CZ2000376A3 - Compounds of 2-acylaminopropanamines functioning as antagonists of tachykinin receptor - Google Patents

Abstract

The present invention relates to non-peptide 2-acylaminopropanamine receptor antagonists. Tachykinins are a class peptides having a common amidated carboxy terminal sequence. The compounds are useful in the treatment of various conditions including Alzeimer's disease. They are further discussed pharmaceutical compositions containing such compounds.

Description

tachykinin receptor

Technical field

The invention relates to 2-acylaminopropanamine compounds and their use as tachykinin receptor antagonists.

BACKGROUND OF THE INVENTION

Tachykinins are a class of peptides having a common amidated carboxy-terminal sequence. Substance P was the first peptide of this class to be isolated, although its purification and determination of its primary sequence did not occur until the early 1970s.

Between 1983 and 1984 several groups reported the isolation of two new mammalian tachykinins, now called neurokinin Ά (also known as substance K, neuromedin L, and neurokinin a), and neurokinin B (also known as neuromedin K and neurokinin β). See J.E.Maggio, Peptides, 6 (Supplement 3): 237-243 (1985) for an overview of these discoveries.

Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from the nerves and perform a variety of biological activities, which in most cases depend on activation of specific receptors expressed on the target cell membrane. Tachykinins are also produced by a variety of non-natural tissues.

antagonists • · • ·

Mammalian tachykinins of substance P, neurokinin A and neurokinin B act via three major receptor subtypes, designated NK-1, NK-2 and NK-3, respectively. These receptors are present in a number of organs.

Substance P is believed to be involved, inter alia, in neurotransmission of pain, including pain associated with migraine headaches and arthritis. These peptides also participate in gastrointestinal disorders and gastrointestinal disorders such as inflammatory bowel disease. It is also believed that tachykinins play a role in a number of diseases, as discussed below.

Tachykinins play an important role in mediating sensation and transmission of pain or nociception, especially migraine headaches.

See, for example, S T. Shepheard et al., British Journal of Pharmacology. 108: 11-20 (1993); S.M. Moussaoui et al., European Journal of Pharmacology. 238: 421-424 (1993); and W.S. Lee et al., British Journal of Pharmacology. 112: 920-924 (1994).

Due to the large number of clinical diseases associated with excess tachykinins, the development of tachykinin receptor antagonists will serve to manage these clinical conditions. The first tachykinin receptor antagonists were peptide derivatives. These antagonists had only limited pharmaceutical utility due to their metabolic instability.

9 9 9 99 99 9 99 9 9 99 9 9 99 9 9 99 9 9 9 9 99 99 99 · 9 99 99> ·>

Recent publications have described new classes of non-peptide tachykinin receptor antagonists, which generally have better oral bioavailability and metabolic stability than prior classes of tachykinin receptor antagonists. Examples of such newer non-peptide tachykinin receptor antagonists can be found in U.S. Pat. No. 5,491,140, issued Feb. 13, 1996; U.S. Pat. No. 5,328,927, issued Jun. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S. Pat. No. 5,344,830, issued September 6, 1994; U.S. Pat. No. 5,331,089, issued Jul. 19, 1994; European Patent Publication

591,040 A1, published Apr. 6, 1994; PCT Publication WO 94/01402, published Jan. 20, 1994; PCT Publication WO

94/04494, published Mar. 3, 1994; PCT Publication WO

93/011609, published Jan. 21, 1993; Canadian Patent Application 2154116, published Jan. 23, 1996; European Patent Publication 693,489, published Jan. 24, 1996; and Canadian Patent Application 2151116, published December 11, 1995.

U.S. Pat. No. 5,530,009, issued June 25, 1996, discloses 1,2-diacylaminopropane for use in treating conditions associated with excess tachykinins. This patent also discloses methods for preparing these compounds.

In principle, the present invention relates to potent non-peptide tachykinin receptor antagonists similar to those described in U.S. Pat. No. 5,530,009. Because of their non-peptide nature, the compounds of the present invention do not have the disadvantages related to metabolic instability of tachykinin receptor antagonists based on peptides.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of formula I

in which:

R ¹ and R ² are each independently hydrogen, halogen, C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkoxy;

R ⁵ , R ⁶ , and R ⁷ independently of one another are hydrogen, halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, trifluoromethyl or hydroxy;

R ³ represents hydrogen, C 2 -C 7 alkanoyl, glycyl or

99 9 9

I 9 99

9999 dimethylglycyl;

n is equal to 1-6;

D represents -S (O) _m -, -NH-, -C (O) - or -O-, m is equal to 0, 1 or 2;

R ⁸ and R ⁹ are each independently hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy (C 1 -C 6 alkylenyl) -, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkoxycarbonyl (C 1 -C 6 alkylenyl) -, trifluoromethoxy, trichloromethoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, di (C 1 -C 6 alkyl) amino, formyl, cyano, halogen, trifluoromethyl, R ¹⁰ R ^{1: L} N (C 1 -C 6 alkylenyl) ~ C6 alkylenyl) -, pyrrolyl, triazolyl, imidazolyl, tetrazolyl, thiazolyl, thiazolinyl, thiadiazolyl, thiadiazolinyl, piperidyl, pyrrolidyl, morpholinyl, morpholinocarbonyl, hexamethyleneiminyl, methylsulfonyl, methylsulfinyl, phenoxy, benzyloxy, carboxy, carbamoyl or C ₂ -C ₇ alkylcarbamoyl (C 1 -C 8 alkylenyl) -,

R ¹⁰ and R ^u independently represent hydrogen or _Ci-C6 alkyl, said Οχ-Οβ alkyl or C1-C6 alkoxy groups may be optionally substituted by one, two or three groups selected from the group consisting of hydroxy, halogen cyano, amino, nitro, carboxy, carbamoyl and thiol groups;

or R ⁸ and R ⁹ may be linked to the benzo ring to which

9,999 9 • 9

9 9 9 • 99 8

9

9

Are attached and form naphthyl, dihydronaphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl,

A 2-cumaranonyl, 3-cumaranonyl, benzothiazolyl, benzimidazolyl indolyl, benzothienyl, benzofuryl, 2,3-dihydrobenzofuryl, indolinyl or 2,3-dihydrobenzothienyl group which may be linked to D at any position on the bicyclic group;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention relates to a method of treating conditions associated with excess tachykinins, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a pharmaceutical composition comprising, as active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carrier, diluent or excipient.

Detailed description and preferred embodiments

The terms and abbreviations used in the appended examples have their usual meaning unless otherwise indicated. For example, ° C means degrees Celsius; N is normal or normality; mol means moles or moles; mmol means millimole or millimoles; g is gram or grams; kg means kilogram or kilograms; 1 is liter or liters; ml is milliliters or milliliters; M represents molar or molarity; MS refers to mass spectrometry; NMR refers to nuclear magnetic resonance spectroscopy. C 1 -C ₆ alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C 1 -C ₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term C 1 -C ₆ alkoxy includes C 1 -C 4 alkoxy and C 1 -C 3 alkoxy as defined herein. As used herein, the term C1-C12 alkyl means straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl , pentyl, isopentyl, and hexyl. The term C 1 -C 12 alkyl includes C 1 -C ₆ alkyl and C 1 -C ₄ alkyl in its definition. C ₂ -C ₇ alkanoyloxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl group attached via an oxygen atom. Typical C 2 -C 7 alkanoyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.

C 3 -C 8 cycloalkyl represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms. Typical C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Halogen represents chlorine, fluorine, bromine or iodine. C 1 -C ₆ alkylthio represents a straight or branched alkyl chain having from one to six carbon atoms bound to the sulfur atom. Typical C 1 -C ₆ alkylthio groups include 44b 44444444

4445 4 4 · 4 4 4 4

44 44 4444 4444 ~ 4444444 444444 - Η— 4444 4444 4444

44 44 44 4444 methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.

C 1 -C 12 alkylenyl means a straight or branched, divalent, saturated C 1 -C 12 aliphatic chain and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl , octylenyl, 3-methyloctylenyl, decylenyl. The term C 1 -C 6 alkylenyl is included in the term C 1 -C 12 alkylenyl.

C 1 -C 10 alkylamino represents a group of the formula NH (C 1 -C 10 alkyl) in which the alkyl chain has from one to ten carbon atoms and is bound to the amino group. Typical C 1 -C 4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.

C ₂ -C ₆ alkanoyl represents a straight or branched alkyl chain having from one to five carbon atoms attached to the carbonyl group. Typical C ₂ -C ₆ alkanoyl groups include ethanoyl (acetyl), propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl,

3-methylpentanoyl and the like.

C ₂ -C ₇ alkoxycarbonyl represents a straight or branched alkoxy chain having from one to six carbon atoms attached to the carbonyl group. Typical C ₂ -C ₇ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.

• ·

9999 9 9 9 9 9 99

9 9 9 9

99

9

9 9 9 9 9 • 9 9 9 9

9 9 9 9 9

9 9 9 9 9

99 99

The term carbamoyl as used herein means a group having one of the following structures.

The term C 2 -C 7 alkylcarbamoyl as used herein means a branched or unbranched chain of 1 to 6 carbon atoms combined with a carbamoyl group as defined above. This group has the following structure.

C 1 -C 6 alkyl

As used herein, the term haloformate means a haloformate ester, which is a compound having the general formula:

O

II

X — CL

OR ^d in which X represents a halogen atom, and R ^d represents C 1 -C 8 alkyl. Preferred haloformates are bromoformates

4 • 4 ·· 4444 • · 4 4

9 9 φ · · 4 4 4

4 4 4 4 • 44

4 4

4 4

4 4

4 4 and chloroformates. Chloroformates are particularly preferred. Those haloformates in which R ^d represents C ₃ -C 6 alkyl are particularly preferred. Most preferred is isobutyl chloroformate.

The compounds prepared by the process of the present invention have asymmetric centers. As a result of this presence of chiral centers, the compounds produced according to the present invention may exist as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers.

The terms R and S are used herein in the manner customary in organic chemistry to denote specific chiral center configurations. The term R (rectus) refers to chiral center configurations with clockwise arrangement of groups according to their priorities (highest to second lowest) when viewed along the bond to the lowest priority group.

The term S (sinister) refers to chiral center configurations with an anti-clockwise arrangement of groups according to their priority (highest to second lowest) as viewed along the bond to the lowest priority group. The priority of groups is based on their atomic number (in the direction of decreasing atomic numbers). A partial list of priorities and discussion of stereochemistry is included in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINPIPLES AND PRACTICE, (J. H. Fletcher et al., Eds., 1974) on pages 103-120.

In addition to using the (R) - (S) system, this application also includes • · • · 0

0

0 0 · 0 0

uses an older D-L system to denote absolute configuration, especially in amino acid labeling. In this system, the Fischer projection pattern is oriented so that the backbone carbon 1 is up. The prefix D is used to denote the absolute configuration of the isomer in which the functional (determining) group is located on the right side of the carbon in the chiral center and L is the isomer in which it is on the left side.

The term amine protecting group as used herein refers to amino group substituents that are commonly used to block or protect the amine function during the reactions of other compound functional groups. Examples of such amine protecting groups include formyl, trityl (abbreviated herein as Tr), phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urea-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,

2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,

4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,

3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,

2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,

3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,

4-cyanobenzyloxycarbonyl, t-butoxycarbonyl (abbreviated herein as BoC), 1,1-diphenyleth-1-yloxycarbonyl,

1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop2-yloxycarbonyl, 2- (p-toluyl) -prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 4-methylcyclohexanyloxycarbonyl, -toluylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl,

4444

4 4 4

4 4

4 4

4 4 4

4 9

2- (triphenylphosphino) ethoxycarbonyl, fluorenylmethoxycarbonyl (FMOC), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl,

4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl,

2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl,

4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl, 2-nitrophenylsulfenyl, diphenylphosphine oxide and the like amine protecting groups.

The type of amine protecting group used is usually not critical if the amine derivative it generates is stable under subsequent reaction conditions at other positions in the intermediate molecule and can be selectively removed at the appropriate point in the reaction sequence without damaging the rest of the molecule, including other amine groups protecting groups. Preferred amine protecting groups are trityl, t-butoxycarbonyl (t-BOC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups falling under the above term are described in the monograph E. Haslam, Protective Groups in Organic Chemistry, (J.G.W. McOmie, ed., 1973), in Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), Chapter 7.

The term carboxyl protecting group, as used herein, refers to carboxyl group substituents that are commonly used to block or protect a carboxyl function during the reactions of other compound functional groups. Examples of such carboxyl protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, pmethoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, and the like. 9999 9 9 9 9 9 9 9 9

9

9 9 9 9 99

2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,

4,4'-dimethoxybenzhydryl, 2,2 ', 4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4-trimethoxytrityl, 2- phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl,

2.2.2-trichloroethyl, 2- (di (N-butyl) methylsilyl) ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) prop-1-en-3-yl and the like. Preferred carboxyl protecting groups are allyl, benzyl and t-butyl. Further examples of these groups are found in E. Haslam, cited in Chapter 5 above, and T.W. Greene, et al., Cited above in Chapter 5.

The term hydroxyl protecting group, as used herein, means hydroxyl substituents that are commonly used to block or protect a carboxyl function during the reactions of other compound functional groups. Examples of such hydroxyl protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,

2- (trimethylsilyl) ethoxymethyl, methylthiomethyl,

2,2-dichloro-1,1-difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, C 1 -C ₆ alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl. Further examples of these groups can be found in TW Greene and PGM Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) in Chapter 3.

The term cleavable group, as used herein, means " *** ", " **, ", ", ", " " A group of atoms which can be separated from the carbon atom by the action of a nucleophile in a nucleophilic substitution reaction.

The term leaving group, as documented, includes non-limiting groups.

is used in this way to activate succinimidoxy, benzenesulfonyloxy,

The term activating group, as used herein, means a leaving group which, when considered with the carbonyl (-C = O) group to which it is attached, is more likely to enter an acylation reaction than if it were this group was not present, as in the free acid. Such activating groups are well known to those skilled in the art and may be, for example, phthalimidoxy, benzotriazolyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido or -O-CO- (C 4 -C 7 alkyl).

As mentioned above, the present invention also relates to pharmaceutically acceptable salts of the compounds of the general formula I. The compound of the present invention may contain sufficiently acidic functional groups, sufficiently basic functional groups, or both, and react accordingly with organic and inorganic organic bases of acids to form an acceptable salt.

with any of a number of and inorganic and pharmaceutically acceptable

The term pharmaceutically acceptable salt as used herein means salts of compounds of the above formulas which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those that have been

99 prepared by reacting the compounds of the present invention with a pharmaceutically acceptable inorganic or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and basic addition salts.

The acids commonly used to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like and organic acids such as ptoluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid , succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogen sulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, hydrochloride, dihydrochloride, dihydrochloride, dihydrochloride, dihydrochloride, dihydrochloride. succinate, suberate, sebacate, fumaran, maleic, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, acrylate, isobutyrate, formate, caproate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelan and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with inorganic acids such as hydrochloric acid and acid.

hydrobromic acid and those which are acids such as methanesulfonic acid.

formed with organic maleic and acid

Salts of amino groups may also include quaternary ammonium salts in which the nitrogen of the amino group carries suitable organic groups such as alkyl, alkenyl, alkynyl or aralkyl.

Base addition salts include salts derived from inorganic bases such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Thus, such bases useful for preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. Potassium and sodium salts are particularly preferred.

It should be understood that the nature of a particular ion forming any of the salts of the present invention is usually not critical as long as the salt as a whole is pharmacologically acceptable and until that ion contributes to the undesirable properties of the salt as a whole.

The present invention further relates to pharmaceutically acceptable solvates of compounds of formula I. Many compounds of formula I may be combined with solvents such as water, methanol, ethanol, and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanol, and acetonitrile.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The present invention also relates to pharmaceutically acceptable prodrugs of compounds of Formula I. A prodrug is a substance that has been chemically modified and may be biologically inactive at its site of action, but which can be degraded or modified by one or more enzymatic or other in vivo processes to produce the original biologically active forms. This precursor should have a different pharmacokinetic profile than the parent compound, allowing easier absorption by the mucosal epithelium, better salt formation or solubility, or improved systemic stability (e.g., increase in plasma half-life).

Such chemical modifications typically include:

1) ester or amide derivatives which can be cleaved by esterases or lipases;

2) peptides that can be recognized by specific or non-specific proteases; or

3) derivatives that accumulate at the site of action by membrane selection of a precursor form or a modified precursor form;

or any combination of items 1 to 3 above. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in H, Bundgaard, DESIGN OF PRODRUGS, (1985).

The compounds of formula (I) are generally prepared by reacting a compound of formula (II): 4 4 4 4 4 4

II with an appropriately substituted carboxylic acid, carboxylic anhydride or carboxylic acid halide in the presence of typical peptide coupling reagents such as N, N'-carbonyldiimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide (EDC). A polymer supported form of EDC has been described (Tetrahedron Letters. 34 (48): 7685 (1993)), which is very useful for the preparation of the compounds of the present invention. Isolation of the products from those reactions in which the polymer bound reagent was used is greatly simplified and only requires filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. The product of these reactions can be purified by chromatography or recrystallized from a suitable solvent if desired.

Another preferred method of preparing compounds of formula I wherein D is -O- is by reacting a compound of formula III.

/

X

Wherein X represents a leaving group, preferably a halogen group, most preferably a bromine atom, with a suitably substituted phenol, naphthol and the like. The most preferred method currently known for the synthesis of intermediates of formulas II and III is shown in Scheme I below. Many steps of this synthesis are described in PCT Publication WO 95/14017, published May 26, 1995; Published European Patent Application 693,489, published Jan. 24, 1996; and U.S. Pat. No. 5,530,009, issued June 25, 1996, which are incorporated herein by reference in their entirety.

• · • ·

·· ·· ·· ··

Scheme I

wherein Tr is a trityl group and NMM is N-methylmorpholine.

Scheme I (continued)

4 ·· · ··· 4 4 4 4

4 4 4 4 · 4 44 4 444

44 «4,444 44 4

4 · 44 4 · 44 4

44 * 4 ··

• · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 9 · 9 «4 · 4

94,949 4,449 44 4 • 944 4999 4494 • 94 94 49 49 99 49

Another method for preparing the intermediates of formulas II and III, Steps a) and b) may be carried out as described in U.S. Pat. No. 60 / 021,849, filed July 16, 1996. In this method, a compound of formula (I) is used

prepared by reaction of a compound of formula

OH with bis (trimethylsilyl) amine in acetonitrile, followed by addition of trityl chloride, N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine, in the presence of acetonitrile, and then addition of 2-methoxybenzylamine.

99

9

9 98 9 9

9 9 9 9 9

9

9999 99

99

9 9 9 9

9 9 9 9 • 9 9 9 9

99 99

The factor ultimately identified as critical for the combination of steps was desilylation of the compound of formula A in step (a), before ester formation by addition of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). In step (a), desilylation was achieved by adding excess water prior to isolation, which also dissolved any salt present.

During desilylation of compound A in the combined chemical process, stoichiometry becomes extremely important. The presence of excess HMDS used in the original silylation of D-tryptophan must be considered. Simply adding a stoichiometric amount of methanol (or water) relative to D-tryptophan will not allow the subsequent esterification process. Methanol must also be added to quench the remaining unreacted HMDS. However, excess methanol consumes CDMT and prevents complete esterification. Once the desilylation of the compound of formula A and the decomposition of the excess HMDS is complete, the chemical process of step (b) proceeds as expected and the desired intermediate of high quality and good yield is obtained.

In the above process, amine intermediates are reduced to amines by methods well known to those skilled in the art. These reductions can be carried out using lithium aluminum hydride as well as using many other different aluminum-containing hydrides. A particularly preferred reagent used in this reduction is RED-AL®, which is the trade name for a 3.4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene. Alternatively, amides can be reduced by catalytic hydrogenation, although high temperatures and pressures are usually required. Sodium borohydride in combination • I MM • I · «• 9 9 9

9 99

9 9 9

9 9 9

99

9 9

9 9

9

9 9 9

99

99

9 9 9

9 9 9

9 9 9 • · · 9

99 with other reagents can be used to reduce the amide. Borane complexes such as borane-dimethylsulfide complex are particularly suitable for these reduction reactions.

The acylation of the secondary amine can be accomplished using any of a variety of methods commonly used by one of ordinary skill in organic chemistry. One such reaction scheme is substitution using an anhydride such as acetic anhydride. Another frequently used reaction scheme for the acylation of a secondary amine uses a carboxylic acid preferably with an activating agent. The amino-dealcoxylation type of the reaction uses esters as a means to acylate the amine. Activated esters which are known to provide increased selectivity are highly effective acylating agents. One such preferred activated ester is a p-nitrophenyl ester such as pnitrophenylacetate.

The primary amines may also be acylated using amides to carry out a process that is essentially an exchange reaction. This reaction is usually carried out with an amine salt. Boron trifluoride, usually in the form of a complex and boron trifluoride and diethyl ether, is often added to this reaction for complexation with cleaved ammonium.

An additional step is one of the amine substitutions. For most compounds of Formula I, this substitution is a substitution of compositions.

alkylation, acylation or sulfonation. Typically, alkylation can be achieved using alkyl halides and the like, as well as using well

4444

• 4 4

4 4 • 4 4 4 4

4 4 4

44

4 4

4 4

4 4 4

44

44

4 4 4

4 4 4

4 4 4 4

4 4 4

44 known reductive alkylation methods using aldehydes or ketones. Many of the acylation reaction protocols discussed above also effectively acylate secondary amines. The alkyl and aryl sulfonyl chlorides can be used for sulfonating the secondary amine.

In many cases, one of the last steps in the synthesis of compounds of formulas II and III is the removal of the amine or carboxyl protecting group. Such methods, which vary depending on the type of protecting group as well as the relative lability of other portions of the compound molecule, are described in detail in many standard reference monographs such as T.W. Greene, et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991).

DETAILED DESCRIPTION OF THE INVENTION

The following Examples and Preparations further illustrate the compounds of the present invention and methods for their synthesis. The examples are not intended to limit the scope of the present invention in any way and should not be construed as such. All experiments were carried out under positive pressure of anhydrous nitrogen or argon. All solvents and reagents were purchased from commercial sources and used as supplied unless otherwise noted. Anhydrous tetrahydrofuran (THE) was obtained by distillation from sodium or sodium benzophenone ketyl prior to use.

Proton nuclear magnetic resonance spectra ^(X H NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz on a Bruker AM-500 or at 500 MHz spectrometer • 9999 • 9 9 9 9 9 «« • · 99 9 9 9

9 9 999 9 9 • 99 9 9 99 9

99 99 99

9

9

9

9

9

Bruker AC-200P at 200MHz.

(Unless otherwise indicated, the term NMR as used herein means proton nuclear magnetic resonance). Free atom bombardment mass spectroscopy (FAB) was performed on a VG ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) was performed on either VG 70SE or Varian MAT 731.

Optical rotation was measured with a Perkin-Elmer 241 polarimeter. Chromatographic separation on a Waters Prep 500 LC was usually performed using a linear gradient of the solvents listed herein unless otherwise noted.

Reactions were generally monitored to determine their completion using thin layer chromatography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 F 254 plates, 5 cm x 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates coated with a solution of clear ammonium molybdate [75 g ammonium molybdate and 4 g cerium sulphate in 500 ml 10% aqueous sulfuric acid] and then heated on a hot plate). Preparative thin layer centrifugal chromatography was performed on a Harrison Model 7924A Chromatotron chromatograph using an Analtech silica gel GF centrifuge.

Cation exchange chromatography was performed using Dowex® 50X8-100 ion exchange resin. Anion exchange chromatography was performed with β-Rad AG® 1-X8

44 • 4 • 44 • 4 • 4 • 4 · ·

44 · ♦ ·

4 · • 44

4 4 4

44

44

4 4 4 • 4 4

4 4 4

44 anion exchange resins (acetate form converted to hydroxide form). Flash chromatography was performed as described by Still et al., Journal of Organic Chemistry, 43: 2923 (1978).

Optical rotations are described to the D-line of sodium (354 nm). Elemental analyzes for carbon, hydrogen, and nitrogen were performed on a Control Equipment Corporation 440 Elemental Analyzer or were performed at the Universidad Complutense Analytical Center (Facultad de Farmacia, Madrid, Spain). Melting points were determined in open glass capillaries on a Thomas Hoover capillary melting point or Buchi melting point and are uncorrected.

The following methods provide illustrative protocols for preparing compounds of Formula I as depicted in the Schemes above. In the Preparations and Examples below, the terms NMR, IR, and UV 'mean that proton nuclear magnetic resonance, infrared, and ultraviolet spectroscopy were consistent with the structure of the desired title product.

Preparation 1

Preparation of (R) -3- (1H-indol-3-yl) -N- (2-methoxybenzyl) -2- (N-triphenylmethylamino) propanamide.

• 3 · «3 ·

• 44 · · ·

4 4 4 4

4 4 4

4 «och ₃

In a 50 gallon glass reactor, L-tryptophan (4.50 kg, 22.0 mol) was added to acetonitrile (30 L, 6.7 vol) at 20 ° C. This reactor was vented to a scrubber containing water to remove the ammonium formed during the silylation reaction and the HCl formed during the tritylation and esterification reactions. Bis (trimethylsilyl) amine (HMDS, 5.81 L, 27.5 mol, 1.25 equiv) was transferred under self-weight to the Ltryptophan suspension in a plastic container. The carbohydrate was washed with acetonitrile (0.5 L). The suspension was heated to 55 ° C and stirred until completion of the reaction. The end of the reaction was defined as the moment when the slurry completely went into solution. At the completion of the reaction, the reaction mixture was bright yellow and the reaction lasted approximately 2 hours.

Trityl chloride (6.45 kg, 23.1 mol, 1.05 equiv) was suspended in acetonitrile (30 L, 6.7 vol) and added to the reactor at 47 ° C using a vacuum at 325 mm Hg.

N-methylmorpholine (5.38 L, 48.9 mol, 2.20 equiv) was also transferred to the reactor at this point. Reaction suspension

44 4 • 4 44 49 • 4 4 4 4

44 44

4 4 4 4 4 5

4 4 4 4 4

44 44

44

4 4 4

4 4 4

4 4 4

4 4 4

44 was heated and maintained at 55 ° C until completion of the reaction determined by high performance liquid chromatography analysis. The reaction time was approximately 2.5 hours.

The reactor was isolated from the scrubber and cooled to 35-40 ° C. Methanol (2.29 L, 56.5 mol, 2.55 equiv) was charged to the reactor and the mixture was cooled to 25 ° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 4.14 kg, 23.61 mol, 1.07 equiv) was added to the acetonitrile reactor (28 L, 6.2 vol.) at 25 ° C. The reactor was again vented to the scrubber. The reaction suspension was stirred at ambient temperature until completion of the reaction. The moment of completion of the reaction was determined by high performance liquid chromatography analysis. The reaction time was approximately 2 hours. After the reaction was carried out, the reactor was separated from the scrubber.

2-methoxybenzylamine (3.11 L, 23.8 mol, 1.08 equiv) was fed from the plastic demijohn to the reactor at its own weight. The suspension was thickened with the addition of 2-methoxybenzylamine. The reaction slurry was heated to 35 ° C and stirred until completion of the reaction as determined by HPLC analysis. The reaction time was 2.5 hours.

Water (45 kg, 10 vol.) Was previously weighed into a separate 50 gallonon glass tank. The water was transferred to the reaction slurry under pressure over approximately 45 minutes. The resulting yellow-colored suspension was cooled to 0-5 ° C over two hours and stirred overnight.

The title intermediate was isolated by a vertical basket. · «Vertikální vertikální vertikální vertikální vertikální vertikální vertikální vertikální vertikální

Centrifuge insulation using a 3 micron multi-fiber polyethylene insulating sachet. The speed during centrifugation was generally between 900-1050 rpm, the wash speed was 900-1500 rpm, and the base speed was 1500-2300 rpm.

The title intermediate was then dried in a rotary vacuum dryer.

Yield: 86.4% with an isomeric purity of 99.6%.

Preparation 2

Reduction of carbonyl

Preparation of (R) -3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) amino] 2- (N-triphenylmethylamino) propane

N

H

RED-AL®, [3,4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved »4 • · 4 4

4 4 4

4 44

4 4 4 4 4 5

4 4 4 4 4 5

44 44 44

4 4 4

4 4 4

4,444 in anhydrous tetrahydrofuran (400 mL) was slowly added using a funnel to a solution of the refluxed acylation product, (R) -3- (1H-indol-3-yl) N- (2-methoxybenzyl) -2- ( N-triphenylmethylamino) propanamide (228.6 g, 0.404 mol), prepared as described above, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was terminated after at least 20 hours by slowly adding an excess of a saturated solution of Rochell's salt (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2x), dried over anhydrous sodium sulfate, filtered and concentrated to an oil on a rotary evaporator. No further purification was performed and the product was used directly in the next step.

Preparation 3

Acylation of secondary amine

Preparation of (R) -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] -2- (N-triphenylmethylamino) propane.

- 32 · * 99 · * 99 * 9 99> 9 ·· 99 9 · 9 ·

99 99 9 999

99,999,999,999 9,999,999,999,99 99,999,999,999,999,999

(R) -3- (1H-indol-3-yl) 0.404 mol) in anhydrous sodium, rotary

Into the stirred solution

1- [N- (2-methoxybenzyl) amino] 2- (N-triphenylmethylamino) propane tetrahydrofuran (1.2 L) under nitrogen at 0 ° C was added triethylamine (56.5 mL, 0.477 mol) and acetic anhydride ( 45.0 mL, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2x) and brine (2x), dried over anhydrous sulfate, filtered, and concentrated to a solid in the evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1: 1 mixture of ethyl acetate and hexanes. The product was then crystallized from ethyl acetate / hexanes. The resulting product (R) -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] 2- (N-triphenylmethylamino) propane was crystallized and isolated in three batches to give 208, 97 g (87% yield) of analytically pure material.

Analysis for C40H39N3O2:

Theory: C, 80.91; H, 6.62; N, 7.08.

»4444

44 • 4 4 • 4 44 • 4 4 4

4 4 4

44 * 4 ·

4 4

4 4 •

44

4 «4

4 4 4 • 4 4 4 4 • 4 4 4

Found: C, 81.00; H, 6.69; N, 6.94.

Preparation 4

Deprotection

Preparation of (R) -2-amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane dihydrochloride

A stirred solution of (R) -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] -2- (N-triphenylmethylamino) propane in two volumes of methylene chloride was cooled to a temperature between -40 ° C and -50 ° C. Anhydrous hydrogen chloride gas was added at a rate such that the temperature of the reaction mixture did not exceed 0 ° C. The reaction mixture was stirred for 30 minutes to one hour at 0-10 ° C.

To this reaction mixture were added two volumes of methyl t-butyl ether and the resulting mixture was allowed to stir for 30 minutes to one hour at 0-10 ° C. The resulting crystalline solid was collected by filtration and then washed with methyl t-butyl ether. The reaction product was dried under vacuum at 50 ° C.

······················································· I · I (Yield> 98%)

Analysis for C 21 H 25 N 3 O 2. 2 HC1:

Theory: C, 59.44; H, 6.41; N, 9.90.

Found: C, 60.40; H, 6.60; N, 9.99.

Preparation 5

Preparation of (R) -2 - [(2-bromo) acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane

To a stirred solution of (R) -2-amino-3- (1H-indol-3-yl) -1- [N (2-methoxybenzyl) acetylamino] propane (7.51 g, 21.369 mmol) in anhydrous tetrahydrofuran (100 mL) ) under nitrogen atmosphere at 0 ° C was added diisopropylethylamine (4.1 mL, 23.537 mmol) and bromoacetyl bromide (2.05 mL, 23.530 mmol). After 2 hours, ethyl acetate was added and the reaction mixture was washed twice with water, 1.0 N hydrochloric acid (2x), saturated sodium bicarbonate solution (2x), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a brown foam in a rotary evaporator. In this way it was obtained

2 - [(2-bromo) acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane in quantitative

• 9 9

9 9

9 9 9

9 9 9

9 9 9

99 yield. No further cleaning was necessary.

Preparation 6

Preparation of polystyrene bonded isocyanate resin

To a stirred suspension of 50 grams (61 mmol) of aminomethylated polystyrene resin (1.22 mmol / g) in 800 mL of toluene was added 193 mL (366 mmol) of 1.9 M phosgene in toluene. After stirring the reaction mixture for 10 minutes, 67 mL (482 mmol) of triethylamine was added and the reaction mixture was stirred for 18 hours at ambient temperature. The mixture was filtered and the resulting solid was washed 10 times with dichloromethane. A light pink resin mixed with a white solid was obtained. This solid mixture was resuspended in 700 mL of dichloromethane, stirred for 10 minutes and then filtered and washed well with dichloromethane. The resulting solid was resuspended, stirred, and washed with dichloromethane to obtain the desired resin.

IR (KBr): 2252 cm ^-1 (characteristic peak for -N = C = O)

General procedure

To a suspension of three equivalents of polymer bound

Of 1-piperidine in 1 mL of chloroform was dissolved (R) -2-amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane dihydrochloride (10 mg, 0.024 mmol, 1) equiv.). To this mixture was added the appropriate carboxylic acid (0.036 mmol, 1.5 equiv.) And polymer bound 1- (3-dimethylaminopropyl) 3-propylcarbodiimide hydrochloride (108 mg, 0.108 mmol, 4.5 equiv.).

• · · · · · ·

The resulting mixture was shaken at ambient temperature for approximately 2-3 days. Unreacted (R) -2-amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane dihydrochloride was removed by addition of excess polystyrene-bound isocyanate resin and cradled for four hours. The reaction mixtures were filtered and the filtrates were concentrated.

General Procedure II

Potassium tert-butoxide (19.38 mg, 0.158 mmol, 3 equiv) and appropriately substituted phenol or naphthol (0.158 mmol, 3 equiv) were added to the reaction vial in 0.7 mL anhydrous tetrahydrofuran. To this mixture was added (R) 2 - [(2-bromo) acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane (25 mg, 0.053 mmol). , 1 equiv.) And the resulting mixture was heated at 80 ° C for two hours. The solvents were removed in vacuo and the residue was redissolved in methylene chloride and washed once with water. The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo.

Example 1

Preparation of (R) -2 - [(2-Phenoxy) acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 2

Preparation of (R) -2 - [[2- (4-methoxymethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane ·

44 • 444 4 · 4 · 44 44 44 4444

NMR was consistent with the proposed structure of the title compound.

Example 3

Preparation of (R) -2 - [[2- (4-carboxy) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-ethoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 4

Preparation of (R) -2 - [[2- (4-ethoxy) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • 9 99 99 9999 99 99 • 9 9 * 9 9 9 9999

9999 ·· · 9999

NMR was consistent with the proposed structure of the title compound.

Example 5

Preparation of (R) -2 - [[2- (4-methoxycarbonyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 6

Preparation of (R) -2 - [[2- (4-Trifluoromethoxy) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane * · · · ·

NMR was consistent with the proposed structure of the title compound.

Example 7

Preparation of (R) 2 - [[2- [4 - [[(methoxy) carbonyl] methyl]] phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl)] acetylamino] propane

1 «···· • 4 4 4 4

4 4 4 4 4 •

4 4 4 4 4 4 ·· · 4 4 4 4 ·

44

4 4 4

4 4 4

ρ

HgC

NMR was consistent with the proposed structure of the title compound.

Example 8

Preparation of (R) 2 - [[2- [4 - [[(methoxy) carbonyl] ethyl]] phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl)] acetylamino] propane • 0 0 * 0 99 9 9 9 9 0 9 9 0 0 9 9 0 0 0 0 0 0

0 «

0 · 9 • 9 9 9

0 · 0 0

0 0 0 0 0 0

\ ch ₃

NMR was consistent with the proposed structure of the title compound.

Example 9

Preparation of (R) -2- [2- (naphth-2-yloxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 10

Preparation of (R) -2- [2- (4-acetylphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane * 4 4 4 4 * 4

4 * 44 · 4 * 44

4 44 44 4 444 44 4

44 4 4 * 4 4 4 * 4 4

4 44 44 · · 4 * 44

h ₃ c

NMR was consistent with the proposed structure of the title compound.

Example 11

Preparation of (R) -2- [2- (4-hydroxyphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

M * 4 • 4 4 ·

4 ··

4 4 4 • 4 4 4

4 * »9 * 5

4 4 4

4 4 4 4

4 4 4

4 9 4

9 4 4

NMR was in the title.

Example 12

Preparation (R)

3-yl) -1- [N- (consistent with the proposed structure of compound z

-2- [2- (4-chlorophenoxy) acetyl] amino-3- (1H-indol-2-methoxybenzyl) acetylamino] propane

9 «9999

9 9

9 9 9

9 9 9 9

9 9 9 **

NMR was consistent with the proposed structure of the title compound.

Example 13

Preparation of (R) -2- [2- [4- (benzyloxy) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane <9 »» ·· • 4 4 4 • 4 · 4

4 4 «4 • 4 4

44

4 4 · 4

4 * 4 4

4 * «4

4 4

1 2 3 4 »

4 4 ♦ ♦

NMR was consistent with the proposed structure of the title compound.

Example 14

Preparation of (R) -2- [2- (4-hydroxymethylphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane »· ····

9 9 9 9 9

9 98 9 9 9

9 9 9 9 9 9

9 9 9 9 9 9

99 99 * 99 99

9 9 9

9 9

99

NMR was consistent with the proposed structure of the title compound.

Example 15

Preparation of (R) -2- [2- (4-methoxyphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane. 9 9 9 9 99 99 9 9 9 9 9 9

\ (

0CH3

NMR was consistent with the proposed structure of the title compound.

Example 16

Preparation of (R) -2- [2- (3-methoxyphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane> 4 4 »» ··· · »4

NMR was consistent with the proposed structure of the title compound.

Example 17

Preparation of (R) -2- [2- (2-methoxyphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

h ₃ co · * 9 · 9 9 9 9 • • 9 9 9 9 99 99

»•» * * * · · · · ·

NMR was consistent with the proposed structure of the title compound.

Example 18

Preparation of (R) -2- [2- (2-chlorophenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 19

Preparation of (R) -2- [2- (2-carbamoylphenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • 4 '4 • 4 4 4

• 4 9 • 9 9 9 9 • 9 9 9

49

MM • 9 4

9 4 4

4 9 9

99

NMR was consistent with the proposed structure of the title compound.

Example 20

Preparation of (R) -2- [2- (3,4-dichlorophenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

·· · »

NMR was consistent with the proposed structure of the title compound.

Example 21

Preparation of (R) -2- [2- (4-fluorophenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

0000

00 • 000 00 · 0 0 0 0 00 00 00 0 0000 0 00 000 · 000 00 0 9000 0000 0000 • 0 00 09 00 00 00

NMR was consistent with the proposed structure of the title compound.

Example 22

Preparation of (R) -2- [2- (4-nitrophenoxy) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane · ·· · 4 • 9 9 9 9 9 9

9

99

9

9

9

9

98 99 • 4 ····

r \

NOž

NMR was consistent with the proposed structure of the title compound.

Example 23

Preparation of (R) -2- [2- [4- (2-hydroxyethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

ΦΦ ΦΦΦΦ

ΦΦ · · φ φ φ φ φ φ φ φ φ φ φ φ φ

φ • φ · · · · · φ φ φ

NMR was consistent with the proposed structure of the title compound.

Example 24

Preparation of 2- [2- [4- (3-hydroxypropyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane jane · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ·· ·· ·· ··

NMR was in the title.

Example 25

Preparation of 23- (1H-indole according to proposed structure of compound from [2- [4- (2-carbamoylethyl) phenoxy] acetyl] amino-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane ·· ·

NMR was consistent with the proposed structure of the title compound.

Example 26

Preparation of 2- [2- [4- (triazol-1-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

N — JN

NMR was consistent with the proposed structure of the title compound.

Example 27

Preparation of 2- [2- [4- (ethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane · · ·

4 49 ·· · 9 4 4 · · · 4 4 4 · 4 4 9 9 · 9

NMR was in the title.

Example 28

Preparation of 2-indol-3-yl) in accordance with the proposed structure of the compound from [2- [4- (N-propyl) phenoxy] acetyl] amino-3- (1H-1- [N- (2-methoxybenzyl) acetylamino] propane)

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

NMR was consistent with the proposed structure of the title compound.

Example 29

Preparation of 2- [2- [2- (hydroxymethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 30

Preparation of 2- [2- [4- (2-methoxyethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 31

Preparation of 2- [2- [4 - [(morpholin-4-yl) carbonyl] phenoxy] acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane ·

NMR was consistent with the proposed structure of the title compound.

Example 32

Preparation of 2- [2- [4- (4-hydroxybutyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • 4 4 4 • 44 • 4

4 4 4 4 4 5

44 4 ·

NMR was consistent with the proposed structure of the title compound.

Example 33

Preparation of 2- [2- [2-coumaranoN-5-yloxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

44

4445 4 · 4 4 * 4 *

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

44 44 44 44

NMR was in the title.

Example 34

Preparation of 2- [2- [benzothiazol-6-yloxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • 9 9 9 # 9 ♦ 9 · · 9 9 9 • 999 9 · 9 * · 9 9 ♦ · · 99 99 999 «

NMR was consistent with the proposed structure of the title compound.

Example 35

Preparation of 2- [2- [4- (methylsulfonyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

4 44 4 ·

4 44

4444 4 4 4 4 44

43 44 4 4 # 4 4

44,444 4,444 44 4

NMR was consistent with the proposed structure of the title compound.

Example 35

Preparation of 2- [2- [4- (methylsulfonyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

44

9 9 4 4 99

4 9 4

4 9 9

9 44

MM

4 4

4 4

4 4

4 4 4 <4

94

4 9 4

9 4 4

9 4 9

4 4 9

44

NMR was in the title.

Example 36

Preparation of 2- [2- [quinolin-6-yl] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane ··· 9 9 9

9 9 • 9 9 9 9

9 9 9

99

9999 · »··

9 9

9 9

9 9

9 9

9

NMR was consistent with the proposed structure of the title compound.

Example 37

Preparation of 2- [2- [4- (3-cyanopropyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

4 · 44

NMR was in the title.

Example 38

44

· 4

4 4 ·

consistency with the proposed structure

4 4

4 4

4 4

4 »4

44

44

4 4 4

4 4 4

4 4 4

4 4 4

44 compounds

Preparation of 2- [2- [4- (imidazol-1-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

9.99 9 9

9 9

9 9

99

9 9 ····

9 9

9 9

9 9

9 9 9

99

99

9 9 9

9 9 9

9 9 9

9 9 t ·· ·

NMR was in the title.

Example 39

Preparation of 2-indol-3-yl)

[2- [4- (cyanomethyl) phenoxy] acetyl] amino-3- (1H-1- [N- (2-methoxybenzyl) acetylamino] propane)

4 4

44

4 4 4

4 4 4 4 ** 4

4 4 4

4 4

4 4 ·

44

4 ·

4 4

4 4

4 4

4 4

NMR was in the title.

Example 40

Preparation of 2-indol-3-yl)

[2- [4- (isopropyl) phenoxy] acetyl] amino-3- (1H- [N- (2-methoxybenzyl) acetylamino] propane)

4 4

44 · 4

4 9 • * 4 ·· 4

4 4

9 9 • 4 ·

4 4 9

4 ·

94

4 4 4

9 9 9 9

4 9 4

44

NMR was the title.

Example 41

in accordance with the proposed ₃ structure of the compound of

Preparation of 2- [2- [3- (hydroxymethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • 9 9999

NMR was consistent with the proposed structure of the title compound.

Example 42

Preparation

2- [2- [4 - [[(methylamino) carbonyl] methyl] phenoxy] acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane * 00 ·

NMR was in the title.

Example 43

• 0 0

0 · 0 0 0

09 according to

the proposed structure

00

9 9 0 • 0 0

9 9 0

Compounds of

Preparation of 2- [2- [4- (formyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

4 4 4

4 ··

4 4 4 4

44 • 4,444 ·

4 4

4 4

4 4

4 4 *

44

4 44 44 • 4 4 ·

4 4 4 4

4 4 4

4 4 4

NMR was consistent with the proposed structure of the title compound.

Example 44

Preparation of 2- [2- [4- (thiazolin-2-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane • »• 9

II 99 * ·> ····

9 9

9 9

9 9

9 9 9

99

99

9 9 9 9

9 9 9

99

NMR was consistent with the proposed structure of the title compound.

Example 45

Preparation of 2- [2- [4- (cyano) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

4 «• 4

4 ·

44

4 4 4

4 · i * ····

4 «

4 * • 4

4 4 4

4 · 44 · · 44 • 4 4

4 4 • 4 4 4

NMR was consistent with the proposed structure of the title compound.

Example 46

Preparation of 2- [2- [4- (3-methyl-2-pyrazolin-5-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] ] propane

NMR was in the title.

Example 47

- 81 44 44 44 »444 ·· 44 ···· 44 4,444

44 44 4,444

44,444 4,444 44 4

44 44

4 4

44

4 4 4

44

CHs consistent with the proposed structure of the compound of

Preparation of 2- [2- [4- [2- (acetyl) ethyl] phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane * · · · · · · · · · · · ~ · ~ · ~ 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 · ··

h ₃ c

NMR was consistent with the proposed structure of the title compound.

Example 48

Preparation of 2- [2- [3- (2-hydroxyethyl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

NMR was consistent with the proposed structure of the title compound.

Example 49

Preparation of 2- [2- [4 [[(butylamino) carbonyl] amino] phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

Example 50

Preparation of 2- [2- [4- (3,5-dichlorophenoxy) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

9 · 9 9 9 9

9 9 9 9

99 999

9 9 9 9 9

NMR was consistent with the proposed structure of the title compound.

Example 51

Preparation of 2- [2- [4- (acetamido) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

CH ₃ ^{0 =} <

NMR was consistent with the proposed structure of the title compound.

Example 52

Preparation of 2- [2- [4- (acetoxy) phenoxy] acetyl] amino-3- (1H-indol 3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane ····

NMR was consistent with the proposed structure of the title compound.

Example 53

Preparation of 2- [3-phenylsulfonyl) propanoyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

* · ····

NMR was consistent with the proposed structure of the title compound.

Example 54

Preparation of 2- [4- (2,4-dichlorophenoxy) butanoyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

tt ····

NMR was consistent with the proposed structure of the title compound.

Example 55

Preparation of 2- [3- [benzothiazol-2-ylthio] propanoyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

4

4 ··

444 ·

4 · · ♦

NMR bn ⁿ nn of the title.

Example 56 NNN ^N N ^{N N} NN nnnn nnnnnn nnnn®nnnn n ⁿ nn ⁿ nn ⁿ nn

Preparation of 2- [2- [4- (imidazol-1-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane

0000

09 · 0 0 0 0

0 00 0 9 9 • 9 9 9 9 9

0 0 0 0 0 0

00 00

09 /

9 9 9

9 9 9

0 0 9

9 9 9

9 99

About me

NMR was consistent with the proposed structure of the title compound.

Example 57

Preparation of 2- [2- [4- (imidazol-1-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-chlorobenzyl) acetylamino] propane

99

9999 99 99 • 9-9 9 9 9

9 9 9 9 9 ·

9,999 99 ·

99 9 9

99 99 99

NMR was consistent with the proposed structure of the title compound.

Example 57

Preparation of 2- [2- [4- (1,2,3-thiadiazol-4-yl) phenoxy] acetyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] ] propane

99

9 9 9

9 99 • «I 9

9 9 9 ·· 99

9999

9 «

9 • 9

9 9

9

9

9 9

9 9 *

9 9 9

9

9 9 9

9 99

About me

NMR was consistent with the proposed structure of the title compound.

MS-FD 569 (M &lt; + &gt;).

Example 58

Preparation of 2- [3-benzoyl] ethanoyl] amino-3- (1H-indol-3-yl) 1- [N- (2-methoxybenzyl) acetylamino] propane • 4 44

9 9 9 9 9 9 9 9 9

9 99 9 9 9 9 9 · · 9 9 9 9 9 9 9 9 9 9 ·

45 ·· 4 4 4 4 9 9 9 9

99 99 44 99 99

NMR was consistent with the proposed structure of the title compound.

MS-FD 569 (M &lt; + &gt;).

The compounds of the present invention have tachykinin receptor activity. The biological activity of compounds believed to be effective as tachykinin receptor antagonists can be confirmed using an initial screening assay that rapidly and accurately measures the binding of the test compound to known NK-1 and NK-2 receptor sites. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, eg, J. Jukic, et al., Life Sciences, 49: 1463-1469 (1991); N. Kucharczyk et al.,

Journal of Medicinal Chemistry, 36: 1654-1661 (1993); N.

Rouissia et al., Biochemical and Biophysical Research Communications, 176: 894-901 (1991).

444 · 4 44 · · ·

4 44

4 4 4

4 4 4

44

4 4

4 4

4 4

4 4 4

44

44 * 4 4

4 4 ·

4 4 4

44

NK-1 receptor binding assays

Radio-receptor binding assays were performed using a variation of previously published protocols. DG Payan et al., Journal of Immunology, 133: 3260-3265 (1984). In this assay, an aliquot of IM9 cells (1 x 10 ⁶ cells per tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 µM ¹²⁵ I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4 ° C.

The IM9 cell line is a well characterized cell line that is readily accessible to the public. See, for example, Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London). 251: 443-444 (1974); Proceedings of the National Academy of Sciences (USA) 71: 84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 µg / ml gentamicin sulfate and 10% fetal calf serum. The reaction was terminated by filtration through a glass fiber filter system using filters prewetted for 20 minutes in 0.1% polyethyleneimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.

Many of the compounds used in the methods of the present invention are also potent NK-2u receptor antagonists.

NK-2 receptor binding assay

4444

44

4 4 4

4 4 • 4 4 4 4

4 4 4

44

4 4

4 4

4 4

4 4 4

44

44

4 4 4

4 4 4

4 4 4

4 4 4

44

CHO-hNK-2R cells, a CHO-derived cell line transformed with human NK-2 receptor, expressing approximately 400,000 such receptors per cell, were grown in 75 cm ² flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of human NK-2 receptors is described in NP Gerard, et al., Journal of Biological Chemistry. 265: 20455-20462 (1990).

To prepare the membranes, 30 confluent roller bottle cultures were dissolved by washing each vial of calcium and magnesium phosphate-buffered cell-free enzyme bottle with 10 ml Dulbecco's saline (PBSi followed by addition of 10 ml dissociation solution (PBS-based, from Specialty Media, Inc). After an additional 15 minutes, the dissociated cells were collected and centrifuged at 1,000 rpm for 10 minutes in a clinical centrifuge.The membranes were prepared by homogenizing the cell pellets in 300 ml of 50 mM Tris buffer, pH 7.4, using a Tekmar® homogenizer for 10 minutes. -15 seconds, followed by centrifugation at 12,000 rpm (20,000 xg) for 30 minutes using a Beckman JA-14. The pellets were washed once using the above procedure and the final pellets were resuspended in 100-120 ml of 50 mM Tris buffer, pH 7.4, and 4 ml aliquots were stored frozen at -70 ° C the concentration of this formulation was 2 mg / ml.

For receptor binding assays, one 4 ml aliquot of the CHOhNK-2R membrane preparation was suspended in 40 ml assay buffer containing 50 mM Tris, pH 7.4, 3 mM magnesium chloride, 0.02% bovine serum albumin.

4 ·· 4 • 9 • 4 9

9 • 9

9

4 4

4 4

4 4 9

4 9 9

94

99

4 4 4

4 4 4

4 4 4

4 9 4

44 (BSA) and 4 gg / ml chymostatin. A volume of 200 μΐ homogenate (40 μς protein) was used per sample. The radioactive ligand was [ ¹²⁵ L] iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci / mmol. The ligand was prepared in assay buffer with 20 nCi per 100 μΐ; the final assay concentration was 20 pM. Non-specific binding was determined using 1 μΜ eledoisin. Ten concentrations of eledolsin from 0.1 to 1000 nM were used to generate a standard concentration-response curve.

All samples and standards were added for incubation at 10 μΐ dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μΐ DMSO to determine the IC ₅ o. The order of additions for incubation was 190 or 195 μί assay buffer, 200 μΐ homogenate, 10 or 5 μΐ of sample in DMSO, 100 μΐ of radioactive ligand. The samples were incubated for 1 hour at ambient temperature and then filtered in a cell collector through filters that were pre-soaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed three times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter rings were then placed in 12 x 75 mm polystyrene tubes and read in a gamma counter.

Animal and human clinical models demonstrating the efficacy of the methods of the present invention are well known to those skilled in the art. For example, the following experiment clearly demonstrates the inhibitory effect of the compounds of the present invention in an animal model useful for predicting migraine treatment.

• ft »· * * * * 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

99 99 99 99 99

Neurogenic plasma extravasation in the dura layer induced by electrical stimulation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) were anesthetized with sodium pentobarbital (65 mg / kg and 45 mg / kg, intraperitoneally, respectively) and placed in a stereotaxic frame (David Kopf Instruments) with an incision knife set at -3.5 mm for rats or -4.0 mm for guinea pigs. After medial sagittal scalp incision, two pairs of bilateral holes were drilled through the skull (6 mm posterior, 2.0 and 4.0 mm lateral in rats; 4 mm posterior and 3.2 and 5.2 mm lateral in guinea pigs, all coordinates relative to bregma). Through the holes in both hemispheres, pairs of stainless steel stimulation electrodes (Rhodes Medical Systems, Inc.) Were introduced to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from drows.

The femoral vessel was exposed and a dose of test compound (1 ml / kg) was injected intravenously. Approximately 7 minutes later, a dose of 50 mg / kg of Evans Blue, a fluorescent dye, was injected intravenously. Evans Blue complexes with proteins in the blood and acts as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion was stimulated for 3 minutes with a current intensity of 1.0 mA (5 Hz, 4 msec duration) using potentiostat / galvanostat.

Fifteen minutes after stimulation, the animals were killed and bled with 20 ml of saline. The upper part of the skull was removed to facilitate removal of the dural membrane.

9 • • ♦ 9 • W «9« «♦ ♦ ♦ 9 9 9 9 9

99 99 99

99 • 9 9 9 • 9

9 9 9

9 9 9

99

The membrane samples were taken from both hemispheres, rinsed with water and spread on microscope slides. After drying, the tissues were covered with a 70% glycerol / water solution.

A fluorescence microscope (Zeiss), equipped with a grid monochromator and spectrophotometer, was used to measure the amount of Evans blue in each sample. An excitation wavelength of approximately 535 nm was used and the emission intensity at 600 nm was determined. The microscope was equipped with a motorized support and connected to a personal computer. This made it possible to perform computer-controlled movements of the slide and to perform fluorescence measurements at 25 points (500 μιη step) on each dural sample. The mean and standard deviation of the measurements were determined by a computer.

Dural extravasation induced by electrical stimulation of the trigeminal ganglia had an ipsilateral effect (ie, occurred only on the side of the dura where the trigeminal ganglion was stimulated. This allowed the second, unstimulated, half dura to be used as a control. Controls represented by saline gave a ratio of approximately 2.0 for rats and 1.8 for guinea pigs, whereas a compound that effectively prevents extravasation in the dock on the stimulated side should have a ratio of approximately The dose response curve was determined and the dose that inhibited extravasation by 50% (ID 50) was approximated ·

Compounds prepared by the methods of the present invention

- 100 44 ··

4 4

4 4 «

4 4 «

44

444 · »4 4» 4 4

I »4 4 4

44

4 · 44 ► 4 · 4 4 4 4 4 4 4 4 4 4 4 4 4

44 are useful as tachykinin receptor binding compounds. As such, they can be used as antagonists or agonists of various tachykinins. These compounds are therefore useful in the treatment or prevention of conditions associated with an excess or deficiency of tachykinins. The term physiological disorder associated with an excess or deficiency of tachykinins includes those related to inappropriate receptor stimulation, regardless of the actual amount of tachykinins present at the site of interest.

disorders that tachykinin sclerosis and peripheral

These physiological disorders may include central nervous system disorders such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-related dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral other neuropathological disorders such as neuropathy such as diabetic and chemotherapy-induced neuropathy and post-herpetic and other neuralgia; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, cough and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; musculoskeletal disorders such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders; ocular diseases such as conjunctivitis, vernal conjunctivitis and the like; skin diseases such as contact dermatitis, atopic

- 101 44 44

4 · 4 · 4 44 4

4 4 4

4 4 • 4 44 • 4 4 4 4 4 4

4 · · 4 4 4

4944 dermatitis, urticaria and other eczematic dermatitis disorders; abuse of substances such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder / hand syndrome; dysthymic disorders; adverse immunological responses such as rejection of transplent tissue and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; gastrointestinal disorders or diseases related to neuronal control of visceral organs such as ulcerative colitis, Crohn's disease and intestinal irritation syndrome; bladder function disorders such as bladder detrusor hyper-reflection and incontinence; atherosclerosis; fibrotic and colagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; circulatory disorders due to vasodilation and vasospastic diseases such as angina, migraine and Reynau's disease; emesis; and pain or nociception, for example, one that is attributable to or associated with any of the above conditions, especially pain transmission in migraine. For example, the compounds of Formula I may be advantageously used to treat central nervous system disorders such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm diseases such as osteoarthritis and asthma; is inflammatory bowel rheumatoid arthritis;

immunological disorders such as rejection of gastrointestinal disorders or disorders related to neuronal inflammatory diseases, unfavorable transplent tissue; diseases such as the control of visceral organs such as ulcerative colitis,

102 · 6 · 6 · · · · · · · · · · ·

Φ

Crohn's disease and intestinal irritation syndrome; incontinence; circulatory disorders due to vasodilation; and pain or nociception, for example, one attributable to or associated with any of the above conditions, or the transmission of pain in migraine.

The results of several experiments show that many compounds of Formula I are selective tachykinin receptor antagonists. These compounds preferentially bind one subtype of tachykinin receptor over other receptors. Such compounds are particularly preferred.

For example, NK-1 antagonists are particularly useful in the treatment of pain, especially chronic pain such as neuropathic pain, post-operative pain and migraine, arthritis-related pain, cancer-related pain, chronic lower back pain, cluster headache, herpes neuralgia, phantom pain limb pain, central pain, dental pain, sunburn pain, neuropathic pain, opioid resistance pain, visceral pain, surgical pain, bone injury pain, pain before labor and delivery, burn pain, post part pain , angina pain and genitourinal tract pain, including cystitis.

In addition to the treatment of pain, NK-1 antagonists are particularly useful in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; gastrointestinal motility disorders such as bowel irritation syndrome; acute and chronic obstructive

9990

- 103 · 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 · Respiratory diseases such as bronchospasm, bronchopneumonia, asthma and respiratory distress syndrome in adults; atherosclerosis; inflammatory conditions such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergy, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, irritation-induced miosis; rejection of transplanted tissue; plasma extravasation caused by cytokine chemotherapy and the like; spine trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.

NK-2 antagonists are particularly useful in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, gastrointestinal motility disorders such as intestinal irritation syndrome and pain.

In addition to the in vitro binding assays described above, many of the compounds prepared by the methods of the present invention have also been tested in in vivo model state systems

-r associated with an excess of tachykinins. Of the compounds tested in vivo, many showed an effect against these conditions.

While it is possible to administer the compound used in the methods of the present invention directly, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered in a variety of ways.

104 • · · · · ·

routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Many of the compounds used in the methods of the present invention are effective as both injectable compositions and oral compositions. Such compositions are prepared in a manner well known to those skilled in the art of pharmacology and comprise at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, (16th edition, 1980).

In forming the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or surrounded by a carrier, which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which serves as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may take the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound. soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

When formulating the formulation, it may be necessary to grind the active compound to achieve a suitable particle size prior to combining it with the other ingredients. If the active compound is substantially insoluble, it is usually ground to particles having a mesh size of 200 mesh. If the active compound is substantially water-soluble, the particle size is normally adjusted to achieve 4

- 105

4 4 4 • · ·· · · · ·

4 4 ·

4 4 · 4 4 4

A substantially uniform distribution in the formulation, for example, to a size corresponding to a mesh size of 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present invention may be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to a patient using procedures well known to those skilled in the art.

The compositions are preferably formulated in a unit dosage form and each dose contains from about 0.05 to about 100 mg, more usually from about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to a physically discrete unit, aqueous as a unit dosage for humans or other mammals, and each unit contains a predetermined amount of active material, designed to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compounds are generally effective over a wide dosage range. For example, daily dosages normally fall within the range of about 0.01 to about 30 mg / kg body weight. During healing • · ·

106

an adult human is in the range of about 0.1 to about 15 mg / kg / day, in single or divided doses, particularly preferred. However, it will be appreciated that the amount of the compound to be actually administered will be determined by the physician depending on the relevant circumstances, including the condition to be treated, the route of administration chosen, the particular compound or compounds to be administered, the age, weight and response of the individual. patient and the severity and severity of the patient's symptoms, and therefore the above dosages are not intended to limit the scope of the present invention in any way. In some cases, doses below the lower limit of the above range may be more appropriate, while in other cases even larger doses may be used without deleterious side effects, provided such high doses are subdivided into smaller doses administered several times a day.

Example of preparation 1

Hard gelatin capsules containing the following ingredients were prepared:

Component

Quantity (mg / capsule)

Active ingredient

Starch

Magnesium stearate

30.0

305, 0

5.0 * · • · 4

107 • 4

The above ingredients are mixed and filled into hard gelatin capsules in an amount of 340 mg.

Example of preparation 2

Tablets were prepared using the following ingredients:

Component

Active ingredient

Cellulose, microcrystalline

Colloidal silica

Stearic acid

The components are mixed and compressed with 240 mg.

Example of preparation 3

A dry powder of the following ingredients was prepared:

Component

Active ingredient

Quantity (mg / tablet)

25, 0

200.0

10.0

5.0> tablets in the form of an inhalation formulation containing

Mass %

Lactose

4 4 • · · ·

108 • 4 • · · · * <

The active mixture is mixed with lactose and the mixture is placed in a dry powder inhalation formulation.

Example of preparation 4

Tablets, each containing 30 mg of active ingredient, are prepared as follows:

Amount

Ingredient (mg / tablet)

Active Ingredient 30.0 mg

Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg 4 Magnesium stearate 0.5 mg Talc 1.0 mg Overall 120.0 mg

The active ingredient, starch and cellulose are sieved through a sieve with a mesh size of no. 20 mesh U.S. sieve and thoroughly ·· · 4 · 4

- 109

4 4

4 «

44 mix. The polyvinylpyrrolidone solution is mixed with the resulting powder which is passed through a No. 7 mesh screen. 16 mesh U.S. sieve. The granules so formed are dried at 50-60 ° C and sieved through a No. 7 mesh screen. 16 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously sieved through a sieve with mesh size no. 30 mesh U.S. The sieve is then added to the granules which, after mixing, are compressed into tablets in a tabletting machine to form tablets each weighing 120 mg.

Example of preparation 5

Capsules, each containing 40 mg of the drug, are prepared as follows:

Component Amount (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Overall 150.0 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, sieved through a No. 2 mesh screen. 20 mesh U.S. sieve and filled into hard gelatin capsules in an amount of 150 mg.

- 110 ·· ··

9 9 9 9 9 9

9 · · ····

9 9 9 9 9 9 9 9

Example of β

Suppositories each containing 25 mg of active ingredient are prepared as follows:

Component Quantity

Active Ingredient 25 mg

Saturated fatty acid glycerides up to 2,000 mg

The active ingredient is sieved through a No. 2 mesh screen. 60 mesh U.S. sieve and suspended in saturated fatty acid glycerides previously dissolved using minimal heat. The mixture is then poured into molds with a nominal capacity of 2.0 g and allowed to cool.

Example of preparation 7

Suspensions, each containing 50 mg of drug per 5.0 ml dose, were made as follows:

Component

Amount

Active Ingredient 50.0 mg

Xanthan gum 4.0 mg

Sodium carboxymethyl cellulose (11%),

- 111

4 4 • 4 4 4 4 4 4 4 4 4 44 4444 4444 4 4 4 4

I 4 4 I> 4 4 <

4 · · 4 microcrystalline cellulose (89%) 50.0 mg

Sucrose 1.75 g

Sodium benzoate 10.0 mg »

Flavoring and coloring agent q.v.

Pure water to 5.0 ml

The drug, sucrose and xanthan gum are mixed, sieved through a No. 2 mesh screen. 10 mesh U.S. sieve and then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to achieve the desired volume.

Example of preparation 8

Capsules, each containing 15 mg of drug, are prepared as follows:

Component Amount (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg

Magnesium stearate

3.0 mg

- 112

44

4 4 4

4 44

4 4 4

4 4 4

44

4444

4 4 4

4 4 4

4 4 4 4

4 4 4 4

44 4 «

Total 425.0 mg

The active ingredient, cellulose, starch and magnesium stearate are mixed together, sieved through a No. 2 mesh screen. 20 mesh U.S. sieve and filled into hard gelatin capsules in an amount of 425 mg.

Example of preparation 9

An intravenous formulation can be prepared as follows:

Component Quantity

Active Ingredient 250.0 mg

Isotonic saline 1000 ml

Example of preparation 10

A topical preparation may be prepared as follows:

Component

Amount

Active ingredient

Emulsifying wax

1-10 g g

Liquid paraffin g

- 113 »4 9443

9 4 4 · 44

. 4 4 4 .4 4 4 4

44

White soft paraffin to

100 g

The white soft paraffin is heated to thaw. The liquid paraffin and emulsifying wax are added and mixed until dissolved. The active ingredient is added and stirring is continued until dispersion is achieved. The mixture was then cooled to solidification.

Example of preparation 11

Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:

Amount Component on tablet Active ingredient 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium citrate 4.5 mg Polyvinyl alcohol 26.5 mg Polyvinylpyrrolidone 15,5 mg Overall 410.0 mg

Glycerol, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone are mixed together by continuous

- 114

09 • 0 0 0

0 00 • 0 0 · _0

0 ·

0900

0 ·

0 0 0 0 t

0 0 0

00 9 9 9 9 9

9 9 9

9 · 9 9 9

9 9 0

9 to 90 with stirring while maintaining the temperature at about 90 ° C. When the polymers enter the solution, the solution is cooled to about 50-55 ° C and the drug is mixed slowly. The homogeneous mixture is poured into molds made of an inert material to form a diffusion metric containing the active ingredient having a thickness of about 2-4 mm. The diffusion metric is cut into individual tablets having a suitable size.

Other preferred formulations use the present invention transdermal. Such obtaining in the method of the patch formulation can be or intermittent (patches). used for transdermal continuous administration of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the administration of pharmaceutical agents is well known in the art. See, inter alia, U.S. Pat. No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference. Such patches may be designed for continuous administration, pulse administration or administration as needed for pharmaceutical agents.

It is often desirable or necessary to administer the pharmaceutical compositions to the brain, either directly or indirectly. Direct techniques typically involve placing the catheter for drug delivery into the host's ventricular system to cross the blood-brain barrier. One such implantable delivery system used to transport biological factors to specific anatomical areas of the body is described in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which is incorporated herein by reference.

115 ^J ··

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Indirect techniques that are generally preferred typically involve the formation of compositions for generating fabric latency by converting hydrophilic materials into lipid soluble materials or precursors thereof. Latency is usually achieved by blocking the hydroxy, carbonyl, sulfate, and primary amine groups present in the molecule to convert it to a more lipid soluble substance and accessible for transport across the blood-brain barrier. Alternatively, the delivery of hydrophilic substances may be enhanced by intra-arterial infusion of hypertonic solutions, which may temporarily open the blood-brain barrier.

The type of formulation that is used to administer the compounds used in the methods of the present invention may be dictated by the particular compound employed, the type of pharmacokinetic profile desired from the route of administration, and the compound or compounds and the condition of the patient.

9 «9949

JUDr. Otakar Švorčík attorney

120 00 Prague 2, Halkova 2

9 9 4 9 9 · 9 · · ·

9 9 9 9 9

9 ··. 9 9

99 94

99

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94 94

Claims (5)

PATENT CLAIMS A compound of the general formula wherein: R ¹ and R ² are each independently hydrogen, halogen, C 1 -C ₆ alkyl, hydroxy or C 1 -C ₆ alkoxy; R ⁵ , R ⁶ and R ⁷ represent hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl or hydroxy; R ³ represents hydrogen, C 2 -C 7 alkanoyl, glycyl or 4 «44 4 4 4 * 4 4 4 4 4 4 4 · 4 4 44 44 - 117 i 44 4444 4 44 · 4 4 4 4 · 4 4 4 44 ·· 4 4 4 4 dimethylglycyl; n is 1-6; D is -S (O) _m -, -NH-, -C (O) - or -O-, m is 0, 1 or 2; R ⁸ and R ⁹ are independently hydrogen, hydroxy, C -C alkyl, Οχ Οβ-alkoxy-Οχ Οβ alkylthio, Οχ-Οβ alkoxy (C _x-C6 alkylenyl) -, C2-C7 alkoxycarbonyl, C ₂ - C ₇ alkoxycarbonyl (C 1 -C ₆ alkylenyl) -, trifluoromethoxy, trichloromethoxy, C 1 -C ₆ alkylthio, C 1 -C 6 alkylamino, di (C 1 -C ₆ alkyl) amino, formyl, cyano, halogen, trifluoromethyl, R ¹⁰ R ¹¹ N (C 1 -C 8 alkylenyl) -, pyrrolyl, triazolyl, imidazolyl, tetrazolyl, thiazolyl, thiazolinyl, thiadiazolyl, thiadiazolinyl, piperidyl, pyrrolidyl, morpholinyl, morpholinocarbonyl, hexamethyleniminyl, methylsulfonyl, methylsulfinyl, phenoxy, benzoyl, phenoxy, benzoyl, phenoxy, benzyl alkylcarbamoyl (C1-C6 alkylenyl) -, R ¹⁰ and R ¹¹ are each independently hydrogen or C 1 -C 6 alkyl, said C 1 -C 6 alkyl or C 1 -C ₆ alkoxy optionally substituted with one, two or three groups selected from hydroxy, halogen, cyano , amino, nitro, carboxy, carbamoyl, and thiol; or R ⁸ and R ⁹ together with the benzo ring to which they are attached form naphthyl, dihydronaphthyl, - 118 ·......... <. Tetrahydronaphthyl, quinolinyl, isoquinolinyl, 2-coumaronyl, 3-coumaronyl, benzothiazolyl, benzimidazolyl, indolyl, a benzothienyl, benzofuryl, 2,3-dihydrobenzofuryl, indolinyl or 2,3-dihydrobenzothienyl group which may be attached to D at any position of the bicyclic group; or a pharmaceutically acceptable salt or solvate thereof. 2. A method of treating conditions associated with excess tachykinins, wherein _f comprises administering to a mammal in need thereof an effective amount of a compound of formula in which: R ¹ and R ² are each independently hydrogen, atom 44 44 4 4 4 4 4 4 4 4 4 4 4 4 4 ·· · 44 44 5 «·· ♦ · - 119 • 4 44 4 4 4 4 4 4 4 4 4 U 4 4 4 44 44 halogen, C 1-4 alkyl, hydroxy or C 1 -C 6 alkoxy; R ⁵ , R ⁶ and R ⁷ represent hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, trifluoromethyl or hydroxy; R ³ represents a hydrogen atom, C 2 -C 7 alkanoyl, glycyl or dimethylglycyl; n is 1-6; D is -S (O) _m -, -NH-, -C (O) - or -O-, m is 0, 1 or 2; R ⁸ and R ⁹ are each independently hydrogen, hydroxy, C 1 -C ₆ alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C ₄ -C ₆ alkoxy (C 1 -C 6 alkylenyl) -, C ₂ -C 7 alkoxycarbonyl, C ₂ - C ₇ alkoxycarbonyl (C _x-C6 alkylenyl) -, trifluoromethoxy, trichloromethoxy, _C-C6 alkylthio, C1-C6 alkylamino, di (Ci-C6 alkyl) amino, formyl, cyano, halogen, trifluoromethyl, R @ ¹⁰ R @ ^{1 L} N (C 1 -C 6 alkylenyl) -, pyrrolyl, triazolyl, imidazolyl, tetrazolyl, thiazolyl, thiazolinyl, thiadiazolyl, thiadiazolinyl, piperidyl, pyrrolidyl, morpholinyl, morpholinocarbonyl, hexamethyleniminyl, methylsulfonyl, methylsulfinyl, phenoxy, carbosulfinyl, phenoxy, carboxylic acid -C7 alkylcarbamoyl (C1- _C6 alkylenyl) -, R ¹⁰ and R ⁿ are independently hydrogen or C1-C6 alkyl groups, said groups C -C alkyl or alkoxy Οχ-Οβ are «4» · »· · 44 ♦ • 4 · 4 4 4 ·· 4 4 4 4 4—4 4 · 4 · ·· - 120 • 3 · 4 · · 4 4 * 4 4 · · 44 4 4 • 4 4 4 · 4 4 4 · · 4 4 · Optionally substituted with one, two or three groups selected from hydroxy, halogen, cyano, amino, nitro, carboxy, carbamoyl, and thiol; or R ⁸ and R ⁹ together with the benzo ring to which they are attached form naphthyl, dihydronaphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 2-coumaronyl, 3-coumaronyl, benzothiazolyl, benzimidazolyl, indolyl, benzothienyl, benzofurenzofuran, 2,3-diofrobenzyl. an indolinyl or 2,3-dihydrobenzothienyl group which may be attached to D at any position of the bicyclic group; or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising a compound of the general formula 44 ···· - 121 • · · 4 4 4 ·· · · · · 4— · · · · 44 · 4 · 4 · 4 · 4 ♦ · · 44 44 44 44 • 4 V · • · 4 ♦ 4 4 4 4 44 44 in which: R ¹ and R ² are each independently hydrogen, halogen, C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkoxy; R ⁵ , R ⁶ and R ⁷ represent hydrogen, halogen, alkyl, C 1 -C ₆ alkoxy, trifluoromethyl or hydroxy; R ³ represents hydrogen, C ₂ -C ₇ alkanoyl, glycyl dimethylglycyl; n is 1-6; D represents a -S (O) _m -, -NH-, -C (O) - or -O- atom C 1 -C ₆ or m is 0, 1 or 2; • 9,999 - 122 9 9 < 9 9 9 R ⁸ and R ⁹ independently of one another are hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkoxy, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkoxycarbonyl (Οχ-β beta alkylenyl) -, trifluoromethoxy, trichloromethoxy, Οχ-β beta alkylthio, Οχ-β beta alkylamino, di (Οχ-β beta alkyl) amino, formyl, cyano, halogen atom, trifluoromethyl, R ¹⁰ R ¹¹ N (0χ-0 ₆ alkylenyl) -, pyrrolyl, triazolyl, imidazolyl, tetrazolyl, thiazolyl, thiazolinyl, thiadiazolyl, thiadiazolinyl, piperidyl, pyrrolidyl, morpholinyl, morpholinocarbonyl, hexamethyleniminyl, methylsulfonyl, methylsulfinyl, phenoxy, _2'- carbamyl, _7- carbamido, _7- carboxy, carbamyl, _7- carbamino, -Οβ alkylenyl) -, R ¹⁰ and R ¹¹ independently represent hydrogen or Οχ-Οβ alkyl wherein said groups 0χ-0 ₆ alkyl or Οχ-Οβ alkoxy are optionally substituted with one, two or three groups selected from the group consisting of hydroxy, halogen, cyano, , amino, nitro, carboxy, carbamoyl, and thiol; or R ⁸ and R ⁹ together with the benzo ring to which they are attached form naphthyl, dihydronaphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 2-coumaronyl, 3-coumaronyl, benzothiazolyl, benzimidazolyl, indolyl, benzothienyl, benzofurenzofuran, 2,3-diofrobenzyl. an indolinyl or 2,3-dihydrobenzothienyl group which may be attached to D at any position of the bicyclic group; - 123 · 123 123 123 123 123 123 123. 123 123....... ·· ·· 99 9999 · · · · · · · · · · · · · · · · · 9 9 9 9 9 9 • 9 9 Or a pharmaceutically acceptable salt or solvate thereof in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.