride and ethyl acetate.

After separation of the aqueous and organic phases, the aqueous layer was extracted 3 times, and the combined organic extracts were washed 2 times with water, and after drying, they were concentrated.

The residue was chromatographed to give the desired title compound in 27.0% yield.

• ·

n-naphthylaulfanyl)-methyl[-1-(4-([(4J-carbonyl)-benzyl]-1H-indol-5-yl}

4444

Example 46)

Preparation of 3-chloro-2-[(2nitrophenyl)sulfonyl]-aminocyclopentanecarboxamide

Level 1)

By an analogous procedure described above in the previous Example 45), Step 1), after adding the appropriate sulfonamide, to 4-(3-chloro-5-(cyclopentylcarbonyl)-amino)-2-(2-naphthylsulfonyl)-methyl)-1H-indol-1-yl- _c -methyl)-benzoic acid prepared in the above-described Example 26), the desired acylsulfonamide mentioned in the title was obtained in a yield of 43.0%.

Example 47)

Preparation of 3-chloro-1-[44· ({(2-methylphenyl)sulfonyl)amino]carbonyl)benzyl]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}cyclopentanecarboxamide

Level 1)

By an analogous procedure to that described above in Example 45), Step 1), after addition of the appropriate sulfonamide, to the acid

4-(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthylsulfonyl)methyl]-tri-indol-1-ylmethyl]-benzoic acid, prepared in the same manner as in Example 26 above), afforded the title desired acylsulfonamide in 40.0% yield.

Example 48) i

Preparation of N-[3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-(4-[(phenylsulfonyl)amino]carbonyl]-benzyl)-1H-indol-5-yl] cyclopentanecarboxamide

S t e r 1)

By an analogous procedure described above in Example 45), Step 1), after adding the appropriate sulfonamide to 4-(S3-chloro-5-[(-cyclopentylcarbonyl)-amino]-2-[(2-naphthylsulfonyl-methyl]-1H-indol-1-yl? -methyl)-benzoic acid, prepared in Example 26 described above, the title acylsulfonamide of interest was obtained in a yield of 40.0%♦

Example 49)

Preparation of N-[3-chloro-2-(2-naphthylsulfanyl)-methyl]-1-[4-([(trifluoromethyl)-sulfonyl]-8amino]-carbonyl)-benzyl]-1H-indol-5-yl]-cyclopentanecarboxamide

ΦΦ φ • φ ·· • · » φ • φ φφφ» φ*· φφ φ · φ • · • · • · φφφφ

Φ· φ φ φφφ • φ φ • φ φ ·· φφφ

Level 1)

By an analogous procedure to that described above in Example 45), Step 1), the desired acylsulfonamide was obtained in a yield of 67.0% after addition of the appropriate sulfonamide to 4-[3-chloro-5-(cyclopentylcarbonyl)amino]-2-((2-naphthylsulfonyl)methyl]-1H-indol-1-yl]-methyl]benzoic acid, prepared in Example 26).

Example 50)

Preparation of 4-(5-[(cyclopentylcarbonyl)amino]-2-(2-sulfoxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]-butanoic acid

Level 1)

Preparation of the intermediate product, crude acid **

To a solution prepared by dissolving ethyl 5-nitroindole- ₂ -carboxylate (1.0 equivalent) in a 0.21 M solution of tetrahydrofuran:methanol:water (3.0:1.0:1.0), lithium hydroxide hydrate (1.38 equivalent) was added, and the resulting reaction mixture was stirred at 25.0°C overnight.

Then, after acidifying the reaction mixture with 1N hydrochloric acid solution to pH 1.0, the mixture was extracted with ethyl acetate. After subsequent treatment of the extract with water, brine, and after drying, concentration, the desired crude intermediate in the title was obtained in a yield of 99.0%.

jot • 44 • ·

4444

444

4 · ·· ····

9 • · ·· • · · · • · · • 4,444 • ·

Level 2)

Preparation of the intermediate product "crude indole alcohol"

To a solution prepared by dissolving the intermediate "crude acid" obtained in the previous, above-described Step 1), (1.0 equivalent), in tetrahydrofuran, (0.14 M), was added carbonyldiimidazole, (1.0 equivalent), and the resulting reaction mixture was stirred at 25.0 °C for 1.50 hours. Then, after cooling the reaction mixture to 0.0 °C, sodium borohydride, (2.86 equivalent), was added in several portions, and then, after subsequent addition of ethanol, (0.71 M), the mixture was stirred at 25.0 °C overnight.

The reaction mixture was then acidified with 2N hydrochloric acid to pH 2.0, and then extracted with ethyl acetate. After treatment of the extract with water and brine, and after drying and concentration, the desired crude intermediate, the title compound, was obtained in 95.0% yield.

Level 3)

Preparation of the “protected indole” intermediate

To the oven-dried reaction flask was added the intermediate "crude indole alcohol" (1.0 equivalent), obtained in the previous, above-described Step 2), followed by anhydrous N,trithiol formamide (0.135 M). To the resulting mixture was then added imidazole (1.30 equivalent), and tert-butyldimethylsilyl chloride (TBSC) (1.20 equivalent), and the reaction mixture was stirred at 25.0°C for 1.0 hour.

After treatment with ethyl acetate/water and subsequent purification, the desired title intermediate was obtained in 70.0% yield.

Level 4)

Preparation of the intermediate “alkylated indole”

To a solution prepared by dissolving the intermediate product "protected inflol" (1.0 equivalent), obtained in the previous, above-described Step 3), in anhydrous N,N-dimethylformamide (0.13 M), placed in an oven-dried reaction flask, was added sodium hydride (60% dispersion in mineral oil) (1.20 equivalent), and the resulting reaction mixture was stirred at 25.0 °C for 1.0 hour.

Ethyl 4-bromobutyrate, (1.20 equivalents), and potassium iodide, (1.20 equivalents), were then added to the reaction mixture, and the reaction mixture was heated at 60.0°C for 2.0 hours.

After work-up with ethyl acetate/water and chromatography purification, the desired title intermediate was obtained in 93.0% yield. <

Level 5)

Preparation of the intermediate product “indole alcohol”

To a solution prepared by dissolving the intermediate "alkylated indole" obtained in the previous, above-described Step 4), (1.0 equivalent), in tetrahydrofuran, (0.05 M), was added dropwise, at a temperature of 25.0 °C, tetrabutylammonium fluoride (TBAF), (1M, tetrahydrofuran, 1.10 equivalent), and the resulting reaction mixture was stirred for 1.0 hour.

After workup with ethyl acetate/water, followed by chromatography, the desired title intermediate was obtained in quantitative yield.

• ·

33ο

S u r e n 6)

Preparation of the intermediate “chloraldehyde derivative”

To a solution prepared by dissolving the intermediate "indole alcohol" (1.0 equivalent), obtained in the previous, above-described Step 5), in anhydrous N,N-dimethylformamide (0.16 M), phosphorus oxychloride was added dropwise at 0.0 °C, and the resulting reaction mixture was heated at 80.0 °C overnight, (POCl2 = 10.0 equivalent).

After treatment with ethyl acetate/water, and separation of the aqueous and organic phases, the organic layer was washed with 1N sodium hydroxide solution and brine, and after subsequent concentration and purification of the residue by chromatography, the desired title intermediate was obtained in a yield of 64.0%.

Level 7)

Preparation of the intermediate product, naphthyloxyindole derivative

A mixture prepared by mixing the intermediate, chloraldehyde derivative, obtained in the previous, above-described Step 6), (1.0 equivalent), potassium carbonate, (2.40 equivalent; 325.0 mesh), 2-naphthol, (1.20 equivalent), and potassium iodide, (1.20 equivalent), in anhydrous acetonitrile, (0.2 M), was heated at 70.0 °C for 1.50 hours.

After treatment with ethyl acetate/water, followed by chromatographic purification, the desired title intermediate was obtained in 65.0% yield.

• · tttttt • · · tt · • · · · · ·· ···· ··

Grade 8)

Preparation of the intermediate, aminoindole derivative

To a solution prepared by dissolving the intermediate "naphthyloxyindole derivative" obtained in the previous, above-described Step 7) (1.0 equivalent) in anhydrous tetrahydrofuran (0.023 M), a 5% platinum on activated carbon catalyst (40.0 weight percent) was added under a nitrogen atmosphere, and the resulting reaction mixture was hydrogenated in a round-bottomed reaction flask with a valve for 2.50 hours.

The reaction mixture was then filtered through silica, and after concentration, the desired title intermediate was obtained as a crude product in a yield of 96.0%.

Grade 9)

Preparation of the intermediate product “indole”

To a solution prepared by dissolving the intermediate “aminoindole derivative” obtained in the previous, above-described Step 8), (1.0 equivalent), in anhydrous dichloromethane, (0.07 M), was added dropwise, and, at a temperature of 0.0 °C, triethylamine, (1.40 equivalent), and cyclopentanecarbonyl chloride, (1.20 equivalent), and the resulting reaction mixture was stirred at a temperature of 25.0 °C, for 0.50 hour.

Then the reaction mixture was mixed with saturated aqueous sodium bicarbonate solution, and stirred overnight. After separation of the aqueous and organic phases, the organic layer was washed with brine, and dried. After subsequent recrystallization of the residue from 30% ethyl acetate/hexane, the desired intermediate was obtained in the title compound in a yield of 66.0

Grade 10)

Preparation of the intermediate "acid"

1.0 equivalent of the intermediate "indole", obtained in the previous "Step 9" described above, was weighed into the reaction flask, together with sodium dihydrogen phosphate (12.0 equivalent), t-butyl alcohol (0.13 M), water (0.13 M), 2-methyl-2-butene (46.0 equivalent), and sodium chlorite (12.0 equivalent) was added to the resulting reaction mixture at a temperature of 25.0 °C.

After the resulting reaction mixture was heated at 65.0 °C overnight, it was treated with ethyl acetate/water, and then triturated with dichloromethane:hexane (4.0:6.0) at 0.0 °C for 1.0 h to afford the desired title intermediate in 63.0% yield.

Grade 11)

Preparation of the intermediate amide

To a reaction flask, into which was weighed 1.0 equivalent of the intermediate "acid", obtained in the previous, above-described Step 10), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (EDCI), (3 equivalent), then 1.20 equivalent of 4-dimethylaminopyridine, (DMAP), then pyrrolidine. (1.20 equivalent), and then anhydrous tetrahydrofuran, (0.018 M), and the resulting reaction mixture was heated under reflux for 18.0 hours.

After subsequent work-up with ethyl acetate/water, the organic and aqueous phases were separated, and the organic layer was washed successively with 1N hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and brine, and after subsequent recrystallization of the residue from ethyl acetate/hexane (3.0:7.0), the desired title intermediate was obtained in 89.0% yield.

Step 12) Preparation of 4-(5-[(cyclopentylcarbonyl)amino]-2-(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]-butanoic acid

To a solution prepared by dissolving the intermediate “amide” obtained in the previous, above-described Step 11), (1.0 equivalent), in a mixture of tetrahydrofuran:methanol:water, (3.0:1.0:1.0), (0.025 M), was added lithium hydroxide hydrate, (1.20 equivalent), and the resulting reaction mixture was stirred at 25.0 °C, overnight.

After treatment of the mixture with ethyl acetate and water, and subsequent recrystallization from a mixture of dichloromethane : hexane, (1.0 : 1.0), the desired title compound was obtained in a yield of 98.0

Example 51)

Preparation of 4-{[?~/(cyclopentylcarbonyl)-amino]-3-(morpholinecarbonyl)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-butanoic acid

S t e r 1 )

44 4 ·

Preparation of the intermediate, morpholinamide

By an analogous procedure to that described above in the previous Example 50), Step 11), using morpholine, the desired title intermediate was obtained by recrystallization in 87.0% yield.

S t u ρ β i 2)

Preparation of 4-[5-[(cyclopentylcarbonyl)-amino]-3-(methylcarbonyl)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-butanoic acid

By an analogous procedure described above in the previous Example 50, Step 12), using the intermediate "morpholinamide" obtained in the previous, above-described Step 1), the desired title compound was obtained after recrystallization in a yield of 96.0%.

Example 52)

Preparation of N-(2-[(2-naphthyloxy)-methyl]-1-(4-oxo-4-{[(trifluoromethyl)-sulfonyl]-amino]-butyl)-3-(1-pyrrolidinylcarbonyl)-1H-indol-5-yl]-cyclopentanecarboxamide

To 4-(5-[(cyclopentylcarbonyl)-amino]-2-((2-naphthyloxy)-methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]-butanoic acid, obtained in the above-described Example 50 (1.0 equivalent), unweighed into a reaction flask, was added 1-(3-dimethylformamide)

(ethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (EDCI), (3 equivalents), then 4-dimethylaminopyridine, (1.20 equivalents), and trifluoromethanesulfonamide, (1.20 equivalents), followed by anhydrous tetrahydrofuran, (0.04 M), and the resulting reaction mixture was stirred at 25.0 °C for 1 h.

After working up with ethyl acetate/water, and separating the organic and aqueous phases, the organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. After trituration of the crude product with dichloromethane:hexane (1.0:2.0) for 1.0 h at 0.00°C, the desired title compound was obtained in 96.0% yield.

Example 53)

Preparation of N-(3-(morpholinocarbonyl)-2-(2-naphthyloxy)-methyl)-1-(4-[4-[alpha]-4-[(trifluoromethyl)-sulfonyl]-amino]-butyl)-1-indole-5-yl]-cyclopentanecarboxamide

By an analogous procedure to that described above in the preceding Example 52), Step 1), and using the appropriate acid from Example 51), (Step 4), Scheme 4), the desired title compound was obtained in 96.0% yield.

Example 53A)

Preparation of 4-[5-[(cyclopentylcarbonyl)-amino]-3-formyl-2-[(2-naphthylhexyl)-methyl]-1H-indol-1-yl]-butanoic acid

Level 1)

To a solution prepared by dissolving the intermediate "indole" obtained in Example 50, Step 9, above (1.0 equivalent) in a mixture of tetrahydrofuran:methanol:water (3.0:1.0:1.0; 0.025 M), lithium hydroxide hydrate (1.20 equivalent) was added and the resulting reaction mixture was stirred at 25.0°C for 4.0 hours.

After treatment with ethyl acetate/1N hydrochloric acid solution, followed by trituration with dichloromethane/hexane, the desired title compound was obtained in 74.0% yield.

Example 53B)

Preparation of N-(3-formyl-2-(2-naphthyloxy)-methyl)-1-(4-oxo-4-(trifluoromethyl)-sulfonyl)-amino-4-butyl)-1H-indol-5-yl)-cyclopentanecarboxamide

Level 1)

To 4-[5-(cyclopentylcarbonyl)-amino]-3-formyl]-2-(2-naphthyloxy)-methyl]-1H-indol-'-yl]-butanoic acid, obtained in the above-described, previous Example 53A), Step 1), weighed into a reaction flask, (.1.0 Equivalent), was added 1 — 0 — dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (EDCI), (1.35 equivalent), then 4-dimethylaminopyridine, (DMAP), (1.10 equivalent), and trifluoromethanesulfonamide, (1.05 equivalent), and anhydrous tetrahydrofuran, (0.026 M), 8 the resulting reaction mixture was stirred at a temperature of 25.0 ° C for 3.0 hours.

The reaction mixture was then treated with ethyl acetate/water. After separation of the organic and aqueous phases, the organic layer was washed successively with 0.05 N hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and brine, and after chromatographic purification, the desired title compound was obtained in a yield of 94.0%.

Example 54)

Preparation of 5-[(cyclopentylcarbonyl)-amino]-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-[(trifluoromethyl)-sulfonyl]-amino]-butyl)-1H-indole-3-carboxylic acid

Level 1)

The product obtained in the previous, above-described Example 53B), Step 1), i.e. N-(3-formyl-2-[(2-naphthyloxy)-methyl]-1-(4-[OxO-4-[(trifluoromethyl)-sulfonyl]-amino-butyl)-1H-indol-5-yl]-cyclopentanecarboxamide, (1.0 equivalent), was weighed into a reaction flask, together with sodium dihydrogen phosphate, (12.0 equivalent), t-butyl alcohol, (0.12 M), water, (0.12 M), and 2-methyl-2-butene, (50.0 equivalent), and sodium chlorite, (11.80 equivalent), was added to the resulting reaction mixture at a temperature of 25.0 °C.

After work-up with ethyl acetate/water, followed by chromatographic purification and trituration with dichloromethane:hexane (1.0:1.0), the desired title compound was obtained in 57.0% yield.

and

P ř ί k X a d 55)

Preparation of 3-((4-/5-/(cyclopentylcarbonyl)-amino/-2-/(2-naphthyloxy)-methyl/-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl/-but8noyl| amino)-benzoic acid

Level 1)

Preparation of the intermediate "ester"

To the compound obtained in the above-described Example 50), i.e. 4-(5-[(cyclopentylcarbonyl)-amino]-2-(2-naphthyloxy)-methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]-butanoic acid, weighed into a reaction flask (1.0 equivalent), N-ethyl[3-dimethylaminopropyl]-carbodiimide hydrochloride, (EDCI), (3.0 equivalent), then 4-dimethylaminopyridine, (DMAP), (1.20 equivalent), and methyl-3-aminobenzoate, (1.20 equivalent), followed by anhydrous tetrahydrofuran, (0.04 M), and the resulting reaction mixture was stirred at 25.0 °C for 2.0 days.

After treatment with ethyl acetate/water, and after separation of the organic and aqueous phases, the organic layer was washed with 1N hydrochloric acid solution, then with saturated aqueous sodium bicarbonate solution, and with brine. After recrystallization of the residue from ethyl acetate/hexene, the desired title compound was obtained in a yield of 88.0

Level 2)

Preparation of 3-(4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]-butanoylamino)benzoic acid

4·· · · · · · · »·» • ··»· · · · · * ♦ · ··· · · · · · · · · · · 9· ···· ·· *··

To a solution prepared by dissolving the intermediate "ester" obtained in the previous, above-described Step 1), (1.0 equivalent), in a mixture of tetrahydrofuran:methanol:water, (3.0:1.0:1.0), was added lithium hydroxide hydrate, (1.20 equivalent), and the resulting reaction mixture was stirred at 25.0 °C overnight. Then, additional lithium hydroxide hydrate, (1.20 equivalent), was added to the reaction mixture, and the mixture was stirred for 2.0 hours.

After treatment with a mixture of ethyl acetate x 1% hydrochloric acid solution, followed by trituration with a mixture of dichloromethane/hexane (1.0:1.0) at 0.0°C for 1.0 hour, the desired title compound was obtained in 92.0% yield.

Example 56)

Preparation of 2-((4-^5-/(cyclopentylcarbonyl)-amino/-3-(morpholine·carbonyl)-2-((2-maphthyloxy)-methyl/-1H-indol-1-yl?-butanoyl)amino/-benzoic acid

Step 1) (Preparation of the intermediate, morpholine

By an analogous procedure described above in the previous Example 55), Step 1), and using the product obtained in the above-described Example 51), (see Synthesis Scheme 4), the desired intermediate was obtained after chromatographic purification in a yield of 85.0%» q $ t u p e ň 2)

Preparation of 2-[(4-^5-[(cyclopentylcarbonyl)-amino]-3-(morpholinecarbonyl)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl-butanoyl)amino]-benzoic acid

By an analogous procedure described above in the previous Example 55), Step 2), using the appropriate intermediate "morpholine", prepared in the previous, above-described Step 1), the desired compound stated in the title was obtained in a yield of 91.0%.

Example 57)

Preparation of N-(2-[(C 2-naphthyloxy)-methyl]-1-[4-oxo-4-(3-[(trifluoromethyl)-sulfonyl]-amino]-carbonyl)-aniline]-butyl]-3-[pyrrolidinylcarbonyl]-1H-indol-5-yl]-cyclopentanecarboxamide

S t e r 1)

To the compound obtained in the above-described Example 55), (1.0 equivalent), weighed into a reaction flask, was added N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride, (EDCI), (3.0 equivalent), further 4-dimethylaminopyridine, (DMAP), (1.2 equivalent), _and trifluoromethanesulfonimide, (1.2 equivalent), and anhydrous tetrahydrofuran, (0.04 M).

The resulting reaction mixture was stirred at 25°C overnight and then worked up with ethyl acetate/water.

4 4 · ·· «4 4 ···· 4 4*4 44 44

4 444 44 4

4444 444 44 4444 44 444

After separation of the organic and aqueous phases, the organic phase was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, and then triturated with dichloromethane:hexane (8.0:2.0) to give the title compound in 84.0% yield.

Example 58)

Preparation _of N-(3-(morpholinecarbonyl)-2-[(2-naphthyloxy)-methyl]-4-[((trifluoromethyl)-sulfonyl)-amino]-carbonyl)-aniline]-butyl-1H-indol-5-yl]-cyclopentanecarboxamide

By an analogous procedure to that described above in the previous Example 57), Step 1), using 3-(4-[5-[(cyclopentylcarbonyl)-amino]-3-(morpholinecarbonyl)-2-(2-naphthyloxy)-methyl]-1H-indol-1-yl-butanoyl)-amino]-benzoic acid obtained in the above-described Example 56), the desired title compound was prepared in a yield of 84.0%.

Example 59)

Preparation of 2-(4-[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]-methylphenyl)acetic acid

Level 1)

Go

I··· »··

Preparation of the intermediate product,, ton

To a solution prepared by dissolving methylmagnesium bromide in butyl ether (1MJ 1.20 equivalent), cooled in an ice-cooled bath, was added a solution obtained by dissolving benzyloxyindole (1.0 equivalent), in dichloromethane (0.5 M), and the resulting reaction mixture was warmed to 25.0 °C.

After a solution prepared by dissolving 1-naphthoyl chloride (1.0 equivalent) in dichloromethane (1.0 M) was added to the reaction mixture, the reaction mixture was heated under reflux for 3.0 hours.

After subsequent mixing of the mixture with an aqueous solution of ammonium chloride, the mixture was extracted with chloroform, and the crude intermediate "ketone" was obtained, which was purified by recrystallization from a mixture of chloroform: methanol, and the desired intermediate, mentioned in the title, was obtained in a yield of 53.0

Level 2)

Preparation of 2-(4-[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl]-phenyl)-acetic acid

To an ice-cold solution prepared by dissolving the intermediate ketone obtained in the previous, above-described Step 1) (1.0 equivalent) in N,N-dimethylformamide (0.2M) was added hydride (60% product in mineral oil) (2.50 equivalent) and after 15.0 minutes a solution prepared by dissolving 4-bromophenylacetic acid (1.10 equivalent) in N,N-dimethylformamide (0.4M) and the resulting reaction mixture was stirred at 25.0°C overnight.

; Then the reaction mixture was mixed with 1N acid solution * ·· ·· ·· • 4 · 4 4444 444 · 444 444

4444 444 44 «444 44 444 hydrochloric acid, and extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic extracts were dried and concentrated.

After chromatographic purification and recrystallization of the residue from hexane:ethyl acetate, the desired title compound was obtained in a yield of 68.0%.

Example 60)

Preparation of 2-(4-[5-(benzyloxy)-3-(2-naphthoyl)-1H-indol-1-yl]methylphenyl)acetic acid

Level 1)

Preparation of the ketone intermediate

By an analogous procedure, described above in the framework of the previous Example 59), Step 1), using the appropriate acyl chloride, and after recrystallization from a hexane:chloroform mixture, the desired intermediate ketone was prepared in a yield of 42.0%.

Level 2)

Preparation of 2-(4-[5-(benzyloxy)-3-(2-naphthoyl)-1H-indol-1-yl]methyl-phenyl)-acetic acid

9 99 9 99·

9 9 9 · 9 9 9 9 9

9,999,999

9999 999 99 9999 9· 999

By an analogous procedure to that described above in the previous Example 59), Step 2), the desired title compound was obtained in a yield of 35.0% after chromatographic purification and recrystallization from an acetone:pentane mixture.

Example 61)

Preparation of 2-[4-(5-(benzyloxy)-3-(3,5-bis-(trifluoromethyl)benzoyl)-1H-indol-1-yl-methyl)phenyl]-acetic acid

Level 1)

Preparation of the ketone intermediate

By an analogous procedure to that described above in Example 59), Step 1), using the appropriate acyl chloride and after recrystallization from a mixture of hexane:dichloromethane:ethyl acetate, the desired intermediate ketone was prepared in a yield of 30.0

Level 2)

Preparation of 2-[4-([5-(benzyloxy)-3-(3,5-bis-(trifluoromethyl)benzoyl)-1H-indol-1-yl]-methyl)-phenyl]-acetic acid

By an analogous procedure to that described above in Example 59), Step 2), the desired title compound was obtained in a yield of 73.0% after chromatographic purification and recrystallization from a chloroform:methanol mixture.

Example 62)

Preparation of 4-(£3-benzoyl-5-(benzyloxy)-2-/(2-nitrophenylsulfanyl)methyl/-1H-indol-1-yl(-methyl)-benzoic acid

Level 1)

Preparation of the intermediate product “crude alcohol”

Under a nitrogen atmosphere, and at a temperature of ^0.09 °C, the starting material, i.e. ethyl 5-benzyloxyindole-2-carboxylate, (see Scheme £1; Step 1), was reacted with lithium tetrahydroaluminum, (1.30 equivalents), in tetrahydrofuran, (0.27 M), for 1.0 hour.~ .....

After treatment with sodium hydroxide and water, followed by concentration, the desired title intermediate was obtained in 100.0% yield.

Level 2)

Preparation of the intermediate “silyl ether”

The solution, prepared by dissolving the intermediate product "crude alcohol" obtained in the previous, above-described • · φ φ φφφφ φ φ φ φφφφ φ φφφφ φφφφ φφφφ φφφφ φφφφ

426

Step 1), in N,N-dimethylformamide, (0.38 M), was reacted at 25.0°C with t-butyldimethylsilyl chloride, (1.16 equivalent), and imidazole, (1.26 equivalent), for 1.0 hour. After subsequent work-up and chromatographic purification, the desired title intermediate was obtained in pure form, in a yield of 93.0%.

S t e g e 3)

Preparation of the intermediate product, N-BOC-silyl ether

A solution prepared by dissolving the intermediate "silyl ether" obtained in the previous, above-described Step 2) in dichloromethane, (0.26 M), was mixed sequentially with BOC-anhydride = di-tert.-butyl pyrocarbonate, (1.24 equivalent), triethylamine, (1.53 equivalent), and 4-dimethylaminopyridine, (0.21 equivalent), at a temperature of 25.0 °C, and the reaction mixture was maintained at said temperature for 3.0 days.

After subsequent work-up and chromatographic purification, the desired title intermediate was obtained in pure form in a yield of 99.0%.

Level 4)

Preparation of the intermediate product "alcohol"

The intermediate N-BOC-silyl ether obtained in the previous, above-described Step 3) was reacted at a temperature of 25.0 °C with a mixture of acetic acid:water:tetrahydrofuran.

0« Φ φφφφ φφ Φ

Φ ΦΦ* « ΦΦ Φ V ΦΦΦ ·· φ · φφφφ φ φφφφ φφφφ φ φ φ φφφ φφ* φφφφ φφφ φφ φφφφ φφ φφφ

42/ϊ ( 3.0 :: 1.0 : 1.0), ( 0.04 Μ), for 1.0 days.

After subsequent workup and chromatographic purification, the desired title intermediate was obtained in pure form and in a yield of 100.0%.

Level 5)

Preparation of the intermediate product, B0C-thioether

A solution prepared by dissolving the intermediate "alcohol" obtained in the previous, above-described Step 4) in dichloromethane (0.2 M) was reacted for 1.0 hour with triethylamine (1.33 equivalents) and mesyl chloride (1.23 equivalents) under a nitrogen atmosphere at a temperature of minus 40.0°C.

and

Into a separate dried reaction flask was weighed n8fthelen2-thiol, (1.31 equivalent), and after addition of tetrahydrofuran, (1.0 M), a 1% solution of lithium hexamethyldisilazide, in tetrahydrofuran, (1.0 equivalent), was added, and the resulting reaction mixture was stirred at 25.0 °C for 30.0 minutes. Τ'·; The reaction mixture^,,, in solution, was then added dropwise, at minus 40.0 °Q,, over 30.0 minutes, to the mesylate solution prepared in the above-described operation.

Then, after warming the reaction mixture to 25.0 °C, the mixture was stirred for 4.50 hours. Ρ _Λ subsequent work-up and chromatographic purification yielded the desired intermediate, BOC-thioether ^M .

Level 6)

• w « · • ·· ·« « ♦ ·· • . · ·· « · • • · • e • · • • · • ···· • · · ·· • · · · ·· ···

Preparation of the ‘free*’ indole thioether intermediate

The purified intermediate BOC-thioether obtained in the previous, above-described Step 5) was heated under nitrogen at 160.0-170.0 °C for 1.25 hours. After subsequent recrystallization from ethyl acetate and hexane, the desired title intermediate was obtained in 64.0% yield.

Level 7)

Preparation of the intermediate ketone

To a solution prepared by dissolving the intermediate "free indole thioether" (1.0 equivalent), obtained in the previous, above-described Step 6), in dichloromethane (0.125 M), and cooled in an ice-cooled bath, was added a 1M solution of methylmagnesium bromide (1.20 equivalent), in butyl ether, and the resulting reaction mixture was stirred for 30.0 minutes. ,

Then, after warming the reaction mixture to 25.0°C, benzoyl chloride was added dropwise to the mixture, and the reaction mixture was heated under reflux for 3.0 hours, and then stirred at 25.0°C overnight.

After mixing with ammonium chloride, the mixture was extracted with dichloromethane. After separating the organic and aqueous phases, the organic extracts were washed with brine, and concentrated.

After subsequent chromatographic purification of the residue, the desired intermediate product, ketone, was obtained in a yield of 55.0%.

• 4 • fr * fr · ·· • fr · • · >· • · ···· ·«· • fr «··· • · · • fr frfrfr

Grade 8)

Preparation of an intermediate designated as "pure material"

To a solution prepared by dissolving the intermediate "ketone" (1.0 equivalent), obtained in the previous, above-described Step 7), in dried N,N-dimethylformamide (0.1 M), was added sodium hydride (1.05 equivalent), in the form of a 60% product in mineral oil, and after 1.0 hour, methyl 4-bromomethylbenzoate (1.20 equivalent), was added to the reaction mixture at a temperature of 25.0 °C, and this mixture was stirred for 1 h.

After treatment with ethyl acetate/water, the crude material was obtained, which was purified by chromatography, and the desired intermediate was obtained in 56.0% yield.

Grade 9)

Preparation of 4-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl-methyl)-benzoic acid

The intermediate obtained in the previous, above-described Step 8), (1.0 equivalent), was hydrolyzed by the action of lithium hydroxide hydrate, (1.20 equivalents), in a mixture of tetrahydrofuran : methanol : water, (3.0 1.0 : 1.0), (0.07 M),

After the reaction mixture was stirred at 25°C overnight, it was treated with acetic acid, and the solvent was evaporated.

After workup with ethyl acetate/water and chromatographic purification, the desired title compound was obtained in 78.0% yield.

0 ·· ·· 00 · ···· 0 0 0 0 0 9 00

0 · · 9 0 0 0 • 9 0 9 9 0 0 9 9 0 · 9 0 9 990 ···· 090 90 0900 00 009

P ř ί k 1 a d 63)

Preparation of 4-(| 5-(benzyloxy)-3-isobutyryl-2-/(2-naphthylsulfanyl)-methyl/-1H-indol-1-ylmethyl)-benzoic acid

Level 1)

Preparation of the intermediate “ketone”

By an analogous procedure to that described above in Previous Example 62), Step 7), using isopropyl chloride and subsequent chromatography, the desired title intermediate was prepared.

Level 2)

Preparation of the intermediate “N-alkylated material”

By an analogous procedure described above in the previous Example 62), Step 8), the desired title intermediate was prepared after chromatographic purification in a yield of 50.0%.

Level 3)

Preparation of 4-(^5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)-methyl]-1H-indol-1-yl-methyl)-benzoic acid!

By an analogous procedure described above in the previous Example 62), Step 9), the intermediate obtained in the previous, above-described Step 2) was hydrolyzed, and after subsequent chromatography, the desired title compound was obtained in a yield of 67.0%.

Example 64)

Preparation of 2-[3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]-acetic acid

S t e g e 2)

Preparation of the intermediate “methyl ester”

By an analogous procedure described above in Example 62), Step 8), after prior alkylation of the intermediate obtained in Example 80), Step 1), described below, with methyl bromoacetate, and subsequent recrystallization from ethyl acetate, the desired title intermediate was prepared in a yield of 65.0%.

S t e g e 3)

Preparation of 2-[(2-naphthylsulfanyl)ethyl]-1H-indole-1'-yl]-acetic acid

ΊΧ ··’·· ·

By an analogous procedure described above in Example 62), Step 9, the intermediate "methyl ester", obtained in the previous, above-described Step 2), was hydrolyzed, and after subsequent recrystallization, the desired product stated in the title was obtained in a yield of 84.0%.

Example 65) Preparation of 2-[5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfenyl)methyl]-1H-indol-1-yl-acetic acid

S t e g e 2)

Preparation of the intermediate, Ν-alkylated material

By an analogous procedure described above in Example 63), Step 2), using methyl bromoacetate and the ketone intermediate obtained in Example 63), Step 1), and after subsequent chromatographic purification, the desired title intermediate was prepared in a yield of 66.0%.

Level 3)

Preparation of 2-[5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]-acetic acid

4$ζ • · · ·

By an analogous procedure described above in Example 63), ₍ S,step 3), the intermediate obtained in the previous, above-described Step 2), was hydrolyzed, and after subsequent chromatography, the desired title compound was obtained in a yield of 50.0%.

Example 66)

Preparation of 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl(-butanoic acid

Level 1)

Preparation of the intermediate “ketone”

To a solution prepared by dissolving ethylmagnesium bromide in ether (3NJ 2.17 equivalents), cooled to minus 70.0 °C, was added 1.0 equivalent of the intermediate "silyl ether", obtained in the above-described Example 62), Step 2), in ether,/ 0.55 Μ), β the resulting reaction mixture was stirred at minus 70.0 °C for 2.0 hours.

After the addition of benzoyl chloride (3.0 equivalents) in ether (1.5 M), the reaction mixture was stirred at minus 40.0 °C for 2.0 hours, and then, after mixing with saturated aqueous sodium bicarbonate at minus 40.0 °C, the mixture was warmed to 25.0 °C.

After subsequent workup with ethyl acetate/water, and recrystallization from hexane:ethyl acetate, the desired title intermediate was obtained in 89.0% yield.

Level 2)

A solution prepared by dissolving the intermediate ketone obtained in the previous, above-described Step 1) (1.0 equivalent) in dichloromethane (0.25 M) was mixed with triethylamine (2.0 equivalent), BOC-anhydride (1.24 equivalent), and 4-dimethylaminopyridine (0.21 equivalent), and the resulting reaction mixture was stirred at 25.0 °C for 20.0 minutes.

Then, after treatment with dichloromethane and water, the desired pure material, usable in the next Step 3), was obtained after subsequent trituration with hexane in a yield of 97.0%.

Level 3)

Preparation of the intermediate product "alcohol"

A solution prepared by dissolving the material obtained in the previous Step 2A (1.0 equivalent) in tetrahydrofuran (0.3 M) was mixed with excess pyridine and excess HF-pyridine at 0.0 °C, and the resulting reaction mixture was stirred at 25.0 °C for 1.50 h.

After treatment with ethyl acetate/water mixture and subsequent chromatographic purification, the desired intermediate, alcohol, was obtained in a yield of 86.0%.

Level 4)

Preparation of the intermediate "chloride"

A solution prepared by dissolving the intermediate "alcohol" (1.0 equivalent), obtained in the previous, above-described Step 3), in dichloromethane (0.4 M), was mixed with 2,6-lutidine (2.50 equivalent), and then with sulfochloride (1.20 equivalent).

After 30.0 minutes at 25.0 °C, the reaction mixture was treated with ethyl acetate and water, and the crude product obtained was purified by chromatography, and after trituration with hexane, the desired intermediate, "e-chloride", was obtained in 75.0% yield.

Level 5)

Preparation of the intermediate "ether"

A mixture prepared by mixing the intermediate chloride (1.0 equivalent) obtained in the previous, above-described Step 4), potassium carbonate (2.40 equivalent) 325.0 mesh, beta-naphthol (1.20 equivalent), and potassium iodide (1.20 equivalent) in methyl cyanide (0.3 M) was heated under reflux for 2.0 hours.

Then, after treatment with ethyl acetate/water, followed by trituration with hexane:ethyl acetate, 8 chromatography of the mother liquors gave the desired intermediate, ether, in 70.0% yield.

Level 6)

Preparation of intermediate product, indole compound • ♦ · · · · 4 ► · ·· · · · • · ♦ ·

To a solution of sodium methoxide in methanol, prepared by dissolving sodium, (3.0 equivalents) _in methanol, (0.2 M), was added 1.0 equivalents of the intermediate "ether", obtained in the previous, above-described Step 5) _, in tetrahydrofuran, (0.04 M), and the resulting reaction mixture was stirred at 25.0 °C for 3.0 hours.

After workup with ethyl acetate/water, followed by trituration with hexane:ethyl acetate, the desired title intermediate was obtained in 93.0% yield.

Level 7)

Preparation of the intermediate “ester”

To a solution prepared by dissolving the intermediate "indole compound" (1.0 equivalent), obtained in the previous Step 6, above, in dried N,H-dimethylformamide (0.1 M), was added 1.10 equivalents of sodium hydride (60% product in mineral oil).

After 1.0 hour, methyl 4-bromobutyrate (1.20 equivalents) and potassium iodide (1.20 equivalents) were added to the resulting reaction mixture, and the reaction mixture was stirred at 75.0°C for 3.0 hours.

After subsequent treatment with ethyl acetate/water, and after chromatographic purification, the desired intermediate "ester" was obtained in a yield of 96.0%.

Level 8) • ·· ·· ·· · ··· · · 0 · · 0·· • · 00 0 0 0 0

Preparation of 4-(3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)methyl)-1H-indol-1-yl)-butanoic acid

The intermediate "ester" (1.0 equivalent), obtained in the previous, above-described Step 7), was hydrolyzed by the action of lithium hydroxide hydrate (1.20 equivalent), in a mixture of tetrahydrofuran:methanol:water, (3.0:1.0:1.0), (0.2 M).

After the reaction mixture was stirred at 25.0°C for 2.0 hours, it was mixed with 1N hydrochloric acid solution, and then extracted with ethyl acetate and dichloromethane. After separating the organic and aqueous phases, the organic extracts were combined, and after washing and drying, they were concentrated.

The crude material was purified by trituration in hexane:ethyl acetate to afford the desired title compound in 86.0% yield.

Example 67)

Preparation of 37(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-butanoyl)-amine]-benzoic acid

Level 1)

Preparation of the intermediate amide

The compound prepared in the previous Example 66), i.e. 4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indole-1,1,2-butanoic acid, (1.0

99 99

9 9 9 9 9 9

9 9 9 9

999 9 9

9 9 9 9

9999 ·· «·· equivalent), was reacted with N-ethyl-N-(3-dimethylamino- ^4- propyl)-carbodiimide, hydrochloride, (1.37 equivalent), and methyl-3-aminobenzoate, (1.05 equivalent), in N,N-dimethylformamide, (0.09 M), in the presence of 4-dimethylaminopyridine, (DMPA), (0.20 equivalent), and the resulting reaction mixture was stirred at 25.0 °C for 1.50 hours.

After treatment with ethyl _acetate /water, followed by flash chromatography, the desired intermediate "amide" was obtained in 81.0% yield.

Level 2)

Preparation of 3-[(4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl-butanoyl]-amino]-benzoic acid

By an analogous procedure to that described above in Example 66), Step 2), the desired title compound was prepared in 98.0% yield after purification by trituration in hexane:ethyl acetate.

Example 68) ^preparation of 4-[ 3-benzoyl-5-( benzyloxy)-2-( 2-naphthyloxy)-methyl-(1H-indol-1-yl)-N-] 3-([(trifluoromethyl)-sulfonyl]-aminocarbonyl)-phenyl]-butanamide

Degree t) • 99 ·9·0 99 9

99 9 9 9 9 9 • · 9 9 9 9

By an analogous procedure described above in the previous Example 67), Step 1), and using 3-((4-(3-benzoyloxy)-2-(2-naphthyloxy)-methyl)-1H-indol-1-yl-butanoyl)amino)-benzoic acid, obtained in the aforementioned Example 67), and the appropriate sulfonamide, the desired product was prepared after an overnight reaction and analogous work-up, from which the desired title compound was obtained after trituration in a hexane:ethyl acetate mixture, in a yield of 100.0

Example 69)

Preparation of 4-((4-[3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl]-1H-indol-1-yl-butanoyl)-amino)-benzoic acid

Level 1)

Preparation of the intermediate “amide”

By an analogous procedure to that described above in Example 67), Step 1), using 4-(3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)methyl)-1H-indol-1-yl)butanoic acid and the corresponding aniline, the desired intermediate, amide ^M , was prepared in 76.0% yield.

Level 2)

I • 4 • 4 4 sfoO ···· ·

Preparation of 4-[(4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-butanoyl]-amino]-benzoic acid

By an analogous procedure to that described above in Example 67), Step 2), the desired title compound was prepared in a yield of 78.0% after subsequent purification by trituration in a hexane:ethyl acetate mixture.

Example 70)

Preparation of 2-((4-^3-benzoyl)-5-(benzyloxy)-2-((2-naphthyloxy)-methyl)-1H-indol-1-yl(-butanoyl)-amino)-benzoic acid

S t e r 1)

Preparation of the intermediate “amide”

By an analogous procedure, described above in Example 67), Step 1), using 4-£ 3-benzoyl-5-(benzyloxy)-2-/(2-naphthyloxy)-methyl/-1H-indol-1-yl^-butanoic acid, obtained in Example 66) described above, and the appropriate aniline, the desired intermediate "amide" was prepared after subsequent chromatography, in a yield of 36.0%, ,

Level 2) ·· • ·

• tt tttttttt · • · · • · tt • · · • tt ttttttt • ·· «· •

tt · · tttttt • · · • tt tt··

Preparation of 2-((4-{J-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)methyl)-1H-indol-1-yl-butanoyl)-amino)-benzoic acid

By an analogous procedure to that described above in Example 67), Step 2), the desired title compound was prepared in 67.0% yield after subsequent purification by trituration in hexane:ethyl acetate.

Example; 71)

Preparation of 3-(4-(1-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl)-1H-indol-1-yl-butanoyl)-amino)-propanoic acid

Stage (i)

Preparation of the intermediate “amide”

By an analogous procedure described above in Example 67), Step 1), using 4-<~3-benzoyl-5» (benzyloxy)-2-/(2-naphthyloxy)-methyl/-1H-indol-1-yl-butanoic acid, obtained in Example 66), and the appropriate aniline, the desired intermediate "amide" was prepared after subsequent chromatography in a yield of 96.0%.

Grade 2) 'S

·· • · • • • · • • 9 9 · 99 9 9 9 99 9 9 9 · 9 • · • • • • · • • · • ···· ··« ·· 9999 99 ···

Preparation of 3-[(4-(3-benzoyl-5-ylbenzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-butanoyl]-amino]-propenoic acid

By an analogous procedure to that described above in Example 67), Step 2), the desired title compound was prepared in 90.0% yield after subsequent purification by trituration in hexane:ethyl acetate.

Example 72) Preparation of 3-[(4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl-butanoyl)-amino]-propanoic acid

By an analogous procedure to that described above in Example 67), Step I), using 4-[3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl]-1H-indol-1-yl-butanoic acid, obtained in Example 66), and the corresponding sulfonamide, the desired title compound was prepared in 100.0% yield.

Example 73)

Preparation of N-(4-3-benzoyl-5-(benzyloxy)-2-/(2-naphthyloxy)-methyl/-1H-indol-1-yl? -butanoyl)-2-methylbenzenesulfonamide <7 • · • · · ·

By an analogous procedure* described above in Example 67), Step 1), using 4-[3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)methyl]-1H-indol-1-yl]-butanoic acid, obtained in Example 67) above, and the corresponding sulfonamide, the desired title compound was prepared in 80% yield.

Example; 74)

Preparation of 5-[2-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-pentanoic acid

Level 1)

Preparation of the intermediate "ester"

To a solution prepared by dissolving the intermediate "indole compound" obtained in Example 66, Step 6, above (1.0 equivalent) in dried N,N-dimethylformamide (0.1 M) mixed with sodium hydride (60% product in mineral oil) (1.10 equivalent) after 1.0 hour, ethyl 4-bromopentanoate (1.20 equivalent) and potassium iodide (1.20 equivalent) were added, and the resulting reaction mixture was stirred at 75.0 °C for 2.0 hours.

After treatment with ethyl acetate/water and subsequent purification of the residue by chromatography, the desired title compound was obtained in a yield of 92.0%.

Level 2)

Preparation of 5-[3-benzoyl-5-(benzyloxy)-2-[(1H-indol-1-yl]-pentanoic acid]

2-Naphthyloxy)-methyl/The intermediate "ester", (1.0 equivalent), obtained in the previous, above-described Step 1), was hydrolyzed by the action of lithium hydroxide. hydrate, (1.30 equivalent), in a mixture of tetrahydrofuran:methanol:water, (3.0:1.0:1.0),

0.2 M). After the reaction mixture was stirred at 25.0°C for 3.50 hours, it was mixed with 1N hydrochloric acid solution, extracted with ethyl acetate and dichloromethane.

The combined organic extracts were washed, dried and concentrated. The crude residue was purified by trituration in hexane:ethyl acetate to give the title compound in 95.0% yield.

Example 75)

Preparation of 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indole-1-yl]-pentanoyl]-amino]-benzoic acid

Level 1)

Preparation of the intermediate “amide”

5-[3-Benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)methyl]-1H-indol-1-yl? -pentanoic acid, (1.0 equivalent), obtained in the previous, above-described Example 74), was reacted with N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide. ^! hydrochloride, (1»37 equivalent), and methyl-3-aminobenzoate, (1.05 equivalent), in N,N-dimethylformamide _p (0.09 M), in the presence of 4-dimethylaminopyridine, (DMAP), (0.20 equivalent).

After the reaction mixture was stirred at 25.0 °C for 2.50 hours, it was worked up with ethyl acetate/water, followed by flash chromatography.

The desired intermediate, amide, was obtained in a yield of 78.0%.

Level 2)

Preparation of 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-pentenoyl)-amino]-benzoic acid

By an analogous procedure to that described above in the previous Example 74), Step 2), the desired title compound was obtained in 83.3% yield after purification by trituration in a mixture of hexane and ethyl acetate.

Example 76)

Preparation of 5-[3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl]-1H-indol-1-yl]-N-[3-([(trifluoromethyl)-sulfonyl]-amino]-carbonyl)-phenyl]-pentanamide

Level 1)

Toilet

By an analogous procedure described above in Example 68) ₍ Step 1), using 3-[(5-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl-pentanoyl)amino]-benzoic acid, obtained in the previous, above-described Example 75), and ^the _{corresponding} sulfonamide, the desired title compound was prepared after an overnight reaction and subsequent analogous workup in a yield of 83.0% ►

Example 77)

Preparation of 2-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl-acetic acid

Grade 1)

Preparation of the intermediate amide

By an analogous procedure described above in Example 74), Step Ί),.. using the appropriate bromide, and subsequent chromatography, the desired intermediate, amide, was prepared in a yield of 80.0

Level 2)

Preparation of 2-£3-benzoyl-5-(benzyloxy)-2-/(2-nsphthyloxy)-methyl/1H-indol-1-ylZ -acetic acid tyf • » · · ···· • · » · · ···· 4 • · 4 4 4 4 9 4

9444 499 49 4444 44 444

By an analogous procedure to that described above in Example 74), Step 2), the desired title compound was prepared after subsequent trituration in a mixture of hexane · T : ethyl acetate, in a yield of 90.0

Example* 78)

Preparation of (E)-4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-2-butanoic acid

S t e r 1)

Preparation of the intermediate “amide”

By an analogous procedure described above in Example 74), Step 1), using the appropriate bromide, the desired intermediate "amide" was obtained after chromatography in a yield of 33.0%.

Preparation of (E)-4-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-2-butanoic acid

By an analogous procedure to that described above in Example 74), Step 2), the desired title compound was prepared in 70.0% yield after subsequent trituration in hexane:ethyl acetate.

Example 1 8 d 79)

Preparation of 3-({3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl}-1H-indol-1-yl-methyl)-benzoic acid

Level 1)

Preparation of the intermediate, “amide”

By an analogous procedure described above in Example 74), Step 1), using the appropriate bromide, the desired title intermediate "amide" was obtained after chromatography in a yield of 75.0%.

Example 80)

Step 2) Preparation of 3-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-methyl)-benzoic acid

By an analogous procedure, described above in Example 74),

Step 2) was prepared after subsequent trituration in a mixture of hexane:ethyl acetate, the desired title compound, in yield

92.0%.

• ·· ·

Preparation of 1-£ 1-/4-(1,3-benzothiazol-2-yl-carbonyl)-benzyl/-5-, (benzylsulfanyl)-2-/(2-naphthylsulfanyl)-methyl/-1H-indol-3-yl(1-ethanone

Grade Ό

-A solution prepared by dissolving the intermediate "free indole thioether", obtained in the framework of the above-described Example 62) Step 6), in dichloromethane, _; (0.12 ®), was mixed, under a nitrogen atmosphere, and at a temperature of 0.0 °C, with methylmagnesium bromide, (1.10 equivalents), and the resulting reaction mixture was stirred in the temperature range from 0.0 °C to 25.0 °C, for 1.0 hour.

Acetyl chloride (1.17 equivalents) was then added to the reaction mixture, cooled again to 0.0°C, and after 1.0 hour at 0.0°C, the reaction mixture was mixed with half a saturated aqueous solution of ammonium chloride, and then treated with dichloromethane.

After chromatographic purification of the residue, the desired intermediate was obtained in pure form and in a yield of 37.0%.

Level 2)

Preparation of the intermediate, the corresponding para-amide

By an analogous procedure described below in Example 81), Step 1), and using p-toluoyl chloride, the title intermediate was obtained.

Level 3) ·· ·· ··

4 4 4 4 4 444

4 4 4 4 4

VSO • · · · · · •·· ·· 44·· 44 4

By an analogous procedure to that described in Example 81), Step 2), using the intermediate "the corresponding para-amide" obtained in the previous, above-described Step 2), the desired intermediate usable in the following Step 4) was prepared.

Level 4)

Preparation of the intermediate “benzyl bromide”

By an analogous procedure described below in Example 81), Step 3), the desired intermediate "benzyl bromide" was prepared using the intermediate obtained in the previous, above-described Step 3).

S t e g e 5)

Preparation of 1-{1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5(.....benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl|

1-ethanone'

By an analogous procedure described below in Example 181), Step 3), the desired title compound was prepared after coupling the intermediate "benzyl bromide" obtained in the previous, above-described Step 4) with the intermediate obtained in the above-described Step 1).

Example 81) • 9

We

Preparation of 1-[1-[3-(1,3-benzothiazol-2-yl-carbonyl)-benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)-methyl]-1H-indol-3-yl]-1-ethanone

Stepping)

Preparation of the intermediate amide

To a solution prepared by dissolving triethylamine (2.44 equivalents) and methoxymethylamine hydrochloride (1.10 equivalents) in dichloromethane, m-toluyl chloride (0.8M) was added over 20.0 minutes at 0.0°C, and the resulting reaction mixture was warmed to 25.0°C and stirred at that temperature for 1.0 day.

After subsequent work-up with dichloromethane and water, the desired intermediate, the amide, was obtained in crude form in a yield of 100.0%.

S t e g e 2)

Preparation of the intermediate "tolyl ketone"

To a solution prepared under anhydrous conditions by dissolving benzothiazole in tetrahydrofuran (0.35 M), 1.10 equivalents of butyllithium were added at a temperature of minus 78.0 °C. The resulting reaction mixture was mixed after 1.0 hour at a temperature of minus 78.0 °C for 15.0 minutes with the intermediate amide obtained in the previous, above-described Step 1) in tetrahydrofuran. _

After warming to 25.0 °C, the reaction mixture was

stirred for 1 day, and then, after treatment with ethyl acetate, and water, and subsequent chromatography, the desired intermediate, tolyl ketone, was obtained in pure form, and in a yield of 52.0

Level 3)

Preparation of the intermediate "bromobenzyl ketone"

To a solution prepared by dissolving the intermediate "tolyl ketone" obtained in the previous, above-described Step 2) in carbon tetrachloride (0.19 M), N-bromosuccinimide, (NBS) (1.20 equivalents), and 2,2-azobis-(2-methylpropionitrile), (AIBN), (0.11 equivalents), were added. After 1.0 day, when the reaction mixture was maintained at a temperature of 60.0 °C, both the starting material and the product were present in the mixture, in a ratio of approximately 1.0:1.0. After repeating the reaction under the same conditions, and subsequent filtration and recrystallization from ethyl acetate, the desired intermediate, stated in the title, was obtained in the form of a pure substance, and in a yield of 28.0%.

Level 4)

Preparation of 1-{1-[3-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl}-1-ethanone

To a solution prepared by dissolving the intermediate "indole", obtained in Example 80, Step 1, described above, in dried N,N-dimethylformamide, (0.04 M), was added •4 9 99 ·· 99 •·99 9 99 9 999 • 9 9 9 9 · * • 9 *99 999

9999 999 99 9999 99 99 999 i5i sodium hydride, (1.25 equivalent), and after 45.0 minutes, when the resulting reaction mixture was maintained at a temperature of 25.0 °C, the intermediate "bromobenzyl ketone ^M" , (1.25 equivalent), obtained in the previous, above-described Step 3), was added, and the resulting reaction mixture was stirred at a temperature of 25.0 °C for 1.0 hour.

After subsequent work-up, chromatography and recrystallization from ethyl acetate:hexane mixtures, the desired title compound was obtained as a pure substance in 45% yield.

Example 82)

Preparation of 2-(3-(3-acetyl-5-(benzyloxy)-2-(2-naphthylsulfanyl)methyl)-1H-indol-1-yl-methyl)-benzyl)-1,3-benzothiol-6-carboxylic acid

Level 1)

Preparation of the intermediate “thiocyanate”

Sodium thiocyanate (4.10 equivalents) was added to a solution prepared by dissolving ethyl 4-aminobenzoate in a mixture of 95% acetic acid and water (volume ratios), (0.4 M), at a temperature of 25.0 °C, and the resulting reaction mixture was stirred at a temperature of 25.0 °C for 20.0 minutes.

The mixture was then cooled to 5.0 °C, and bromine (1.17 equivalents) was added in 95% acetic acid/water (volume ratios), and after 1.0 hour, when the reaction mixture was maintained at 0.0 °C, it was mixed with water, and

After subsequent treatment with a mixture of ethyl acetate and sodium bicarbonate solution, the desired intermediate product was obtained in pure form in 81.0% yield.

Level 2)

Preparation of the intermediate “thiophenol”

In the previous, above-described Step 1), the prepared intermediate "thiocyanate" was mixed with sodium sulfide monohydrate in water (1.20 equivalents, 1.3 M), and the resulting reaction mixture was heated under reflux for 45.0 minutes.

After cooling, the reaction mixture was filtered, and after acidification with acetic acid to pH 6.0, it was extracted with ethyl acetate, and the obtained extract was concentrated.

The desired intermediate product "thiophenol" was prepared in a yield of

91.0

Level 3)

Preparation of the intermediate , 'benzothiazole ester'

To a solution prepared by dissolving the intermediate "thiophenol" obtained in the previous, above-described Step 2) in a 90% mixture of formic acid and water (volume ratios), (3.30 M), a catalytic amount of zinc in the form of dust was added, and the resulting reaction mixture was heated under reflux for 3.0 hours.

4 4 4 4

4 44 4 • 4 4 4 ♦ 44

444· • 4 4 4 4 4 4 •44 44 4444 44 444

After subsequent treatment with ethyl acetate and alkali, the desired intermediate, the benzothiazole ester, was obtained in pure form and in a yield of 60.0%.

Level 4)

Preparation of the intermediate "benzothiazolic acid"

To a solution prepared by dissolving the intermediate "benzothiazole ester" obtained in the previous, above-described Step 3) in a mixture of tetrahydrofuran:methane:water (0.34 M), (8.0:3.0:3.0), lithium hydroxide (2.0 equivalents) was added, and the resulting reaction mixture was stirred at 25.0 °C for 2.0 hours.

_After subsequent workup (ethyl acetate/aqueous acid), the desired title intermediate was obtained in 100.0% yield.

Level 5)

Preparation of the intermediate "tolyl-ketone acid" from ⁴

To a solution prepared under anhydrous conditions by dissolving the intermediate "benzothiazolic acid", obtained in the previous, above-described Step 4), in tetrahydrofuran, (0.052 M), was added butyllithium (2.20 equivalents) at a temperature of minus 78.0 °C, and after 1.0 hour, when the reaction mixture was maintained in the temperature range from minus 78.0 °C to 0.0 °C, the intermediate "amide", (1.28 equivalents), obtained in the previous, above-described Example 81), Step 1), was added thereto, over 5.0 minutes, and at a temperature of minus 78.0 °C.

-T ·/ ' ' in tetrahydrofuran.

5After 0.50 hours, when the reaction mixture was maintained at a temperature of minus 78.0 °C, it was warmed to a temperature of 25.0 °C, and after subsequent stirring at a temperature of 25.0 °C for 2.0 hours, it was treated with ethyl acetate and water, and after chromatography, the desired title intermediate was obtained, in pure form, and in a yield of 64.0%,

Level 6)

Preparation of the intermediate “tolyl ketone ester”

To a suspension prepared by suspending the intermediate "tolyl ketone acid" obtained in the previous, above-described Step 5) in a mixture of tetrahydrofuran:ethanol, (1.0:1.0), (0.075 M), was added an excess of concentrated sulfuric acid.

After the resulting reaction mixture was heated under reflux for 1.0 day, it was treated with ethyl acetate, then with sodium bicarbonate solution, and after subsequent chromatography, the desired title product was obtained in pure form in ^69.0 % yield.

Level 7)

Preparation of the intermediate product "bromobenzyl ketone"

To the solution prepared by dissolving the intermediate product ,,tolyl·* * ·· «0 »· 0 • · ·· 4 9 9 9 9 4 44

4 9 9 4 9 4 9

4 4 4 4 4 4 4 4

4444 944 44 4444 94 449 ketone ester”, obtained in the previous, above-described Step 6), in carbon tetrachloride, (0.05 M), N-bromosuccinimide, (1.20 equivalent), and 2,2-azobis-(2-methylpropionitrile),(AIBN), (0.15 equivalent), were added, and the resulting reaction mixture was heated under reflux for 1.25 hours.

Then, another portion (0.3 equivalent) of N-bromosuccinimide and 2,2-azobis-(2-methylpropionitrile) (0.07 equivalent) was added to the reaction mixture, and after subsequent filtration and recrystallization from ethyl acetate, the desired title intermediate was obtained in pure form, and in a yield of 22.0%.

Grade 8)

Preparation of the intermediate “crude ester”

To a solution obtained by dissolving the intermediate "indole", prepared in the above-described Example 80), Step 1), in dried N,N-dimethylformamide, (0.06 M), sodium hydride, (1.10 equivalent), was added, and after 45.0 minutes, when the reaction mixture was maintained at a temperature of 25.0 °C, the intermediate "bromobenzyl ketone", obtained in the previous, above-described Step 7), (1.25 equivalent), was added, and the resulting reaction mixture was stirred at a temperature of 25.0 °C for 1.0 hour.

After subsequent workup, the desired title intermediate was obtained, which was used as such in the following Step 9).

Degree 9) φφ · φ φφ φφ φφ φ φ φφφ φ φφ φ « φφφ φ φ ΦΦΦ ΦΦ· φφφφ φφφ φφ φφφφ φφ φφφ

All

Preparation of 2-(3-(3-acetyl-5-(benzyloxy)-2-(2-naphthylsulfanyl)methyl)-1H-indol-1-ylmethyl)benzyl)-1,3-benzothiazole-6-carboxylic acid

To a solution prepared by dissolving the intermediate "crude ester" obtained in the previous, above-described Step 8) in a mixture of tetrahydrofuran:methane:water, (8.0::2:2), (0.013 M), was added lithium hydroxide, (4.30 equivalents), portionwise, while the reaction mixture was stirred at 25.0 °C, for a total period of 3.0 to 4.0 days.

After subsequent workup (ethyl acetate/aqueous hydrochloric acid solution), and chromatographic purification, the desired title compound was obtained in pure form, 8, in a yield of 31.0%.

Example 83)

Preparation of 5-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)-methyl]-1H-indol-1-yl]-2-oxopentanoic acid

Level 1)

Preparation of the intermediate "alkyl chloride"

To a solution prepared by dissolving the intermediate "indole compound" obtained in Example 66 (Step 6) described above in dried M,N _T dimethylformamide (0.17 M), sodium hydride (1.20 equivalent) was added, and after 1.50 hours at 25.0 °C, 3-iodo-1-chloro-

44 4 44 ·· 44 4 • 4 • 4 « 4 • 4 • • 4 4 • • • • • 4 • 4 * 4 • 4 4 • 4 4 4 • 44 4 • 4 4 • 4 44*4 44 «4 4

of propane, and the reaction mixture was stirred at 25.0 °C for 4.0 hours.

Then, after subsequent workup (ethyl acetate/sodium bicarbonate solution), and trituration (ethyl acetate.hexanes mixture), the desired title intermediate was obtained in 89.0% yield.

Level 2)

Preparation of the intermediate "iodide"

To a solution prepared by dissolving the intermediate "alkyl chloride" obtained in the previous, above-described Step 1) in methyl ethyl ketone (0.036 M), sodium iodide (1.60 equivalents) was added, and the resulting reaction mixture was stirred at reflux in the dark for 1.0 day.

After subsequent treatment with ethyl acetate/water, the desired intermediate "iodide" was obtained in 97.0% yield.

Level 3)

Preparation of the intermediate dithianyl ester

To sodium hydride, (1.0 equivalent), weighed into a dried reaction flask, was added dried benzene, (0.14 M),

In a separate reaction flask, at a temperature of 0.0 °C, dried N,N-dimethylformamide (0.4 M), ethyl-2-carboxy1,3-dithiane (1.0 equivalent), and the intermediate iodide (1.0 equivalent), obtained in the previous, above-described

·· • ·· ·· ·· 4 • · ·· • • • · « • • · • • • • • 9 • t • • • 4 • • • • ···· ··· ·· ···* • and ·« ·

Step 2), (the reaction flask used was previously dried), and this mixture was then added, at a temperature of 0.00°C, to the benzene suspension prepared in the above-described operation.

The resulting reaction mixture was then warmed to 25.0 °C and stirred at this temperature for 3.0 hours.

After subsequent workup (ethyl acetate/water) and chromatography, the desired title intermediate was obtained in 54.0% yield.

Level 4)

Preparation of the intermediate "ketoester"

To a solution prepared by dissolving silver nitrate (4.50 equivalents) and N-chlorosuccinimide (NOS) (4.0 equivalents) in a mixture of acetonitrile:water (4.0:1.0 by volume) (approx. 0.04 M) was added at 25.0°C a solution obtained by dissolving the intermediate, "dithi8nyl ester", obtained in the previous, above-described Step 3), (1.0 equivalents), and the resulting reaction mixture was stirred at 25.0°C for 5.0 minutes.

Then, sodium sulfite solution was added to the reaction mixture, and after one minute, sodium carbonate solution.

After subsequent workup (ethyl acetate(water) and chromatography, the desired intermediate "ketoester" was prepared in a yield of 17.0%.

S t e g e 5)

Preparation of 5-[3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-2-oxopentanoic acid

• ·

To a solution prepared by dissolving the intermediate "keto ester" obtained in the previous, above-described Step 4) in a mixture of tetrahydrofuran:water (8.0:1.0), (0.03 M), lithium hydroxide (1.5 equivalents) was added, and the resulting reaction mixture was stirred at 25.0 °C for 2.0 hours.

After subsequent workup (ethyl acetate/aqueous hydrochloric acid solution) and chromatographic purification, the desired title compound was obtained in pure form and in a yield of 64.0%.

Example 84)

Preparation of 3-[(5-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl? -2-oxopentanoyl)-amino]-benzoic acid

Level 1)

Preparation of the intermediate “dithianyl acid”

To a solution prepared by dissolving the intermediate, dithianyl ester, obtained in the previous Example 83), Step 3), in a mixture of tetrahydrofuran:ethanol:water, (5.0:2.0:2.0), (0.008 M), was added lithium hydroxide, (1.10 equivalents), and the resulting reaction mixture was stirred at 50.0 °C for 1.0 day.

After subsequent workup (ethyl acetate/aqueous hydrochloric acid solution) and chromatography, the desired title intermediate was obtained in pure form and in a yield of 90.0%.

<2

Level 2)

Preparation of the intermediate “dithianyl ester”

To a solution prepared by dissolving the intermediate, dithianyl acid, in dried dichloromethane (0.08 M) in the presence of a catalytic amount of N,N-dimethylformamide, was added oxalyl chloride (1.20 equivalents), and the resulting reaction mixture was stirred at 25.0 °C for 0.50 h.

After concentration of the reaction mixture, the residue was dissolved in dried dichloromethane, and at 0.0 °C, methyl 3-aminobenzoate, (1.0 5 equivalents), and triethylamine, (1.0 equivalents) were added to the resulting solution. The reaction mixture was warmed to 25.0 °C, and then stirred for 3.0 hours.

After subsequent workup (ethyl acetate/aqueous acid) and chromatographic purification, the desired title intermediate was obtained in a yield of 89.0

Level 3)

Preparation of the intermediate product ‘dithianyl acid j i . ‘

To a solution prepared by dissolving the intermediate "dithianyl ester" obtained in the previous, above-described Step 2) in a mixture of tetrahydrofuran:methanol:water, (6.0:4.0:3.0), (0.02 M), lithium hydroxide, (4.30 equivalents), was added, and the resulting reaction mixture was stirred at 25.0 °C for 3.0 hours.

After subsequent workup (ethyl acetate/aqueous hydrochloric acid solution), the desired title intermediate "dithianyl acid, (R - 3-COOH)" was obtained in a yield of 91.0%.

S t e g e 4)

Preparation of 3-((5-[3-benzoyl-5-(benzyloxy-2-(2-naphthyloxy)methyl)-1H-indol-1-yl)-2-oxopentanoyl)-amino)-benzoic acid

To a solution prepared by dissolving silver nitrate (4.60 equivalents) and 4-chlorogluc^inimide (NCS) (4.0 equivalents) in a mixture of acetonitrile:water (4.0:1.0 by volume) (approx. 0.03 M) was added at 25.0 °C a solution obtained by dissolving the intermediate "dithianyl acid" prepared in the previous, above-described Step 3) in acetonitrile (0.009 M), and the resulting reaction mixture was stirred at 25.0 °C for 10.0 minutes.

Then sodium sulfite solution was added to the mixture, and after 1.0 min sodium carbonate solution was added. After subsequent workup (ethyl acetate/aqueous acid) and chromatography, the desired title compound was obtained in 82.0% yield.

Example 85)

Preparation of 4-(5-(3-benzoyl-5-(benzyloxy)-2-(2-naphthyloxy)-methyl)-1H-indol-1-yl-2-oxopentanoyl)-amino)-benzoic acid

S t e r 1)

Preparation of the intermediate dithianyl ester • ·

4GL{

By an analogous procedure described above in the context of the previous Example 84), Step 2), the intermediate "dithianyl acid", obtained in the context of the previous, above-described Example 84), Step 1), and ethyl 4-aminobenzoate, 8 were reacted, after subsequent purification by chromatography, to prepare the desired intermediate, (R - 4-0000^^), in a yield of 30.0%.

Level 2)

Preparation of the intermediate product ‘dithianyl acid*’

By an analogous procedure described above in the framework of the previous Example 84), Step 3), the intermediate "dithianyl ester", obtained in the framework of the previous, above-described Example 84), Step 1), was processed, and after chromatographic purification, the desired, title intermediate, (R » 4-COOH), was obtained in a yield of 89.0%.

Level 3)

Preparation of 4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-2-oxopentanoyl)-amino]-benzoic acid

By an analogous procedure described above in the previous Example 84), Step 4), the intermediate "dithianyl acid", obtained in the previous, above-described _Step 2), was processed. After repeated purification by chromatography, and subsequent trituration in pentane, the desired title compound was obtained in a yield of 30.0

165 ·««« ·« ···

Example 86

Table I shows the data for the compounds of the invention described in the previous examples regarding the inhibition of cPLA ₂ . The IC50 values are given, which are the concentrations of the compounds at which 50% inhibition of the activity of the phospholipase enzyme occurs. If a numerical value is missing, the designation "NA" means that the test was not performed.

Efficacy assays (a) Vesicle assay mCi/mmol l-palmitoyl-2-[ ¹⁴ C]arachidonylphosphatadylcholine (final concentration 6 M) and 1,2-dioleoylglycerol at a final concentration of 3 M were mixed and the mixture was dried under a stream of nitrogen. 50 mM Hepes pH 7.5 was added to the lipids (2x final lipid concentration) and the suspension was sonicated for 3 minutes at 4°C. 50 mM Hepes pH 7.5, 300 mM NaCl, 2 mM DTT, 2 mM CaCl ₂ and 2 mg/ml bovine serum albumin BSA (Sigma A7511) were then added to the suspension to 1.2x final lipid concentration. A typical assay consists of the sequential addition of 5 µl of inhibitor in DMSO to 85 µl of lipid mixture along with 10 ng of cPLA ₂ for an automated system or 1 ng of this substance for a manual assay, in 10 µl of BSA buffer. The assay was performed manually or automatically as described below.

(b) Soluble substrate assay (LysoPC)

166

mCi/mmol of 1-[ ¹⁴ C]-palmitoyl-2-hydroxyphosphatidylcholine (final concentration 4.4 M) is dried under a stream of nitrogen. The lipid is resuspended by mixing with 80 mM Hepes pH 7.5 with 1 mM EDTA (1.2x final concentration). A typical assay is performed in 85 L of lipid suspension, to which 5 L of inhibitor in DMSO and 200 ng of cPLA ₂ in 80 mM Hepes pH 7.5 with 2 mM DTT and 1 M EDTA are added sequentially. This assay is performed manually or on an automated device, as will be described below.

(c) Automatic test execution

The lipid suspension and inhibitor are pre-incubated for 7 minutes at 37°C. The enzyme is added and the mixture is incubated for a further 30 minutes. The reaction is then stopped by adding 150 l of a mixture of decane, isopropanol and trifluoroacetic acid in a ratio of 192:8:1. A 50 l portion is passed through a 5.30 x 2.1 mm Rainin Spheric-5 silica column, eluting with a mixture of heptane, methanol and TFA in a volume ratio of 97:3:0.1. The concentration of [ ¹⁴ C] arachidonic acid is analysed using a Radiomatic Flo-One/Beta counter (Packard) integrated directly into the device.

(d) Manual execution of the test

The lipid, inhibitor and enzyme mixture is incubated for 30 minutes at 37°C. The reaction is stopped by adding 200 l of a mixture of heptane, isopropanol and 0.5 M sulfuric acid in a volume ratio of 105:20:1. Half of the layer is applied to the top of a disposable silica gel column with a volume of

167

4 ml (Whatman SIL) under vacuum, the column is placed above the scintillation vial. Free [ ¹⁴ C]-arachidonic acid is eluted after addition of 1 ml ethyl ether. The radioactivity level is measured by liquid scintillation counting.

(e) PMN test

PMN are isolated using Ficoll-Hipaque according to the manufacturer's instructions. Red blood cells contaminating the PMN are removed by disruption in hypotonic medium and the PMN pellet is washed once and then resuspended in Hanks buffered solution at a concentration of 2 x 10 ⁶ cells/ml. The cells are then preincubated with inhibitors for 15 minutes at 37°C and stimulated with 2 microM A23187. When monitoring LTB ₄ production as a measure of cPLA ₂ inhibition, the reaction is stopped by adding an equal volume of ice and cold phosphate-buffered saline. The cell material is centrifuged and LTB ₄ in the cell supernatant is measured by scintillation counting (Amersham) according to the manufacturer's instructions. In the assays listed in the above-mentioned tables, LTB ₄ is measured. When monitoring arachidonic acid production, the reaction is stopped with methanol containing D8-arachidonic acid as an internal reference standard. Lipids are extracted according to Bligh et al. 1959, Can. J. Biochem. Physiol., 37,

911-917 and the fatty acids are converted to pentafluorobenzyl esters and analyzed by gas chromatography and mass spectrometry according to the method of Ramesh and Taylor, 1991, Anal. Biochem. 192, 173-180.

(f) RBL test • ·

168

RBL-2H3 cells are routinely grown at 37°C in a 5% carbon dioxide atmosphere in minimal essential medium containing non-essential amino acids and 12% fetal calf serum. The day before the experiment, the cells are seeded into flasks at 3 x ¹⁰⁵ cells/ml and 100 ng/ml of DNP-specific IgE is added. After 20 hours, the cells are separated by centrifugation, washed once with serum-free minimal essential medium and then resuspended in serum-free medium at 2 x ¹⁰⁶ cells/ml. The cells are preincubated with inhibitor in DMSO (1% v/v) or in DMSO alone (1% v/v) for 15 minutes at 37°C, followed by stimulation with DNP-BSA at 300 ng/ml. After 6 minutes, the cell material is centrifuged and the supernatant is assayed for PGD ₂ content in a known manner.

(g) Coumarin test

7-Hydroxycoumarinyl-6-heptenoate was used as a monomeric substrate for cPLA ₂ according to Huang Z. et al., 1994, Analytical Biochemistry 222, 110115. The inhibitors were mixed with 200 microliters of assay buffer containing 80 mM Hepes pH 7.5, mM EDTA and 60 microM 7-hydroxycoumarinyl-6-heptenoate. The reaction was initiated by adding 4 micrograms of cPLA ₂ in 50 microliters of assay buffer. The hydrolysis of 7-hydroxycoumarinyl-6-heptenoate was monitored fluorometrically by excitation at 360 nm and emission at 460 nm. The enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of the cPLA ₂ inhibitor, the rate of increase is slower.

• ·

169

Example 87

The compounds of the invention were also tested in vivo using the rat paw edema assay as described below. The results are summarized in Table II.

Rat paw edema test after carrageenan.

Each compound was suspended in a mixture of 0.3 ml absolute ethanol, 0.1 ml Tween-80 and 2.0 ml Dulbecco's PBS without calcium or magnesium. To this mixture was added 0.1 ml 1 N NaOH. After complete dissolution, another portion of PBS was added to a concentration of 1 mg/ml. All substances were maintained in solution. The compounds were administered intravenously in a volume of 5 ml/kg to male Sprague Dawley rats and edema was induced by injecting 0.05 ml 1% type IV carrageenan into the hind paw. Paw volume was measured before drug administration and 3 hours after carrageenan administration.

Represented by:

áa£áBSMB«»fi acaffií.

Claims (109)

1. Phospholipase inhibitors of the general formula Rs where Rx and Ri- independently represent a hydrogen atom, a halogen atom, -CF3, -OH, Cl-ClOalkyl, -S-Cl-ClOalkyl, Cl-ClOalkoxy, -CN, _-NO2 , _-NH2 , -HN(Cl-C6alkyl), -N(C1-C6alkyl)2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or any of the groups R· 9 9 9 9 ♦9 9999 171 R ₆ represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, -N0 ₂ , -NH ₂ , -CN, -CF ₃ or -OH, R ₇ represents -OH, -CF ₃ , C 1 -C 6 alkyl, C 1 -C 6 alkoxy group, -NH-(Cl-C6alkyl), -N-(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy group, -NO ₂ , -NH ₂ , -CN, -CF ₃ or -OH, R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, Cl-ClOalkoxy, -CHO, -CN, -NO ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -SO ₂ -Cl-C6alkyl, R ₃ is selected from the group of hydrogen atom, -CF ₃ , C 1-C 6 alkyl, C 1-C 6 alkoxy group, C 3-C 10 cycloalkyl, C 1-C 6 alkylC 3-Cl 0 cycloalkyl, -CHO, halogen atom or L ² -M ² group, L ² represents a linking or bridging group of the formula -(CH ₂ ) _n -, -S-, -O-, -C(0)-, -(CH ₂ ) _n -C(O)-, -(CH ₂ ) nC(O)-(CH ₂ ) _n - or - (CH ₂ ) _n -S-(CH ₂ ) _n -, -C(O)C(O)X, where X represents an oxygen or nitrogen atom, M ² is selected from the group C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, phenyl or benzyl, wherein the phenyl, benzyl and cycloalkyl rings are optionally substituted with 1 to 3 substituents from the group halogen atom, C1-ClOalkyl, C1-ClOalkoxy, -N0 ₂ , -NH ₂ , -CN or -CF ₃ or means 172 ·» ·»»· a) a 5-membered heterocyclic ring, containing in the ring 1 or 2 heteroatoms from the group N, S or O, for example furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, pyrrolidinyl or tetrazolyl, the 5-membered heterocyclic ring is optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-ClOalkyl, Cl-ClOalkoxy group, -NO2, _-NH2 , -CN or -CF3 or means b) a 6-membered heterocyclic ring, containing in the ring 1, 2 or 3 heteroatoms from the group N, S or O, for example pyridinyl, pyrimidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-ClOalkyl, Cl-ClOalkoxy group, -N0 ₂ , -NH ₂ , -CN, -CHO, -OH or -CF 3 or means c) a bicyclic ring group containing 8 to 10 atoms in the rings and optionally 1 to 3 heteroatoms from the N group, S or O, for example benzofuranyl, indolyl, indolinyl, naphthalenyl, purinyl or quinolinyl, wherein the bicyclic ring group is optionally substituted with 1 to 3 substituents from the group halogen atom, C1-C10alkyl, C1-C10alkoxy, _-N02 , _-NH2 , -CN, -CHO, -OH or _-CF3 , n represents an integer from 0 to 3, R ₄ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) n ~C3-C6cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C5cycloalkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -C3-C5cycloalkyl or one of the groups a) - (CH ₂ ) η-phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(0-CH ₂ ~phenyl) ₂ , -CH ₂ -phenyl-C(0)-benzothiazolyl or groups of the formula: 173 x-( ^c Ho)ns. (CH ₂ ) n\ o-^ Y , where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2, Y represents C3-C5cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-NO2 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or O, preferably S or O or b) groups of the formula -(CH ₂ ) _n -A, - (CH ₂ ) _n ~SA, or -(CH ₂ ) _n -OA, where A means a group B where D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or -CF3, B and C are independently selected from the group consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 44 ·>·· 174 or 2 substituents from the group hydrogen or halogen atom -CF3, -OH, C1-C6alkyl, C1-C6alkoxy or -N0 ₂ or c) groups of formulas where Z is O or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group consisting of halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy, -NH ₂ or -N0 ₂ , R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n ^- C(0)• · fr fr 175 • •fr · -COOH, - (CH ₂ ) n-COOH, -CH=CH-COOH, - (CH ₂ ) n-tetrazolyl, -P You are N ^(C _r C ₆ alkyl) -P ^(C-1-C6 haloalkyl) M P—OH II O or r ₉ II with II OH or a group of the formula -IŘ-M ¹ , where L ¹ is a bridging or connecting group from the group of single chemical bonds -(CH2)n ^- S-, -0-, -C(O)-Z -(CH ₂ )nC(0)-, -(CH ₂ ) _n -C(O)-(CH ₂ )n-, -(CH ₂ ) _n -O-(CH ₂ ) _n -, - (CH ₂ ) _n -S- (CH ₂ ) _n -, -C(Z)-N(R ₆ )-, -C(Z)-N(R ₆ )-(CH ₂ )n-/ -C(O)-C(Z)-N(R ₆ )-, -C(O)-C(Z)-N(R ₆ )-(CH ₂ ) _n -, -C(Z)-NH-SO ₂ or -C(Z)-NH-SO ₂ -(CH ₂ )n-, M ¹ is selected from the group -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (0) -COOH, tetrazolyl or any of the groups where R 5 , R 9 or R _X o can be attached at any point of the cyclic or bicyclic system, Rg is independently selected from the group consisting of hydrogen, -COOH, - (CH ₂ ) n-COOH, -(CH ₂ ) nC (0) -COOH, tetrazolyl, o -P-OH O R ₉ is selected from the group of hydrogen or halogen atom, -CF ₃ , -OH, -COOH, - (CH ₂ ) n -COOH, - (CH ₂ ) _n ~C (0)-COOH, Cl-C 6 alkyl, -O-Cl-C 6 alkyl, -NH(Cl-C 6 alkyl or -N(Cl-C 6 alkyl) ₂ , R10 is selected from the group consisting of hydrogen or halogen, _-CF3 , -OH, -( _CH2 )n-COOH, -( _CH2 )nC(O)-COOH, Cl-C6alkyl, -O-Cl-C6alkyl, -NH(Cl-C6alkyl or -N(Cl-C6alkyl)2, ( _CH2 ) _n '( _CH2 ) _n - _r9 178 ·· 4 II 44 • 444 4 · 4 4 ♦ 4 4 4 4 • 4 4 4 4 4 • 4 4 4 4 ···· 444 44 4444 Rn is selected from the group of hydrogen atom, C1-C6alkyl, C1-C6cycloalkyl, _-CF3 , -COOH, -( _CH2 ) _n -COOH, -( _CH2 ) _n -C(0)-COOH, provided that the complete group in position 1 of the indole or indoline group, formed by any combination of groups _R5 , _R6 , R8, R10 and/or R10 _, will contain at least one group of acidic nature, which is selected from the group of carboxyl group, tetrazolyl or a group of formula n represents an integer from 0 to 3, as well as pharmacologically acceptable salts of these substances. 2. Phospholipase inhibitors according to claim 1, of the general formula: r ₄ : where r ₃ Rs. R5 179 R3 represents a hydrogen atom and R1, _R2 , _R4 and _R5 have the meaning set forth in claim 1, as well as pharmaceutically acceptable salts thereof. 3. Phospholipase inhibitors of the formula: according to claim 2, wherein R 1 , R ₂ , R ₃ , R ₄ and R ₅ have the meaning given in claim 2, as well as pharmaceutically acceptable salts thereof. 4. Phospholipase inhibitors according to claim 2, of the general formula: 180 9« • 9 9 • • 9 • 99 9 9 • 9 ·· • · • 99 • 9 • 9 99 • 9 9 9 9 9 · 9999 999 • 9 ···· 99 99 wherein R 1 , R ₂ , R ₃ , R ₄ and R 5 have the meanings given in claim 2 as well as pharmaceutically acceptable salts thereof. 5. Phospholipase inhibitors of the general formula where R1 represents a hydrogen or halogen atom, ~ _CF3 , C1-C6alkyl, C1-C6alkoxy, _-N02 , _-NH2 , -C6alkyl), -N(C1-C6alkyl) ₂ <phenyl, -O-phenyl -O-benzyl or any of the groups -OH, -HN(Cl, benzyl) • · 181 Rg represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, -N0 ₂ , -NH ₂ , -CF ₃ or -OH, R ₇ represents - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) ₂ , -(CH ₂ ) n ~ -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -NH ₂ , -N0 ₂ , ~CF ₃ or -OH, R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy group, -CHO, -CN, -N0 ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -SO ₂ -Cl-C6alkyl, R ₃ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) _n -C3-C6cycloalkyl, -(CH ₂ ) _n ~S-(CH ₂ ) _n ~C3-C6cycloalkyl or one of the groups a) - (CH ₂ ) n ^_ phenyl-O-phenyl·, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, -(CH ₂ ) _n ~ -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) ₂ , -CH ₂ ~ -phenyl-C(0)benzothiazolyl or any of the groups A _o / ^Y , ^/<CH2K v , o ^A^ / ^(CH 2 ⁾ⁿ \Y χ ^(0Η2 Αο^ ^υ / ^(CH2)n \ _e (CH ₂ )n\ • · 182 tt ·· · · • · · · · · · · ^(CHs)^ where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2, Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-N02 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or b) groups of the formula -(CH ₂ ) _n -A, -(CH ₂ ) _n -SA, or -(CH ₂ )n~OA, where A means the group I B where D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or -CF3, B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2 substituents from the group of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy or -N0 ₂ or c) groups of the formula .0· 183 wherein the phenyl and pyrimidinyl rings in each group are optionally and independently substituted with 1 to 3 substituents selected from the group consisting of halogen, -CF ₃ , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -N0 ₂ , R ₄ is selected from the group of hydrogen or halogen, -CF ₃ , -OH, Cl-C6alkyl, Cl-C6Alkoxy, Benzyl, Benzyloxy, Phenyl, Phenyloxy, -C(O)-phenyl, -O(0)-benzyl, -CH ₂ -(C3-C6cycloalkyl), -C(O)-OH, -CH=0, -C(0)-Cl-C6alkyl, -C(0)-O-Cl-C6alkyl, -C(O)-CF ₃ , -(CH ₂ ) _n — S—CH ₂ —(C3-C6cycloalkyl), wherein the phenyl and benzyl rings of the respective R ₃ groups are optionally substituted with 1 to 3 groups from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy group, -N0 ₂ , 184 “CF ₃ , -C(O)-OH or -OH, n is an integer from 0 to 3, R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) n ^- C(0)-COOH, -(CH ₂ ) _n -C00H, -CH=CH-C00H, O About • · ’ · · R ₈ means H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O)-COOH, tetrazolyl, OH Rg represents a hydrogen or halogen atom, -CF3, -OH, -( _CH2 ) ⁿ -COOH, -( _CH2 ) _n -C(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , R10 represents a hydrogen or halogen atom, -CF3, -OH, -( _CH2 ) _n -COOH, -( _CH2 )nC(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(Cl-C6alkyl), -N (Cl-C6alkyl) ₂ , O 186 (C _r C ₆ alkyl (CrC ₆ haloalkyl; alkyl). R _u represents a hydrogen atom, C1-C6alkyl, _-CF3 , -COOH, -( _CH2 ) _n- COOH, -( _CH2 ) _n -C(0)-COOH or a group provided that the entire group in position 1 of the indole or indoline ring, formed by any combination of groups _R5 , Rg, Rg<R10 and/or Rn, will contain at least one acidic group selected from a carboxylic acid residue, a tetrazolyl group or a group of the formula About ·· φφ 187 • · as well as pharmaceutically acceptable salts thereof. 6. Phospholipase inhibitors of the general formula where R1 represents a hydrogen or halogen atom, _-CF3 , -OH, C1-C6alkyl, C1-C6alkoxy, _-N02 , _-NH2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a group of the formula R ₆ represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and ·· 44 188 benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ , -CF ₃ or -OH, R7 means - (CH ₂ ) _n ~COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) ₂ , -(CH ₂ ) _n ~ -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -N0 ₂ , -CF ₃ or -OH, R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkyl, -CHO, -CN, -N0 ₂ , -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO ₂ -Cl-C6alkyl or -S0 ₂ -Cl-C6alkyl, R ₃ is selected from the group consisting of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH ₂ -(C3-C6 cycloalkyl) , -C(0)-OH, -CH=O, -C(O)-Cl-C6alkyl, -C(0)-O-Cl-C6alkyl, -C(O) _-CF3 , -( _CH2 ) _n —S— _CH2— (C3-C6cycloalkyl), wherein the phenyl and benzyl rings of the respective _R3 groups are optionally substituted with 1 to 3 groups from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy group, _-N02 , -CF ₃ , -C(O)-OH or -OH, n is an integer from 0 to 3, R ₄ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) n -C3-C5cycloalkyl, -(CH _Z ) n -S-(CH ₂ ) _n -C3-C5cycloalkyl, -(CH ₂ ) n -O-(CH ₂ ) _n ~C3-C5cycloalkyl or one of the groups a) - (CH ₂ ) „-phenyl-O-phenyl, - (CH ₂ ) „-phenyl-CH ₂ -phenyl, -(CH ₂ ) „-O-phenyl-CH ₂ -phenyl, - (CH ₂ ) „-phenyl-(0-CH ₂ -phenyl) ₂ , -CH ₂ -phenyl-C(0)benzothiazolyl or any of the groups 189 O (CH ₂ )^ ^(CH a )^ X ^{(CH 2 )n} \o^Y / ^{(CH 2} KS. O » ' (CH ₂ )n' (CH ₂ )^ where n represents an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2, Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, _-CF3 , -OH, Cl~C6alkyl, Cl-C6alkoxy group, _-NH2 , _-N02 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or b) groups of the formula -(CH ₂ )“-A, - (CH ₂ ) “-SA, or - (CH ₂ ) “-0-A, where A means the group | B 190 «« *· .· • · · · . . • · · · • · · · · where D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or _-CF3 , B and C are independently selected from the group phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2 substituents from the group hydrogen or halogen -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy or -NO ₂ or c) groups of formulas or 4« 44 • · · 4 4 • 4 ♦ · 4 ·· 4444 191 Z is O or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group consisting of a halogen atom, -CF ₃ , -OH, C1-C6 alkyl, C1-C6 alkoxy group, -NH ₂ or -N0 ₂ , R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n ~C (O)-COOH, - (CH ₂ ) _n -COOH, -CH=CH-COOH, O O *· 0* • · · · • · 0 • · 0 • 0 0 ·· »·0» 192 Rg means Η tetrazolyl, -COOH, - (CH ₂ ) _n -COOH, -(CH ₂ ) n C(O) -COOH, Oh Rg represents a hydrogen or halogen atom, _-CF3 , -OH, ~( _CH2 )n··-COOH, -( _CHZ ) _n -C(0)-COOH, Cl-C6alkyl, -O-Cl-C6alkyl, -NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , R10 represents a hydrogen or halogen atom, _-CF3 , -OH, -( _CH2 ) _n ~-COOH, -( _CH2 )nC(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , O 193 R _u represents a hydrogen atom, C1-C6alkyl, -CF3, -COOH, -( _CH2 ) _n- COOH, -( _CH2 ) _n -C(O)-COOH or a group provided that the complete group in position 1 of the indole or indoline ring, formed by any combination of groups _R5 , Rg, Rg, R10 and/or Ru, will contain at least one acidic group selected from a carboxylic acid residue, a tetrazolyl group or a group of the formula O Oh N • 4 194 as well as pharmaceutically acceptable salts thereof. 7. Phospholipase inhibitors of the general formula where R 1 represents a hydrogen or halogen atom, -CF 3 , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy group, -N0 ₂ , -NH ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl or a group of the formula Rg represents a hydrogen atom, C1-C6alkyl, C1-C6alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein phenyl and 195 the benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ , -CF ₃ or -OH, R7 means - ( _CH2 )n-COOH, - ( _CH2 ) _n ^- N-(Cl-C6alkyl) ₂ , -( _CH2 ) _n- NH-(Cl-C6alkyl), _-CF3 , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N.(Cl-C6alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy group, _-N02 , _-CF3 or -OH, R ₂ represents a hydrogen or halogen atom, -CF ₃ , -OH, Cl-ClOalkyl, preferably Cl-C6alkyl, Cl-ClOalkoxy, -CHO, -CN, -NO2, -NH ₂ , -NH-Cl-C6alkyl, -N(Cl-C6alkyl) ₂ , -N-SO2~Cl-C6alkyl or -SO ₂ -Cl-C6alkyl, R ₃ represents a C1-C6alkyl, a C1-C6alkoxy group, -(CH ₂ ) _n -C3-C6cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C6cycloalkyl or one of the groups a) - (CH ₂ ) _n -phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-CH ₂ -phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -phenyl-(O-CH ₂ -phenyl) ₂ , -CH ₂ -phenyl-C(0)benzothiazolyl or any of the groups • · · · 196 where n is an integer from 0 to 3, preferably from 1 to 3 and especially 1 or 2, Y represents C3-C6cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF3, -OH, Cl-C6alkyl, Cl-C6alkoxy group, _-NH2 , _-N02 or a 5-membered heterocyclic ring containing 1 heteroatom from the group of N, S or 0, preferably S or 0 or b) groups of the formula -(CH ₂ ) _n -A, -(CH ₂ ) _n -SA, or - (CH ₂ ) _n -O-A, where A means a group D· •c B where D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or -CF3, B and C are independently selected from the group of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of these groups being optionally substituted with 1 to 3, preferably 1 or 2, substituents from the group of hydrogen or halogen, -CF3, -OH, C1-C6alkyl, C1-C6alkoxy or _-NO2 or c) formula groups FROM 197 where Z is O or S and the phenyl and pyrimidinyl rings of these groups are optionally and independently substituted with 1 to 3 substituents from the group halogen atom, -CF ₃ , -OH, C1-C6alkyl, C1-C6alkoxy, -NH ₂ or -N0 ₂ , R ₄ is selected from the group consisting of hydrogen or halogen, -CF ₃ , -OH, C 1-C 6 alkyl, C 1-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(0)-benzyl, -CH ₂ -(C3-C6cycloalkyl) , -C(O)-OH, -CH=0, -C(0)-Cl-C6alkyl, -C(0)-O-Cl-C6alkyl, -C(O)-CF ₃ , -(CH ₂ ) _n —S-CH ₂ —(C3-C6cycloalkyl), 198 wherein the phenyl and benzyl rings of the respective R3 groups are optionally substituted with 1 to 3 groups from the group halogen atom, C1-C6alkyl, C1-C6alkoxy group, -N0 ₂ , -CF ₃ , —C (0) —OH or -OH, n is an integer from 0 to 3, R ₅ is selected from the group -COOH, -C(O)-COOH, - (CH ₂ ) _n ~C (O) -COOH, - (CH ₂ ) _n -COOH, -CH=CH-COOH, O About 199 Rg is independently selected from the group -( _CH2 ) _n -COOH, -( _CH2 ) _n -C(O)-COOH, hydrogen, tetrazolyl, -COOH, OH ' O Oh Rg is selected from the group of hydrogen or halogen, _-CF3 , -OH, -COOH, -( _CH2 )n-COOH, -( _CH2 ) _n- C(0)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ , R10 is selected from the group consisting of hydrogen or halogen, -CF3, -OH, -( _CH2 )n-COOH, -( _CH2 ) _n -C(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ , 200 • 4 · · · 9494 999 49 9999 alkyl) . Rn is selected from the group of hydrogen atom, C1-C6alkyl, C1-C6cycloalkyl, _-CF3 , -COOH, -( _CH2 ) _n -COOH, -( _CH2 ) _n ~C(O)-COOH, provided that the complete group in position 1 of the indole or indoline group, formed by any combination of groups _R5 , Rg, R9, R10 and/or Ru, will contain at least one group of acidic nature, which is selected from the group of carboxyl group, tetrazolyl or a group of the formula as well as pharmacologically acceptable salts of these substances. 201 8. Phospholipase inhibitors Rs where _R1 represents _-NH2 , -O-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl or a group of the general formula Re· R· • 4 4 4 ·· ·· 44 • · 202 • · 4 · 4 4 4 4 · • · · · · · ·· ··· 4· R ₆ represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents from the group of a halogen atom, a C1-C6alkyl, a C1-C6alkoxy group, -NO ₂ , -NH ₂ , -CF ₃ or -OH, R ₇ represents - (CH ₂ ) _n ^- COOH, - (CH ₂ ) _n -N-(Cl-C6alkyl) ₂ , —(CH ₂ ) _n — -NH-(Cl-C6alkyl), -CF ₃ , Cl-C6alkyl, C3-C5cycloalkyl, Cl-C6alkoxy, -NH-(Cl-C6alkyl), -N(Cl-C6alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups being optionally substituted with 1 to 3 substituents from the group halogen atom, Cl-C6alkyl, Cl-C6alkoxy, -NH ₂ , -NO ₂ , -CF ₃ or -OH, n represents an integer from 0 to 3, R ₃ is selected from the group of halogen atom, C1-C6 alkyl, C1-C6 alkoxy group, -CF ₃ , -CH=O, -C(O)Cl-C6 alkyl, -O(0)-O-Cl-C6 alkyl, -C(O)-OH, -C(O)-CF ₃ , -C(0)-phenyl, -C(0)-benzyl, -C(0)-pyrrolyl, -C(0)-thienyl, -C(0)-furanyl or -C(0)-morpholinyl, R ₄ is selected from the group - (CH ₂ ) _n -C3-C6 cycloalkyl, -(CH ₂ ) _n -S-(CH ₂ ) _n -C3-C6 cycloalkyl, - (CH ₂ ) _n -O-(CH ₂ ) _n -C3-C6 cycloalkyl, - (CH ₂ ) _n -S-Cl-C6alkyl or any of the groups a) -C (0)-0-(CH ₂ ) _n -C3-C5cycloalkyl, - (CH ₂ ) _n -phenyl, -(CH ₂ ) _n -O-phenyl, - (CH ₂ ) _n -S-phenyl, - (CH ₂ ) _n -S-(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -phenyl-O-phenyl, - (CH ₂ ) _n -phenyl-(CH ₂ ) "-phenyl, -(CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) "-phenyl-(0-CH ₂ -phenyl) ₂ , -0(0)-0-phenyl, -C(0)-O-benzyl, -C(0)-O-pyridinyl, -0(0)-0-naphthyl, - (CH ₂ ) _n -S-naphthyl, - (CH ₂ ) _n -S-pyridinyl -(CH ₂ ) _n ^_ -pyridinyl or -(CH ₂ ) _n -naphthyl, -(GH ₂ ) _n -O-naphthyl, where the phenyl pyridinyl and naphthyl in these groups are 203 optionally substituted with 1 to 3 substituents from the group of hydrogen or halogen atom, -CF ₃ , -OH, C1-C6alkyl, C1-C6alkoxy group, -NO ₂ or a 5-membered heterocyclic ring containing one heteroatom from the group of N, S or O, or b) a group of the general formula -(CH ₂ ) _n -A, -(CH ₂ ) _n ~SA or ^- (CH ₂ ) n ^- OA, where A means a group where D represents a hydrogen atom, a C1-C6alkyl, a C1-C6alkoxy group or _CF3 , R ₅ is selected from the group -COOH, -C(O)-COOH, -(CH ₂ ) _n C (O) -COOH, -(CH ₂ ) _n -COOH, -CH=CH-COOH, O N' •OH 99 « ·· ·· ·· ·*♦··#*· 9 9 9 204 9 9 9 9 9 9 9 9 9999 999 99 9999 99 999 R ₈ is independently selected from the group consisting of hydrogen, -COOH, -(CH ₂ ) n -COOH, -(CH ₂ ) n C(O) -COOH, tetrazolyl, OH Rg is selected from the group of hydrogen or halogen, _-CF3 , -OH, -COOH, -( _CH2 )n-COOH, -( _CH2 ) _n -C(O)-COOH, C1-C6alkyl, -O-C1-C6alkyl, -NH(C1-C6alkyl or -N(C1-C6alkyl) ₂ , R 10 is selected from the group consisting of hydrogen or halogen, -CF ₃ , -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) nC (O) -COOH, C 1-C 6 alkyl, -O-C 1-C 6 alkyl, -NH(C 1-C 6 alkyl or -N(C 1-C 6 alkyl) ₂ , • fr · frfr ·· ·· • · ·· « · · · frfr* 205 • · · · · · · frfrfr· frfrfr frfr fr··· frfr · Rn is selected from the group of hydrogen atom, C1-C6alkyl, C1-C6cycloalkyl, _-CF3 , -COOH, -( _CH2 ) _n -COOH, -( _CH2 ) _n- C(O)-COOH, Rg, provided that the complete group in position 1 of the indole or indoline group, formed by any combination of groups R5 _{/ R8} , Rg, R10 and/or Rn, will contain at least one group of acidic nature, which is selected from the group of carboxyl group, tetrazolyl or a group of the formula as well as pharmaceutically acceptable salts of these substances. 206 9. A pharmaceutical composition comprising as its active ingredient a phospholipase inhibitor according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 10. A pharmaceutical composition comprising as its active ingredient a phospholipase inhibitor according to claim 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 11. A pharmaceutical composition comprising as its active ingredient a phospholipase inhibitor according to claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 12. A pharmaceutical composition comprising as its active ingredient a phospholipase inhibitor according to claim 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 13. A pharmaceutical composition comprising as its active ingredient a phospholipase inhibitor according to claim 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. • tt tttt • · · · • tt · • · * • · · •tt ···· • tt • tt • • tttttt 207 tt· « « · • tt • · • · • tt tt 14. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 15. The phospholipase inhibitor of claim 1, which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 16. The phospholipase inhibitor of claim 1, which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(4-hydroxy-6-phenyl-2-pyrimidinyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 17. The phospholipase inhibitor of claim 1, which is 4-{[3-chloro-5-[(cyclopentylcarbonyl)amino]-2- (([4-(2-thienyl)-2-pyrimidinyl]sulfany1}methyl}-1H-indol-1-yl]methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 18. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2,4-dibromophenoxy)methyl]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 19. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(cyclopentylsulfanyl)methyl]-1H-indole-1208 acid ·· ···· -ylmethyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(propylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 21. The phospholipase inhibitor of claim 1, which is 4-({2-{[4-(tert-butyl)phenoxy]methyl}-3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-ylmethyl)benzoic acid or a pharmaceutically acceptable salt thereof. 22. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-quinolinylsulfanyl)methyl]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 23. The phospholipase inhibitor of claim 1, which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-([(cyclopropylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 24. The phospholipase inhibitor of claim 1, which is 4-({2-[(benzhydrylsulfanyl)methyl]-3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 209 25. The phospholipase inhibitor of claim 1, which is 4-((5-[(3-carboxypropanoyl)amino]-3-chloro-2-[(phenethylsulfanyl)methyl[(phenethylsulfanyl)methyl]-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 26. The phospholipase inhibitor of claim 1, which is 4-[(5-[(3-carboxypropanoyl)amino]-3-chloro-2-{[(3-methylbenzyl)sulfanyl]methyl(-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 27. The phospholipase inhibitor of claim 1, which is 4-((2-(([4-(tert-butyl)benzyl]sulfanyl}methyl)-5-[(3-carboxypropanoyl)amino]-3-chloro-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 28. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-(3-furoylamino)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 29. The phospholipase inhibitor of claim 1, which is 4-((5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-ΙΗ-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 30. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-{[3-(diethylamino)propanoyl]amino}-2-[(2-naphthylsulfanyl)210 acid -methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 31. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 32. The phospholipase inhibitor of claim 1, which is 4-({5-{[benzylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 33. The phospholipase inhibitor of claim 1, which is 4-({5-{[(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 34. The phospholipase inhibitor of claim 1, which is 3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid or a pharmaceutically acceptable salt thereof. 35. The phospholipase inhibitor of claim 1, which is 4-{[5-(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)-ΙΗ-indol-1-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof. 211 • · · • · · · · · 36. The phospholipase inhibitor of claim 1, which is 4-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 37. The phospholipase inhibitor of claim 1, which is 4-{[5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-3-(2,2,2-trifluoroacetyl)-ΙΗ-indolyl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof. 38. The phospholipase inhibitor of claim 1, which is 4-((5-((4-aminobutanoyl)amino]-3-chloro-2-[(2-naphthylsulfanyl)methyl]-ΙΗ-indol-1-yl (methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 39. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 40. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(2-quinoxalinylcarbonyl)amino]-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 41. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(2,2-dimethylpropanoyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl(methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 212 42. The phospholipase inhibitor of claim 1, which is 4-({5-{[(benzyloxy)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl[methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 43. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-{[(cyclopentyloxy)carbonyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 44. The phospholipase inhibitor of claim 1, which is 4-({5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 45. The phospholipase inhibitor of claim 1, which is 4-((5-([(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl[methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 46. The phospholipase inhibitor of claim 1, which is 4-((5-([(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl[methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 47. The phospholipase inhibitor of claim 1, which is 4-((3-chloro-5-[(morpholinocarbonyl)amino]-2-[(2213 ·· · · · -naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 48. The phospholipase inhibitor of claim 1, which is 4-({5-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 49. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenoxybenzyl)amino]-ΙΗ-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 50. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-5-[(cyclopentylcarbonyl)(methyl)amino]-2-[(2-naphthylsulfanyl)methyl]-ΙΗ-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 51. The phospholipase inhibitor of claim 1, which is 4-({5-[acetyl(benzyl)amino]-3-chloro-2-[(2-naphthylsulfanyl)methyl]-ΙΗ-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 52. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(tetrahydro-3-furanylcarbonyl)amino]-1H-indol-1-ylmethyl)benzoic acid or a pharmaceutically acceptable salt thereof. 53. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5214 acid -[(3-thienylcarbonyl)amino]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 54. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(1-adamantylcarbonyl)amino]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 55. The phospholipase inhibitor of claim 1, which is 3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid or a pharmaceutically acceptable salt thereof. 56. The phospholipase inhibitor of claim 1, which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenylpropanoyl)amino]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 57. The phospholipase inhibitor of claim 1, which is 4-({5-amino-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 58. The phospholipase inhibitor of claim 1, which is N-{3-chloro-1-(4-{[(methylsulfonyl)amino]carbonyl]benzyl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 59. The phospholipase inhibitor of claim 1, which is 215 ···· N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-[4-({[(4-nitrophenyl)sulfonyl]amino)carbonyl)benzyl-1H-indol-5-yl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 60. The phospholipase inhibitor of claim 1, which is N-{3-chloro-1-[4-({[(2-methylphenyl)sulfonyl]amino}carbonyl)benzyl]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 61. The phospholipase inhibitor of claim 1, which is N-[3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-(4-{[(phenylsulfonyl)amino]carbonyl}benzyl)-1H-indol-5-yl}cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 62. The phospholipase inhibitor of claim 1, which is N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-[4-({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 63. The phospholipase inhibitor of claim 1, which is 4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butanoic acid or a pharmaceutically acceptable salt thereof. 64. The phospholipase inhibitor of claim 1, which is 4{5-[(cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1• acid 216 -yljbutanoic acid or a pharmaceutically acceptable salt thereof. 65. The phospholipase inhibitor of claim 1, which is N-[2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino]butyl)-3-(1-pyrrolidinylcarbonyl)-1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 66. The phospholipase inhibitor of claim 1, which is N-[3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino]butyl)-1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 67. The phospholipase inhibitor of claim 1, which is 5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino]butyl)-1H-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 68. The phospholipase inhibitor of claim 1, which is 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 69. The phospholipase inhibitor of claim 1, which is 2-(4-{[5-(benzyloxy)-3-(2-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 44 44 44 • 444 4 4 4 • 4 · · 4 217 4 4 4 4 44 4444 44 70. The phospholipase inhibitor of claim 1, which is 2-(4-{[5-(benzyloxy)-3-[3,5-bis(trifluoromethyl)benzoyl]-1H-indol-1-yl]methyl}phenyl]acetic acid or a pharmaceutically acceptable salt thereof. 71. The phospholipase inhibitor of claim 1, which is 4-({3-benzoyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 72. The phospholipase inhibitor of claim 1, which is 4-({5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 73. The phospholipase inhibitor of claim 1, which is 2-{3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 74. The phospholipase inhibitor of claim 1, which is 2-{5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 75. The phospholipase inhibitor of claim 1, which is 4-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl)butanoic acid or a pharmaceutically acceptable salt thereof. • · 76. The phospholipase inhibitor of claim 1, which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 77. The phospholipase inhibitor of claim 1, which is 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-N-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]-butanamide or a pharmaceutically acceptable salt thereof. 78. The phospholipase inhibitor of claim 1, which is 4-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 79. The phospholipase inhibitor of claim 1, which is 2-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 80. The phospholipase inhibitor of claim 1, which is 3-[(4-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]butanoyl)amino]propanoic acid or a pharmaceutically acceptable salt thereof. 81. The phospholipase inhibitor of claim 1, which is 3-[(4-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]butanoyl)amino]propanoic acid or a pharmaceutically acceptable salt thereof. • · • · 219 82. The phospholipase inhibitor of claim 1, which is N-(4-{3-benzoyl-5-(benzyloxy)-2-[(-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)-2-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof. 83. The phospholipase inhibitor of claim 1, which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}pentanoic acid or a pharmaceutically acceptable salt thereof. 84. The phospholipase inhibitor of claim 1, which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}pentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 85. The phospholipase inhibitor of claim 1, which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-N-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]pentanamide or a pharmaceutically acceptable salt thereof. 86. The phospholipase inhibitor of claim 1, which is 2-(3-benzoyl)-5-(benzyloxy)-2-[(2- -naphthyloxy)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 87. The phospholipase inhibitor of claim 1, which is (E)-4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-butanoic acid or a pharmaceutically acceptable salt thereof. 0 0 220 0 0 0 0 0 0 • 00 0 0 >000 88. The phospholipase inhibitor of claim 1, which is 3-({3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 89. The phospholipase inhibitor of claim 1, which is 1-{1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl}-1-ethanone or a pharmaceutically acceptable salt thereof. 90. The phospholipase inhibitor of claim 1, which is 1-{1-[3-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl}-1-ethanone or a pharmaceutically acceptable salt thereof. 91. The phospholipase inhibitor of claim 1, which is 2-[3-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoyl]-1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. 92. The phospholipase inhibitor of claim 1, which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-ΙΗ-indol-1-yl}-2-oxopentanoic acid or a pharmaceutically acceptable salt thereof. 93. The phospholipase inhibitor of claim 1, which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]-2-oxopentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. ·· « ·· ·· ·· • · ·· ··· · · · • · · · · · · 221 • · · · · · · ··· ··· ·· ·· ·· ·· 94. The phospholipase inhibitor of claim 1, which is 4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 95. The phospholipase inhibitor of claim 1, which is 3-((4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butanoyl}amino)benzoic acid or a pharmaceutically acceptable salt thereof. 96. The phospholipase inhibitor of claim 1, which is 3-[(4-{5-[(cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 97. The phospholipase inhibitor of claim 1, which is N-[2-[(2-naphthyloxy)methyl]-1-{4-oxo-4-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl)aniline]butyl}-3-(1-pyrrolidinylcarbonyl)-1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 98. The phospholipase inhibitor of claim 1, which is N-(3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1-{4-oxo-4-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl)aniline]butyl}-1H-indol-5-yl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. ΦΦ φ φφ *· ·· • φ φ · φφφφ φ φ φ · φ · φφφ 222 φ φ φφφ φ φ φφφφ φφφ φφ φφφφ φφ 99. The phospholipase inhibitor of claim 1, which is 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 100. A method of inhibiting phospholipase enzyme activity in mammals, comprising administering an effective amount of a pharmaceutical composition according to claim 9. 101. A method of inhibiting phospholipase enzyme activity in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 10. 102. A method of inhibiting phospholipase enzyme activity in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 11. 103. A method of inhibiting phospholipase enzyme activity in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 12. 104. A method of inhibiting phospholipase enzyme activity in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 13. 105. Method for treating an inflammatory reaction in mammals, 223 •4 44 44 4·4· 444 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 444444 44 4 characterized in that an effective amount of the pharmaceutical composition according to claim 9 is administered. 106. A method of treating an inflammatory reaction in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 10. 107. A method of treating an inflammatory reaction in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 11. 108. A method of treating an inflammatory reaction in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 12. 109. A method of treating an inflammatory reaction in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 13.