SK4132003A3 - Propionic acid derivatives, the process for their preparation, pharmaceutical composition comprising them, use thereof and intermediates for producing them - Google Patents

Abstract

The invention relates to the PPAR-alpha activating compounds of general formula (I), for treating for example coronary heart diseases, and to a method for producing said compounds, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A and X are defined as in claim 1.

Description

PROPIONIC ACID DERIVATIVES, METHOD OF MANUFACTURING THEREOF, ACTIVE SUBSTANCES CONTAINING THESE, USE AND INTERMEDIATES FOR PRODUCTION

Technical field

The invention relates to novel potent PPAR-alpha activated compounds for the treatment of, for example, coronary heart disease, a process for their preparation, medicaments containing them, their use and intermediates for their production.

BACKGROUND OF THE INVENTION

Despite many successes in therapy, coronary heart disease (CVD) remains a serious public health problem. While treatment with statins that inhibit HMG-CoA reductase both plasma LDL-cholesterol concentration and mortality of patients at risk is very successful, there is a lack of a convincing treatment strategy for the treatment of patients with poor HDL / LDL-cholesterol or hypertriglyceridemia.

Fibrates are now the only therapy option for patients in these risk groups. They act as weak agonists of peroxisome-proliferator-activated receptors (PPAR) -alpha (Nature 1990, 347, 645-50). The disadvantage of so far permissible fibrates is their only weak interaction with the receptor, leading to high daily doses and significant side effects.

WO 00/23407 discloses PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes.

It is therefore an object of the present invention to provide novel compounds which could be used as PPAR-alpha modulators.

SUMMARY OF THE INVENTION

It has now been found that the propionic acid derivatives of the general formula

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32101 / H

in which

A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -,

X is oxygen, sulfur or CH ₂ ,

R ¹ , R ² and R ³ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, hydroxy, C 1 -C 6 alkoxy, aryloxy 6 to 10 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, alkylaminosulfonyl, nitro or cyano, or

R ¹ and R ² are attached to two adjacent carbon atoms and together form an fused cyclohexane or benzene ring, the latter being optionally substituted by an alkylsulfonylmethyl group having 1 to 4 carbon atoms, and

R ³ is as defined above,

R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group,

R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or a benzyl group, wherein said aromatics themselves may be substituted one or three times the same or differently by an alkyl group

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32101 / H of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy or halogen,

R ⁸ represents a hydrogen atom, an aryl group having 6 to 10 carbon atoms or an alkyl group having 1 to 4 carbon atoms, which may itself be substituted by hydroxy, trifluoromethoxy, alkoxy having 1 to 4 carbon atoms or phenoxy, which themselves are optionally once to twice substituted with trifluoromethyl, or may be substituted with an aryl group of 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all of said aryl and heteroaryl rings alone being once up to three times the same or differently substituted by halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino,

R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and

R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates, fulfill this task and exhibit a pharmacological effect and can be used as medicaments or in the manufacture of medicament preparations.

Within the scope of the present invention, R ¹³ in the definition of R ^{13 is} hydrolyzable

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32101 / H c 4 a group which, in particular in the body, leads to the conversion of the group -C (O) OR ¹³ to the corresponding carboxylic acid (R ¹³ = hydrogen). Such groups are, for example, and preferably: benzyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, which may optionally be mono- or poly-substituted, as well or differently substituted by halogen, hydroxy, amino, C1-alkoxy (C atóm-Cboxy), carboxyl, (C až-Cyk) alkoxycarbonyl, (C až-C alko) alkoxycarbonylamino or (C až-C alk) alkanoyloxy, or especially C 1-C alkyl (C alkyl-C alkyl) alkyl; one or more times, equally or differently substituted by halogen, hydroxy, amino, C 1 -C 4 alkoxy, carboxyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonylamino or alkano C 1 -C 4 -alkyloxy.

In the context of the present invention, an alkyl group having 1 to 6 carbon atoms and having 1 to 4 carbon atoms is a straight or branched alkyl radical having 1 to 6 carbon atoms, optionally having 1 to 4 carbon atoms, with an alkyl radical having 1 to 4 carbon atoms being preferred. . By way of example and preferably, methyl, ethyl, n-propyl, isopropyl and t-butyl are mentioned.

Aryl of 6 to 10 carbon atoms in the context of the present invention is an aromatic radical of 6 to 10 carbon atoms, by way of example, and preferably an aryl radical is a phenyl group.

C 3 -C 8 -cycloalkyl and C 4 -C 7 -cycloalkyl are within the scope of the present invention a C 3 -C 8 or C 4 -C 7 cycloalkyl radical, examples of which are preferably cyclobutyl, cyclopentyl and cyclohexyl group.

In the context of the present invention, an alkoxy group having 1 to 6 carbon atoms means a straight or branched alkoxy radical having 1 to 6 carbon atoms.

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32101 / H with carbon atoms, a straight or branched alkoxy radical having 1 to 4 carbon atoms is preferred. By way of example and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy are mentioned.

C 6 -C 10 aryloxy means within the scope of the present invention an aromatic radical having 6 to 10 carbon atoms attached through an oxygen atom. By way of example and preferably, the aryloxy group is a phenoxy group.

C 1 -C 6 alkoxycarbonyl in the context of the present invention means a straight or branched C 1 -C 6 alkoxy radical attached through a carbonyl group, with a straight or branched C 1 -C 4 alkoxycarbonyl radical being preferred. By way of example and preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl are mentioned.

In the context of the present invention, an alkoxycarbonylamino group having 1 to 6 carbon atoms in the alkoxy radical is an amino group having a straight or branched alkoxycarbonyl substituent having from 1 to 6 carbon atoms in the alkoxy radical and attached via a carbonyl group with 1 to 4 carbon alkoxycarbonylamino radicals being preferred. alkoxy. By way of example and preferably, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino are mentioned.

C 1 -C 6 Alkanoyloxy means within the scope of the present invention a straight or branched C 1 -C 6 alkyl radical which carries a double bonded oxygen atom at the 1-position and is attached via the other oxygen atom at the 1-position. By way of example and preferably, acetoxy, propionoxy, n-butyloxy, ibutyloxy, pivaloyloxy and n-hexanoyloxy are mentioned.

C1-6alkylaminosulfonyl means v

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32101 / H

Within the scope of the present invention, an amino group which is attached via a sulfonyl group and which has a straight or branched alkyl substituent having 1 to 6 carbon atoms. Preferred is an alkylaminosulfonyl radical having 1 to 4 atoms. By way of example and preferably, mention may be made of methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl and t-butylaminosulfonyl.

In the context of the present invention, halogen represents fluorine, chlorine, bromine and iodine, preferably chlorine or fluorine.

In the context of the present invention, a 5- to 6-membered heteroaryl group having up to 3 heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen is generally a monocyclic heteroaromate which is attached via a ring carbon atom, optionally also via a ring nitrogen atom of a heteroaromate. By way of example and preferably, there may be mentioned a furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl and pyridazinyl group, with furanyl, thienyl and oxazolyl groups being preferred.

The compounds of the present invention, depending on the substitution pattern, may exist in stereoisomeric forms which exist either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their corresponding mixtures. Like the diastereomers, the racemic forms can be resolved into stereoisomerically uniform moieties by known methods.

Furthermore, certain compounds may exist in tautomeric forms. This is known to those skilled in the art and such compounds are also included within the scope of the present invention.

The compounds of the present invention may also exist as salts. Physiologically acceptable salts are preferred within the scope of the present invention.

Physiologically acceptable salts may be salts of the compounds of the present invention with inorganic or organic acids. Preferred are salts with

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Ί inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, acid tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be salts of the compounds of the present invention with bases such as metal salts or ammonium salts. Preferred examples are alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), as well as ammonium salts derived from ammonia or organic amines such as ethylamine, diethylamine, triethylamine , ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-efenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds of the present invention may also exist in the form of their solvates, in particular in the form of their hydrates.

Preferred are the propionic acid derivatives of the general formula I in which

A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -,

X is oxygen, sulfur or CH ₂ ,

R ¹ , R ² and R ³ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano .

R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

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R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group,

R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or a benzyl group, said aromatics alone being one to three times the same or differently substituted by an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, hydroxy or halogen,

R ⁸ represents a hydrogen atom, an aryl group of 6 to 10 carbon atoms or an alkyl group of 1 to 4 carbon atoms which may itself be substituted by an aryl group of 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all of said ring systems alone being one to three times equally or differently substituted by halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino.

R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and

R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

Particularly preferred are propionic acid derivatives of the general formula

I, in which

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32101 / H t · f

A is -CH 2 - or -CH 2 CH 2 -,

X is oxygen, sulfur or CH 2,

R ¹ , R ² and R ³ are the same or different and independently of one another are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro or fluoro, trifluoromethyl, trifluoromethoxy, nitro or cyano .

R ⁴ represents a hydrogen atom or a methyl group,

R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group,

R ⁷ represents a hydrogen atom, a C 1 -C 4 alkyl group or a benzyl group,

R ⁸ represents a hydrogen atom, a phenyl group, a benzyl group or a five-membered heteroarylmethyl group with up to two heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, said ring systems alone being one to three times same or differently substituted by chlorine, fluorine or bromine , hydroxy, (C1-C4) -alkyl, (C1-C4) -alkoxy, trifluoromethyl or amino,

R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl or fluorine or chlorine,

R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or a methyl or ethyl group or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring and

R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid.

as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

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32101 / H

Very particularly preferred are the propionic acid derivatives of the general formula I in which

A is -CH ₂ - or -CH ₂ CH ₂ -,

X is oxygen, sulfur or CH ₂ ,

R ¹ represents a hydrogen atom, a methyl group or a methoxy group

R ² and R ³ are the same or different and are independently methyl, trifluoromethyl, methoxy, trifluoromethoxy or chloro or fluoro,

R ⁴ represents a hydrogen atom,

R ⁵ and R ⁶ together with the carbon atom to which they are attached represent a carbonyl group,

R ⁷ represents a methyl group, an ethyl group, an n-propyl group or in particular a hydrogen atom,

R ⁸ represents a phenyl group, a furanylmethyl group or a thienylmethyl group, wherein said ring systems themselves may be monosubstituted or substituted by one or two methyl or ethyl groups,

R ⁹ and R ¹⁰ are the same or different and independently of one another represent a hydrogen atom or a methyl group and in particular a hydrogen atom,

R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or a methyl group, and in particular a methyl group, and

R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

The abovementioned general or preferred ranges of residue definitions apply both to the end products of the general formula I and to the starting materials or intermediates necessary for their preparation.

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32101 / H ·

The individual residue definitions given in the respective combinations or preferred combinations of residues may be used independently of these combinations in any other defined combination of residues.

Of particular interest are the propionic acid derivatives of the formula I in which R @ ⁴ represents a hydrogen atom.

Also of particular interest are the propionic acid derivatives of the formula I in which R ⁵ and R ⁶ together with the carbon atom to which they are attached form a carbonyl group.

Also of particular interest are the propionic acid derivatives of the general formula I in which

R ¹ represents a hydrogen atom, a methyl group or a methoxy group;

R ² and R ³ are the same or different and independently of one another are methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro or fluoro.

Also of particular interest are the propionic acid derivatives of the general formula I in which

R ⁸ is phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, wherein said ring systems themselves may be substituted one to two times with methyl, or are 2-methoxyethyl.

Of particular interest are the propionic acid derivatives of formula IA

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32101 / H in which

A is -CH 2 - or -CH 2 CH 2 -,

X is oxygen or sulfur,

R ¹ represents a hydrogen atom, a methyl group or a methoxy group

R ² and R ³ are the same or different and independently of one another are methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro or fluoro and

R ⁸ is phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, wherein said ring systems themselves may be substituted one to two times with methyl, or are 2-methoxyethyl.

The present invention further provides a process for the preparation of propionic acid derivatives of the general formula I, which comprises reacting [A] with compounds of the general formula II

wherein A, X, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above and

T represents a benzyl group, an alkyl group having 1 to 6 carbon atoms or a polymeric carrier suitable for solid phase synthesis, first by activating the carboxyl group of formula II with

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32101 / H t t 9 p p P * * * * * f f f f f f f inami zlúčen zlúčen zlúčen zlúčen zlúčen

R ³

NH "(ΠΙ), in which R ¹ , R ² and R ^{3 are} as defined above, to compounds of formula Ia

(Ia) in which A, X, T, R ¹ , R ² , R ³ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, or are reacted [B] compounds of formula IV

(IV),

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32101 / H in which A, X, T, R ^8, R ^9, R ^10, R ¹¹ and R ¹² as hereinbefore defined in the presence of a base with compounds of the formula V

R ^:

R 7 wherein R ¹ , R ² , R ³ and R ^{7 are} as defined above and a

Q represents a suitable leaving group, such as halogen, mesylate or tosylate, preferably bromine or iodine, as well as the compounds of the formula Ia, then the compounds of the formula Ia are converted to compounds of the formula I by optionally known amide-alkylation or amide-reduction methods ib

R 'in which A, X, T, R ¹ , R ² , R ³ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 have} the above

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32101 / H, then the acids or bases are converted to the acids of formula 1c corresponding to the carboxylic acid

(1c) in which A, X, T, R ^{1 have the} meaning,

R @ ² , R @ ³ , R @ ⁷ , R @ ⁸ , R @ ⁹ , R @ ¹⁰ , R @ ¹¹ and R @ ^12, and these are optionally further modified by reaction with compounds of the formula VI using known esterification methods.

R ¹³ -Z (VI), wherein R ¹³ is as defined above and

Z represents a suitable leaving group, such as halogen, mesylate or tosylate, or represents a hydroxyl group.

The process of the present invention is generally carried out under normal pressure. However, it is also possible to operate at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

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Suitable solvents for the process are the customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene chlorobenzene and further ethyl acetate, pyridine, dimethylsulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane. Mixtures of the abovementioned solvents may also be used.

Preferred solvents for process step II + III-1a are dichloromethane and dimethylformamide. For process step IV + V -> 1a, it is dimethylformamide.

The process step of the present invention II + III -> 1a is carried out generally at a temperature in the range of 0 ° C to 100 ° C, preferably 0 ° C to 40 ° C. The process step IV + V -> 1a is generally carried out at a temperature in the range of 0 ° C to 120 ° C, preferably 50 ° C to 100 ° C.

The amide-forming auxiliaries in process step II + III -> 1a are preferably the usual condensing agents such as carbodiimides, for example Ν, Ν'-diethylcarbodiimide, Ν, Ν'-dipropylcarbodiimide, N, N'diisopropylcarbodiimide, Ν, Ν 1'-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDO), or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2- oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazoliumumperchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo) -3-oxazolidinyl) phosphoryl chloride, or benzotriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, or O (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- ( 2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O (7-azabenzotr thiazol-1-yl) -N, N-N ', N'-tetramethyluronium hexafluorophosphate (HATU), optionally in combination with other excipients such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, as well as bases with carbonates

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32101 / H alkali metals, for example sodium or potassium carbonate or bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. Particularly preferred is a combination of EDC, N-methylmorpholine and 1-hydroxybenzotriazole, EDC, triethylamine and 1-hydroxybenzotriazole or HATU and diisopropylethylamine.

Suitable bases for reaction IV + V-1a are customary inorganic bases such as alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium, calcium or cesium carbonate, or sodium or potassium bicarbonate; and further organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. Sodium bicarbonate is preferred.

Hydrolysis of the carboxylic acid ester in process step 1a or 1, respectively. 1b-1c is carried out by conventional methods by treating the ester in inert solvents with bases, whereby the initially formed salts are converted by treatment with acids into the free carboxylic acids. In the case of tert-butyl esters, the hydrolysis is preferably carried out by means of acids.

Suitable solvents for the hydrolysis of carboxylic acid esters are water or organic solvents customary for the resolution of esters. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butyl alcohol, ethers such as tetrahydrofuran or dioxane, and furthermore dimethylformamide, dichloromethane or dimethylsulfoxide. It is also possible to use mixtures of the solvents mentioned. Preference is given to mixtures of water and tetrahydrofuran and, in the case of reaction with trifluoroacetic acid, dichloromethane, and, in the case of hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases for hydrolysis are the customary inorganic bases. These preferably include alkali metal or alkaline earth metal hydroxides, such as sodium, lithium, potassium or barium hydroxide, alkali metal carbonates, such as sodium or potassium carbonate, or sodium bicarbonate. Sodium hydroxide or sodium hydroxide is particularly preferred

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32101 / H lithium hydroxide.

Suitable acids are generally trifluoroacetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid and acetic acid or mixtures thereof, optionally with the addition of water. Preferred is hydrogen chloride or trifluoroacetic acid for the tert-butyl ester and hydrochloric acid for the methyl ester.

In the case of the compounds of the formula Ia and 1b, respectively, bound to the polymeric support via a carboxylic acid group produced by solid-phase synthesis, cleavage from the resin to the compounds of the formula 1c is carried out using conventional methods for the hydrolysis of carboxylic acid esters. Preferably, trifluoroacetic acid is used herein.

In carrying out the hydrolysis, the base or acid is used in an amount of 1 to 100 mol, preferably 1.5 to 40 mol, per mole of ester.

The hydrolysis is carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The compounds of the formula II are novel and can be prepared by first reacting [a] the compounds of the formula VII

(VD).

In which X, T, R, R, R and R are as defined above a

B represents a bond or a methylene group,

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32101 / H e in the presence of a suitable reducing agent with compounds of formula VIII

R ¹⁴ - NH ₂ in which

R ¹⁴ [a-1] is as defined above for R ⁸ or [a-2] means a group of formula (VIII),

R 5 -Q ¹ wherein R ⁷ is as defined above, and

R ¹⁵ represents an alkyl group having a trimethylsilyl group, up to 4 carbon atoms, or to compounds of formula IX

(IX), wherein B, X, T, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{14 are} as defined above, are then reacted in the presence of a base with compounds of formula X

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32101 / H

R ¹⁶ -Y (X) wherein

R ¹⁶ for process variant [a-1] represents a group of the formula

wherein R ⁷ and R ^{15 are} as defined above, or in the case of process variant [a-2], is as defined above for R ^8, and

Y represents a leaving group such as a halogen atom, a mesylate or a tosylate, preferably a bromine or iodine atom, to the compounds of formula XI

(XI) wherein B, X, T, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{14 are} as defined above, and finally the carboxylic esters group -COOR is selectively hydrolyzed in these compounds ¹⁵ to a carboxylic acid, or [b] a compound of formula XII

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32101 / H

(XU)

wherein A, X, T, R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, reacted with compounds of formula XIII in the presence of a suitable reducing agent

R ¹⁷ -CHO (XIII) wherein

R ¹⁷ represents a hydrogen atom, an aryl group of 6 to 10 carbon atoms, a 5- to 6-membered heteroaryl group of up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur or an alkyl group of 1 to 3 carbon atoms which may itself be substituted by hydroxy , trifluoromethoxy, (C 1 -C 4) alkoxy or phenoxy, each of which is optionally optionally substituted once or twice with trifluoromethyl, or may be substituted with an aryl group of 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the nitrogen group; , oxygen and / or sulfur, all of said aryl and heteroaryl rings alone may be substituted one to three times, equally or differently, by halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms. with carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino,

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32101 / H to compounds of formula XIV

(XIV), wherein A, X, T, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{17 are} as defined above, are then reacted with compounds of formula XV in the presence of a base

wherein R ⁷ , R ¹⁵ and Y are as defined above for compounds of formula XVI

(XVI),

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32101 / H in which A, X, T, R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ and R ^{17 are} as defined above, and finally the carboxylic acid ester group -COOR is selectively hydrolyzed in these compounds ¹⁵ to a carboxylic acid.

The whole process can also be carried out as a solid phase synthesis. In this case, the compounds of formula (VII) or (XII) are coupled as a carboxylic acid ester to a suitable carrier resin, further reactions are carried out on the solid phase, and the target compound is then cleaved from the resin. Solid phase synthesis as well as resin binding and cleavage are common standard techniques. An extensive literature is exemplified by Linkers for Solid Phase Organic Synthesis, Lan W. James, Tetrahedron 55, 4855-4946 (1999).

The reaction of VII + VIII -> IX or XII + XIII -> XIV is carried out in the reductive amination of customary and inert solvents under the reaction conditions, optionally in the presence of an acid. These solvents include, for example, water, dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane or alcohols such as methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol. Mixtures of the abovementioned solvents may also be used. Methanol and ethyl alcohol with the addition of acetic acid are preferred.

Suitable reducing agents for reaction VII + VIII -> IX or XII + XIII - »XIV are complex aluminum hydrides or borohydrides, such as diisobutylaluminium hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or tetrabutylammonium borohydride, or the catalyst can be hydrogenated, transition metals such as palladium, platinum, rhodium or Raney nickel. Preferred reducing agents are sodium cyanoborohydride, sodium acetoxyborohydride and tetrabutylammonium borohydride.

Reaction VII + VIII -> IX, optionally XII + XIII -> XIV is carried out

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32101 / H generally at a temperature in the range of 0 ° C to 40 ° C.

The reaction of IX + X -> XI or XIV + XV -> XVI is carried out in customary inert solvents under the reaction conditions. Dimethylformamide, tetrahydrofuran and dioxane are preferred.

Suitable bases for reaction IX + X → XI or XIV + XV → XVI are customary inorganic or organic bases. Triethylamine is preferred.

Reaction IX + X → XI or XIV + XV → XVI is generally carried out at a temperature in the range of 0 ° C to 100 ° C.

Reaction XI -> II or XVI -> II is carried out under reaction conditions for the cleavage of esters by customary inert solvents. In the case of ester hydrolysis, tetrahydrofuran, dioxane and alcohols such as methanol and ethyl alcohol in admixture with water are preferred. In the case of cleavage of the silica ester, dioxane or tetrahydrofuran is preferably used.

Suitable bases for reaction XI -> II or XVI -> II are, in the case of hydrolysis, customary inorganic bases. Lithium, potassium and sodium hydroxide are preferred. In case of cleavage of the siyl ester, tetrabutylammonium fluoride is preferably used.

Reaction XI -> II or XVI -> II is generally carried out at a temperature between 0 ° C and 100 ° C.

Compounds of formula IV correspond to compounds of formula IX or XIV, respectively, and can be prepared as described above.

Compounds of formulas III, V, VI, VII, VIII, X, XII, XIII and XV are commercially available, known, or obtainable by conventional methods (see, for example, PJ Brown et al., J. Med. Chem. 42, 3785-). 88, 1999)).

The compounds of the formula I according to the invention show a surprising and valuable spectrum of pharmacological action and can therefore be used as multilateral medicaments. They are particularly suitable for the treatment of coronary heart disease, for the prophylaxis of myocardial infarction, as well as for the treatment of restenosis after coronary angioplasty or stenting. Preferred are suitable

PP 0413-2003

32101 / H of a compound of the present invention of formula I for the treatment of arteriosclerosis and hypercholesterolemia, for increasing the disease-lowered level of HDL, as well as for decreasing the elevated level of triglycerides, fibrinogen and LDL. In addition, they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dislipidemia and high blood pressure due to insulin resistance), liver fibrosis and cancer.

The activity of the compounds of the present invention can be tested, for example, in vitro in the examples described by the transactivation experiment.

The in vivo efficacy of the compounds of the present invention can be tested, for example, in the examples described by the assays.

For the application of the compounds of the formula I, all customary administration forms, i.e. oral, parenteral, inhalative, nasal, sublingual, rectal or external, such as transdermal administration, particularly preferably oral or parenteral administration, are suitable. For parenteral administration, particularly intravenous, intramuscular and subcutaneous administration may be mentioned, for example as a subcutaneous depot. Oral administration is particularly preferred.

The active compounds can be applied alone or in the form of preparations. For oral administration, tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions are suitable as preparations. The active ingredient must be present in an amount such that a therapeutic effect is obtained. In general, the active ingredient is present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight. In particular, the concentration of active ingredient should be 0.5 to 90% by weight, i.e. the active ingredient should be present in an amount sufficient to achieve a given effective dosage space.

For this purpose, the active compounds can be converted into conventional preparations by known methods. This is done using inert, nontoxic, pharmaceutically acceptable carriers, excipients, solvents, vehicles,

PP 0413-2003

32101 / H «» F · · f. emulsifiers and / or dispersants.

Excipients which may be mentioned are, for example: water, non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethyl alcohol and glycerol), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flours (for example talc or silicates), sugar (for example milk sugar), emulsifying agents, dispersing agents (for example polyvinylpyrrolidone) and lubricants (for example magnesium sulfate).

Of course, for oral administration, the tablets may also contain ingredients such as sodium citrate along with ingredients such as starches, gelatin and the like. Aqueous preparations for oral administration can also be further treated with flavor enhancers or colorants.

For oral administration, the dosage is from about 0.001 mg / kg to about 5 mg / kg, preferably from about 0.005 mg / kg to about 3 mg / kg of body weight per 24 hours.

The present invention is illustrated by the following non-limiting examples.

In the following examples, the following abbreviations are used which:

means: Ac acetyl Bu butyl DC thin layer chromatography DCI direct chemical ionization (for MS) DCM dichloromethane DIC diisopropylcarbodiimide DMAP 4-N, N-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimetyisulfoxid EDO N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride

PP 0413-2003

32101 / H

El

ESI

Et nas.

HATU

HOBt

HPLC

LC-MS

Me

MS

NMR

RF

Rf

RT

rt

TBAF

TBAI

TFA

THF electron bombardment (for MS) electrospray-ionization (for MS) ethyl saturated

O- (7-azabenzotriazol-1-yl) -N, N, NN'-tetramethyl uonium hexafluorophosphate

1-hydroxy-1H-benzotriazole x H2O high pressure, high performance liquid chromatography liquid chromatography - double mass spectroscopy methyl mass spectroscopy nuclear resonance spectroscopy backflow retention index (at DC) room temperature retention time (HPLC)

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

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32101 / H

Example 1-1

Tert-butyl-2-methylpropionate

A solution of 73.0 g (0.985 mol) of tert-butanol, 190 g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750 ml of dichloromethane is mixed with a solution of 100 g (0.939 mmol) of isobutyric acid chloride under ice cooling. in 150 ml of dichloromethane and after stirring the reaction mixture is stirred overnight. 500 ml of 2M hydrochloric acid are then added, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated. Purification of the crude product by distillation afforded 65.5 g (48%) of tert-butyl 2-methylpropionate.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.11 (d, 6H), 1.44 (s, 9 H), 2.42 (sept., 1H).

Example I-2

Tert-Butyl-3- (4-bromophenyl) -2,2-dimethypropionate

br

To a solution of 10.0 g (69.34 mmol) of tert-butyl 2-methylpropionate (Example 1-1) in 100 mL of tetrahydrofuran at -78 ° C was slowly added dropwise 34.7 mL (69.4 mmol)

PP 0413-2003

32101 (H mmol) of a 2 M solution of lithium diisopropylamide. After the addition was complete, the reaction mixture was stirred for one hour at -78 ° C, after which 15.76 g (63.04 mmol) of 4-benzyl bromide in 10 ml of tetrahydrofuran was added and stirred for one hour at -78 ° C. . The reaction mixture is then allowed to reach room temperature, poured into 100 ml of 1 N hydrochloric acid, the phases are separated and the aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed with sodium bicarbonate solution, dried over anhydrous sodium sulphate and the solvent is removed in vacuo. Purification of the residue by distillation in a vacuum pump oil yielded 16.75 g (85%) of tert-butyl 3- (4-bromophenyl) -2,2-dimethylpropionate.

¹ H-NMR (200 MHz, DMSO): δ = 1.06 (s, 6H), 1.38 (s, 9H), 2.74 (s, 2H), 7.10 (d, 2H), 7 47 (d, 2H).

Example I-3

Tert-Butyl-3- (4-formylphenyl) -2,2-dimethypropionate

A solution of 6.00 g (19.16 mmol) of tert-butyl 3- (4-bromophenyl) -2,2-dimethylpropionate (Example I-2) in 80 ml of tetrahydrofuran was slowly treated with 13.5 ml at -75 ° C. (22.98 mmol) of a 1.7 M solution of tert-butyllithium in pentane, maintaining the temperature below -60 ° C. The reaction mixture was stirred for 15 minutes, then 1.82 g (24.90 mmol) of Ν, Ν-dimethylformamide was added and the mixture was stirred for a further 4 hours at -75 ° C. It is then slowly warmed to -20 ° C, mixed with 20 ml of water with vigorous stirring and then warmed to room temperature. The aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried using a mixture of sodium sulphate and sodium carbonate.

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32101 / H

And the solvent is removed in vacuo. Distillation of the residue in an oil pump vacuum gave 2.54 g (51%) of tert-butyl 3- (4-formylphenyl) -2,2-dimethylpropionate.

¹ H-NMR (300 MHz, _CDCl3): δ = 1.16 (s, 6H), 1.42 (s, 9 H), 2.90 (s, 2H), 7.32 (d, 2H); 7.78 (d, 2H); 9.98 (s, 1H).

Example I-4

Tert-butyl 2- (4-formyl-phenoxy) -2-methylpropionate

ABOUT

A solution of 4-hydroxybenzaldehyde (24.4 g, 200 mmol) in DMF (100 mL) was treated with cesium carbonate (97.75 g, 300 mmol) and stirred at 90 ° C for 1 h. A solution of 66.93 g (300 mmol) of 2-bromo-isobutyrate in tert-butylformamide (100 ml) was added dropwise and the reaction mixture was stirred overnight at 90 ° C. After distilling off the dimethylformamide in vacuo, the residue is taken up in ethyl acetate, washed twice with water, twice with 1 N sodium hydroxide and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. 16.6 g (31%) of tert-butyl 2- (4-formylphenoxy) -2-methylpropionate are obtained.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.40 (s, 9 H), 1.63 (s, 6H), 6.90 (d, 2H), 7.78 (d, 2H); 9.88 (s, 1 H).

Example I-5

Tert-butyl 3- (4 - {[(2-furylmethyl) amino] methyl} phenyl) -2,2-dimethypropionate

PP 0413-2003

32101 / H r r ·

A solution of 1.00 g (3.81 mmol) of tert-butyl 3- (4-formylphenyl) -2,2-dimethylpropionate (Example I-3) and 0.37 g (3.81 mmol) of furylamine in 10 ml of dichloroethane is stirred at room temperature for 30 minutes, treated with 1.21 g (5.72 mmol) of sodium triacetoxyborohydride and stirred for 22 hours at room temperature. 6 ml of saturated sodium hydrogen carbonate solution and 10 ml of ethyl acetate are added, the phases are separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined and dried over sodium sulphate. Removal of the solvent in vacuo afforded 720 mg (55%) of tert-butyl-3- (4 - {[(2-furylmethyl) amino) after chromatography on silica gel (cyclohexane → cyclohexane / ethyl acetate 10: 1 -? - 2: 1). ] phenyl} -2,2-dimethyl propionate.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.11 (s, 6H), 1.42 (s, 9H), 1.62 (breites with, 1H), 2.70 (s, 2H) 3.76 (s, 2H), 3.80 (s, 2H), 6.18 (d, 1H), 6.32 (dd, 1H), 7.10 (d, 2H), 7.20 (d, 2H) d, 2H), 7.35 (d, 1 H).

Example I-6

Tert-butyl 3- [4- (anilinomethyl) phenyl] -2,2-dimethypropionate

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32101 / H

Analogously to Example 1-5, 200 mg (0.762 mmol) of tert-butyl 3- (4-formylphenyl) -2,2-dimethylpropionate (Example 1-3), 71 mg (0.762 mmol) of aniline are reacted and 210 mg (0.991 mmol) of sodium acetoxyborohydride in 2 ml of dichloroethane per 223 mg (86%) of tert-butyl 3- [4- (anilinomethyl) phenyl] -2,2-dimethylpropionate.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.11 (s, 6H), 1.42 (s, 9H), 2.81 (s, 2H), 3.98 (breites s, 1H) 4.29 (s, 2H), 6.64 (d, 2H), 6.71 (t, 1H), 7.12 (d, 2H), 7.17 (t, 2H),

7.25 (d, 2 H).

Example I-7

Tert-Butyl-2,2-dimethyl-3- (4 - {[(4-methylphenyl) amino] methyl} phenyl) propionate

Analogously to Example I-5, 200 mg (0.762 mmol) of tert-butyl 3- (4-formylphenyl) -2,2-dimethylpropionate (Example I-3), 82 mg (0.762 mmol) of toluidine are reacted and 210 mg (0.991 mmol) of sodium acetoxyborohydride in 2 mL of dichloroethane to 206 mg (76%) of tert-butyl 2,2-dimethyl-3- (4 - {[(4-methylphenyl) amino] methyl} phenyl) propionate.

¹ H-NMR (400 MHz, _CDCl3): δ = 1.11 (s, 6H), 1.42 (s, 9 H), 2.23 (s, 3H), 2.81 (s, 2H); 3.87 (breites s, 1H), 4.27 (s, 2H), 6.57 (d, 2H), 6.98 (d, 2H), 7.12 (d, 2H),

7.25 (d, 2 H).

Example I-8

Methyl 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxo-ethoxy) benzyl] amino} butyrate

PP 0413-2003

32101 / H yy

Analogously to Example 1-5, 1.20 g (4.54 mmol) of tert-butyl 2- (4-formylphenoxy) -2-methylpropionate (Example I-4), 0.70 g (4 g) were reacted. (54 mmol) of DL-2-aminobutyric acid methyl ester, 0.92 g (9.08 mmol) of triethylamine and 1.44 g (6.81 mmol) of sodium acetoxyborohydride at room temperature in 10 ml of dichloroethane. Further addition of 0.9 g (4.25 mmol) of sodium acetoxyborohydride and 0.35 g (2.27 mmol) of DL-2-aminobutyric acid methyl ester and heating to 40 ° C for 3 hours gave 1.47 g (89%). methyl 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxo-ethoxy) benzyl] amino} butyrate.

¹ H-NMR (300 MHz, DMSO): δ = 0.84 (t, 3H), 1.38 (s, 9H), 1.47 (s, 6H), 1.57 (dt, 2H), 2 29 (breites s, 1H); 3.08 (t, 1H); 3.47 (d, 1H); 3.62 (s, 3H); 3.65 (d, 1H); 6.73 (d) 2 H, 7.18 (d, 2H).

Example 1-9

Tert-butyl 3- (4 - {[(2-ethoxy-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2dimetylpropionát

A solution of 600 mg (1.75 mmol) of tert-butyl 3- (4 - {[(2-furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionate (Example I-5), 323 mg (0.87) mmol) · tetra-nPP 0413-2003

32101 / H • * · e * e * r t »

Ethyl tert-butylammonium iodide and 265 mg (2.62 mmol) of triethylamine in 10 ml of tetrahydrofuran were treated with 438 mg (2.62 mmol) of ethyl bromoacetate and the reaction mixture was heated at reflux overnight. After cooling, the mixture is concentrated in vacuo, taken up in water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. Removal of the solvent in vacuo afforded 702 mg (94% of tert-butyl-3- (4 - {[(2-ethoxy-2-oxoethyl) (2-ethoxy-2-oxoethyl)) after silica gel chromatography (cyclohexane → cyclohexane / ethyl acetate 10: 1). furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (400 MHz, _CDCl3): δ = 1.11 (s, 6H), 1.27 (t, 3H), 1.42 (s, 9 H), 2.80 (s, 2H); 3.31 (s, 2H), 3.76 (s, 2H), 3.84 (s, 2H), 4.17 (q, 2H), 6.20 (d, 1H), 6.32 (dd) 1 H, 7.10 (d, 2H), 7.25 (d, 2H), 7.38 (d, 1H).

Example 1-10

Tert-butyl 3- (4 - {[N- (2-ethoxy-2-oxo) ethyl-N-phenylamino] methyl} phenyl) -2,2dimetylpropionát

Analogous to that described in Example I-9, from 198 mg (0.583 mmol) of tert-butyl 3- [4- (anilinomethyl) phenyl] -2,2-dimethylpropionate (Example I-6) was obtained, 108 mg (0.292 mmol). tetra-n-butylammonium iodide, two times each 89 mg (0.875 mmol) triethylamine and three times each 146 mg (0.875 mmol) ethyl bromoacetate in 2 ml tetrahydrofuran and 2 ml dimethylformamide 191 mg (77%) tert-butyl-3- (4 - {[(2-ethoxy-2-oxoethyl) (2-phenyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

PP 0413-2003

32101 / H ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.11 (s, 6H), 1.25 (t, 3H), 1.42 (s, 9H), 2.70 (s, 2H), 4.05 (s, 2H), 4.20 (q, 2H), 4.62 (s, 2H), 6.69 (d, 2H), 6.73 (t, 1H), 7, 07 7.25 (m, 6H).

Example 1-11

Tert-butyl 3- (4 - {[N- (2-ethoxy-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl-2,2-

Analogously to Example I-9, from tert-butyl 2,2-dimethyl-3- (4 - {[4- (methylphenyl) amino] methyl} phenyl) propionate (181 mg (0.512 mmol)) was obtained (Example I-7), 95 mg (0.256 mmol) of tetra-n-butylammonium iodide, two portions of 78 mg (0.768 mmol) of triethylamine and three portions of 128 mg (0.768 mmol) of ethyl bromoacetate each in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide. (78%) tert-butyl 3- (4 - {[N- (2-ethoxy-2-oxo) ethyl-N- (4-methyl} phenyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (400 MHz, _CDCl3): δ = 1.11 (s, 6H), 1.25 (t, 3H), 1.42 (s, 9 H), 2.22 (s, 3H); 2.80 (s, 2H), 4.02 (s, 2H), 4.19 (q, 2H), 4.59 (s, 2H), 6.60 (d, 2H), 7.00 (d 2 H, 7.10 (d, 2H), 7.17 (d, 2H).

Example 1-12

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32101 / H e

A solution of 785 mg (1.83 mmol) of tert-butyl 3- (4 - {[(2-ethoxy-2-oxoethyl) (2-furylmethyl) amino] methylphenyl) -2,2-dimethylpropionate (Example I-9) in 15 ml of ethyl alcohol were mixed with 5.5 ml (5.5 mmol) of 1 N sodium hydroxide and the mixture was heated at 80 ° C for one hour. After cooling, the mixture was concentrated in vacuo, taken up in a small amount of water, acidified with 1 N hydrochloric acid, and extracted three times with ethyl acetate. The combined organic extracts were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. 728 mg (99%) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-propyl) benzyl] -N- (2-furylmethyl) glycine is obtained.

¹ H-NMR (200 MHz, DMSO): δ = 1.06 (s, 6H), 1.37 (s, 9H), 2.74 (s, 2H), 3.24 (s, 2H), 3 76 (s, 2H), 3.84 (s, 2H), 6.32 (m, 1H), 6.41 (m, 1H), 7.11 (d, 2H), 7.26 (d, 2H) 2H), 7.63 (d, 1H), 12.20 (breites with, 1H).

Example 1-13

Analogously to Example 1-12, tert-butyl-3- (4 - {[(2-ethoxy-2-oxoethyl) (2-phenyl) amino] methyl} phenyl) was obtained from 175 mg (0.411 mmol). 2,2-dimethylpropionate (Example 1-10) and 1.23 ml (1.23 mmol) of 1 N sodium hydroxide in ml of ethanol 162 mg (99%) of N- [4- (3-tert-butoxy-2,2-dimethyl) -3PP 0413-2003

32101 (trans-propyl) benzyl] -N-phenylglycine.

¹ H-NMR (300 MHz, DMSO): δ = 1.04 (s, 6H), 1.36 (s, 9H), 2.73 (s, 2H), 4.12 (s, 2H), 4 56 (s, 2H), 6.56 (d, 2H), 6.61 (t, 1H), 7.07 (d, 2H), 7.11 (d, 2H), 7.19 (d, 2H) 1H), 12.53 (breitess, 1H).

Example 1-14

N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (4-methylphenyl) glycine

Analogously to Example 1-12, tert-butyl-3- (4 - {[N- (2-ethoxy-2-oxo) -ethyl-N- (4-methylphenyl)] was obtained from 153 mg (0.348 mmol). amino] methyl} phenyl) -2,2-dimethylpropionate (Example 1-11) and 1.23 mL (1.23 mmol) of 1 N sodium hydroxide in 3 mL of ethyl alcohol 141 mg (99%) of N- [4- (3 tert-butoxy-2,2-dimethyl-3oxopropyl) benzyl] -N- (4-methylphenyl) glycine.

¹ H-NMR (300 MHz, DMSO): δ = 1.04 (s, 6H), 1.36 (s, 9H), 2.14 (s, 3H), 2.72 (s, 2H), 4 Δ 08 (s, 2H), 4.52 (s, 2H), 6.48 (d, 2H), 7.08 (d, 2H), 7.18 (d, 2H), 12.48 (breites with , 1H).

Example 1-15

2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy) benzyl] amino} butyric acid

PP 0413-2003

32101 / H r r r r r p p

Analogously to Example 1-12, methyl 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy) benzyl] amino} butyrate is obtained from 750 mg (2.05 mmol). (Example I-8) and 6.20 mL (6.20 mmol) of 1 N sodium hydroxide in 6 mL of ethyl alcohol 640 mg (89%) of 2 - {[4- (2-tert-butoxy-1,1-dimethyl- 2-oxoethoxy) benzyl] amino} butyric acid.

¹ H-NMR (300 MHz, DMSO): δ = 0.91 (t, 3H), 1.40 (s, 9H), 1.51 (s, 6H), 1.84 (m, 2H), 3 25 (breites s, 1 H), 3.57 (t, 1 H), 3.99 (s, 2 H), 6.81 (d, 2 H), 7.38 (d, 2 H).

Implementing examples

Example 1-1

Tert-butyl 3- (4 - {[(2- (2,4-dimethylphenyl) amino-2-oxo-ethyl) - (2-furylmethyl) amino] methyl} phenyl) -2,2-dimethypropionate

To a solution of 200 mg (0.498 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-propyl) benzyl] -N- (2-furylmethyl) glycine (Example 1-12) and 91 mg (0.747) mmol) of 2,4-dimethylaniline in 8 ml of dimethylformamide is added at 0 ° C 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3- (3-dimethylamino) hydrochloride propylcarbodiimide, 151 mg (1.444 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine were added and the reaction mixture was stirred at room temperature for 1 h. It is further stirred for 9 hours at room temperature and then mixed with 10 ml of water. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N hydrochloric acid, a saturated solution.

PP 0413-2003

32101 / H sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. Chromatographic purification of the residue on silica gel (cyclohexane / ethyl acetate 10: 1 -> 3: 1) afforded 228 mg (91%) of tert-butyl-3- (4 {[(2- (2,4-dimethylphenyl) amino) - 2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2dimetylpropionátu.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.10 (s, 6H), 1.40 (s, 9H), 2.26 (s, 3H), 2.28 (s, 3H), 2.80 (s, 2H), 3.29 (s, 2H), 3.71 (s, 2H), 3.74 (s, 2H), 6.25 (d, 1H), 6.32 (dd) 1 H, 6.99 (m, 2H), 7.11 (d, 2H), 7.23 (d, 2H), 7.37 (d, 1H), 7.84 (d, 1H), 9 12 (breites s, 1 H).

Example 1-2

Tert-butyl 3- (4 - {[(2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxoethyl) (2furylmetyl) amino] methyl} phenyl) -2,2-dimethypropionate

Analogously to Example 1-1, 200 mg (0.498 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (2-furylmethyl) glycine was reacted ( Example 1-12), 113 mg (0.747 mmol) of 4-methoxy-2,5-dimethylaniline, 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3- (3) hydrochloride -dimethylamino) propylcarbodiimide, 151 mg (1.444 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine in 8 ml of dimethylformamide per 241 mg (90%) of tert-butyl-3- (4 - {[(2- ( 4-methoxy-2,5-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

PP 0413-2003

32101 / H ¹ H-NMR (200 MHz, DMSO): δ = 1.05 (s, 6H), 1.35 (s, 9H), 2.08 (s, 3H), 2.14 (s, 3H) ), 2.75 (s, 2H), 3.18 (s, 2H), 3.69 (s, 2H), 3.74 (s, 3H), 3.76 (s, 2H), 6.35 (d, 1H), 6.41 (dd, 1H), 6.75 (s, 1H), 7.11 (d, 2H), 7.28 (d, 2H), 7.31 (s, 1H) 7.61 (d, 1H); 9.02 (breitess, 1H).

Example 1-3

Tert-butyl 3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino] methyl} phenyl) -2,2-dimethypropionate

Analogously to Example 1-1, 65 mg (0.164 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N-phenylglycine (Example 1-13) was reacted. , 30 mg (0.245 mmol) of 2,4-dimethylaniline, 29 mg (0.213 mmol) of 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) of 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride, 50 mg (0.491) mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of 4-dimethylaminopyridine in 2 ml of dimethylformamide per 65 mg (79%) of tert-butyl-3- (4 - {[N-2,4-dimethylphenyl) amino-2] oxo) ethyl) -Nfenylamino] methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.10 (s, 6H), 1.41 (s, 9H), 1.90 (s, 3H), 2.26 (s, 3H), 2.79 (s, 2H), 4.09 (s, 2H), 4.66 (s, 2H), 6.80-6.95 (m, 4H), 6.98 (d, 1H), 7 12 (s, 4H), 7.27 (m, 2H), 7.67 (d, 1H), 8.11 (breites with, 1H).

Example 1-4

Tert-butyl 3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino] methyl} phenyl) -2,2-dimethypropionate

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32101 / H e r r

Analogously to Example 1-1, 65 mg (0.164 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N-phenylglycine (Example 1-13) was reacted. 37 mg (0.245 mmol) of 4-methoxy-2,5-dimethylaniline, 29 mg (0.213 mmol) of 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) of 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride , 50 mg (0.491 mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of 4-dimethylaminopyridine in 2 ml of dimethylformamide per 78 mg (90%) of tert-butyl-3- (4 - {[N- (2- ( 4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl) -N-fenylaminojmetyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.11 (s, 6H), 1.42 (s, 9 H), 1.96 (s, 3H), 2.16 (s, 3H); 2.80 (s, 2H), 3.77 (s, 3H), 4.09 (s, 2H), 4.67 (s, 2H), 6.57 (s, 1H), 6.83 (dd) (1H), 6.89 (d, 2H), 7.13 (s, 4H), 7.24 (d, 2H), 7.34 (m, 1H), 7.94 (breites with, 1H).

Example 1-5

Tert-butyl 3- (4 - {[N-2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethypropionate

Analogously to Example 1-1, 50 mg (0.121 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (4- (3-tert-butyloxy) benzene) was reacted. -tercPP 0413-2003

32101 / H • butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (4-methylphenyl) glycine (Example 1-14), 22 mg (0.182 mmol) 2.4 dimethylaniline, 21 mg (0.158 mmol) of 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) of 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride, 37 mg (0.364 mmol) of N-methylmorpholine and 0.1 mg (0.001 mmol) of 4- dimethylaminopyridine in 2 ml dimethylformamide per 40 mg (64%) tert-butyl-3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.10 (s, 6H), 1.40 (s, 9H), 1.92 (s, 3H), 2.27 (s, 6H), 2.79 (s, 2H), 4.02 (s, 2H), 4.58 (s, 2H), 6.80 (d, 2H), 6.91 (s, 1H), 6.98 (d 1 H, 7.06 (d, 2H), 7.11 (d, 2H), 7.13 (d, 2H), 7.67 (d, 1H), 8.18 (breites with, 1H).

Example 1-6

Tert-butyl 3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2 -dimetylpropionát

Analogously to Example 1-1, 50 mg (0.121 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (4-methylphenyl) glycine was reacted ( Example 1-14), 28 mg (0.182 mmol) of 4-methoxy-2,5-dimethylaniline, 21 mg (0.158 mmol) of 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) of 1-ethyl-3- (3- dimethylamino) propylcarbodiimide, 37 mg (0.364 mmol) of N-methylmorpholine and 0.1 mg (0.001 mmol) of 4-dimethylaminopyridine in 2 ml of dimethylformamide per 58 mg (88%) of tert-butyl-3- (4 - {[N- ( 2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl) -N- (4-methylphenyl) amino] methyl} phenyl) -2,2dimetylpropionátu.

¹ H-NMR (300 MHz, _CDCl3): δ = 1.10 (s, 6H), 1.41 (s, 9 H), 1.96 (s, 3H), 2.15 (s,

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3Η), 2.26 (s, 3H), 2.79 (s, 2H), 3.77 (s, 3H), 4.02 (s, 2H), 4.60 (s, 2H), 6, 57 (s, 1H), 6.80 (d, 2H), 7.07 (d, 2H), 7.10 (d, 2H), 7.13 (d, 2H), 7.37 (s, 1H) 8.01 (breites s, 1H).

Example 1-7

Tert-butyl 2- (4 - {[1 - {[(2,4-dimethylphenyl) amino] carbonyl} propyl) -methyl} -phenoxy) -2metylpropionát

Analogously to Example 1-1, 320 mg (0.90 mmol) of 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy) benzyl] amino} butyric acid was reacted ( Example 1-15), 160 mg (1.36 mmol) of 2,4-dimethylaniline, 160 mg (1.18 mmol) of 1-hydroxy-1H-benzotriazole, 230 mg (1.18 mmol) of 1-ethyl-3 hydrochloride (3-dimethylamino) propylcarbodiimide, 270 mg (2.71 mmol) of N-methylmorpholine and 1 mg (0.01 mmol) of 4-dimethylaminopyridine in 5 ml of dimethylformamide per 190 mg (46%) of tert-butyl-2- (4- {[(1 - {[(2,4-dimethylphenyl) amino] carbonyl} propylaminojmetyl} phenoxy) -2-methylpropionate.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.99 (t, 3H), 1.43 (s, 9H), 1.56 (s, 6H), 1.74 (m, 2H), 2.21 (s, 3H), 2.28 (s, 3H), 3.22 (dd, 1H), 3.69 (d, 1H), 3.82 (d, 1H), 6.83 (d 2H, 6.98 (s, 1H), 7.02 (d, 1H), 7.18 (d, 2H), 7.93 (d, 1H), 9.32 (breites with, 1H).

Example 1-8

Tert-butyl 2- (4 - {[(1 - {[(4-methoxy-2,5-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionate

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32101 / H

Analogously to Example 1-1, 320 mg (0.90 mmol) of 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy) benzyl] amino} butyric acid was reacted ( Example 1-15), 210 mg (1.36 mmol) of 4-methoxy-2,5-dimethylaniline, 160 mg (1.18 mmol) of 1-hydroxy-1H-benzotriazole, 230 mg (1.18 mmol) of hydrochloride 1 -ethyl-3- (3-dimethylamino) propylcarbodiimide, 270 mg (2.71 mmol) of N-methylmorpholine and 1 mg (0.01 mmol) of 4-dimethylaminopyridine in 5 ml of dimethylformamide per 130 mg (30%) of tert-butyl-2- (4 - {[(1 - {[(4-methoxy-2,5-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionate.

¹ H-NMR (200 MHz, _CDCl3): δ = 0.99 (t, 3H), 1.44 (s, 9 H), 1.56 (s, 6H), 1.74 (m, 2H); 2.19 (s, 3H), 2.22 (s, 3H), 3.22 (dd, 1H), 3.71 (d, 1H), 3.80 (s, 3H), 3.82 (d) 1H, 6.64 (s, 1H), 6.83 (d, 2H), 7.19 (d, 2H), 7.65 (s, 1H), 9.13 (breites with, 1H).

Example 1-9

3- (4 - {[(2- (2,4-Dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionic acid

A solution of 192 mg (0.380 mmol) of tert-butyl 3 - {[(2- (2,4-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionate (Example 1) -1) in 1 ml of dichloromethane is mixed with 1 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. The reaction mixture is then concentrated in vacuo, taken up

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32101 / H is added to ethyl acetate, the organic phase is washed twice with water, once with 20% sodium acetate solution, once with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and the solvent is removed in vacuo. Purification of the residue by chromatography on silica gel (dichloromethane → dichloromethane / methanol 20: 1) afforded 150 mg (88%) of 3- (4 - {[(2- (2,4-dimethylphenyl) amino-2-oxoethyl) acid. ) (2-furylmethyl) aminojmetyl} phenyl) -2,2-dimethyl-propionic.

¹ H-NMR (200 MHz, CDCl ₃ ); δ = 1.16 (s, 6H), 2.26 (s, 3H), 2.28 (s, 3H), 2.87 (s, 2H), 3.30 (s, 2H), 3.71 (s, 2H), 3.74 (s, 2H), 6.26 (d, 1H), 6.32 (dd, 1H), 6.99 (m, 2H), 7.12 (d, 2H) 7.24 (d, 2H), 7.37 (d, 1H), 7.83 (d, 1H), 9.12 (breites with, 1H).

Example 1-10

3- (4 - {[(2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2-dimethylpropionic acid

Analogously to Example 1-9, 170 mg (0.318 mmol) of tert-butyl-3- (4 - {[(2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxoethyl)) was reacted ( 2-furylmethyl) aminomethyl} phenyl) -2,2-dimethylpropionate (Example 1-2) with 1 ml of trifluoroacetic acid in 1 ml of dichloromethane per 133 mg (87%) of 3- (4 - {[(2- (4-methoxy-2, 5-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl} -2,2dimetylpropiónovej.

¹ H-NMR (00 MHz, DMSO); δ = 1.04 (s, 6H), 2.07 (s, 3H), 2.13 (s, 3H), 2.76 (s,

2H), 3.18 (s, 2H), 3.70 (s, 2H), 3.74 (s, 2H), 3.76 (s, 2H), 6.39 (d, 2H), 6 , 87 (s,

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Δ), 7.12 (d, 2H), 7.28 (d, 2H), 7.30 (s, 1H), 7.61 (s, 1H), 9.02 (breites with, 1H), 12 18 (breites s, 1 H).

Example 1-11

3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino) methyl} phenyl-2,2-dimethylpropionic acid

Analogously to Example 1-9, 48 mg (0.096 mmol) of tert-butyl-3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino)] was reacted. methyl} phenyl) -2,2-dimethylpropionate (Example 1-3) with 1 ml of trifluoroacetic acid in 2 ml of dichloromethane for 36 mg (85%) of 3- (4 - {[N- (2- (2,4-dimethylphenyl) phenyl]) ) amino-2-oxo) ethyl-N-phenylamino] methyl} phenyl} -2,2dimetylpropiónovej.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.19 (s, 6H), 1.90 (s, 3H), 2.26 (s, 3H), 2.87 (s, 2H), 4.08 (s, 2H), 4.66 (s, 2H), 6.80-6.95 (m, 4H), 6.98 (d, 1H), 7.14 (s, 4H), 7 27 (m, 2H), 7.67 (d, 1H), 8.08 (breites with, 1H).

Example 1-12

3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino] methyl} phenyl) -2,2-dimethylpropionic acid

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32101 / H r t f y r * f

Analogously to Example 1-9, 61 mg (0.115 mmol) of tert-butyl-3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl) ethyl] was reacted. -N-phenylamino] methyl} phenyl) -2,2-dimethylpropionate (Example 1-4) with 1 mL of trifluoroacetic acid in 2 mL of dichloromethane to 46 mg (85%) of 3- (4 - {[N (2- ( 4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N-phenylamino] methyl} -2,2dimetylpropiónovej.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.19 (s, 6H), 1.94 (s, 3H), 2.15 (s, 3H), 2.86 (s, 2H); 3.77 (s, 3H), 4.08 (s, 2H), 4.66 (s, 2H), 6.56 (s, 1H), 6.83 (dd, 1H), 6.88 (d (2H), 7.13 (s, 4H), 7.24 (d, 2H), 7.34 (m, 1H), 7.93 (breites with, 1H).

Example 1-13

3- (4 - {[N- (2- (2,4-Dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethylpropionic acid

Analogously to Example 1-9, 23 mg (0.049 mmol) of tert-butyl-3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N)] was reacted. - (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethylpropionate (Example 1-5) with 1 ml of trifluoroacetic acid in 2 ml of dichloromethane per 20 mg (91%) of 3- (4 - {[N (2- (2,4-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl} -2,2dimetylpropiónovej.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.17 (s, 6H), 1.92 (s, 3H), 2.25 (s, 6H), 2.86 (s, 2H); 4.02 (s, 2H), 4.60 (s, 2H), 6.79 (d, 2H), 6.91 (s, 1H), 6.98 (d, 1H), 7.06 (d .

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2Η), 7.13 (s, 2H), 7.17 (d, 2H), 7.68 (d, 1H), 8.19 (breites with, 1H).

Example 1-14

3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2- dimethylpropionic

Analogously to Example 1-9, 40 mg (0.073 mmol) of tert-butyl-3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl) ethyl] was reacted. -N- (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethylpropionate (Example 1-6) with 1 ml of trifluoroacetic acid in 2 ml of dichloromethane per 33 mg (93%) of 3 (4 - {[N - (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N- (4-methylphenyl) amino] methyl} phenyl) -2,2-dimethyl-propionic.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.18 (s, 6H), 1.96 (s, 3H), 2.15 (s, 3H), 2.26 (s, 3H); 2.86 (s, 2H), 3.76 (s, 3H), 4.03 (s, 2H), 4.61 (s, 2H), 6.57 (s, 1H), 6.80 (dd) 2H, 7.07 (d, 2H), 7.14 (s, 4H), 7.36 (s, 1H), 8.02 (breites with, 1H).

Example 1-15

2- (4 - {[(1 - {[(2,4-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionic acid

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32101 / H e

Analogously to Example 1-9, 170 mg (0.374 mmol) of tert-butyl-2- (4 - {[(1 - {[(2,4-dimethylphenyl) amino] carbonyl} propyl) amino] methyl is reacted phenoxy) -2-methylpropionate (Example 1-7) with 0.72 mL (9.35 mmol) of trifluoroacetic acid in 3 mL of dichloromethane per 113 mg (72%) of 2- (4 {[(1 - {[( 2,4-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2metylpropiónovej.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.01 (t, 3H), 1.53 (d, 6H), 1.95 (m, 2H), 2.10 (s, 3H), 2.23 (s, 3H), 3.67 (breites s, 1H), 4.02 (m, 1H), 4.55 (m, 1H), 6.61 (d, 2H), 6.82 ( d, 1H), 6.89 (s, 1H), 7.10 (d, 2H), 7.11 (s, 1H), 9.53 (breites with, 1H).

Example 1-16 2- (4 - {[(1 - {[(4-methoxy-2,5-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionic acid

Analogously to Example 1-9, 115 mg (0.237 mmol) of tert-butyl-2- (4 - {[(1 - {[(4-methoxy-2,5-dimethylphenyl) amino] carbonyl} propyl) is reacted (amino) methyl} phenoxy) -2-methylpropionate (Example 1-8) with 0.46 ml (5.93 mmol) trifluoroacetic acid in 3 ml dichloromethane per 100 mg (93%) 2- (4 - {[( 1 - {[(4-methoxy-2,5-dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionic acid ethyl ester.

¹ H-NMR (300 MHz, _CDCl3): δ = 1.05 (t, 3H), 1.55 (d, 6H), 1.97 (m, 2H), 2.10 (s,

6H), 3.75 (s, 3H), 3.78 (m, 1H), 4.08 (m, 2H), 4.50 (m, 2H), 6.50 (s, 1H), 6, 64 (d, 2H), 6.94 (s, 1H), 7.14 (d, 2H), 7.65 (s, 1H), 9.38 (breites with, 1H).

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Starting compounds II

Example 11-1

2 - [(4-bromophenyl) thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

4-Bromothiophenol (100 g) and tert-butyl 2-bromoisobutyrate (118 g) were dissolved in 1 L of ethyl alcohol and treated with 29 g of potassium hydroxide. The reaction mixture is stirred at reflux for 2 hours, cooled and the potassium bromide filtered off. The filtrate was concentrated and recrystallized from n-hexane. 93.6 g of a colorless solid are obtained.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.48 (s, 15H), 7.38 (m, 4 H).

Example II-2

2 - [(4-Formylphenyl) thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

1.0 g of 2 - [(4-bromophenyl) thio] -2-methylpropanoic acid 1,1-dimethyl ester was dissolved in 20 ml of tetrahydrofuran and treated with 189 ml (3.02 mmol, 1 equivalent) of n- butyllithium in hexane. It is then treated directly with 0.46 ml of dimethylformamide, warmed to room temperature and stirred for one hour. The reaction is quenched by the addition of 1 ml of 1 N hydrochloric acid, the mixture is concentrated and the residue is taken up in ethyl acetate. It is then shaken with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Purification by chromatography (dichloromethane) gave 550 mg of a pale yellow oil.

LC-MS: acetonitrile (30% aqueous HCl / water (gradient): R f = 4.86 min ([M + H] ⁺ = 281).

Example 11-3

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2 - [[4 - [[(2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

550 mg of 2 - [(4-formylphenyl) thio] -2-methylpropanoic acid 1,1-dimethyl ester are introduced with 381 mg of furylamine into 100 ml of methanol and mixed with 1 ml of glacial acetic acid, followed by stirring for 15 minutes at at room temperature, boiled briefly and then mixed at 0 ° C in portions with 493 mg of sodium cyanoborohydride. After stirring overnight at room temperature, the reaction mixture was treated with 1 N hydrochloric acid and stirred for 30 minutes, then basified with sodium carbonate solution and extracted twice with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Concentration and chromatographic purification (dichloromethane / ethyl acetate 10: 1) gave 430 mg of a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ): 1.42 (s, 15H), 3.79 (s, 2H), 3.80 (s, 2H), 6.15 (m, 1H), 6, 28 (m, 1H); 7.25-7.45 (m, 5H).

Example II-4

2 - [[4- [2 - [(2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

5.4 g of 2 - [[4 - [[furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester are dissolved in 270 ml of tetrahydrofuran and mixed with 2.27 g of triethylamine, 3.74 g of ethyl bromoacetate and 14.85 g of tetra-butylammonium iodide. The reaction mixture was stirred at 90 ° C for 48 hours, cooled and treated with water and ethyl acetate. The organic phase was separated and washed twice with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, concentrating and chromatographic purification (cyclohexane / ethyl acetate 5 + 1), 6.4 g of a colorless oil are obtained.

¹ H-NMR (200 MHz, CDCl ₃ ); 1.28 (t, 3H, J = 8.7 Hz), 1.40 (s, 9H), 1.42 (s, 6H), 3.32 (s, 2H), 3.78 (s, 2H) 1.84 (s, 2H), 4.15 (q, J = 8.7 Hz), 6.17 (m, 1H), 6.30

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32101 / H (m, 1H); 7.25-7.45 (m, 5H).

Example II-5

2 - [[4- [2 - [(carboxymethyl) - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

192 mg of 2 - [[4- [2- [2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester is added to 5 ml of ethyl alcohol and mixed with 0.4 ml of 1 N sodium hydroxide, whereupon the reaction mixture is stirred for one hour at 80 ° C. After DC-control (dichloromethane / methanol 10 + 1), it is cooled, concentrated and the residue is dissolved in a small amount of water. It is then acidified with 1N hydrochloric acid, extracted three times with ethyl acetate, the organic phases are combined, washed twice with water and twice with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Purify the solution on silica gel by flash chromatography (dichloromethane → dichloromethane / methanol 50 + 1 → 25 + 1). A colorless oil which solidifies under high vacuum is thus obtained.

¹ H-NMR (200 MHz, DMSO): 1.32 (s, 9H), 1.39 (s, 6H), 3.18 (s, 2H), 3.22 (s, 2H), 3.23 (s, 2H), 6.27 (m, 1H), 6.40 (m, 1H), 7.34 (d, 2H, J = 9.0 Hz), 7.50 (d, 2H, J = 9.0 Hz), 7.59 (m, 1H), 12.38 (breites with, 1H).

Example II-6

2 - [[4- [2 - [(2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

4.0 g of 2 - [[4- (2-aminoethyl) phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester [(PJ Brown et al., J. Med. Chem. 42, 3785-88 (1999)] Dissolve in 100 ml of methanol and mix with 2.6 g of furalum, add 9.3 ml of glacial acetic acid and boil briefly (10 minutes), then cool to 0 ° C, add in portions 4.25 g of sodium cyanoborohydride,

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32101 / H * r

F * *

F ~ _r · '' f frr stirred overnight, treated with 1 N hydrochloric acid until acidic and the mixture is stirred for 30 minutes. It is concentrated, basified with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated. After chromatographic purification (dichloromethane / methanol 15 + 1), 2.4 g of the title compound is obtained in Rf (dichloromethane / methanol 10 + 1) = 0.57.

Example II-7

2 - [[4- [2 - [(2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

2.4 g of 2 - [[4- [2 - [(carboxymethyl) - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoate 1,1-dimethylethyl ester are dissolved with 1.5 g of ethyl ester of bromoacetic acid, 0.97 g of triethylamine and 7.8 g of tetra-butylammonium iodide in 100 ml of tetrahydrofuran and allowed to reflux overnight. The reaction mixture was then treated with ethyl acetate and water and shaken with water and saturated sodium chloride solution. Concentration and chromatography of the residue (petroleum ether / ethyl acetate 10 + 1) gave 1.38 g of the title compound.

¹ H-NMR (200 MHz, DMSO): 1.18 (t, 3H, t, J = 7.8 Hz), 1.37 (s, 15H), 2.77 (m, 4H), 3.32 (s, 2H), 3.81 (s, 2H), 4.06 (q, 2H, J = 7.8 Hz), 6.21 (m, 1H), 6.34 (m, 1H), 7 16 (d, 2H, J = 9.6Hz), 7.32 (d, 2H, J = 9.6Hz), 7.58 (m, 1H).

Example II-8

2 - [[4- [2 - [(carboxymethyl) - (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

Mix 1.0 g of 2 - [[4- [2 - [(2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoate 1,1-dimethylethyl ester with 6, 5 ml of 1 N sodium hydroxide in 10 ml of ethyl alcohol, stirred for 1 hour at room temperature

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32101 / H at 80 ° C, concentrated, the residue is dissolved in water and acidified with 1N hydrochloric acid. Extraction three times with ethyl acetate and chromatography (dichloromethane / methanol 5 + 1) afforded 744 mg of the product as a colorless oil.

¹ H-NMR (200 MHz, DMSO): 1.36 (s, 15H), 2.75 (m, 4H), 3.20 (s, 2H), 3.72 (s, 2H), 6.18 (m, 1H), 6.88 (m, 1H), 7.12 (d, 2H, J = 9.5 Hz), 7.32 (d, 2H, J = 9.5 Hz), 7.56 (m, 1 H).

Example II-9

1,1-Dimethyl-2 - [[4 - [[(2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoate

7.9 g of 2 - [(4-formylphenyl) thio] -2-methyl-propanoic acid 1,1-dimethyl ester are introduced with 4.23 g of methoxyethylamine in 100 ml of methanol and mixed with 19 ml of acetic acid. The reaction mixture is stirred for 15 minutes at room temperature, boiled briefly and then treated at 0 ° in portions with 8.9 g of sodium cyanoborohydride. After stirring overnight at room temperature, it was treated with 1 N hydrochloric acid and allowed to stir for 30 minutes, then basified with sodium carbonate solution and extracted twice with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Concentration and purification by chromatography gave 5.6 g (58%) of the product as a colorless oil.

¹ H-NMR (200 MHz, DMSO): δ = 1.36 (s, 6H), 1.42 (s, 9H), 2.45 (m, 3H, CH ₂ + NH), 3.37 (s 3H), 3.88 (s, 2H), 7.25-7.52 (m, 4H).

Example 11-10

2 - [[4 - [[(2-methylfuran-methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester

8.0 g of 2 - [(formylphenyl) thio] -2-methylpropanoic acid 1,1-dimethyl ester

PP 0413-2003

32101 / H * * is introduced with 6.3 g of 5-methyl-2-furanomethylamine in 100 ml of methanol and mixed with 16 ml of acetic acid, stirred for 15 minutes at room temperature, boiled briefly and At 0 DEG C., 5.7 g of sodium cyanoborohydride are added. After stirring overnight at room temperature, the reaction mixture was treated with 1 N hydrochloric acid and allowed to stir for 30 minutes, then basified with sodium carbonate solution and extracted twice with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After concentration and purification by chromatography, 4.8 g (45%) of the product are obtained as a colorless oil which tends to decompose and is stored at -25 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.42 (s, 15H), 1.72 (s, 1H, NH), 2.28 (s, 3H), 3.79 (s, 2H) ), 3.78 (s, 2H), 5.88 (m, 1H), 6.03 (m, 3H), 7.28 (dd, 2H, J = 11 Hz), 7.45 (m, 2H) , J = 11Hz).

Example 11-11

2-bromo-N- (2,4-dimethylphenyl) acetamide

117 g of triethylamine and 140 g of 2,4-dimethylaniline are dissolved in 2 l of 4-methylene chloride and mixed with a solution of 233 g of α-bromoacetyl bromide in 400 ml of methylene chloride at a maximum of 15 ° C for 15 minutes under ice cooling. After a reaction time of 30 minutes, the precipitate formed is filtered off with suction, the residue is dissolved in 3 l of methylene chloride, combined with the filtrate and washed twice with 2 l of water and 2 l of saturated sodium chloride solution. It is dried over sodium sulphate, filtered off with suction and the residue is crystallized from ethanol. 193 g of the title compound are obtained.

Example 11-12

2-bromo-N- (2,4-dichlorophenyl) acetamide

This compound was prepared analogously to Example 11-11 of

PP 0413-2003

32101 / H

4.2 g of 2,4-dichloroaniline, 5.76 g of bromoacetyl bromide and 2.89 g of triethylamine in methylene chloride. 5.9 g (80.4%) of the title compound are obtained.

Rf (dichloromethane): 0.38

MS (EI pos.): M ⁺ = 238.

Production examples

Example 2-1

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester

Method a)

250 mg of 2 - [[4- [2- (carboxymethyl) (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester was mixed with 89 mg of hydroxybenzotriazole, 249 ml of triethylamine, 82 mg. 2,4-dimethylaniline and 131 mg of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and dissolved in 5 ml of dichloromethane. The reaction mixture is stirred for 20 hours at room temperature and extracted with 1N sodium hydroxide, 1N hydrochloric acid and saturated sodium chloride solution, the combined organic phases are dried over anhydrous magnesium sulphate and purified by chromatography (dichloromethane / ethyl acetate 25 + 1). 200 mg of product are obtained in the form of a viscous oil.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 4.87 min ([M + H] ⁺ = 523)

Method b)

1.5 g of 2 - [[4 - [[(2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester (Example II-3) and 1.1 g of 2- bromo-N- (2,4-dimethylphenyl) acetamide (Example II-9) was dissolved in 20 mL of dimethylformamide and treated with 0.4 g of sodium bicarbonate, whereupon the reaction mixture was heated to

PP 0413-2003

32101 / H

P P at 90 ° C, concentrated and purified by chromatography (dichloromethane / ethyl acetate 10: 1 and 5: 1). 2.1 g of the title compound are obtained.

Example 2-2

2 - [[4 - [[[2 - [(2,4,6-trimethylphenyl) amino] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester

250 mg of 2 - [[4- [2 - [(carboxymethyl) (2-furanylmethyl) amino] methyl] phenyl] thio-2-methylpropanoic acid 1,1-dimethyl ester is mixed with 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mg of 2 4,6-triethylaniline and 130 mg of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and dissolved in 5 ml of dichloromethane. The reaction mixture was stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous magnesium sulfate and chromatographed (dichloromethane / ethyl acetate 25 + 1) to give 210 mg of a viscous oil.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 5.32 min ([M + H] ⁺ = 537).

Example 2-3

2 - [[4 - [[[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester

250 mg of 2 - [[4- [2 - [(carboxymethyl) (2-furanylmethyl) amino] methyl] phenyl] thio-2-methylpropanoic acid 1,1-dimethyl ester were mixed together with 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mg of 2.5 -dimethyl-4-methoxyaniline and 130 mg of N '- (3-dimethylaminopropyl) -N-ethyl-carbodiimide hydrochloride and dissolved in 5 ml of dichloromethane. The reaction mixture is stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution.

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32101 / H

The organic phases were combined, dried over anhydrous magnesium sulfate and chromatographed (dichloromethane / ethyl acetate 25 + 1) to give 190 mg of a viscous oil.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 4.90 min ([M + H] = 552)

Example 2-4

2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester

250 mg of 2 - [[4- [2 - [(carboxymethyl) (2-furanylmethyl) amino] methyl] phenyl] thio-2-methylpropanoic acid 1,1-dimethyl ester is mixed with 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mg of 2 of methyl 4-methoxyaniline and 130 mg of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and dissolved in 5 ml of dichloromethane. The reaction mixture was stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution. The organic phases are combined, dried over anhydrous magnesium sulphate and chromatographic purification (dichloromethane / ethyl acetate 25 + 1) yields 190 ml of a viscous oil.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 4.69 min ([M + H] + = 538)

Example 2-5

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

OH

PP 0413-2003

32101 / H mg 2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methyl- tert-butyl ester of propanoic acid is dissolved in 5 ml of dichloromethane and treated with 0.1 ml of trifluoroacetic acid. After stirring at room temperature for 4 hours, concentration and chromatographic purification (dichloromethane / methanol 100 + 1), 80 mg of the title compound is obtained as a foamy solid.

Rf (dichloromethane / methanol 10 + 1) = 0.3 ¹ H-NMR (400 MHz, D ₆ -DMSO): δ = (s, 6H, CH ₃ ), 2.16 (s, 3H, CH ₃ ), 2.23 (s, 3H, _CH3), 3.24 (s, 2H, _CH2), 3.76 (s, 2H, _CH2), 3.78 (s, 2H, CH _2), 6, 38-6.40 (m, 2H, 2x furanyl-H), 6.93-6.95 (d, 2H, Ar-H), 7.0 (s, 1H, Ar-H), 7.38 7.51 (m, 4H, Ar-H), 7.60-7.61 (m, 1H, furanyl-H), 9.14 (s, 1H, NH).

MS (EI pos.): M ⁺ = 467 ([M + H] ⁺ , m / z = 489 ([M + Na] +)

R _t = 3.76 min ([M + H] + = 467).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.76 min ([M + H] + = 467).

Example 2-5-a

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic dicyclohexylammonium salt

500 mg of 2 - [[4 - [[[2- [2,4-dimethylphenylamino] -2-oxoethyl]] - (2PP 0413-2003)

32101 [H (furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid (ex. 2-5) was dissolved in 500 mg acetonitrile and 194 mg dicyclohexylamine was added. Water is then added, part of the acetonitrile is distilled off until cloudy and lyophilized. 445 mg of a powder is obtained.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.76 min ([M + H] ⁺ = 467).

Example 2-5-b

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid hydrochloride

OH x HCl

1.20 g of 2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid ( Ex. 2-5) was dissolved in 100 mg of ethyl acetate hot and stirred with 1 N HCl / diethyl ether until cloudy. The precipitated crystals are suctioned off and washed with dried diethyl ether. 1 g of the title compound is obtained.

Mp: 158 ° C (ethanol / diethyl ether).

Example 2-6

2 - [[4 - [[[2 - [(2,4,6-trimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

PP 0413-2003

32101 / H à *

ΌΗ

210 mg of 2 - [[4 - [[[2 - [(2,4,6-trimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methyl tert-butyl ester -propanoic acid is dissolved in 5 ml of dichloromethane and treated with 1 ml of trifluoroacetic acid. After stirring at room temperature for 4 hours, concentration and chromatographic purification (dichloromethane / ethyl acetate 50 + 1), 187 mg of the title compound is obtained as a foamy solid.

¹ H-NMR (200 MHz, DMSO): 1.42 (s, 6H), 2.04 (s, 6H), 2.23 (s, 3H), 3.58 (breites s, 2H), 4, 05 (s, 2H), 4.12 (s, 2H), 6.55 (m, 2H), 6.87 (s, 2H), 7.48 (d, 2H, J = 9.0 Hz), 7.51 (d, 2H, J = 9.0 Hz), 7.72 (m, 1H), 9.40 (breites with, 1H).

Example 2-7

2 - [[4 - [[[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methyl- propane

OH

190 mg of 2 - [[4 - [[[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio acid tert-butyl ester 2-Methyl-propanoic acid is dissolved in 5 ml of dichloromethane and treated with 1 ml of trifluoroacetic acid. After stirring for 20 hours at room temperature, concentration and chromatographic purification (dichloromethane / methanol 50 + 1), 166 mg of the title compound is obtained as a foamy solid.

PP 0413-2003

¹ H-NMR (200 MHz, DMSO): 1.39 (s, 6H), 2.08 (s, 3H), 2.11 (s, 3H), 3.7 (s, 3H), 4.00 (breites s, 4H), 6.48 (m, 1H), 6.51 (m, 1H), 6.76 (s, 1H), 7.08 (s, 1H), 7 48 (m, 4H), 7.72 (m, 1H), 9.35 (breites with, 1H), 12.65 (breites with, 1H).

Example 2-8

2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

200 mg of 2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-tert-butyl ester of methyl-propanoic acid is dissolved in 5 ml of dichloromethane and treated with 1 ml of trifluoroacetic acid. After stirring for 20 hours at room temperature, concentration and chromatographic purification (dichloromethane / methanol 50 + 1), 174 mg of the title compound is obtained as a foamy solid.

¹ H-NMR (200 MHz, DMSO): 1.38 (s, 6H), 2.12 (s, 3H), 3.7 (s, 3H), 3.80 (breites s, 2H), 4, Δ (breites s, 2H), 6.45 (m, 1H), 6.55 (m, 1H), 6.65 (m, 1H), 6.78 (m, 1H), 7.25 (m, 1H) 1H), 7.48 (m, 4H), 7.71 (m, 1H), 9.37 (breites with, 1H), 12.65 (breites with, 1H).

Example 2-9

2 - [[4- [2 - [[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester

104 mg of 2 - [[4- [2 - [[2 - [(2,4-dimethylphenyl) amino] 2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methyl- 1,1-dimethyl ester propane mix

PP 0413-2003

32101 / H together with 36 mg hydroxybenztriazole, 0.1 ml triethylamine, 29 mg 2,4dimethylaniline and 53 mg N '- (3-dimethylaminopropyl) -ethylcarbodiimide hydrochloride and dissolved in 5 ml dichloromethane. The reaction mixture was stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution. The organic phases are combined, dried over anhydrous magnesium sulphate and purified by chromatography (dichloromethane / ethyl acetate 5 + 1). 190 mg of a viscous oil are obtained.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 5.3 min ([M + H] ⁺ = 537).

¹ H-NMR (200 MHz, CDCl ₃ ): 1.38 (s, 9H), 1.40 (s, 6H), 2.08 (s, 3H), 2.28 (s, 3H), 2, 82 (m, 4H), 3.32 (s, 2H), 3.78 (s, 2H), 6.22 (m, 1H), 6.95 (m, 1H), 7.00 (m, 1H) 7.05 (d, 2H, J = 10.0 Hz), 7.35 (d, 2H, J = 10.0 Hz), (m, 1H), 7.79 (m, 1H), 8 95 (breites s, 1 H), 12.60 (breites s, 1 H).

Example 2-10

2 - [[4- [2 - [[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid tert-butyl ester mg 2 - [[4- [2 - [[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2,2-dimethyl ester methylpropanoic acid is mixed with 33 mg of hydroxybenzotriazole, 0.09 ml of triethylamine, 34 mg of 2,5-dimethyl-4-methoxyaniline and 49 mg of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and dissolved in 5 ml of dichloromethane. The reaction mixture was stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution. The organic phases are combined, dried over anhydrous magnesium sulphate and purified by chromatography (dichloromethane / ethyl acetate 5 + 1). 48 mg of a viscous oil are obtained.

R t = 0.65 min ([dichloromethane / ethyl acetate = 10 + 1).

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32101 / H

Example 2-11

2 - [[4- [2 - [[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid

0 mg of 2 - [[4- [2 - [[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methyl- tert-butyl ester of propanoic acid is dissolved in 5 ml of dichloromethane and mixed with 0.27 ml of trifluoroacetic acid. The reaction mixture is stirred for 24 hours at room temperature, taken up in toluene and the residue purified by chromatography (dichloromethane / methanol 10 + 1). 33 mg of product are obtained in the form of a colorless oil.

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 3.38 min ([M + H] ⁺ = 481).

Example 2-12

2 - [[4- [2 - [[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methyl -propanoic

O .OH

ABOUT

PP 0413-2003

32101 / H

PP mg 2 - [[4- [2 - [[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thio] - tert-butyl ester - 2-Methyl-propanoic acid is dissolved in 5 ml of dichloromethane and treated with 0.20 ml of trifluoroacetic acid. The reaction mixture is stirred for 24 hours at room temperature, taken up in toluene and the residue purified by chromatography (dichloromethane / methanol 10 + 1). 27 mg of product are obtained in the form of an air-dark oily substance. LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.78 min ([M + H] ⁺ = 511).

¹ H-NMR (200 MHz, DMSO): 1.35 (s, 9H), 2.05 (s, 3H), 2.10 (s, 3H), 2.82 (m, 4H), 3.25 (s, 2H), 3.72 (s, 3H), 3.82 (s, 2H), 6.33 (m, 2H), 6.72 (m, 1H), 7.15 (d, 2H, J = 9.8 Hz), 7.24 (d, 2H, J = 9.8 Hz), (m, 1H), 7.62 (m, 1H), 8.88 (breites with, 1H), 12 55 (breites s, 1 H).

The following exemplary compounds are obtained in an analogous manner:

Example 2-13

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(2,4-dichlorophenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

Cl

OH

Yield: 343 mg (68%) ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.50 (s, 6H, 2 x CH ₃ ), 2.19 (s, 3H, CH ₃ ), 3, 38 (s,

2H, _CH2), 3.78 (s, 2H, _CH2), 3.83 (s, 2H, _CH2), 4.30 (s, br, 1H, COOH), 5.85 (m,

1H, furanyl-H), 6.16 (m, 1H, furanyl-H), 7.18-7.49 (m, 6H, Ar-H), 8.30 (m, 1H,

PP 0413-2003

32101 / H

Ar-H), 9.68 (s, 1H, NH).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.42 min ([M + H] ⁺ = 521).

Example 2-14

2-Methyl-2 - [[4 - [[[(5-methyl-2-furyl) methyl] -2-oxo-2 - [(2,4,6-trichlorophenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

Yield: 90 mg (36%) ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.53 (s, 6H, 2 x CH ₃ ), 2.29 (s, 3H, CH ₃ ), 3, 75 (s, 2H, _CH2), 4.25 (s, 2H, _CH2, 4.28 (s, 2H, _CH2), 5.95 (m, 1H, furanyl-H), 6.49 ( m, 1H, furanyl-H), 7.35 (s, 2H, Ar-H), 7.38-7.51 (m, 4H, Ar-H), 9.51 (s, 1H, NH). LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 3.05 min ([M + H] + = 555).

Example 2-15

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(2,4,6-trimethylphenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

PP 0413-2003

32101 / H yy

Yield: 46 mg (26%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 4.18 min ([M + H] = 494).

Example 2-16

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(2,4-dimethylphenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

OH

Yield: 183 mg (41%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.80 min ([M + H] ⁺ = 481).

Example 2-17

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(2,5-dimethyl-4-methoxyphenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

OH

PP 0413-2003

32101 / H

Yield: 149 mg (67%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 4.10 min ([M + H] ⁺ = 511).

Example 2-18

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(4-chloro-2-trifluoromethylphenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

Yield: 63 mg (22%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 3.48 min ([M + H] ⁺ = 555).

Example 2-19

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] -2-oxo-2 - [(4-methoxy-2-methylphenyl) amino] ethyl] amino] methyl] phenyl] thio] propanoic acid

PP 0413-2003

32101 / H yy

Yield: 24 mg (18%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.59 min ([M + H] + = 497).

Example 2-20

2 - [[4 - [[[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid \

ABOUT

OH

Yield: 60 mg (60%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.15 min ([M + H] ⁺ = 475).

Example 2-21

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(2,4-bistrifluoromethylphenyl] amino] ethyl] amino] methyl] phenyl ] thio] propanoic acid

CF.

OH

Yield: 16 mg (20%)

PP 0413-2003

32101 / H •

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.59 min ([M + H] ⁺ = 589).

Example 2-22

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(2-methyl-4-trifluoromethoxy-5-chlorophenyl) amino] ethyl] amino acid ] methyl] phenyl] thio] propanoic acid

OH

Yield: 89 mg (81%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.36 min ([M + H] ⁺ = 585).

Example 2-23

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(2-trifluoromethyl-4-trifluoromethoxyphenyl] amino] ethyl] amino] methyl] phenyl ] thio] propanoic acid

N

H

OH

Yield: 22 mg (34%).

PP 0413-2003

32101 / H

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 3.52 min ([M + H] ⁺ = 605).

Example 2-24

2 - [[4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

Yield: 26 mg (20%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.05 min ([M + H] ⁺ = 553).

Example 2-25

2 - [[4 - [[[2 - [[2,4-dichlorophenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

Yield: 61 mg (27%).

PP 0413-2003

32101 / H ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.38 (s, 6H, 2 x CH ₃ ), 2.82 (m, 2H, CH ₂ ), 3.23 (s, 3H) , OMe), 3.32 (s, 2H, _CH2), 3.50 (m, 2H, _CH2), 3.73 (s, 2H, _CH2), 5.28 (s, 1H, COOH) 7.15-7.48 (m, 6H, Ar-H); 8.35 (m, 1H, Ar-H); 9.90 (s, 1H, NH). LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.76 min ([M + H] ⁺ = 485).

Example 2-26

2 - [[4 - [[[2 - [[2,4-dimethylphenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

Yield: 50 mg (75%) ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.50 (s, 6H, 2 x CH ₃ ), 2.15 (s, 3H, Me), 2.28 (s, 3H, Me), 3.34 (s, 3H, OMe), 3.40 (m, 2H, _CH2), 3.68 (m, 2H, _CH2), 3.83 (s, 2H , CH ₂ ), 4.32 (s, 2H, CH ₂ ), 5.40 (s, 1H, COOH), 7.00 (m, 2H, Ar-H), 7.32-7.52 (m 7H, Ar-H), 9.00 (s, 1H, NH).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.22 min ([M + H] ⁺ = 445).

Example 2-27

2-Methyl-2 - [[4 - [[[(2-thiophenyl) methyl] [2-oxo-2 - [(2-methyl-4-trifluoromethoxy-5-chlorophenyl) amino] ethyl] amino] methyl] phenyl ] thio] propanoic acid

PP 0413-2003

32101 / H

Yield: 200 mg (99%) ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.50 (s, 6H, 2 x CH ₃ ), 2.20 (s, 3H, Me), 3.61 (s, 2H, _CH2), 4.20 (s, 2H, _CH2), 4.48 (s, 2H, _CH2), 5.60 (s, 1H, COOH), 7.00 (m, 2H, Ar-H), 7.02-7.17 (m, 3H, Ar-H and thienyl-H), 7.36 (m, 3H, Ar-H), 7.50 (m, 2H, Ar -H), 8.00 (s, 1H, Ar-H), 8.88 (s, 1H, NH).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.40 min ([M + H] ⁺ = 587).

Example 2-28

2-Methyl-2 - [[4 - [[[(2-thiophenyl) methyl] [2-oxo-2 - [(2-trifluoromethyl-4-trifluoromethoxyphenyl) amino] ethyl] amino] methyl] phenyl] thio ] -propanoic

Yield: 80 mg (98%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 3.56 min ([M + H] ⁺ = 606).

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Example 2-29

2-Methyl-2 - [[4 - [[[(2-thiophenyl) methyl] [2-oxo-2 - [(2-methyl-4-methoxyphenyl) amino] ethyl] amino] methyl] phenyl] thio ] -propanoic

OH

Yield: 83 mg (83%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.74 min ([M + H] ⁺ = 498).

Example 2-30

2-Methyl-2 - [[4 - [[[(2-furanyl) methyl] [2-oxo-2 - [(2,4-dimethoxyphenyl) amino] ethyl] amino] methyl] phenyl] thio] -propanoic acid

OH

Yield 75 mg (60%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 4.19 min ([M + H] ⁺ = 499).

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32101 / H

Example 2-31

2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino-2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

Yield: 65% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.51 (s, 6H), 2.18 (s, 3H), 3.34 (s, 3H), 3.37 3, 45 (m, 2H), 3.65-3.75 (m, 2H), 3.77 (s, 3H), 3.89 (s, 2H), 4.34 (s, 2H), 6.67 6.78 (m, 2H), 7.35-7.44 (m, 3H), 7.52 (d, 2H), 9.05 (s, 1H).

Example 2-32

2 - [[4 - [[[2 - [(2,4,6-trimethylphenyl) amino-2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

Yield: 89% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.51 (s, 6H), 2.12 (s, 6H), 2.25 (s, 3H), 3.35 (s) .

3H), 3.38-3.54 (m, 2H), 3.65-3.77 (m, 2H), 3.85-3.94 (m, 2H), 4.30-4.45 (m) m, 2H), 6.87 (s, 2H), 7.39 (d, 2H), 7.53 (d, 2H), 8.82 (br s, 1H).

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32101 / H

Starting compounds III

Example 111-1

Tert-butyl (4-formyl-phenoxy) -acetate

ABOUT

To a solution of 27.50 (225.18 mmol) of 4-hydroxybenzaldehyde in 200 mL of dioxane at room temperature was added 31.60 g (281.48 mmol) of potassium tert-butylate and 52.70 g (270.22 mmol) of tert-butylate. butyl bromoacetate and the reaction mixture is heated to boiling overnight. After addition of 1 L of water, it is extracted with diethyl ether, washed with 1 N sodium hydroxide solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is distilled off. After flash chromatography on silica gel (cyclohexane → cyclohexane / ethyl acetate 20: 1 → 10: 1 5: 1), the title compound is obtained after crystallization from pentane.

Yield: 31%

mp: 58-60 ° C

Example III-2

Tert-butyl 2- (4-formyl-phenoxy) -2-methylpropanoate

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32101 / H e r

24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml of N, N-dimethylformamide and treated with 27.64 g (200 mmol) of potassium carbonate. At 100 ° C, 53.55 g (240 mmol) of t-butyl abromoisobutyrate are added dropwise, stirred for one hour, an additional 200 mmol of potassium carbonate and 240 mmol of α-bromoisobutyric acid tert-butyl ester are added and after 4 hours at temperature. At 100 ° C, the reaction mixture was mixed with 1 L of water. After washing with 1N sodium hydroxide and saturated sodium chloride solution and drying over anhydrous magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexene -> cyclohexane / ethyl acetate 20: 1 - »5: 1) and in vacuo. is dried. The title compound is obtained as a colorless crystalline substance. Yield: 42% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H, 1.62 (s, 6H), 6.91 (d, 2H), 7.79 (d, 2H), 9.88 (s, 1H).

MS (ESI): 265 [M + H] +.

The following compounds are obtained analogously to Example III-2:

Example III-3

Ethyl 2- (4-formyl-phenoxy) -2-methylbutanoate

ABOUT.

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32101 / H • e

Yield: 11.71% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.00 (t, 3H), 1.22 (t, 3H), 1.61 (s, 3H), 1.90 2.20 (m, 2H), 4.24 (q, 2H), 6.90 (d, 2H), 7.80 (d, 2H), 9.85 (s, 1H).

MS (ESI): 251 [M + H] < ^{+ &gt};, 273 [M + Na] ⁺ .

Example III-4

Tert-Butyl 2 - [(3-bromophenyl) sulfanyl] -2-methylpropanoate

Yield: 87% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.43 (s, 9H), 1.45 (s, 9H), 1.45 (s, 6H), 7.14%, 28 (m, 1H); 7.39-7.53 (m, 2H); 7.67 (t, 1H).

MS (DCI / NH ₃ ): 348 [M + NH _4] .

Example III-5

Tert-butyl 2- (3-formyl-phenoxy) -2-methylpropanoate

Yield: 35%

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32101 / H ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.44 (s, 9H), 1.61 (s, 6H), 7.14 (dd, 1H), 7.31 7.35 (m, 1H), 7.41 (t, 1H), 7.45-5.52 (m, 1H).

MS (DCI / NH 3): 282 [M + NH ₄ ] ⁺ .

Example III-6

Tert-butyl 2- (3-bromophenoxy) -2-methylpropanoate

Yield: 21% ¹ H-NMR (300 MHz, CDCl 3): δ = 1.44 (s, 9H), 1.56 (s, 6H), 6.74-6.83 (m, 1H), 00-7.04 (m, 1H), 7.06-7.11 (m, 2H).

MS (DCI / NH 3): 332 [M + NH ₄ ] ⁺ .

Example III-7

Tert-Butyl 2- [4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenoxy] -2metylpropanoát

ABOUT

Yield: 24%

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32101 / H

Mp: 142-143 ° C

Example III-8

Tert-Butyl 2 - [(3-formyifenyl) sulfanyl] -2-methylpropanoate

At -78 ° C, 30.00 g (90.56 mmol) of the compound of Example III-4 is dissolved in tetrahydrofuran and treated with 36.2 mL of a 2.5 M solution of n-butyllithium in hexane, to which 13 94 ml (181.12 mmol) of Ν, Ν-dimethylformamide. After 30 minutes, warm the reaction mixture to room temperature and stir for one hour. 30 ml of 1N hydrochloric acid are then added, the solvent is distilled off, the residue is extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After flash chromatography on silica gel (dichloromethane), the title compound was purified by NP-HPLC (cyclohexane / ethyl acetate) to give a yield of 10%.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.43 (s, 9H), 1.46 (s, 6H), 7.50 (t, 1H), 7.77 7.80 (m, 1H), 7.87 (d, 1H), 7.98 - 8.05 (m, 1H), 10.00 (s, 1H), 7.87 (d, 1H), 70.98 - 8.05 (m, 1 H), 10.00 (s, 1 H).

MS (DCI / NH ₃ ): 298 [M + NH ₄ ] ⁺ .

Example III-9

Tert-butyl 2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethenyl] phenoxy} -2metylpropanoát

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Ο

14.93 g (47.37 mmol) of the compound of Example III-6, 10.25 g (59.21 mmol) of vinyl phthalimide, 0.39 g (1.27 mmol) of tris-, were heated in an autoclave at 130 ° C. o-tolylphosphine, 0.07 g (0.32 mmol) and 21.78 g (215.23 mmol) of triethylamine. After addition of a mixture of water and methanol, the precipitate is filtered off with suction and crystallized from a mixture of cyclohexane and ethyl acetate.

Yield: 66% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.50 (s, 6H), 6.73 (dd, 1H), 6.86 δ, 93 (m, 1H); 7.16 (t, 1H); 7.21-7.34 (m, 2H); 7.43 (d, 1H); 7.80-8.00 (m, 4H) . MS (DCI / NH ₃ ): 425 [M + NH ₄ ] ⁺ .

Example 111-10

Tert-butyl 2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -ethyl] -phenoxy} -2metylpropanoát

15.00 g (36.81 mmol) of the compound of Example III-9 are dissolved in 200 ml of tetrahydrofuran and stirred under a hydrogen atmosphere at normal pressure overnight in the presence of a suspension of 2.00 g (2.16 mmol) of Wilkinson's catalyst in 40 ml.

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32101 / H e r

F e r e

ml of ethyl alcohol. After two flash chromatography on silica gel (cyclohexane / dichloromethane 10: 1 → cyclohexane / ethyl acetate 10: 1 → 5: 1 and cyclohexane → cyclohexane / dichloromethane → dichloromethane), the title compound is obtained in a yield of 64%.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.45 (s, 9 H), 1.52 (s, 6H), 2.85 to 3.00 (m, 2H), 3.82 to 3 95 (m, 2H), 6.65-6.80 (m, 2H), 6.88 (d, 1H), 7.15 (t, 1H), 7.62-7.76 (m, 2H) 7.77-7.89 (m, 2H).

MS (ESI): 432 [M + Na] +, 841 [2M + Na] +.

Example 111-11

Tert-butyl 2- (4-aminophenoxy) -2-methylpropanoate

18.88 g (49.50 mmol) of the compound of Example III-7 are dissolved in 25 ml of ethyl alcohol and heated to boiling with 12.04 ml (247.49 mmol) of hydrazine hydrate for 2 hours, then stirred for 12 hours. at room temperature. The precipitate was collected, washed with ethyl alcohol, the filtrate was concentrated and then diluted with 1 L of diethyl ether. This solution was washed with 1 N sodium hydroxide solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent, the title compound is obtained in a yield of 87%.

Mp: 87-88 ° C.

Analogously to Example 111-11, the following compound is obtained:

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32101 / H N.83

Example 111-12

Tert-Butyl 2- [3- (2-aminoethyl) phenoxy] -2-methylpropanoate

Yield: 70% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.31 (breites s, 2H), 1.44 (s, 9H), 1.56 (s, 6H), 2.69 ( t, 2H), 2.94 (t, 2H), 6.64-6.754 (m, 2H), 6.81 (d, 1H). 7.15 (t, 1 H).

MS (ESI): 279 [M < ⁺ &^gt;],

Example 111-13

Tert-butyl 2- (4 - {[(2-furylmethyl) amino] methyl} phenoxy) -2-methylpropanoate

20.00 g (75.67 mmol) of the compound of Example III-2 and 7.35 g (75.67 mmol) of 2-furylamine are stirred in 350 ml of 1,2-dichloromethane with 24.06 g (113.50 mmol). of sodium acetoxyborohydride for 5 hours at room temperature. The reaction mixture is then mixed with saturated sodium bicarbonate solution and ethyl acetate, after which the organic phase is dried over magnesium sulfate and the solvent is distilled off by means of a solvent.

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32101 / H flash chromatography on silica gel (cyclohexane → cyclohexane / ethyl acetate 10: 1- + 2: 1). The title compound is obtained in a yield of 72%.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.61 (breites s, 1H), 1.44 (s, 9H), 1.55 (s, 6H), 3.71 (s, 2H) 3.77 (s, 2H); 6.17 (d, 1H); 6.26-6.36 (m, 1H); 6.70-6.88 (m, 2H); 7.18 (d) (2H), 7.32-7.40 (m, 1H).

MS (ESI): 346 [M + H] +.

Example 111-14

Tert-butyl 2- {4 - [(2-furylmethyl) amino] phenoxy} -2-methylpropanoate

4.97 g (19.06 mmol) of the compound of Example 111-11 and 1.83 g (19.06) of fural are dissolved in 80 ml of 1,2-dichloroethane and stirred in the presence of 6.06 g (28.59). mmol) of sodium acetoxyborohydride for 5 hours at room temperature. The reaction mixture is then mixed with saturated sodium bicarbonate solution and ethyl acetate, the organic phase is dried over anhydrous magnesium sulphate and, after distillation of the solvent, the residue is purified by flash chromatography on silica gel (cyclohexane -> cyclohexane / ethyl acetate 10 1 -> 2 L) and HPLC (cyclohexane / ethyl acetate 10: 1) to give the title compound in 79% yield.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.46 (s, 9 H), 1.48 (s, 6H), 3.80 (broad s, 1H).

4.26 (s, 2H), 6.21 (d, 1H), 6.25-6.35 (m, 1H), 6.50-6.61 (m, 2H), 6.72-6, 85 (m, 2H); 7.30-7.39 (m, 1H).

MS (DCI / NH ₃ ): 332 [M + H] ⁺ , 349 [M + NH ₄ ] ⁺ .

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Example 111-15

Tert-Butyl 2- [4 - [[(2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] methyl] phenoxy] -2-

In 200 ml of tetrahydrofuran, 18.14 g (52.50 mmol) of the compound of Example 111-13, 11 ml of triethylamine and 1.10 g (2.97 mmol) of tetra-butylammonium iodide with 8.77 ml (78.75 mmol) are introduced. of ethyl bromoacetate and the reaction mixture is stirred at room temperature for 1 hour and at 60 ° C for 2 hours. It is then treated with water and ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulphate and, after evaporation of the solvent, the residue is purified by flash chromatography on silica gel (cyclohexane / dichloromethane 4: 1-cyclohexane / ethyl acetate 10). : 1 -> 5: 1). The yield is quantitative.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.26 (t, 3H), 1.43 (s, 9 H), 1.55 (s, 6H), 3.30 (s, 2H); 3.71 (s, 2H), 3.83 (s, 2H), 4.15 (q, 2H), 6.19 (d, 1H), 6.28-6.34 (m, 1H), 6 77.65 (m, 2H); 7.22 (d, 2H); 7.35-7.41 (m, 1H).

MS (ESI): 432 [M + H] < ^{+ &gt};.

Example 111-16

Tert-Butyl 2- [4 - [[(carboxymethyl) (2-furanylmethyl) amino] methyl] phenoxy] -2metylpropanoát

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32101 / H •

ABOUT

22.01 g (51.00 mmol) of the compound of Example 111-15 were stirred in 785 ml of ethyl alcohol in the presence of 6.12 g (153.00 mmol) of sodium hydroxide for one hour at 80 ° C. After distilling off the solvent and adding water, it is acidified with 1N hydrochloric acid and extracted with ethyl acetate, washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and reducing the amount of solvent, the product is filtered off with suction and dried to give the title compound in a yield of 74%.

Mp: 152-155 ° C.

Example 111-17

2-bromo-N- [4-isopropyl-2- (trifluoromethyl) phenyl] acetamide

br

0 g (246.06 mmol) of 4-isopropyl-2- (trifluoromethyl) aniline are introduced together with 27.39 g (270.66 mmol) of triethylamine into 1000 ml of dichloromethane. At 0-5 ° C, 54.63 g (270.66 mmol) of bromoacetyl bromide dissolved in 200 mL of dichloromethane are added dropwise and the batch is stirred for 20 hours at room temperature. Then, the reaction mixture is extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water, and the organic phase is dried over anhydrous sulfate.

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Of sodium and the solvent was evaporated in vacuo. The residue is purified by chromatography, the product is crystallized from a mixture of cyclohexane and n-pentane, filtered off with suction and dried at 40 DEG C. for 20 hours under vacuum. 32.45 g (41% of theory) of the title compound are obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 2.95 (sept, 1H), 4.05 (s, 2H), 7.45 (d, 1H) 7.49 (s, 1H); 8.02 (d, 1H); 8.50 (br s, 1H).

Example 111-18

2-bromo-N- [4-tert-butyl-2-methyl-phenyl) -acetamide

5.5 g (33.69 mmol) of 4-tert-butyl-2-methylaniline are introduced together with 3.75 g (37.06 mmol) of triethylamine in 150 ml of dichloromethane and added dropwise at 0 ° C to 5 ° C. 7.48 g (37.06 mmol) of bromoacetyl bromide, dissolved in 90 mL of dichloromethane, gave a light brown precipitate. The mixture was stirred overnight at room temperature, after which the reaction mixture was treated with 150 ml of ethyl acetate and extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. The residue is purified by chromatography and the product is recrystallized from ethyl acetate and n-pentane, filtered off with suction and dried in vacuo at 40 ° C. 6.53 g (68% of theory) of the title compound are obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.3 (s, 9H), 2.3 (s, 3H), 4.06 (s, 2H), 7.20-7.23 (m 1 H, 7.25 (d, 1 H), 7.7 (d, 1 H), 8.05 (br s, 1 H).

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Example 111-19

2-bromo-N- (4-cyclohexyl-2-methyl-phenyl) -acetamide

Yield: 41.0% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.20-1.50 (m, 5H), 1.65-1.95 (m, 5H), 2.28 ( s, 3H), 2.35-2.55 (m, 1H), 4.07 (s, 2H), 7.00-7.13 (m, 2H), 7.69 (d, 1H), 8 .05 (brs, 1H).

Example III-20

2-bromo-N- (5,6,7,8-tetrahydro-1-naphthalenyl) acetamide

br

Yield: 95.6% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.70-1.90 (m, 4H), 2.55-2.70 (m, 2H), 2.75 2 85 (m, 2H), 4.08 (s, 2H), 6.95 (d, 1H), 7.14 (t, 1H), 7.69 (d, 1H), 8.09 (br s) , 1H).

Example 111-21

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32101 / H

2-bromo-N- [4- (1-naphthyloxy) -2- (trifluoromethyl) phenyl] acetamide

Yield: 80.5% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 4.08 (s, 2H), 7.01, (d, 1H), 7.18 (dd, 1H), 7, 30 7.62 (m, 4H), 7.70 (d, 1H), 7.85-8.17 (m, 3H), 8.47 (br s, 1H).

Example III-22

2-bromo-N- [5-chloro-2- (2-naphthyloxy) phenyl] acetamide

Yield: 77.9% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 3.99 (s, 2H), 6.88 (d, 1H), 7.06 (dd, 1H), 21 7.36 (m, 2H); 7.38-7.57 (m, 2H); 7.68-7.79 (m, 1H); 7.80-7.95 (m, 2H); 51 (d, 1H); 8.85 (brs, 1H).

Example III-23

N- [2,4-bis (trifluoromethyl) phenyl] -2-bromoacetamide

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32101 / H

Yield: 28% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 4.10 (s, 2H), 7.80-7.91 (m, 2H), 8.50 (d, 1H), 8 .80 (brs, 1H).

Example III-24

2-Bromo-N- (2-ethoxy-1-naphthyl) acetamide

Yield: 24% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.46 (t, 3H), 4.10-4.30 (m, 4H), 7.26-7.30 (d, 1H, 7.36 (t, 1H), 7.50 (t, 1H), 7.70-7.87 (m, 3H), 8.07 (br s, 1H).

Example III-25

2-bromo-N- {5 - [(ethylsulfonyl) methyl] -1-naphthyl} acetamide

br

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32101 / H c

Yield: 16% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.37 (t, 3H), 1.54 (s, 1H), 2.91 (q, 2H), 4.20 (s 2H, 4.72 (s, 2H), 7.53-7.70 (m, 3H), 7.90-8.11 (m, 3H), 8.65 (br s, 1H).

Example 111-26

2-bromo-N- [5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] acetamide

Yield: 84.0% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 2.35 (s, 3H), 4.08 (s, 2H), 7.18 (s, 1H), 8.05 8.20 (m, 2 H).

Example III-27

4-methyl-1,3-oxazole-5-carbaldehyde oxime ₃

OH

0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5PP 0413-2003 are introduced in 3 ml of water.

32101 / H carbaldehyde (made from the corresponding alcohol (Chem. Ber. 1961, 1248) by Swern oxidation (Tetrahedron 34, 1651 (1978))) and mixed with 0.66 g (9.45 mmol) of hydrochloride of hydroxylamine in 2 ml of water, then 0.68 g (4.95 mmol) of potassium carbonate are added, after 2 hours the product is filtered off with suction, washed with water and dried at room temperature to yield 0.41 g (72.2% of theory). ).

¹ H-NMR (200 MHz, _CDCl3): δ = 2.21 (s, 3H), 8.20 (s, 1H), 8.33 (s, 1H), 11.48 (s, 1H).

Example III-28 (4-Methyl-1,3-oxazol-5-yl) -methylamine

CH, NH ₂

4.00 g (31.72 mmol) of 4-methyl-1,3-oxazole-5-carbaldehydexime in 70 ml of acetic acid are introduced and 47.70 g (729.50 mmol) of powdered powder are added in small portions at room temperature. zinc. The reaction mixture is allowed to stir at room temperature for 2 hours, after which the zinc powder is filtered off with suction and washed twice more with 50 ml of acetic acid. The filtrate is freed from the solvent in vacuo and the residue is stirred with 20% sodium hydroxide until a pH of 11 is reached. The white crystalline precipitate formed is stirred with ethyl acetate and filtered off with suction. The combined filtrates were stripped of solvent in vacuo and the residue was purified by chromatography. 1.34 g (38% of theory) of the title compound are obtained.

¹ H-NMR (300 MHz, _CDCl3): δ = 1.5 (s, 2H), 2.15 (s, 3H), 3.83 (s, 2H), 7.73 (s,

1H).

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Example 111-29

2 - [(4-bromophenyl) thio] -2-ethyl-butanoic acid 1,1-dimethyl ester

The synthesis is carried out analogously to Example 11-1 from 4-bromothiophenol and 2-bromo-2-ethyl-butanoic acid 1,1-dimethyl ester [for example, according to Liebigs Ann. Chem. 725,106-115 (1969); J. Am. Soc. 77, 946947 (1955) and bromination with N-bromosuccinimide or bromine, for example according to Tetrahedron Lett. 1970, 3431; J. Org. Chem. 40, 3420 (1975)]. yield; 15.9% of theory ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.58-1.74 (m, 4H), 7.28-7.35 (m (2H)), 7.39-7.46 (m, 2H).

Example III-30

2-Ethyl-2 - [(4-formylphenyl) thio] -butyric acid 1,1-dimethyl ester

H

The synthesis is carried out analogously to Example II-2, starting from the compound of Example III-29.

Yield: 70.4% of theory

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32101 / 1H er ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.64-1.87 (m, 4H), 7.60 (d, 2H), 7 78 (d, 2H); 10.1 (s, 1H).

Example 111-31

Tert-butyl-2-ethyl-2 - [(4 - {[(2-furylmethyl) amino] methyl} phenyl) thio] butanoate

The synthesis is carried out analogously to Example 111-13, starting from the compound of Example III-30.

Yield: 83.1% of theory ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.93 (t, 6H), 1.43 (s, 9H), 1.60-1.75 (m, 4H) ), 3.78 (s, 4H), 6.18 (d, 1H), 6.28 - 6.35 (m, 1H), 7.25 (d, 2H), 7.35 - 7.38 ( m, 1H), 7.43 (d, 2H).

Example III-32

Tert-Butyl 2-methyl-2- [4 - ({[(4-methyl-1,3-oxazol-5-yl) methyl} metyljamino) fenoxyjpropanoát

1.25 g (4.73 mmol) of tert-butyl-2- (4-formylphenoxy) -2PP 0413-2003 were added together.

32101 / H • F e r ''. , methyl propanoate (Example 1-4) and 0.64 g (5.67 mmol) of 4-methyl-1,3-oxazol-5-yl) methylamine (Example III-28) in 1,2-dichloromethane and mixed at room temperature with 1.50 g (7.09 mmol) of sodium acetoxyborohydride. The reaction mixture was stirred for 4 hours at room temperature, then treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel (dichloromethane / methanol 30: 1) and then dried in vacuo. 1.104 g (65% of theory) of the title compound are obtained.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.45 (s, 9 H), 1.55 (s, 6H), 2.11 (s, 3H), 3.70 (s, 2H); 3.77 (s, 2H), 6.70 - 6.90 (m, 2H), 7.10 - 7.20 (m, 2H), 7.29 (s, 1H), 7.75 (br s , 1H).

The following compounds are obtained analogously to Example III-32:

Example III-33

Tert-butyl 2- (4 - {[(2-methoxyethyl) amino] methyl} phenoxy) -2-methylpropanoate

Yield: 92.8% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.44 (s, 9H), 1.55 (s, 6H), 2.48 (br s, 1H), 83 (t, 2H), 3.35 (s, 3H), 3.54 (t, 2H), 3.77 (s, 2H), 6.75-6.86 (m, 2H), 7.19 (d, 2 H).

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Example 111-34

Tert-Butyl 2-methyl-2- [4 - ({[(5-methyl-2-furyl) methyl] amino} methyl) phenoxy] propanoate

Yield: 55.1% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.44 (s, 9H), 1.55 (s, 6H), 2.27 (s, 3H), 3.71 (s, 4H), 5.83-5.92 (m, 1H), 6.00-6.08 (m, 1H), 6.75-6.88 (m, 2H), 7.12-7 24 (m, 2H).

Example III-35

Tert-Butyl 2 - [(4 - {[(2-methoxyethyl) amino] methyl} phenyl) sulfanyl] -2-methylpropanoate

4.0 g (14.27 mmol) of tert-butyl 2 - [(4-formylphenyl) sulfanyl] -2-methylpropanoate (Example II-2) and 1.07 g (14 g) were dissolved in 80 ml of 1,2-dichloromethane. (27 mmol) of 2-methoxyethylamine and after 30 minutes and 10 hours were mixed with 4.54 g (21.40 mmol) of sodium acetoxyborohydride. After DC-control ethyl acetate and saturated sodium bicarbonate solution were added and the product was extracted with ethyl acetate. The organic phase is washed with 1N hydrochloric acid, dried over anhydrous magnesium sulphate and, after distilling off the solvent, it is purified by chromatography on silica gel.

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32101 / H

Γ <p (ethyl acetate / cyclohexane 1: 1).

Yield: 2.69 g (55.6%) ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.45 (s, 15H), 2.96 (t, 2H), 3.37 (s, 3H), 3.72 (t, 2H), 4.13 (s, 2H), 7.52 (s, 4H).

Analogously to Example III-35, the following compound is obtained:

Example III-36

Tert-Butyl 2-methyl-2 - {[4 - ({[(4-methyl-1,3-oxazol-5-yl) methyl] amino} methyl) phenyl] sulfanyl} propanoate

Yield: 68.8%

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.43 (s, 15H), 2.12 (s, 3H), 3.77 (s, 2H), 3.78 (s

2H), 7.22-7.33 (m, 2H), 7.46 (d, 2H), 7.75 (s, 1H).

EXAMPLES 3

Example 3-1

Tert-Butyl 2- [4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoate

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0.50 g (1.258 mmol) of the compound of Example 111-16 with 0.23 g (1.88 mmol) of 2,4-dimethylaniline, 0.22 g (1.63 mmol) was stirred in 30 ml of Ν, Ν-dimethylformamide. 1-hydroxy-1H-benzotriazole, 0.31 g (1.63 mmol) EDC x HCl, 0.38 g (3.75 mmol) 4-methylmorpholine and 0.01 g (0.08 mmol) 4-dimethylaminopyridine over 2 hours hours at 0 ° C and overnight at room temperature. After mixing with water and extraction with ethyl acetate, the organic phase is washed with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is then distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane / dichloroethane 2: 1 → cyclohexane / ethyl acetate 10: 1 → 4: 1). After crystallization from n-heptane, the title compound is obtained in a yield of 78%.

MP: Mp 90-91 ° C.

Example 3-2

Tert-Butyl 2- [4 - [[[2- [2,4-dimethyl-phenyl) methylamino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoate

At 0 ° C, 0.51 g (1.00 mmol) of the compound of Example 3-1 and 0.04 g (1.10 mmol) of sodium hydride are stirred for 30 minutes and then mixed with 0.07 ml (1). (10 mmol) of iodomethane and then with water. After extraction with ethyl acetate, it is washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane / dichloromethane 3: 1 → dichloromethane → dichloromethane / ethyl acetate 15) : 1). Crystallization from n-pentane gave the title compound of 51%.

MP: Mp 80-81 ° C

Example 3-3

Tert-Butyl 2- [4 - [[[2 - [(2,4-dimethylphenyl) amino] ethyl] - (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoate

In 5 mL of toluene, 0.25 g (0.50 mmol) of the compound of Example 3-1 was mixed with 0.50 mL of a 2M solution of borane-dimethylsulfide in tetrahydrofuran and heated to boiling for 2 hours. It is then stirred for one hour in the presence of 5 ml of 2N sodium carbonate solution and the organic phase is washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate and distilling off the solvent, the residue is purified by flash chromatography on silica gel (cyclohexane / dichloromethane 3: 1 → cyclohexane / ethyl acetate 10: 1). The title compound is obtained in a yield of 37%.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.43 (s, 9 H), 1.55 (s, 6H), 2.15 (s, 3H), 2.22 (s,

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100

3Η), 2.73 - 2.87 (m, 2H), 3.09 - 3.22 (m, 2H), 3.57 (s, 2H), 3.63 (s, 2H), 6.12 6.19 (m, 1H); 6.28-6.35 (m, 1H); 6.47 (d, 1H); 6.73-6.95 (m, 4H); 7.20 (d, 1H); 1H), 7.34-7.40 (m, IH).

MS (ESI): 493 [M + H] &lt; ^{+ &gt};, 985 [2M + H] &lt; ⁺ &gt; ^.

Example 3-4

2- [4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

7.09 g (14.00 mmol) of the compound of Example 3-1 are stirred in 35 ml of dichloromethane together with 35 ml of trifluoroacetic acid for 2 hours at room temperature. After distilling off the solvent, the residue is dissolved in ethyl acetate, washed with water, 20% sodium acetate solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue obtained after removal of the solvent is purified by flash chromatography on silica gel (dichloromethane → dichloromethane / ethyl acetate 5: 1 → 2: 1 → 1: 1). The title compound is thus obtained in a yield of 82%.

¹ H-NMR (200 MHz, _CDCl3): δ = 1.57 (s, 6H), 2.24 (s, 3H), 2.27 (s, 3H), 3.31 (s, 2H); 3.67 (s, 2H), 3.75 (s, 2H), 6.22-6.36 (m, 2H), 6.88 (d, 2H), 6.93-7.03 (m, 2H), 7.23 (d, 2H), 7.34-7.40 (m, 1H), 7.78 (d, 1H), 8.00 (breites with, 1H), 9.09 (s, 1H).

MS (ESI): 451 [M + H] ⁺ , 901 [2M + H] ⁺ .

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101

The following compounds are obtained analogously to Example 3-4:

Example 3-5

2- [4 - [[[2 - [(2,4-Dimethylphenyl) methylamino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 85% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.46 (s, 6H), 1.92 (s, 3H), 2.24 (s, 3H), 2.73 (q 2H, 3.00 (s, 3H), 3.30 (breites with, 1H), 3.63 (d, 2H), 3.78 (d, 2H), 6.19 (d, 1H),

6.30-6.40 (m, 1H), 6.74 (d, 2H), 6.80-7.10 (m, 5H), 7.52-7.57 (m, 1H).

MS (ESI): 465 [M + H] +, 487 [M + Na +].

Example 3-6

2- [4 - [[[2 - [(2,4-dimethylphenyl) amino] ethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

x 2 CF 3 COOH

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102

Yield: 60% ¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.49 (s, 6H), 2.01 (s, 3H), 2.12 (s, 3H), 2.55 72 (breites m, 2H), 2.97-3.20 (breites m, 2H), 3.46-3.78 (m, 4H), 4.40 (Breites s, 1H), 6.20- 6.50 (m, 3H), 6.68 - 6.88 (m 4H), 7.12 - 7.30 (m, 2H), 7.56 - 7.68 (m, 1H), 13.00 (breites s, 1 H).

MS (ESI): 437 [M + H] &lt; ^{+ &gt};, 873 [2M + H] ⁺ .

Example 3-7

2- [4 - [[(2-methoxyethyl) - [2 - [[4- (1-methylethyl) -2 (trifluoromethyl) phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy 1,1-dimethylethyl ester ] -2-methylpropionic acid ethyl ester

0.533 g (1.65 mmol) of tert-butyl 2- (4 {[(2-methoxyethyl) aminomethyl} phenoxy) -2-methylpropanoate (Example III-33) are introduced in 6 ml of dimethylformamide and treated at room temperature with 0.588 g (1.81 mmol) of 2-bromo-N- [4-isopropyl-2-trifluoromethyl) phenyl] acetamide (Example 111-17) and 0.152 g (1.81 mmol) of sodium bicarbonate are added and the reaction mixture is stirred for 2 hours. hours at 90 ° C. The mixture was then allowed to cool and water was added, followed by extraction with ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulphate and the solvent is removed in vacuo. The residue obtained is purified by chromatography on silica gel (cyclohexane / ethyl acetate 4: 1) and the product is then dried in vacuo. 0.885 g (95% of theory) of the title compound is obtained.

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103 ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.42 (s, 9H), 1.55 (s, 6H), 2.80 (t, 2H) 2.93 (sept, 1H), 3.28 (s, 3H), 3.30 (s, 2H), 3.54 (t, 2H), 3.70 (s, 2H), 6.80 (d, 2H), 7.20 (d, 2H), 7.39 (dd, 1H), 7.45 (d, 1H), 8.17 (d, 1H), 9.65 (brs, 1H) .

Example 3-8

2- [4 - [[(2-methoxyethyl) - [2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy] -2-methylpropionic acid

0.842 g (1.49 mmol) of the compound of Example 3-7 are introduced in 10 ml of dichloromethane, 10 ml of trifluoroacetic acid are added at room temperature and the reaction mixture is stirred for 2 hours at room temperature. The mixture is concentrated in vacuo, the residue is taken up in ethyl acetate and washed with water, 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. The product obtained is purified by chromatography on silica gel (dichloromethane / methanol 30: 1) and the product is then dried under vacuum. 0.648 g (83% of theory) of the title compound is obtained.

¹ H-NMR (200 MHz, CDCl 3): δ = 1.26 (d, 6H), 1.55 (s, 6H), 2.81 (t, 2H), 2.91 (sept, 1H), 3.28 (s, 3H), 3.31 (s, 2H), 3.55 (t, 2H), 3.72 (s, 2H), 6.90 (d, 2H), 7.25 (d 2 H, 7.35-7.49 (m, 2H), 8.12 (d, 1H), 9.62 (brs, 1H).

Example 3-9

2- [4 - [[(2-methoxyethyl)] - [2 - [[4- (1-methylethyl) -2- (trifluoromethyl)] hydrochloride PP 0413-2003

32101 / H

104 phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy] -2-methylpropionic acid

x HCl

0.4 g (0.78 mmol) of the compound of Example 3-7 is dissolved in 4 ml of ethyl acetate and at 40 ° C first mixed with 8 ml of 1N hydrochloric acid (in diethyl ether) and then with 12 ml of diethyl ether. . The reaction mixture is then allowed to stand for one hour at 4 ° C, the precipitated crystals are filtered off with suction, washed with a 1: 1 mixture of ethyl acetate and diethyl ether and then dried under vacuum at 40 ° C for 20 hours. 0.362 g (84.5% of theory) of the title compound is obtained.

¹ H-NMR (200 MHz, DMSO): δ = 1.22 (d, 6H), 1.55 (s, 6H), 2.94-3.08 (m, 1H), 3.28 (s, 3H), 3.30-3.40 (m, 2H), 3.60-3.80 (m, 2H), 4.00-4.20 (m, 2H), 4.30 4.50 (m 2H, 6.86 (d, 2H), 7.20-7.70 (m, 5H), 10.25 (br s, 1H), 13.18 (br s, 1H).

Example 3-10

2- [4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid 1,1-dimethylethyl ester

0.303 g (0.94 mmol) of tert-butyl-2- (4PP 0413-2003) was introduced in 5 ml of dimethylformamide.

32101 / H

105 {[(2-methoxyethyl) amino] methyl} phenoxy) -2-methylpropanoate (Example III-33) and mixed with 0.319 g (1.03 mmol) of 2-bromo-N- (4-cyclohexyl-) at room temperature. 2-methylphenyl) acetamide (Example 111-19) and 0.086 g (1.03 mmol) of sodium bicarbonate. The reaction mixture was stirred for 2 hours at 90 ° C, then allowed to cool and water was added. The mixture is extracted with ethyl acetate, the organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulphate and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 3: 1) and the product is dried in vacuo. 0.464 g (90% of theory) of the title compound is obtained.

¹ H-NMR (300 MHz, _CDCl3): δ = 1.20 to 1.45 (m, 14 H), 1.50 (s, 6H), 1.70 to 1.90 (m, 5H); 2.25 (s, 3H), 2.36-2.48 (m, 1H), 2.80 (t, 2H), 3.25 (s, 5H), 3.5 (t, 2H), 3 69 (s, 2H), 6.80 (d, 2H), 6.98-7.06 (m, 2H), 7.15-7.25 (d, 2H), 7.85 (d, 1H) 9.25 (br s, 1H).

Example 3-11

2- [4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid hydrochloride

0.398 g (0.72 mmol) of the compound of Example 3-10 is introduced in 5 ml of dichloromethane, 5 ml of trifluoroacetic acid are added at room temperature and the reaction mixture is stirred for 2 hours at room temperature. It is then concentrated in vacuo, the residue is taken up in ethyl acetate, washed with water, 20% sodium acetate solution, water and saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate.

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106 of magnesium sulfate and the solvent was removed in vacuo. The product is purified by chromatography on silica gel (dichloromethane / methanol 30: 1). The resulting residue was dissolved in dichloromethane with heating, 1 N hydrochloric acid in diethyl ether was added and n-heptane was added dropwise until light turbidity. The product is filtered off with suction, washed with diethyl ether and dried at 40 [deg.] C. in vacuo. 0.187 g (49% of theory) of the title compound is obtained.

H-NMR (300 MHz, _CDCl3): δ = 1.15 to 1.47 (m, 5 H), 1.55 (s, 6H), 1.68 to 1.90 (m, 5 H), 2 25 (s, 3H), 2.36-2.49 (m, 1H), 2.85 (t, 2H), 3.28 (s, 3H), 3.30 (s,

7.80 (d, 1H); 9.25 (br s, 1H).

The following compounds are obtained analogously to those described in Examples 3-7 and 3-10:

Example 3-12

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] phenoxy 1,1-dimethylethyl ester ] -2-methylpropionic acid ethyl ester

Yield: 88% of theory

Ή-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.55 (s, 6H), 2.15 (s, 3H), 3.30 (s, 2H), 3 65 (s, 4H), 5.85 (m, 1H), 6.12 (d, 1H), 6.81 (m, 2H), 7.20 (m, 2H), 7.25 (m, 2H) 1H), 7.35 (s, 1H), 8.57 (d, 1H), 9.85 (br s, 1H).

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107 r t ŕ e r p f e r *

Example 3-13

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] 1,1-dimethylethyl] - [(4-methyl-5-oxazolyl) ) methyl] amino] phenyl] thio] -2-methylpropionic acid ethyl ester

Yield: 80.2% of theory ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.41 (s, 6H), 2.14 (s, 3H), 29 (s, 3H), 3.32 (s, 2H), 3.73 (s, 2H), 3.77 (s, 2H), 7.13 (s, 1H), 7.23 -7.31 (m, 2H), 7.49 (d, 2H), 7.78 (s, 1H), 8.30 (s, 1H), 9.05 (s, 1H).

Example 3-14

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] 1,1-dimethylethyl ester phenyl] thio] -2-methylpropionic acid ethyl ester

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.39 (s, 9H)

1.41 (s, 6H), 2.30 (s, 3H), 3.31 (s,

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108

2Η), 3.74 (s, 4H), 6.28 (d, 1H), 6.31-6.35 (m, 1H), 7.12 (s, 1H), 7.27 (d, 2H) ), 7.35-7.38 (m, 1H), 7.48 (d, 2H), 8.31 (s, 1H), 9.19 (s, 1H).

Example 3-15

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio-2-ethylbutyric acid 1,1-dimethylethyl ester

Yield: 73.4% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.95 (t, 6H), 1.41 (s, 9H), 1.55-1.78 (m, 4H) .

2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 2H), 3.73 (s, 2H), 3.74 (s, 2H), 6.20-6 38 (m, 2H), 6.90-7.08 (m, 2H), 7.28 (d, 2H), 7.35-7.50 (m, 3H), 7.75-7.88 (m, 1H). 9.05 (s, 1H).

Example 3-16

2 - [[4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropionic acid 1,1-dimethylethyl ester

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32101 / H

109 r f r

Yield: 81.9% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.31-1.47 (m, 18H), 1.70-1.95 (m, 6H), 2.20 2 31 (m, 4H), 2.35-2.51 (m, 1H), 2.82 (t, 2H), 3.28 (s, 5H), 3.51 (t, 2H), 3, 77 (s, 2H), 7.03 (d, 2H), 7.31 (d, 2H), 7.46 (d, 2H), 7.83 (d, 1H), 9.24 (s, 1H) ).

Example 3-17

2 - [[4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] 2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl 1,1-dimethylethyl ester thio] -2-methylpropionic acid ethyl ester

Yield: 82.9% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.29 (s, 12H), 1.40 (s, 9H), 1.42 (s, 6H), 2.82 (t, 2H), 3.29 (s, 5H), 3.51 (t, 2H), 3.77 (s, 2H), 7.13-7.40 (m, 4H), 7.40- 7.53 (m, 2H), 7.86 (d, 1H), 9.26 (brs, 1H).

Example 3-18

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] 1,1-dimethylethyl ester phenyl] thio] -2-ethyl-butyric acid

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110

Yield: 86.8%

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.94 (t, 6H), 1.41 (s, 9H), 1.55-1.75 (m, 4H), 2.30 (s 3H), 3.31 (s, 2H), 3.73 (s, 2H), 3.75 (s, 2H), 6.24-6.38 (m, 2H), 7.12 (s, 2H) 1H), 7.26 (d, 2H), 7.36 (d, 1H), 7.44 (d, 2H), 8.31 (s, 1H), 9.19 (s, 1H).

Example 3-19

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] 1,1-dimethylethyl ester phenyl] thio] -2-methylpropionic acid ethyl ester

Yield: 57.4% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.41 (s, 6H), 2.29 (s, 3H), 2.83 (t, 2H), 3.27 (s, 3H), 3.29 (s, 2H), 3.51 (t, 2H), 3.77 (s, 2H), 7.11 (s, 1H) 7.30 (d, 2H), 7.46 (d, 2H), 8.29 (s, 1H), 9.44 (s, 1H).

Example 3-20

2-Methyl-2- [4 - [[[2 - [[4- (1-methylethyl) -2-trifluoromethyl) phenyl] amino] -2-oxoethyl] - [(5-methyl- 2-furanyl) methyl] amino] methyl] phenoxy] propionate

PP 0413-2003

32101 / H

111

Yield: 94% ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.40 (s, 9H), 1.55 (s, 6H), 2.17 (s 3H), 2.88 (sept, 1H), 3.25 (s, 2H), 3.15 (m, 4H), 5.85 (m, 1H), 6.10 (d, 1H), 6.81 (d, 2H), 7.21 (d, 2H), 7.35 (m, 1H), 7.43 (m, 1H), 8.15 (d, 1H), 9.67 (s) , 1H).

Example 3-21

2- [4 - [[[2 - [(2-ethoxy-1-naphthalenyl) amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] phenoxy 1,1-dimethylethyl ester ] -2-methylpropionic acid ethyl ester

Yield: 95% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.30 (t, 3H), 1.43 (s, 9H), 1.54 (s, 6H), 2.25 (s 3H), 3.44 (s, 2H), 3.78-3.82 (m, 4H), 4.15 (q, 2H), 5.89-5.94 (m, 1H), 6, 15 6.18 (m, 1H), 6.84 (d, 2H), 7.20-7.38 (m, 4H), 7.45 (t, 1H), 7.65 (d, 1H), 7.75 7.85 (m, 2H); 9.05 (br s, 1H).

Example 3-22

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112

2-Methyl-2- [4 - [[[(5-methyl-2-furanyl) methyl] [2-oxo-2 [5,6,7,8-tetrahydro-1-naphthalenyl] 1,1-dimethylethyl ester] amino] ethyl] amino] methyl] phenoxy] propionate

Yield: 91% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.55 (s, 6H), 1.70-1.95 (m, 4H),

2.20 (s, 3H), 2.65-2.82 (m, 4H), 3.24 (s, 2H), 3.67 (s, 4H), 5.86-5.90 (m, 1H) .

6.10 - 6.14 (d, 1H), 6.78 - 6.93 (m, 3H), 7.08 (t, 1H), 7.22 (d, 2H), 7.89 (d, 1H),

9.20 (br s, IH).

Example 3-23

2- [4 - [[[2 - [(2,4-dichlorophenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid 1,1-dimethylethyl ester

Yield: 87% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.39 (s, 9H), 1.53 (s, 6H), 2.81 (t, 2H), 3.24 (s .

3H), 3.29 (s, 2H), 3.51 (t, 2H), 3.70 (s, 2H), 6.80 (m, 2H), 7.10 - 7.30 (m, 3H) )

7.38 (d, 1H), 8.42 (d, 1H), 9.93 (br s, 1H).

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113 9 9

C * * r

Example 3-24

2- [4 - [[(2-methoxyethyl) [2 - [[4- (1-naphthalenyloxy) -2 (trifluoromethyl) phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy] 1,1-dimethylethyl ester -2-methyl-propionic acid

Yield: 95.5% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.41 (s, 9H), 1.55 (s, 6H), 2.80 (t, 2H), 3.28 (s, 3H), 3.30 (s, 2H), 3.54 (t, 2H), 3.70 (s, 2H), 6.80 (d, 2H), 6.95 (d, 1H) 7.13 (m, 3H), 7.34 (d, 1H), 7.40 (t, 1H), 7.47-7.58 (m, 2H), 7.66 (d, 1H); 1H), 7.89 (dd, 1H), 8.07-8.21 (m, 2H), 9.68 (br s, 1H).

Example 3-25

2- [4 - [[[2- [5 - [(ethylsulfonyl) methyl] -1-naphthalenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-dimethylethyl ester methyl-propionic

Yield: 91% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.20-1.37 (m, 12H), 1.55 (s, 6H), 2.83-2.94 (m, 4H), 3.22 (s, 3H), 3.39 (s, 2H), 3.55 (t, 2H), 3.77 (s, 2H), 4.77 (s, 2H), 6, 81

PP 0413-2003

32101 / H »» ♦ r

114 (d, 2H), 7.15-7.30 (m, 2H), 7.50-7.70 (m, 3H), 7.91 (d, 1H), 8.12 (d, 1H) 8.22 (d, 1H), 10.18 (br s, 1H).

Example 3-26

2-methyl-2- [4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] 1,1-dimethylethyl] [(4-methyl- 5-oxazolyl) methyl] amino] methyl] phenoxy] propionate

Yield: 83.5% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.40 (s, 9H), 1.55 (s, 6H), 2.10 (s, 3H), 2.85-3.00 (sept., 1H), 3.28 (s, 2H), 3.66 (s, 2H), 3.75 (s, 2H), 6.82 (d, 2H), 7.20 (d, 2H), 7.38 (dd, 1H), 7.40-7.45 (m, 1H), 7.75 (s, 1H), 8.14 ( d, 1H), 9.45 (brs, 1H).

Example 3-27

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] 1,1-dimethylethyl ester phenoxy] -2-methylpropionic acid ethyl ester

PP 0413-2003

32101 / H • e

115

Yield: 79.5% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.55 (s, 6H), 2.11 (s, 3H), 3.30 (s, 2H), 3.68 (s, 2H), 3.76 (s, 2H), 6.81 (d, 2H), 7.18 (d, 2H), 7.70 - 7.80 ( m, 2H), 7.86 (s, 1H), 8.56 (d, 1H), 9.71 (br s, 1H).

Example 3-28

2- [4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -1-dimethylethyl ester methyl-propionic

Yield: 81% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.30 (s, 9H), 1.40 (s, 9H), 1.55 (s, 6H), 2.38 (s 3H), 2.80 (t, 2H), 3.29 (s, 5H), 3.50 (t, 2H), 3.70 (s, 2H), 6.80 (d, 2H), 7 15.25 (m, 4H), 7.78 (d, 1H), 9.30 (brs, 1H).

Example 3-29

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid 1,1-dimethylethyl ester

PP 0413-2003

32101 / H * r *

116

Yield: 80% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.39 (s, 9H), 1.55 (s, 6H), 2.82 (t, 2H), 3.28 (s 3H), 3.33 (s, 2H), 3.52 (t, 2H), 3.71 (s, 2H), 6.80 (d, 2H), 7.18 (d, 2H), 7, 78 (d 1H), 7.84 (s, 1H), 8.60 (d, 1H), 9.98 (br s, 1H).

Example 3-30

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid 1,1-dimethylethyl ester

Yield: 84% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.55 (s, 6H), 3.30 (s, 2H), 3.65 (s) 2H, 3.75 (s, 2H), 6.20-6.30 (m, 1H), 6.20-6.30 (m, 1H), 6.30-6.38 (m, 1H) H), 6.82 (d, 2H), 7.18 (d, 2H), 7.36-7.39 (m, 1H), 7.75 (d, 1H), 7.90 (s, 1H) ), 8.60 (d, 1H), 9.82 (br s, 1H).

Example 3-31

2 - [[4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-dimethylethyl ester methylpropionic

PP 0413-2003

32101 / H e

117

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.45 (s, 6H), 3.31 (s, 2H), 3.74 3.80 (m, 4H), 6.25 (d, 1H), 6.30-6.38 (m, 1H), 7.22-7.40 (m, 3H), 7.50 (d, 2H), 7.78 (d, 1H), 7.90 (s, 1H), 8.61 (d, 1H), 9.78 (brs, 1H).

Example 3-32

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] [5-methyl-2-furanyl) methyl] amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 83.4% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.56 (s, 6H), 2.15 (s, 3H), 3.29 (s, 2H), 3.69 (s, 2H), 3.71 (s, 2H), 5.80-5.88 (m, 1H), 6.13 (d, 1H), 6.89-6.98 (m, 2H), 7.20 (m, 2H), 7.74 (d, 1H), 7.86 (s, 1H), 8.56 (d, 1H), 9.79 (s, 1H).

Example 3-33

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] acid] [(4PP 0413-2003)

32101 / H

118 methyl-5-oxazolyl) methyl] amino] methyl] phenyl] thio] -2-methylpropionic acid

Yield: 62.8% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.47 (s, 6H), 2.11 (, 3H), 2.28 (s, 3H), 3.35 ( s, 2H), 3.74 (s, 2H), 3.77 (s, 2H), 7.11 (s, 1H), 7.20 - 7.30 (m, 2H), 7.49 (d 2 H, 7.80 (s, 1 H), 8.28 (s, 1 H), 9.04 (s, 1 H).

Example 3-34

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4-trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] 2-methylpropionic acid

Yield: 90.9% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.46 (s, 6H), 2.28 (s, 3H), 3.32 (s, 2H), 3.75 (s, 4H), 6.30 (dd, 2H), 7.10 (s, 1H), 7.29 (d, 2H), 7.36 (d, 1H), 7.48 (d, 2H) 8.27 (s, 1H); 9.16 (s, 1H).

Example 3-35

PP 0413-2003

32101 / H

P r P

119

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-ethylbutyric acid

Yield: 96.6% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.97 (t, 6H), 1.60-1.90 (m, 4H), 2.25 (s, 3H) 2.28 (s, 3H), 3.31 (s, 2H), 3.73 (s, 2H), 3.74 (s, 2H), 6.26 (d, 1H), 6.29- 6.35 (m, 1H), 6.95-7.05 (m, 2H), 7.29 (d, 2H), 7.37 (d, 1H), 7.46 (d, 2H), 7 80 (d, 1H); 9.03 (s, 1H).

Example 3-36

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4-trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-ethyl butyric

Yield: 90.9% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.58-1.87 (m, 4H), 2.28 (s, 3H) .

3.31 (s, 2), 3.73 (s, 2H), 3.76 (s, 2H), 6.26 (d, 1H), 6.30-6.36 (m, 1H), 7 , 10 (s,

1H), 7.27 (d, 2H), 7.34-7.40 (m, 1H), 7.45 (d, 2H), 8.28 (s, 1H), 9.16 (s, 1H) ).

PP 0413-2003

32101 / H

120

Example 3-37

2 - [[4 - [[[2 - [[5-chloro-2-methyl-4- (trifluoromethoxy) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2- propionic

Yield: 83.9% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.46 (s, 6H), 2.27 (s, 3H), 2.84 (t, 2H), 3.27 (s, 3H), 3.31 (s, 2H), 3.50 (t, 2H), 3.77 (s, 2H), 7.10 (br s, 1H), 7.31 (d, 2H) ), 7.48 (d, 2H), 8.24 (s, 1H), 9.43 (s, 1H).

Example 3-38

2-Methyl-2- [4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino ] methyl] phenoxy] propionic acid

Yield: 91% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.55 (s, 6H), 2.17 (s, 3H), 2.91 (sept) 1 H, 3.28 (s, 2H), 3.7 (s, 4H), 5.80-5.90 (m, 1H), 6.13 (d, 1H), 6.90 (m .

2H), 7.17-7.30 (m, 2H), 7.32-7.47 (m, 2H), 8.12 (d, 1H), 9.55 (br s, 1H)

PP 0413-2003

32101 / H

121

Example 3-39

2- [4 [[[2 - [(2-ethoxy-1-naphthalenyl) amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 64% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25-1.32 (t, 3H), 1.60 (s, 3H), 2.25 (s, 3H), 3 45 (s, 2H), 3.82 (s, 4H), 4.15 (quart., 2H), 5.94 (m, 1H), 6.17 (d, 1H), 6.90 7, 00 (m, 2H), 7.23-7.46 (m, 5H), 7.60-7.70 (m, 1H), 7.75-7.80 (m, 2H), 9.05 ( br s, 1H).

Example 3-40

2-Methyl-2- [4 - [[[(5-methyl-2-furanyl) methyl] [2-oxo-2 - [(5,6,7,8-tetrahydro-1-naphthalenyl) amino] ethyl] amino acid ] methyl] phenoxy] propionic acid

Yield: 76% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.55 (s, 6H), 1.75-1.95 (m, 4H), 2.20 (s, 3H),

2.36 (t, 2H), 2.78 (t, 2H), 3.30 (s, 2H), 3.69 (s, 4H), 5.89 (m, 1H), 6.12 (d (1H),

6.83-6.94 (m, 4H), 7.09 (t, 1H), 7.20-7.32 (m, 1H), 7.85 (d, 1H), 9.15 (s, 1H).

PP 0413-2003

32101 / H

122

Example 3-41

2- [4 - [[[2 - [(2,4-Dichlorophenyl) amino] -2-oxoethyl] - (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 69% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.55 (s, 6H), 2.82 (t, 2H), 3.28 (s, 3H), 3.00 (s 2H, 3.54 (t, 2H), 3.75 (s, 2H), 6.90 (m, 2H), 7.18-7.36 (m, 3H), 7.39 (d, 1H), 8.40 (d, 1H), 9.90 (br s, 1H).

Example 3-42

2- [4 - [[(2-methoxyethyl) [2 - [[4- (1-naphthalenyloxy) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 74% ¹ H-NMR (300 MHz, DMSO): δ = 1.45 (s, 6H), 2.72 (t, 2H), 3.18 (s, 3H), 3.25 (s,

PP 0413-2003

32101 / H c r

123

2H), 3.47 (t, 2H), 3.68 (s, 2H), 6.78 (d, 2H), 7.10 (d, 1H), 7.21 (d, 2H), 7, 28 (dd, 1H), 7.40 (d, 1H), 7.48-7.66 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 8.05 (t, 2H), 9.60 (brs, 1H).

Example 3-43

2- [4 - [[[2 - [[5 - [(ethylsulfonyl) methyl] -1-naphthalenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 40.5% ¹ H-NMR (400 MHz, CD ₂ Cl ₂ ): δ = 1.34 (t, 3H), 1.46 (s, 6H), 2.83-3.04 (m, 4H),

3.24 (s, 3H), 3.37 (s, 2H), 3.32-3.64 (m, 2H), 3.78 (s, 2H), 3.78 (s, 2H), 4 72 (s, 2H), 6.83 (d, 2H), 7.31 (d, 2H), 7.46-7.65 (m, 3H), 7.90 (d, 1H), 04 - 8.20 (m, 2H), 10.10 (br s, 1H).

Example 3-44

2-Methyl-2- [4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenylamino] -2-oxoethyl] (4-methyl-5-oxazolyl) methyl] amino] methyl] phenoxy] propionic acid

PP 0413-2003

32101 / H

P t

124

Yield: 69% 1 H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.58 (s, 6H), 2.09 (s, 3H), 2.82 3, 04 (sept., 1H), 3.30 (s, 2H), 3.66 (s, 2H), 3.76 (s, 2H), 6.90 (d, 2H), 7.25 (d 2H) ), 7.35-7.48 (m, 2H), 7.80 (s, 1H), 8.11 (d, 1H), 9.40 (br s, 1H).

Example 3-45

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl) amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenoxy] -2- propionic

Yield: 76% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.60 (s, 6H), 2.10 (s, 3H), 3.32 (s, 2H), 3.70 (s (2H), 3.77 (s, 2H), 6.90 (d, 2H), 7.21 (d, 2H), 7.73-7.90 (m, 3H), 8.55 (d, 2H); 1H), 9.68 (brs, 1H).

Example 3-46

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid

PP 0413-2003

32101 / H • 8 · ·

125

Yield: Π% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.55 (s, 6H), 2.84 (t, 2H), 3.25 (s, 3H), 3.35 (s (2H), 3.55 (t, 2H), 3.75 (s, 2H), 6.90 (d, 2H), 7.15-7.30 (m, 2H), 7.75 (d, 2H); 1H), 7.88 (s, 1H), 8.59 (d, 1H), 9.91 (br s, 1H).

Example 3-47

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 91% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.57 (s, 6H), 3.30 (s, 2H), 3.70 (s, 2H), 3.77 (s 2H, 6.30 (dd, 2H), 6.88 (d, 2H), 7.20-7.35 (m, 2H), 7.37-7.42 (m, 1H), 75 (d, 1H), 7.86 (s, 1H), 8.56 (d, 1H), 9.80 (br s, 1H).

Example 3-48

2 - [[4 - [[- 2 - [[2 ₁ 4-Bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropionic acid

P P 0413-2003

32101 / H

126 ft r ft

Yield: 91% ¹ H-NMR (300 MHz, CDCl 3): δ = 1.46 (s, 6H), 3.32 (s, 2H), 3.75 (s, 4H), 6.25 (dd, 2H), 7.20-7.40 (m, 3H), 7.50 (d, 2H), 7.78 (d, 1H), 7.90 (s, 1H), 7.90 (s, 1H) ), 8.59 (d, 1H), 9.78 (brs, 1H).

The following compounds are obtained analogously to those described in the Examples

3-9 and 3-11.

Example 3-49

2 - [[4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropionic acid hydrochloride

Yield: 53.3% ¹ H-NMR (300 MHz, DMSO): δ = 1.20-1.48 (m, 12H), 1.62-1.87 (m, 5H), 2.14 (s (3H), 3.27 (s, 3H), 3.51 (br s, 2H), 3.74 (br s, 2H), 4.12 (br s, 2H), 4.51 (br s, 2H), 7.02 (d, 2H), 7.16-7.30 (br s, 1H), 7.46-7.68 (m, 4H), 9.93 (br s, 1H),

10.36 (brs, 1H); 12.74 (brs, 1H).

Example 3-50

2 - [[4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2- methylpropionic

PP 0413-2003

32101 / H p

127

Yield: 85.3%

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.29 (s, 9H), 1.56 (s, 6H), 2.26 (s, 3H), 2.86 (t, 2H), 3.29 (s, 3H), 3.35 (s, 2H), 3.53 (t, 2H), 3.74 (s, 2H), 6.88 (d, 2H), 7.15 7, 26 (m, 4H), 7.79 (d, 1 H), 9.26 (s, 1 H).

Example 3-51

2-Methyl-2- [4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] hydrochloride] [(5-methyl-2-furanyl) ) methyl] amino] methyl] phenoxy] propionate

Yield: 99% ¹ H-NMR (300 MHz, DMSO): δ = 1.20 (d, 6H), 1.50 (s, 6H), 2.27 (brs, 3H), 2.96-3, 05 (sep. 1H), 3.95 (br s, 2H), 4.31 (br s, 4H), 6.17 (br s, 1H), 6.63 (br s, 1H), 6, 85 (d, 2H), 7.46-7.57 (m, 5H), 10.23 (br s, 1H), 10.55 (br s, 1H), 13.15 (br s, 1H).

Example 3-52

2- [4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2-methylpropionic acid hydrochloride

PP 0413-2003

32101 / H

128 /

Ο

HO

Yield: 54% ^x

LC-MS: 470 [M &lt; ⁺ &^gt;]

Example 3-53

2- [4 - [[[2 - [(2,4-Dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid, sodium salt

O Na

0.015 g (0.03 mmol) of the compound of Example 3-4 was dissolved in 0.5 ml of ethanol, treated with 0.3 ml of 1N sodium hydroxide, stirred for 5 minutes and then the reaction mixture was evaporated. The residue is taken up in a small amount of toluene and the solvent is evaporated off under vacuum, after which the product is dried under vacuum for 20 hours. 0.15 g (95.5% of theory) of the title compound is obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.21 (s, 6H), 2.10-2.20 (m, 6H), 3.16 (s, 2H), 3.58-3 64 (m, 4H), 6.18-6.25 (m, 2H), 6.73-6.82 (m, 2H), 7.09-7.35 (m, 3H), 7.71 (d, 1H), 9.00 (brs, 1H).

The following compounds are obtained analogously to those described in the Examples

3-7 and 3-10:

PP 0413-2003

32101 / H

129

Example 3-54

2 - [[4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] 1,1-dimethylethyl ester fenyljtio] -2-methylpropionic acid ethyl ester

Yield: 61% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.24 (d, 6H), 1.39 (s, 9H), 1.42 (s, 6H), 2.80 (t 2H), 2.90-3.1 (m, 1H), 3.28 (s, 3H), 3.32 (s, 2H), 3.53 (t, 2H), 3.78 (s, 2H) )

7.25-7.50 (m, 6H), 8.14 (d, 1H), 9.62 (br s, 1H).

Example 3-55

2-Methyl-2 - [[4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] 1,1-dimethylethyl] - [(4- methyl-5-oxazolyl) methyl] amino] methyl] phenyl] thio] propionic acid

Yield: 66% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.40 (s, 9H), 1.43 (s, 6H), 2.10 (s .

PP 0413-2003

32101 / H • e e

130

3H), 2.90-3.10 (m, 1H), 3.29 (s, 2H), 3.70-3.80 (m, 4H), 7.30-7.55 (m, 6H) 7.77 (s, 1H); 8.13 (d, 1H); 9.40 (br s, 1H).

Example 3-56

2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenyl 1,1-dimethylethyl ester ] thio] -2-methylpropionic acid ethyl ester

Yield: 86% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.41 (s, 9H), 1.43 (s, 9H), 2.13 (s, 3H), 2.24 (s 3H), 3.31 (s, 2H), 3.70-3.81 (m, 7H), 6.68-6.80 (m, 2H), 7.30 (d, 2H), 7, 50 (d, 2H), 7.67-7.75 (m, 1H), 7.78 (s, 1H), 8.80 (br s, 1H).

Example 3-57

2 - [[4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] 1,1-dimethylethyl ester phenyl] thio] -2-methylpropionic acid ethyl ester

Yield: 84%

PP 0413-2003

32101 / H f * e r

131 1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.42 (s, 6H), 2.11 (s, 3H), 3.32 (s, 2H) 3.74-3.82 (m, 4H), 7.29 (d, 2H), 7.49 (d, 2H), 7.70-7.85 (m, 2H), 7.87 (s) 1 H, 8.57 (d, 1 H), 9.67 (brs, 1 H).

Example 3-58

2- [4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl} amino] methyl] phenoxy] 1,1-dimethylethyl ester - 2-methylpropionic acid ethyl ester

Yield: 54.8% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.30-1.46 (m, 14H), 1.55 (s, 6H), 1.62-1.94 ( m, 6H), 2.12 (3H), 2.26 (s, 3H), 3.29 (s, 2H), 3.65 (s, 2H), 3.74 (s, 2H), 6 82 (d, 2H); 6.98-7.08 (m, 2H); 7.18 (d, 2H); 7.77 (s, 1H); 7.83 (d, 1H); 96 (br s, 1 H).

Example 3-59

2- [4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] [4-methyl-5-oxazolyl) methyl] amino] 1,1-dimethylethyl ester methyl] phenoxy] -2-methylpropionic acid ethyl ester

PP 0413-2003

32101 / H y r y r

132

Yield: 64.7% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.29 (s, 9H), 1.41 (s, 9H), 1.55 (s, 6H), 2.12 (s, 3H), 2.28 (s, 3H), 3.29 (s, 2H), 3.65 (s, 2H), 3.75 (s, 2H), 6.82 (d, 2H) 7.10 7.30 (m, 4H), 7.77 (s, 1H), 7.85 (d, 1H), 8.98 (brs, 1H).

Example 3-60

2 - [[4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2- propionic

0.248 g (0.43 mmol) of the compound of Example 3-54 are introduced in 5 ml of dichloromethane, 5 ml of trifluoroacetic acid are added at room temperature and the reaction mixture is stirred for 2 hours at room temperature and then evaporated in vacuo. The residue is taken up in ethyl acetate and extracted with water, 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. The product is purified by chromatography on silica gel (dichloromethane / methanol 30: 1) and dried in vacuo. 197 mg (88% of theory) of the title compound are obtained.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.49 (s, 6H), 2.80 (t, 2H), 2.85 3.00 (m, 1 H), 3.30 (s, 3H), 3.32 (s, 2H), 3.49-3.59 (m, 2H), 3.80 (s, 2H), 7.24 7.53 (m, 6H), 8.12 (d, 1 H), 9.58 (brs, 1 H).

The following compounds are obtained analogously to the example

3-60:

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Example 3-61

2-Methyl-2 - [[4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl) amino] -2-oxoethyl] (4-methyl-5-oxazolyl) methyl] amino acid ] methyl] phenyl] thio] propionic acid

Yield: 81% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.50 (s, 6H), 2.07 (s, 3H), 2.85 3, Δ (m, 1H), 3.39 (s, 2H), 3.74-3.78 (m, 4H), 7.30 (d, 2H), 7.36-7.53 (m, 4H) 7.79 (s, 1H); 8.11 (d, 1H); 9.39 (brs, 1H).

Example 3-62

2 - [[4 - [[[2 - [[(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenyl] thio] -2 methyl-propionic

Yield: 84% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.51 (s, 6H), 1.50 (s, 6H), 2.08 (s, 3H), 2.23 (s .

3H), 3.35 (s, 2H), 3.70-3.82 (m, 7H), 6.70-6.80 (m, 2H), 7.28 (d, 2H), 7.48 (d,

2H), 7.63-7.73 (m, 1H), 7.80 (s, 1H), 8.81 (br s, 1H).

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134 · e t t>>>>>>>>>>> p p

Example 3-63

2 - [[4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenyl] thio] -2-methylpropionic acid

Yield: 76% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.49 (s, 6H), 2.09 (s, 3H), 3.35 (s, 2H), 3.74 3, 80 (m, 4H), 7.29 (d, 2H), 7.49 (d, 2H), 7.75-7.82 (m, 2H), 7.87 (s, 1H), 8.56 (d, 1H), 9.66 (brs, 1H).

Example 3-64

2- [4 - [[[2 - [[4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenoxy] -2-methylpropionic acid

Yield: 80%

LC-MS: acetonitrile / 30 aqueous hydrochloric acid / water (gradient): R t = 2.64 min ([M + H] ⁺ = 534).

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Example 3-65

2- [4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] [(4-methyl-5-oxazolyl) methyl] amino] methyl] phenoxy] -2-methylpropionic acid

LC-MS: acetonitrile / 30 aqueous hydrochloric acid / water (gradient): R _t = 2.43 min ([M + H] + = 508).

EXAMPLES 4

Example 4-1

2- [4 - [[[2 - [(2,5-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Step a)

Wang resin (Rapp Polymere, Best.Nr. H 1011) (48.0 g, 14.06 mmol of reactive groups) was suspended in dichloromethane. After addition of 2- (4-formylphenoxy) -2-methylpropionic acid [G. J. Ellymes, C. Glynis, J. Chem. Soc.

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136

Perkin Trans. 2, 1993, 43-48] (8.78 g, 42.18 mmol), diisopropylcarbodimide (10.65 g, 84.35 mmol) and DAMP (3.44 g, 28.12 mmol) were shaken. for 18 hours at room temperature, after which it is filtered, the resin is washed with dichloromethane, DMF and methanol to obtain resin A.

Step b)

Resin A (2.50 g, 0.72 mmol reactive groups) and 2-furylamine (352 mg,

3.62 mmol) is suspended in 20 ml of trimethyl orthoformate, shaken for 20 hours at room temperature, filtered and the resin washed with dimethylformamide. The resin was then suspended in 20 mL of dimethylformamide, treated with tetrabutylammonium hydride (559 mg, 2.17 mmol) and acetic acid (0.42 mL, 7.52 mmol) and shaken for 7 hours at room temperature. The mixture is then filtered and the resin is washed with dichloromethane, dimethylformamide and methanol to give resin B1.

Step c)

Resin B1 (2.5 g, 0.72 mmol reactive groups) was suspended in 40 mL dioxane and treated with triethylamine (3.03 mL, 21.75 mmol) and trimethylsilyl bromoacetate (2.38 mL, 14.5 mL). mmol). The reaction mixture was shaken overnight at 60 ° C, then filtered and the resin washed with dichloromethane, dimethylformamide and methanol. The silyl protecting groups were removed by suspending the resin in 25 ml of dioxane and mixing with a solution of tetrabutylammonium fluoride (1 M in THF, 1 ml). The reaction mixture was shaken for one hour at room temperature, filtered, and the resin was washed with dichloromethane, dimethylformamide and methanol to give resin C1.

Step d)

Resin C1 (2.5 g, 0.72 mmol of reactive groups) was suspended in 20 mL

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137 dimethylformamide and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38 g, 3.63 mmol) and 2,5-dimethylaniline (615 mg, 5.08 mmol). The reaction mixture was shaken for 18 hours at room temperature, filtered and the resin washed with dichloromethane, dimethylformamide and methanol. The resin is then suspended in a mixture of dichloromethane and trifluoroacetic acid, shaken for 30 minutes at room temperature, then filtered and evaporated. The title compound is obtained in the form of a colorless film.

LC-MS: R _t = 3.68; [M + H] ⁺ = 451.3 (100%), [MH] ⁺ = 449.3 (100%).

[Method: Symmetry C18 Saule (Waters), Flow: 0.5 mL / min, Melting point 40 ° C, Pressure 40 MPa, Gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min; 90% A, 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH], ¹ H-NMR (d 6 -DMSO): δ = 1.4 (s, 6H), 2.3 (s, 3H), 2.4 (s, 3H) ), 3.33 (s, 2H), 3.7 (s, 2H), 3.8 (s, 2H), 6.3 (d, 1H), 6.4 (d, 1H), 6.8 (d, 1H), 6.9 (d, 2H), 7.05 (d, 1H),

7.2 (m, 2H); 7.4 (s, 1H); 7.8 (s, 1H).

Example 4-2

2- [4 - [[[2 - [(4-methoxy-2,5-dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] phenoxy] -2-methylpropanoic acid

Resin C1 of Example 4-1, step c) (2.5 g, 0.72 mmol of reactive groups) was suspended in 20 mL of dimethylformamide and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38). g, 3.63 mmol) and 2,5-dimethyl-4PP 0413-2003

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138 with methoxyaniline (756 mg, 5.08 mmol), shake the reaction mixture for 18 hours at room temperature, filter, and wash the resin with dichloromethane, dimethylformamide, and methanol. The resin was then suspended in a mixture of dichloromethane and trifluoroacetic acid, shaken for 30 minutes at room temperature, filtered and evaporated. The title compound is obtained in the form of a colorless film.

LC-MS: R _t = 3.48 min; [M + H] ⁺ = 481.226 (100%), [M-H] ⁺ = 479.226 (100%).

[Method: Symmetry C18 Saule (Waters), Flow: 0.5 mL / min, Melting point 40 ° C, Pressure 40 MPa, Gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90A, 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH]

Example 4-3

2- [4 - [[[2 - [(4-methoxy-2,5-dimethylphenyl) amino] -2-oxoethyl] (2-thienylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid

Step a)

Resin A of Example 4-1 step a) (2.50 g, 0.72 mmol reactive groups) and 2-aminomethylthiophene (409 mg, 3.62 mmol) were suspended in 20 mL of trimethyl formate, shaken overnight at room temperature. room, filtered and the resin washed with dimethylformamide. The resin was then suspended in 20 mL of dimethylformamide, treated with tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid (0.42 mL, 7.25 mmol) and shaken for 7 hours at room temperature. Then the mixture is filtered, the resin is washed

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139 with dichloromethane, dimethylformamide and methanol to give resin B2.

Step b)

Resin B2 (2.5 g, 0.72 mmol of the reactive groups) was suspended in 40 mL of dioxane, treated with triethylamine (3.03 mL, 21.75 mmol) and trimethylsilyl bromoacetate (2.38 mL, 14.5 mL). mmol) and the reaction mixture was shaken overnight at 60 ° C. Then the mixture is filtered and the resin is washed with dichloromethane, dimethylformamide and methanol. The silyl protecting groups were removed by suspending the resin in 25 ml of dioxane, mixing with a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 1 ml), shaking the mixture for one hour at room temperature and then filtering. The resin is washed with dichloromethane, dimethylformamide and methanol to give resin C2.

Step c)

Resin C2 (2.5 g, 0.72 mmol of the reactive groups) was suspended in 20 mL of dimethylformamide, treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38 g, 3.63 mmol) and 2 mL. With 5-dimethyl-4-methoxyaniline (657 mg, 5.08 mmol), the mixture was shaken for 18 hours at room temperature, filtered and the resin was washed with dichloromethane, dimethylformamide and methanol. The resin was then suspended in a mixture of dichloromethane and trifluoroacetic acid, shaken for 30 minutes at room temperature, filtered and evaporated. The title compound is obtained in the form of a colorless film.

LC-MS: R _t = 3.90 min; [M + H] ⁺ = 497.4 (100%), [MH] ⁺ = 495.4 (100%).

[Method: Symmetry C18 Saule (Waters), Flow: 0.5 mL / min, Melting point 40 ° C, Pressure 40 MPa, Gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90% A, 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH].

¹ H-NMR (d 6 -DMSO): δ = 1.5 (s, 6H), 2.1 (s, 3H), 2.2 (s, 3H), 3.3 (s, 2H), 3, 7 (s,

2H), 3.8 (s, 3H), 4.0 (s, 2H), 6.8-7.5 (m, 9H).

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140

Analogously:

Example 4-4

2- [4 - [[[2 - [(4-methoxy-2,5-dimethylphenyl) amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] phenoxy] -2-methyl -propanoic

LC-MS: R _t = 2.76 min; [M + H] + = 495 (100%), [M-H] + = 493 (100%).

[Method: Symmetry C18 Saule (Waters), Flow: 0.5 mL / min, Melting point 40 ° C, Pressure 40 MPa, Gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90% A, 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH].

Example A

Cellular transactivation experiment

Test principle:

The cellular assay is used to identify peroxisome proliferator-activating receptor alpha (PPAR-α) activators.

Since mammalian cells contain various endogenous nuclear receptors that could complicate the interpretation of the results unambiguously, an established chimeric system is used in which the ligand binding domains of the human PPAR-α-receptor are fused to the DNA binding domains of the yeast GALA transcription factor. The resulting GAL4PPAR-α-chimeras are co-transfected in reporter construct CHO cells and

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141 stably expressed.

cloning:

The GAL4-PPARα-expression construct contains PPARα ligand binding domains (amino acids 167-468) that are PCR-amplified and cloned into the pcDNA3.1 vector. This vector already contains the GAL4-DNA-binding domains (amino acids 1-147) of the vector pFC2dbd (stratagens). The reporter construct, which contains five copies of the GAL4-binding site upstream of the thymidine kinase promoter, results in the expression of firefly-luciferase ((Photinus pyralis) upon activation and binding of GAL4-PPARα).

Transactivation experiment (luciferase-reporter):

CHO (chinese hamster ovary) cells are seeded in a plate of 384 plates in DNEM / F12-medium (BioWhittaker) supplemented with 10% fetal serum, 1% penicillin / streptomycin (GIBCO) at a cell density of 2 x 10 ³ ( Greiner). After cultivation for 48 hours at 37 ° C, cells are stimulated. For this, the test substances are added to CHO-A-SFM medium (GIBCO) supplemented with 10% fetal calf serum and 1% penicillin / streptomycin (GIBCO) and added to the cells. After stimulation for 24 hours, luciferase activity is measured with a video camera. The relative light units measured give a sigmoidal stimulation curve, depending on the substance concentration. The EC50 value is calculated using the GraphPad PRISM computer program (version 3.02).

The compounds of the present invention of Examples 3-4, 3-6, 3-60, 1-9, 2-7 and 2-12 exhibit EC 50 values in this assay of 0.04 to 200 nM.

Example B

Determination of fibrinogen

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142

To determine the effect on plasma fibrinogen concentration, male Wistar rats are treated for 4 to 9 days with the test substance using an esophagus probe or admixture with the diet. Citric blood is then obtained by cardiac puncture under terminal anesthesia. Plasma fibrinogen levels are determined using the Clauss method [Clauss A., Acta Haematol. 17, 237-46 (1957)] by measuring thrombin time with human fibrinogen as standard. In some cases, the parallel determination is performed by the turbidometric method [Becker U., Bartl K., Wahlefeld A. W., Thrombosis Res. 35, 475-84 (1984)] using batroxobin instead of thrombin.

Example C

Test description for the detection of pharmacologically active substances that increase apoprotein A1 (ApoA1) and HDL-cholesterin (HDL-C) in the serum of transgenic mice that are transfected with the human ApoA1 gene (hApoAI)

The substances to be tested for their HDL-C enhancing effect in vivo are orally administered to male transgenic HApoAI-mice. Water and feed ad libitum are available to the animals throughout the experiment. The substances are applied once a day for 7 days. For this purpose, the test substances are dissolved in a solution of solutol HS 15 + ethyl alcohol + sodium chloride solution (0,9%) in a ratio of 1 + 1 + 8 or a solution of solutol HS 15 + sodium chloride solution (0,9%) in a ratio 8. Application of the dissolved substances is carried out in a volume of 10 ml / kg body weight using an esophagus probe. Animals treated with solvent (10 ml / kg body weight) without test substance serve as controls.

Prior to the first administration of the substance, each mouse is bled by retro-orbital venenplexus puncture (precedence) for the determination of ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG). Thereafter, the animals are first administered the test substance with an esophageal probe. 24 hours after the last application (day 8 after the start of processing), each animal is removed again

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143 blood was punctured by retro-orbital venenplexus to determine the same parameters. Blood samples are centrifuged and, after serum is obtained, cholesterol and TG are measured photometrically using an EPOS Analyzer 5060 (Eppendorf-Gerätebau, Nethelr & Hinz GmbH, Hamburg). The assay is performed with a commercially available enzyme assay (Boehringer Mannheim, Mannheim).

For the HDL-C assay, the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10. From the supernatant, cholesterol is determined by UV-photometry on a 96-well plate using commercially available reagents (Ecoline 25, Merck, Darmstadt) (BIO-TEK Instruments Inc. USA).

Human ApoA1 murine mice were determined by Sandwich ELISA using polyclonal anti-human ApoA1 and monoclonal anti-human ApoA1 antibodies (Biodesing International, USA). Quantification is performed by UV-photometry (BIO-TEK Instruments, USA) with peroxidase-linked anti-mouse-IGG antibody (KPL, USA) and peroxidase substrate (KPL.USA).

The effect of the test substances on the HDL-C concentration is determined by subtracting the measured value of the 1st blood collection (precedence) from the measured value of the 2nd blood collection (after processing). The difference of all HDL-C values of one group is determined and compared to the mean of the control group differences.

Statistical evaluation is performed by Student's test after prior examination of variations for homogeneity.

Substances that increase the HDL-C of the treated animals by a statistically significant (p <0.05) increase of at least 20% compared to the control group animals are considered pharmacologically active.

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144

Claims (15)

Patents Claims mi Mi Claims 1. Propionic acid derivatives of the general formula I in which: A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen, sulfur or CH ₂ , R ¹ , R ² and R ³ are the same or different and are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, hydroxy, C 1 -C 6 alkoxy, aryloxy 6 to 10 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, alkylaminosulfonyl, nitro or cyano, or R ¹ and R ² are attached to two adjacent carbon atoms and together form an fused cyclohexane or benzene ring, the latter being optionally substituted by an alkylsulfonylmethyl group having 1 to 4 carbon atoms, and R ³ is as defined above, R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group, PP 0413-2003 32101 / H 145 R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or a benzyl group, said aromatics alone being one to three times the same or differently substituted by an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, hydroxy or halogen, R ⁸ represents a hydrogen atom, an aryl group having 6 to 10 carbon atoms or an alkyl group having 1 to 4 carbon atoms, which may itself be substituted by hydroxy, trifluoromethoxy, alkoxy having 1 to 4 carbon atoms or phenoxy, which themselves are optionally once to twice substituted with trifluoromethyl, or it may be substituted with an aryl group of 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all of said aryl and heteroaryl rings alone being one to three times equally or differently substituted by halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino, R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or halogen, R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof. PP 0413-2003 32101 / H • e • r r 146 2. Propionic acid derivatives of the general formula I, in which A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen, sulfur or CH ₂ , R ¹ , R ² and R ³ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano . R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or a benzyl group, said aromatics alone being one to three times the same or differently substituted by an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, hydroxy or halogen, R ⁸ represents a hydrogen atom, an aryl group having 6 to 10 carbon atoms or an alkyl group having 1 to 4 carbon atoms which may itself be substituted by an aryl group having 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all of said ring systems alone being one to three times equally or differently substituted by halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino, R ⁹ and R ¹⁰ are the same or different and independently of one another represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms PP 0413-2003 32101 / H r * f r c ” 147-6 carbon atoms, trifluoromethyl, trifluoromethoxy or halogen, R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof. Propionic acid derivatives according to claim 1 or 2, in which A represents a bond or a group -CH 2 - or -CH 2 CH 2 -, X is oxygen, sulfur or CH ₂ , R ¹ , R ² and R ³ are the same or different and independently of one another are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro or fluoro, trifluoromethyl, trifluoromethoxy, nitro or cyano . R ⁴ represents a hydrogen atom or a methyl group, R ⁵ and R ⁶ represent a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group, R ⁷ represents a hydrogen atom, a C 1 -C 4 alkyl group or a benzyl group, R ⁸ represents a hydrogen atom, a phenyl group, a benzyl group or a five-membered heteroarylmethyl group with up to two heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, said ring systems alone being one to three times same or differently substituted by chlorine, fluorine or bromine , hydroxy, PP 0413-2003 32101 / H 148 alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, trifluoromethyl or amino, R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl or fluorine or chlorine, R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or a methyl or ethyl group or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring and R ¹³ represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof. Propionic acid derivatives according to claim 1, 2 or 3 of the general formula I, in which A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen, sulfur or CH ₂ , R ¹ represents a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and are independently methyl, trifluoromethyl, methoxy, trifluoromethoxy or chloro or fluoro, R ⁴ represents a hydrogen atom, R ⁵ and R ⁶ together with the carbon atom to which they are attached represent a carbonyl group, R ⁷ represents a methyl group, an ethyl group, an n-propyl group or in particular a hydrogen atom, R ⁸ is phenyl, furanylmethyl or PP 0413-2003 32101 / H r · · · r r 149-e-thienylmethyl, wherein the ring systems themselves may be mono- or di-substituted by a methyl or ethyl group, R ⁹ and R ¹⁰ are the same or different and independently of one another represent a hydrogen atom or a methyl group and in particular a hydrogen atom, R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or a methyl group, or in particular a methyl group, and R ¹³ represents a hydrolyzable group which can be degraded to the corresponding carboxylic acid, or in particular a hydrogen atom, as well as their pharmaceutically acceptable salts, hydrates and solvates. in which A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen or sulfur R ¹ represents a hydrogen atom, a methyl group or a methoxy group, R ² and R ³ are the same or different and independently of one another are methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chloro or fluoro and R ⁸ represents a phenyl group, a furanylmethyl group, a thienylmethyl group or an oxazolylmethyl group, wherein said ring PP 0413-2003 32101 / H • r The systems themselves may be substituted one to two times with methyl, or may be 2-methoxyethyl. 6. Propionic acid derivatives of the formula I as defined in claims 1 to 5 for the prevention and treatment of diseases. Medicament, characterized in that it comprises at least one propionic acid derivative of the formula I as defined in claim 1 and inert, non-toxic, pharmaceutically acceptable carriers, excipients, solvents, vehicles, emulsifiers and / or dispersing agents. Use of propionic acid derivatives of the formula I and medicaments as defined in claims 1 to 7 for the prevention and treatment of diseases. Use of propionic acid derivatives of the formula I as defined in claims 1 to 6 for the manufacture of medicaments. Use of propionic acid derivatives of the formula I as defined in claims 1 to 6 for the manufacture of a medicament for the treatment of arteriosclerosis. 11. A method of preventing and treating diseases, characterized in that the compounds of the formula I as defined in claim 1 are allowed to act on animals. A process for the manufacture of medicaments, characterized in that at least one compound of the formula I as defined in claim 1 is converted with auxiliary PP 0413-2003 32101 / H 151 substances and / or carriers per dosage form. Process for the preparation of propionic acid derivatives of the formula I as defined in claim 1, characterized in that the compounds of the formula II are reacted with A, X, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² as defined above and T represents a benzyl group, an alkyl group having 1 to 6 carbon atoms or a polymeric carrier suitable for solid phase synthesis, first by activating the carboxyl group of formula II with compounds of formula III (ΙΠ) in which R ¹ , R ^{2 have} and R ^{3 is} as defined above, PP 0413-2003 32101 / H 152 to compounds of formula Ia wherein A, X, T, R ¹ , R ² , R ³ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, or [B] reacting compounds of formula IV (W) wherein A, X, T, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above in the presence of a base with compounds of formula V (V), PP 0413-2003 32101 / H 153 • < wherein R ¹ , R ² , R ³ and R ^{7 are} as defined above and Q is a suitable leaving group, likewise to the compounds of formula Ia, then the compounds of formula Ia, optionally by known methods by amide-alkylation or amide-reduction, are converted to compounds of formula Ib wherein A, X, T, R ¹ , R @ ² , R @ ³ , R @ ⁷ , R @ ⁸ , R @ ⁹ , R @ ¹⁰ , R @ ¹¹ and R @ ^{12 are} as previously defined, then converted by acids or bases to acids of formula 1c corresponding to the carboxylic acid (1c) , R ^1, R ^2, R ³ above, R ⁷ , R ⁸ , R ⁹ , R ⁹ R ¹¹ and R ¹² above PP 0413-2003 32101 / H 154 e. These may optionally be further modified by reaction with the compounds of the general formula (VI) using known esterification methods. R ¹³ -Z (VI), wherein R ¹³ is as defined above and Z is a suitable leaving group or is a hydroxyl group. Use according to claim 9 for the manufacture of a medicament for the treatment of arteriosclerosis, for increasing a disease-reduced level of HDL and for reducing an elevated level of triglycerides and IDL in arteriosclerosis and / or hypercholesterolemia. Use of the compounds of formula I as defined in claim 1 as peroxisome-proliferator-activated receptor agonists. 16. Compounds of formula II GD. wherein A, X, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above and T represents a benzyl group, an alkyl group having 1 to 6 carbon atoms, or a polymeric carrier suitable for solid phase synthesis?