HRP20030346A2 - Propionic acid derivatives - Google Patents

Description

The present invention relates to new strong PPAR-alpha-activating compounds for the treatment of, for example, coronary heart diseases, and to their preparation.

Despite many successful therapies, coronary heart disease (CHD) remains a serious public health problem. Treatment with statins, which inhibit HMG-CoA reductase, successfully lowers the concentration of LDL cholesterol in plasma and the mortality of high-risk patients; however, until now no convincing treatment strategies are available for the therapy of patients with unfavorable H DL/LDL cholesterol ratio or hypertriglyceridemia.

Currently, fibrates are the only therapeutic option for patients in these risk groups. They act as weak agonists of peroxisome proliferator-activated receptor (PPAR)-alpha (Nature 1990, 347, 645-50). The disadvantage of fibrates that have been established so far is that their interaction with the receptor is only weak, which requires high daily doses and causes significant side effects.

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

The object of the present invention was to provide new compounds that can be used as PPAR-alpha modulators.

It has now been found that this goal is achieved by compounds of the general formula (I)

[image]

where

A represents a bond or represents a group -CH2- or -CH2CH2-,

X represents O, S or CH2,

R1, R2 and R3 are identical or different and independently of each other represent hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C6-alkoxy, (C1-C10)-aryloxy, halogen, trifluoromethyl, trifluoro-methoxy, (C1-C6)alkylaminosulfonyl, nitro or cyano,

or

R1 and R2 are connected to two adjacent carbon atoms and together with them form a fused cyclohexane or benzene ring, whereby the latter can optionally be substituted by a (C1-C4)-alkyl-sulfonylmethyl group,

R5 and R6 represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,

and

R 3 has the meaning as previously defined,

R4 represents hydrogen or (C1-C4)-alkyl,

R5 and R6 represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,

R7 represents hydrogen, (C1-6)-alkyl, phenyl or benzyl, where the mentioned aromatic radicals can in any case be mono- to tri-substituted with identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1 -Ce)-Alkoxy, hydroxyl and halogen,

R 8 represents hydrogen, (C 6 -C 10 )-aryl or represents (C 1 -C 4 -alkyl which in turn may be substituted by hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy or phenoxy groups, which in turn are optionally substituted by trifluoromethyl, or (C6-C10)-aryl or 5- or 6-membered heteroaryl with up to three heteroatoms from the group consisting of N, O and S, where all mentioned aryl and heteroaryl rings can in turn be mono- to trisubstituted with identical or different substituents from groups consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,

R 9 and R 10 are identical or different and each independently represents hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R11 and R12 are identical or different and independently of each other each represents hydrogen or (C1-C6)-alkyl or together with the carbon atom to which they are attached form a (C4-C7)-cycloalkyl ring,

and

R13 represents hydrogen or represents a group that can be hydrolyzed and decomposed to the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, hydrates and solvates,

which have a pharmacological effect and can be used as medicines or for the preparation of medicinal formulations.

In the context of the invention, a hydrolyzable group in the definition of R 13 is a group which, preferably 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, primarily: benzyl, (C1-C6)-alkyl or (C3-C8)-cycloalkyl, which are in each case optionally mono- or polysubstituted with identical or different substituents from the group consisting of halogen, hydroxyl, amino, (C1- C6)-Alkoxy, Carboxyl, (C1-C6)-Alkoxycarbonyl, (C1-C6)-Alkoxycarbonylamino and (C1-C6)-Alkanoyloxy, and preferably (C1-C4)-Alkyl which is optionally mono- or polysubstituted with identical or different by substituents from the group consisting of halogen, hydroxyl, amino, (C1-C4)-alkoxy, carboxyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkoxycarbonylamino and (C1-C4)-alkanoyloxy.

In the context of the invention, (C1-C6)-alkyl and (C1-C4)-alkyl represent a straight-chain or branched alkyl radical with 1 to 6 and 1 to 4 carbon atoms, respectively. A straight-chain or branched alkyl radical with 1 to 4 carbon atoms is preferred. The following radicals can be mentioned first of all, for example: methyl, ethyl, n-propyl, isopropyl and tert-butyl.

In the context of the invention, (C6-C10)-aryl represents an aromatic radical with 6 to 10 carbon atoms. A preferred example is the aryl radical phenyl.

In the context of the invention, (C3-C8)-cycloalkyl and (C4-C7)-cycloalkyl represent a cycloalkyl group with 3 to 8 and 4 to 7 carbon atoms, respectively. The following radicals may first be mentioned by way of example: cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the invention, (C1-C6)-Alkoxy represents a straight-chain or branched Alkoxy radical with 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms. The following radicals may first be mentioned by way of example: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, (C6-C10)-aryloxy represents an aromatic radical with 6 to 10 carbon atoms which is connected through an oxygen atom. A preferred example is the aryloxy radical phenoxy.

In the context of the invention, (C1-C6)-Alkoxycarbonyl represents a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms which is connected via a carbonyl group. Preference is given to a straight-chain or branched alkoxycarbonyl radical with 1 to 4 carbon atoms. The following radicals may first be mentioned by way of example: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, (C1-C6)-Alkoxycarbonylamino represents an amino group with a straight-chain or branched Alkoxycarbonyl substituent with 1 to 6 carbon atoms in the Alkoxy radical and is connected via a carbonyl group. Preference is given to the alkoxycarbonylamino radical with 1 to 4 carbon atoms. The following radicals may first be mentioned by way of example: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the invention, (C1-C6)-alkanoyloxy represents a straight-chain or branched alkyl radical with 1 to 6 carbon atoms that carries a double-bonded oxygen atom in position 1 and is bonded in position l via a further oxygen atom. The following radicals can be primarily mentioned as an example: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

In the context of the invention, (C1-6)-alkylaminosulfonyl represents an amino group that is attached via a sulfonyl group and has a straight-chain or branched alkyl substituent with 1 to 6 carbon atoms. An alkylaminosulfonyl radical with 1 to 4 carbon atoms is preferred. The following radicals may first be mentioned by way of example: methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl and tert-butylaminosulfonyl.

In the context of the invention, halogen represents fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferable.

In the context of the invention, a 5- or 6-membered heteroaryl with up to 3 heteroatoms selected from the group consisting of S, N and O generally represents a monocyclic heteroaromatic radical which is attached via the ring carbon atom of the heteroaromatic radical or, if appropriate, via the ring nitrogen atom of the heteroaromatic radicals. The following radicals may be mentioned primarily by way of example: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl. Preference is given to furanyl, thienyl and oxazolyl.

Depending on the substitution pattern, the compounds of the invention can exist in stereoisomeric forms that either behave as an image and mirror image (enantiomers) or do not behave as an image and mirror image (diastereomers). The invention also relates to enantiomers or diastereomers and their mixtures. Racemic forms, as diastereomers, can be separated in a known manner into stereomerically equal components.

Furthermore, some 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 invention.

The compounds according to the invention can also exist as salts. In the context of the invention, preference is given to physiologically acceptable salts.

Physiologically acceptable salts can be salts of compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as for example hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid or salts with organic carboxylic or sulphonic acids such as for example 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 naphthalenesulfonic acid.

Physiologically acceptable salts can also be salts of compounds according to the invention with bases, such as, for example, metal or ammonium salts. Advantages are, for example, salts of alkali metals (for example, sodium salts or potassium salts), salts of alkaline earth metals (for example, magnesium salts or calcium salts), and also ammonium salts derived from ammonia or from organic amines, such as, for example, ethylamine, di- or triethylamine , ethyldiisopropylamine, monoethanolamine, di-or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also exist in the form of their solvates, preferably in the form of their hydrates.

Preference is given to compounds of the general formula (I), in which

A represents a bond or represents a group -CH2- or -CH2CH2-,

X represents O, S or CH2,

R 1 , R 2 and R 3 are identical or different and independently of each other each represents hydrogen, (C 1-6 )-alkyl, (d-OO-alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano,

R4 represents hydrogen or (C1-C4)-alkyl,

R5 and R6 each represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,

R7 represents hydrogen, (C1-C6)-alkyl, phenyl or benzyl, in which the mentioned aromatic radical can in any case be mono- to tri-substituted by the same or different substituents from the group consisting of (C1-C6)-alkyl, ( C1-C6)-Alkoxy, hydroxyl or halogen,

R8 represents hydrogen, (C6-C10)-aryl or (C1-C4)-alkyl, which in turn is optionally substituted with (C6-C10)-aryl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, whereby all mentioned ring systems can in any case be mono- to tri-substituted with identical or different substituents from the group consisting of halogen, hydroxyl, (C1-6)-alkyl, (C1-6 )-Alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,

R9 and R10 are the same or different and independently of each other each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoro-methoxy or halogen,

R11 and R12 are the same or different and each independently represents hydrogen or (C1-6)-alkyl, or together with the carbon atom to which they are attached form a (C4-C7)-cycloalkyl ring,

R13 represents hydrogen or a group that can hydrolyze and decompose to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates.

Compounds of the general type (I) are particularly advantageous.

where

A represents the group -CH2- or -CH2CH2-,

X represents O, S or CH2,

R 1 , R 2 and R 3 are identical or different and independently of each other each represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano,

R4 represents hydrogen or methyl,

R5 and R6 each represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,

R7 represents hydrogen, (C1-C6)-alkyl or benzyl,

R8 represents hydrogen, phenyl, benzyl or 5-membered heteroarylmethyl with up to two heteroatoms from the group consisting of N, O and S, whereby the mentioned aromatic ring systems can in any case be mono- to tri-substituted and identical or different substituents from the group consisting of chlorine, fluorine, bromine, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl and amino,

R9 and R10 are the same or different and independently of each other represent hydrogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, trifluoromethyl, fluorine or chlorine,

R11 and R12 are identical or different and independently of each other each represents hydrogen, methyl or ethyl, or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring,

and

R13 represents hydrogen or represents a group that can hydrolyze and degrade to the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, hydrates and derivatives.

The compounds of the general formula (I) are particularly advantageous.

where

A represents the group -CH2- or -CH2CH2-,

X represents O, S or CH2,

R1 represents hydrogen, methyl or methoxy,

R2 and R3 are the same or different and each independently represents methyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine,

R4 represents hydrogen,

R5 and R6 together with the carbon atom to which they are attached form a carbonyl group,

R7 represents methyl, ethyl, n-propyl or preferably hydrogen,

R8 represents phenyl, furanylmethyl or thienylmethyl, whereby the mentioned ring systems can in any case be mono- or disubstituted by the same or different substituents from the group consisting of methyl and ethyl,

R9 and R10 are the same or different and each represents hydrogen or methyl, preferably hydrogen,

R11 and R12 are the same or different and each represents hydrogen or methyl, preferably methyl,

and

R13 represents a group that can be hydrolyzed and decomposed to the corresponding carboxylic acid, or preferably represents hydrogen,

and their pharmaceutically acceptable salts, hydrates and solvates.

The general or best definitions of radicals listed above also apply to the final products of formula (I) and, accordingly, to the starting materials and intermediates needed in each stage of preparation.

Individual definitions of radicals given in certain combinations or best combinations of radicals, independently of certain given combinations of radicals, are also replaced by any definition of radicals or other combinations.

Of particular importance are the compounds of formula (I) in which R4 represents hydrogen.

Of particular importance are the compounds of formula (I) in which R5 and R6 together with the carbon atom to which they are attached form a carbonyl group.

Of particular importance are the compounds of formula (I) in which

R1 represents hydrogen, methyl or methoxy,

and

R 2 and R 3 are the same or different and each independently represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine.

Of particular importance are the compounds of formula (I) in which

R8 represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, where the mentioned ring systems can in any case be mono- or disubstituted by methyl, or represents 2-methoxyethyl.

Of very special importance are the compounds of formula (IA)

[image]

where

A represents the group -CH2- or -CH2CH2-,

X represents O or S,

R1 represents hydrogen, methyl or methoxy,

R2 and R3 are the same or different and each independently represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine,

and

R8 represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, where the mentioned ring systems can in any case be mono- or disubstituted by methyl, or represents 2-methoxyethyl.

Furthermore, we have found a process for the preparation of compounds of the general formula (I) according to the invention, indicated that

[A] compounds of the general formula (II)

[image]

where

A, X, R7, R8, R9, R10, R11 and R12 are all as defined above

and

T represents benzyl, (C1-C6)-alkyl or a polymer base suitable for solid phase synthesis,

first, with the activation of the carboxylic acid group in (U), they react with compounds of the general formula (III)

[image]

where

R1, R2 and R3 all have the meaning defined above,

which results in compounds of the general formula (Ia)

[image]

where

A, X, T, R1, R2, R3, R7, R8, R9, R10, R11 and R12 all have the meaning defined above,

or

[B] compounds of general formula (IV)

[image]

where

A, X, T, R8, R9, R10, R11 and R12 have the above meaning, react in the presence of a base with compounds of the general formula (V)

[image]

where

R1, R2, R3 and R7 all have the above meaning,

and

Q is a suitable leaving group, for example halogen, mesylate or tosylate, preferably bromine or iodine, also to compounds of the general formula (Ia).

Compounds of the general formula (Ia) are, if appropriate, converted into compounds of the general formula (Ib) in accordance with known methods of amide alkylation or amide reduction

[image]

where

A, X, T, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the meaning given above,

then converted with acids or bases into corresponding carboxylic acids of the general formula (Ic)

[image]

where

A, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the above meaning,

and these are, if appropriate, using known esterification methods, further modified by reaction with compounds of the general formula (VI)

R13-Z (VI), in which R13 has the meaning defined above,

and

Z represents a suitable leaving group, for example halogen, mesylate or tosylate or represents a hydroxyl group.

The process according to the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out the process under elevated pressure or under reduced pressure (for example in the range of 0.5 to 5 bar).

Solvents suitable for the process are common organic solvents that do not change under the reaction conditions. They include ethers, such as diethylether, dioxane, tetrahydrofuran, glycoldimethylether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate , pyridine, dimethylsulfoxide, dimethylformamide, N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane. It is also possible to apply mixtures of the mentioned solvents.

Preferred solvents for process step (II) + (III) → (Ia) are dichloromethane and dimethylformamide. For process step (IV) + (V) → (Ia), preference is given to dimethylformamide.

Process step (II) + (III) → (Ia) according to the invention is generally carried out in the temperature range from 0°C to +100°C, preferably from 0°C to +40°C. Process step (IV) + (V) → (Ia) is generally carried out in the temperature range from 0°C to +120°C, preferably from +50°C to +100°C.

Auxiliary substances used for amide formation in process step (II) + (III) → (Ia) are primarily common condensation reagents such as carbodiimides, for example N,N'diethyl-, N,N'-dipropyl-, N,N'-diisopropyl -, N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 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-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, 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-azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate (HATU), if appropriate in the van nation with further auxiliary substances such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, and the bases used are primarily alkali metal carbonates, for example sodium carbonate or bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. The combination of EDC, N-methylmorpholine and 1-hydroxybenzotriazole, then EDC, triethylamine and 1-hydroxybenzotriazole, and HATU and diisopropylethylamine is particularly advantageous.

Similar bases for the reaction (IV) + (V) → (Ia) are common inorganic bases, such as alkali metal alkoxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. Sodium bicarbonate is preferable.

Hydrolysis of carboxylic acid esters in the process step (Ia) or (Ib) → (Ic) is carried out by the usual methods, by treating the esters in inert solvents with bases, and the initially formed salts are converted into free carboxylic acids using acid. In the case of tert-butyl ester, hydrolysis is preferably carried out using acids.

Suitable solvents for the hydrolysis of esters of carboxylic acids are water or organic solvents common for ester cleavage. They preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, dimethylformamide, dichloromethane or dimethylsulfoxide. It is also possible to apply mixtures of the mentioned solvents. Water/tetrahydrofuran is preferred, and in the case of reaction with trifluoroacetic acid, dichloromethane is preferred, and in the case of hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane or water are preferred.

Bases suitable for hydrolysis are common inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate. The use of sodium hydroxide or lithium hydroxide is particularly advantageous.

Similar acids are generally trifluoroacetic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and acetic acid, and mixtures thereof, if appropriate with the addition of water. Hydrochloric acid or trifluoroacetic acid is preferred in the case of tert-butyl esters, and hydrochloric acid in the case of methyl esters.

In the case of compounds of the general formula (Ia) or (Ib) prepared by synthesis on the solid phase and attached to the polymer substrate via a carboxylic acid group, cleavage from the resin to obtain the compounds of the general formula (Ic) is also carried out by the above-described usual methods for the hydrolysis of carboxylic esters acid. Trifluoroacetic acid is advantageous here.

When carrying out the hydrolysis, the base or acid is generally applied in an amount of 1 to 100 mol, preferably 1.5 to 40 mol, based on 1 mol of the ester.

The hydrolysis is generally carried out in the temperature range from 0 °C to +100 °C, preferably from 0 °C to +50 °C.

The compounds of general formula (II) are new and can be prepared first

and

[a] compounds of general formula (VII)

[image]

where

X, T, R9, R10, R11 and R12 have the meaning defined above

and

B represents a bond or a methylene group

in the presence of a suitable reducing reagent react with the compound of the general formula (VIII)

R 14 -NH 2 (VIII) wherein R 14 [a-1] has the meaning given above for R 8

or

[a-2] represents a group of formulas in which

[image]

R7 has the meaning defined above

R15 represents (C1-C6)-alkyl or trimethylsilyl, resulting in compounds of the general formula (IX)

[image]

where

B, X, T, R9, R10, R11, R12 and R14 have the meaning defined above,

then these compounds react in the presence of a base with compounds of the general formula (X)

R16-Y (X)

where

R16 in the case of the process variant [a-1] represents a group of the formula

[image]

where R7 and R15 have the meaning defined above

or

in the case of process version [a-2] the meaning of R8 given above

and

Y represents a suitable leaving group, such as halogen, mesiate or tosylate, preferably bromine or iodine,

which results in compounds of the general formula (XI)

[image]

where

B, X, T, R7, R8, R9, R10, R11, R12 and R15 have the above meaning,

and finally in these compounds by selective hydrolysis of the carboxylic acid ester group -COOR15 to carboxylic acid,

or

[b] compounds of general formula (XII)

[image]

where

A, X, T, R9, R10, R11 and R12 have the above meaning

in the presence of a suitable reducing agent they react with compounds of the general formula (XIII)

R17-CHO (XIII),

where

R17 represents hydrogen, (C6-C10)-aryl, 5- or 6-membered heteroaryl with up to three heteroatoms selected from the group consisting of N, O and S, or represents (C1-C3)-alkyl which in turn can be substituted with hydroxyl, trifluoromethoxy, (C1-C4)-alkoxy or phenoxy, which in turn can be optionally mono- or disubstituted with trifluoromethyl, or (C6-C10)-aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the group consisting of N, O and S, where all mentioned aryl and heteroaryl rings can in any case be mono- to tri-substituted with the same or different substituents from the group consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1- 6)-Alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,

which gives rise to compounds of the general formula (XIV)

[image]

where

A, X, T, R9, R10, R", R12 and R17 have the meaning defined above,

then these compounds react in the presence of a base with compounds of the general formula (XV)

[image]

where

R7, R15 and Y have the meaning defined above

which results in compounds of the general formula (XVI)

[image]

where

A, X, T, R7, R9, R10, R11, R12, R15 and R17 have the meaning defined above,

and finally by selective hydrolysis in these compounds of the carboxylic acid ester group -COOR15 to carboxylic acid.

The entire process can also be carried out as a synthesis on a solid phase. In this case, the compounds of general formulas (VII) or (XII) are connected as esters of carboxylic acids to a suitable resin base, further reactions are carried out on a solid phase and the target compound is finally cleaved from the resin. Solid phase synthesis, and bonding and detachment from the resin are common standard techniques. For the sake of mentioning only one example from the wide literature, reference is made to the publication "Linkers for Solid Phase Organic Synthesis", Ian W. James, Tetrahedron 55, 4855-4946 (1999).

The reaction (VII) + (VIII) → (IX) or (XII) + (XIII) → (XIV) is carried out in solvents common for reductive amination and inert under the reaction conditions, if appropriate in the presence of acid. Solvents include, for example, water, dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane or alcohols such as methanol, ethanol, propanol, isopropanol or butanol; it is also possible to use mixtures of the mentioned solvents. Methanol and ethanol are preferred in any case with the addition of acetic acid.

Suitable reducing agents for the reaction (VII) + (VIII) → (IX) or (XII) + (XIII) → (XIV) are complex aluminum hydrides or boron hydrides, such as, for example, diisobutylaluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or tetrabutylammonium borohydride, or other catalytic hydrogenation in the presence of transition metal catalysts, such as for example palladium, platinum, rhodium or Raney nickel. Preferred reducing agents are sodium cyanoborohydride, sodium triacetoxyborohydride and tetrabutylammonium borohydride.

The reaction (VII) + (VIII) → (IX) or (XII) + (XIII) → (XIV) is generally carried out in the temperature range from 0°C to +40°C.

The reaction (IX) + (X) → (XI) or (XIV) + (XV) → (XVI) is carried out in common solvents that are inert under the reaction conditions. Dimethylformamide, tetrahydrofuran and dioxane are preferred.

Similar bases for the reaction (IX) + (X) → (XI) or (XIV) + (XV) → (XVI) are common inorganic or organic bases. Triethylamine is preferred.

The reaction (IX) + (X) → (XI) or (XIV) + (XV) → (XVI) is generally carried out in the temperature range from 0°C to +100°C.

The reaction (XI) → (II) or (XVI) → (II) is carried out in solvents common for ester cleavage, which are inert under the reaction conditions. In the case of ester hydrolysis, these are primarily tetrahydrofuran, dioxane and alcohols such as methanol and ethanol, in any case in a mixture with water. In the case of cleavage of silyl esters, it is advantageous to use dioxane or tetrahydrofuran.

Similar bases for the reaction (XI) → (II) or (XVI) → (II) in the case of hydrolysis are common inorganic bases. Lithium hydroxide, sodium hydroxide and potassium hydroxide are preferred. In the case of cleavage of silyl esters, it is advantageous to use tetrabutylammonium fluoride.

The reaction (XI) → (II) or (XVI) → (II) is generally carried out in the temperature range from 0 °C to +100 °C.

Compounds of general formula (IV) correspond to compounds of general formulas (IX) or (XIV) and can be prepared according to the above description.

Compounds of the general formulas (III), (V), (VI), (VII), (VIII), (X), (XII), (XIII) and (XV) are commercially available, known, or can be prepared by conventional methods [cf. for example PJ. Brown et al., J. Med. Chem. 42, 3785-88 (1999)].

The compounds of formula (I) according to the invention have an unexpected and useful spectrum of pharmacological activities and can therefore be used as multiple medications. First of all, they are suitable for the treatment of coronary heart diseases, for the prophylaxis of myocardial infarction and for the treatment of restenosis after coronary angioplasty or "stenting". The compounds of formula (I) according to the invention are primarily suitable for the treatment of arteriosclerosis and hypercholesterolemia, for increasing pathogenically low levels of HDL and for lowering elevated levels of triglycerides, fibrinogen and LDL. Furthermore, they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia, and high blood pressure due to insulin resistance), hepatic fibrosis, and cancer.

The activity of the compounds according to the invention can be tested, for example, in vitro, by the transactivation assay described in the experimental section.

The activity of the compounds according to the invention in vivo can be tested, for example, by the tests described in the experimental section.

Suitable administration forms for taking the compounds of the general formula (I) are all the usual administration forms, i.e. oral, parenteral, inhalation, nasal, sublingual, rectal or external, for example transdermal, preferably oral or parenteral administration forms. In the case of parenteral administration, we should especially mention intravenous, intramuscular and subcutaneous administration, for example as a subcutaneous depot. Oral administration is particularly advantageous.

Thus, the active compounds can be administered alone or in the form of preparations. Preparations suitable for oral administration are inter alia tablets, capsules, pellets, sugar-coated tablets, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. In them, the active compound must be present in an amount that provides a therapeutic effect. In general, the active compound can be present in a concentration of 0.1 to 100% by weight, preferably 0.5 to 90% by weight, most preferably 5 to 80% by weight. First of all, the concentration of the active compound should be 0.5 - 90% by mass, i.e. the active compound should be present in quantities sufficient to reach the established dosage range.

Finally, the active compounds can be converted into conventional preparations in a manner known per se. This is carried out with the use of inert, non-toxic pharmaceutically suitable excipients, auxiliary substances, solvents, carriers, emulsifiers and/or dispersants.

Excipients that can be mentioned are for example: water, non-toxic organic solvents such as paraffins, vegetable oils (for example sesame oil), alcohols (for example ethanol, glycerol), glycols (for example polyethylene glycol), solid carriers such as natural or synthetic ground minerals (eg talc or silicates), sugar (eg lactose), emulsifiers, dispersants (eg polyvinylpyrrolidone) and glidants (eg magnesium sulphate).

In the case of oral administration, the tablets may of course also contain additives such as sodium citrate, together with additives such as starch, gelatin and the like. Aqueous preparations for oral administration may further contain flavor enhancers or coloring agents.

In the case of oral administration, it is advantageous to administer doses of 0.001 to 5 mg/kg, preferably 0.005 to 3 mg/kg of body weight in 24 hours.

The lower figures illustrate the invention. The invention is not limited to these examples.

The following used abbreviations indicate:

Ac acetyl

Bu butyl

TLC thin layer chromatography

DCI direct chemical ionization ("direct Chemical ionization"; in MS)

DCM dichloromethane DIC diisopropylcarbodiimide

DMAP 4-N,N-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EDC N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide x HCl EI ionization by electron impact

ionization"; in MS)

ESI electron spray ionization ("electron spray ionization"; in MS)

Et ethyl

a watch. sat. (saturated)

HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyl-immersion hexafluorophosphate

HOBt 1-hydroxy-1H-benzotriazole x H2O

HPLC high-pressure, high-performance liquid chromatography

LC-MS coupled liquid chromatography and mass spectroscopy

Me methyl

MS mass spectroscopy

NMR spectroscopy of nuclear magnetic resonance

RF reflux

Rf retention index (in TLC)

RT room temperature

Rt retention time (in HPLC)

TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TFA trifluoroacetic acid

THF tetrahydrofuran

Source materials I

Example I-1

tert-butyl 2-methylpropionate

[image]

With ice cooling, 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 was treated with a solution of 100 g (0.939 mmol) of isobutyryl chloride in 150 ml of dichloromethane. , and then the mixture was stirred overnight. Then 500 ml of 2 M hydrochloric acid was added, the aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, sat. NaHCOs solution and sat. NaCl solution, dried over sodium sulfate and concentrated. 65.5 g (48%) of tert-butyl 2-methylpropionate was obtained by distillation of the solid product.

1H-NMR (200 MHz, CDCl3): δ = 1.11 (d, 6H); 1.44 (s, 9H); 2.42 (Sept., 1H).

Example I-2

tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate

[image]

At -78°C, 34.7 ml (69.4 mmol) of a 2 M solution of lithium diisopropylamide was slowly added dropwise to a solution of 10.0 g (69.34 mmol) of tert-butyl 2-methylpropionate (Example 1-1) in 100 ml of tetrahydrofuran. After completion of the addition, the mixture was stirred at -78°C for 1 h, then a solution of 15.76 g (63.04 mmol) of 4-bromobenzyl bromide in 10 ml of tetrahydrofuran was added, and the mixture was stirred at -78°C for 1 h. The reaction was then brought to room temperature and poured into 100 ml of 1 N hydrochloric acid, the phases were separated and the aqueous phase was extracted 3x with diethyl ether. The combined organic phases were washed with NaHCO3 solution, dried over sodium sulfate and freed from solvent under reduced pressure. 16.75 g (85 %) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate was obtained by distilling the residue under the vacuum of an oil pump. 1H-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-di:ylpropionate

[image]

At -75°C, 135 ml (22.98 mmol) of a 1.7 M tert-butyllithium solution in pentane was slowly added to 6.00 g (19.16 mmol) of tert-butyl 3-(4-bromophenyl)-2,2-dimethyl p -opionate (Example 1-2) in 80 ml of tetrahydrofuran, whereby the temperature was maintained below -60°C. The mixture was stirred for 15 min, and then 1.82 g (24.90 mmol) of N,N-dimethylformamide was added and the mixture was stirred at -75°C for a further 4 h. The mixture was slowly cooled to -20°C, mixed with 20 ml of water with vigorous stirring, and then warmed to room temperature. The aqueous phase was extracted 3x with diethyl ether and the combined organic phases were dried over sodium sulfate/sodium carbonate, and the solvent was desalted under reduced pressure. Distillation of the residue under the vacuum of an oil pump gave 2.54 g (51%) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate. 1H-NMR (300 MHz, CDCl): δ =1.16 (s, 6H); 1.42 (s, 9H); 2.90 (s, 2H); 7.32 (d, 2H); 7.78 (d, 2H); 9.98 (s, 1H).

Example I-4

tert-butyl 2-(4-formylphenoxy)-2-methylpropionate

[image]

A solution of 24.4 g (200 mmol) of 4-hydroxybenzaldehyde in 100 ml of dimethylformamide was treated with 97.75 g (300 mmol) of cesium carbonate and stirred at 90 °C for 1 h. Then a solution of 66.93 g (300 mmol) of tert-butyl 2-bromo-isobutyrate in 100 ml of dimethylformamide was added drop by drop, and the mixture was stirred at 90 °C overnight. Dimethylformamide was distilled off under reduced pressure and the residue was then taken up in ethyl acetate, washed 2x with water, 2x with 1 N aqueous sodium hydroxide solution and 1x with sat. with NaCl solution, dried over sodium sulfate and freed from the solvent under reduced pressure. This gave 16.6 g (31%) of tert-butyl 2-(4-formylphenoxy)-2-methylpropionate.

1H-NMR (200 MHz, CDCl3): δ = 1.40 (s, 9H); 1.63 (s, 6H); 6.90 (d, 2H); 7.78 (d, 2H); 9.88 (s, 1H).

Example I-5

tert-butyl 3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethyl-propionate

[image]

At room temperature, a solution of 1.00 g (3.81 mmol) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example 1-3) and 0.37 g (3.81 mmol) of furfurylamine in 10 ml of dichloroethane was stirred for 30 min, 1.21 g (5.72 mmol) of sodium triacetoxyborohydride was added and the mixture was then stirred at room temperature for 22 h. Then 6 ml sat. NaHCO3 solution and 10 ml of ethyl acetate, the phases were separated, the aqueous phase was extracted 2x with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and 720 mg (55%) of tert-butyl 3-(4-{[(2-furylmethyl) -amino]methyl}phenyl)-2,2-dimethylpropionate.

1H-NMR (300 MHz, CDCl3): δ = 1.11 (s, 6H); 1.42 (s, 9H); 1.62 (wide s, 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); 7.35 (d, 1H).

Example I-6

tert-butyl 3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate

[image]

Similar to the procedure from Example I-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 and 210 mg (0.991 mmol) ) of sodium triacetoxyborohydride in 2 ml of dichloroethane was converted into 223 mg (86 %) of tert-butyl 3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate. 1H-NMR (400 MHz, CDCl3): δ = 1.11 (s, 6H); 1.42 (s, 9H); 2.81 (s, 2H); 3.98 (wide 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, 2H).

Example I-7

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

[image]

Similar to the procedure from Example 1-5, 200 mg (0.762 mmol) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example 1-3), 82 mg (0.762 mmol) of toluidine and 210 mg (0.991 mmol) ) of sodium triacetoxyborohydride in 2 ml of dichloroethane was converted into 206 mg (76 %) of tert-butyl 2,2-dimethyl-3-(4-{[(4-methylphenyl)amino]methyl}phenyl)-propionate. 1H-NMR (400 MHz, CDCl3): δ =1.11 (s, 6H); 1.42 (s, 9H); 2.23 (s, 3H); 2.81 (s, 2H); 3.87 (broad s, 1H); 4.27 (s, 2H); 6.57 (d, 2H); 6.98 (d, 2H); 7.12 (d, 2H); 7.25 (d, 2H).

Example I-8

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

[image]

Similar to the procedure from Example 1-5, 1.20 g (4.54 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropionate (Example 1-4) and 0.70 g (4.54 mmol) of methyl DL-2-aminobutyrate were reacted at at room temperature with 0.92 g (9.08 mmol) of triethylamine and 1.44 g (6.81 mmol) of sodium triacetoxyborohydride in 10 ml of dichloroethane. A further 0.9 g (4.25 mmol) of sodium triacetoxyborohydride and 0.35 g (2.27 mmol) of methyl DL-2-aminobutyrate were added and the mixture was heated at 40 °C for 3 h, yielding 1.47 g (89 %) of methyl 2-{[ 4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate.

1H-NMR (300 MHz, DMSO): δ = 0.84 (t, 3H); 1.38 (s, 9H); 1.47 (s, 6H); 1.57 (dt, 2H); 2.29 (broad s, 1H); 3.08 (t, 1H); 3.47 (d, 1H); 3.62 (s, 3H); 3.65 (d, 1H); 6.73 (d, 2H); 7.18 (d, 2H).

Example I-9

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

[image]

A solution of 600 mg (1.75 mmol) of tert-butyl 3-(4-{[(2-furylmethyl)-amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-5), 323 mg (0.87 mmol) of tetra -n-butylammonium iodide and 265 mg (2.62 mmol) of triethylamine in 10 ml of THF were treated with 438 mg (2.62 mmol) of ethyl bromoacetate and heated under reflux overnight. After cooling, the mixture was concentrated under reduced pressure, the residue was taken up in water and ethyl acetate, the aqueous phase was extracted 2x with ethyl acetate and the combined organic phases were washed with NaCl solution and dried over sodium sulfate. The solvent was removed under reduced pressure, and 702 mg (94%) of tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl) (2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

1H-NMR (400 MHz, CDCl3): δ = 1.11 (s, 6H); 1.27 (t, 3H); 1.42 (s, 9H); 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, 1H); 7.10 (d, 2H); 7.25 (d, 2H); 7.38 (d, 1H).

Example I-10

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

[image]

Similar to the procedure from Example I-9, from 198 mg (0.583 mmol) of tert-butyl 3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate (Example 1-6), 108 mg (0.292 mmol) of tetra-n -butylammonium iodide, two portions in each case of 89 mg (0.875 mmol) of triethylamine and three portions in each case of 146 mg (0.875 mmol) of ethyl bromoacetate in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide yielded 191 mg (77 %) tert -butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-phenyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

1H-NMR (200 MHz, CDCl3): 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 I-11

tert-butyl 3-(4-C[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)amino]-methyl}phenyl)-2,2-dimethylpropionate

[image]

Similar to the procedure from Example I-9, from 181 mg (0.512 mmol) of tert-butyl 2,2-dimethyl-3-(4-{[(4-methylphenyl)amino]methyl)phenyl)propionate (Example 1-7), 95 mg (0.256 mmol) of tetra-n-butylammonium iodide, two portions of 78 mg (0.768 mmol) of triethylamine in each case and three portions of 128 mg (0.768 mmol) of ethyl bromoacetate in each case in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide 176 mg (78 %) of tert-butyl 3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl)phenyl)-2,2-dimethylpropionate were obtained .

1H-NMR (200 MHz, CDCl 3 ): 1.11 (s, 6H); 1.25 (t, 3H); 1.42 (s, 9H); 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, 2H); 7.10 (d, 2H); 7.17 (d, 2H).

Example I-12

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

[image]

A solution of 785 mg (1.83 mmol) of tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl)phenyl)-2,2-dimethylpropionate (Example 1-9) in 15 ml of ethanol was mixed with 5.5 ml (5.5 mmol) of 1 N aqueous sodium hydroxide solution and the mixture was heated to 80 °C for 1 h. After cooling, the mixture was concentrated under reduced pressure and the residue was taken up in a little water, acidified with 1 N hydrochloric acid and extracted 3x with ethyl acetate. The combined organic extracts were washed 2x sat. with NaCl solution, dried over sodium sulfate and freed from the solvent under reduced pressure. This gave 728 mg (99%) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine.

1H-NMR (200 MHz, DMSO): δ = 1.06 (s7 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); 7.63 (d, 1H); 12.20 (wide with, 1H).

Example I-13

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

[image]

Similar to the procedure from Example I-12, from 175 mg (0.411 mmol) tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-phenyl)amino]methyl}phenyl)-2,2- of dimethyl-propionate (Example 1-10) and 1.23 ml (1.23 mmol) of 1 N aqueous sodium hydroxide solution in 3 ml of ethanol yielded 162 mg (99 %) of N-[4-(3-tert-butoxy-2,2- dimethyl-3-oxopropyl)-benzyl]-N-phenylglycine.

1H-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, 1H); 12.53 (wide s, 1H).

Example I-14

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

[image]

Similar to the procedure from Example i-12, from 153 mg (0.348 mmol) tert-butyl 3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl )-2,2-dimethylpropionate (Example 1-11) and 1.23 ml (1.23 mmol) of 1 N aqueous sodium hydroxide solution in 3 ml of ethanol yielded 141 mg (99 %) of N-[4-(3-tert-butoxy- 2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine.

1H-NMR (300 MHz, DMSO): δ = 1.04 (s, 6H); 1.36 (s, 9H); 2.14 (s, 3H); 2.72 (s, 2H); 4.08 (s, 2H); 4.52 (s, 2H); 6.48 (d, 2H); 6.90 (d, 2H); 7.08 (d, 2H); 7.18 (d, 2H); 12.48 (wide with, 1H).

Example I-15

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

[image]

Similar to the procedure from Example 1-12, from 750 mg (2.05 mmol) of methyl 2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate (Example 1-8) and 6.20 ml (6.20 mmol) of 1 N aqueous sodium hydroxide solution in 6 ml of ethanol yielded 640 mg (89 %) of 2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl] amino}butyric acid.

1H-NMR (300 MHz, DMSO): δ = 0.91 (t, 3H); 1.40 (s, 9H); 1.51 (s, 6H); 1.84 (m, 2H); 3.25 (broad s, 1H); 3.57 (t, 1H); 3.99 (s, 2H); 6.81 (d, 2H); 7.38 (d, 2H).

Working examples 1

Example 1-1

tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)-amino]methyl}phenyl)-2,2-dimethylpropionate

[image]

At 0 °C, 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3-(3-dimethylamino)-propylcarbodiimide hydrochloride, 151 mg (1.494 mmol) of N- methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine solution of 200 mg (0.498 mmol) N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl) )glycine (Example 1-12) l 91 mg (0.747 mmol) of 2,4-dimethylaniline in 8 ml of dimethylformamide, and the solution was stirred at that temperature for 1 h. The mixture was then stirred at room temperature for 9 h and then mixed with 10 ml of water. The aqueous phase was extracted 2x with ethyl acetate and the combined organic phases were washed with 1 N hydrochloric acid, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulfate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (cyclohexane/ethyl acetate 10:1 → 3:1) yielded 228 mg (91 %) of tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)-amino-2- oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-di-methyl-propionate.

1H-NMR (200 MHz, CDCl3): 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, 1H); 6.99 (m, 2H); 7.11 (d, 2H); 7.23 (d, 2H); 7.37 (d, 1H); 7.84 (d, 1H); 9.12 (wide s, 1H).

Example 1-2

tert-butyl 3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate

[image]

Similar to the procedure from Example 1-1, 200 mg (0.498 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine (Example 1 -12), 113 mg (0.747 mmol) 4-methoxy-2,5-dimethylaniline, 88 mg (0.648 mmol) 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) 1-ethyl-3-(3-dimethylamino) )propylcarbodiimide hydrochloride, 151 mg (1.494 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine in 8 ml of dimethylformamide was converted into 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.

1H-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 (wide s, 1H).

Example 1-3

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

[image]

Similar to the procedure from Example 1-1, 65 mg (0.164 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine (Example I-13), 30 mg (0.245 mmol) 2,4-dimethylaniline, 29 mg (0.213 mmol) 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) 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 was converted into 65 mg (79 %) of tert-butyl 3-(4-{[N-(2-(2,4-dimethHphenyl)amino -2-oxo)ethyl-N-phenylamino]methyl}-phenyl)-2,2-dimethylpropionate.

1H-NMR (200 MHz, CDCl3): 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 wide 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-dimethylpropionate

[image]

Similar to the procedure from Example 1-1, 65 mg (0.164 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine (Example I-13), 37 mg (0.245 mmol) 4-methoxy-2,5-dimethylaniline, 29 mg (0.213 mmol) 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) 1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 50 mg (0.491 mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of 4-dimethyl-aminopyridine in 2 ml of dimethylformamide were converted into 78 mg (90 %) of fe/t-butyl 3-(4-{[N-(2- (4-Methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino] methyl }phenyl)-2,2-dimethylpropionate. 3-NMR (200 MHz, CDCl3): δ =1.11 (s, 6H); 1.42 (s, 9H); 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 (wide s, 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-dimethylpropionate

[image]

Similar to the procedure from Example 1-1, 50 mg (0.121 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine (Example 1 -14), 22 mg (0.182 mmol) of 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-dimethyl-aminopyridine in 2 ml of dimethylformamide were converted into 40 mg (64 %) of tert-butyl-3-(4-{[N-(2- (2,4-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

1H-NMR (300 MHz, CDCl3): 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, 1H); 7.06 (d, 2H); 7.11 (d, 2H); 7.13 (d, 2H); 7.67 (d, 1H); 8.18 (wide s, 1H).

Example 1-6

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

[image]

Similar to the procedure from Example 1-1, 50 mg (0.121 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine (Example 1 -14), 28 mg (0.182 mmol) 4-methoxy-2,5-dimethylaniline, 21 mg (0.158 mmol) 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) 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 of dimethylformamide was converted into 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)-2,2-dimethylpropionate.

1H-NMR (300 MHz, CDC3): δ = 1.10 (s, 6H); 1.41 (s, 9H); 1.96 (s, 3H); 2.15 (s, 3H); 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 (wide s, 1H).

Example 1-7

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

[image]

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

1H-NMR (200 MHz, CDCl3): 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 (df 1H); 7.18 (d, 2H); 7.93 (d, 1H); 9.32 (wide s, 1H).

Example 1-8

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

[image]

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

1H-NMR (200 MHz, CDCl3): δ = 0.99 (t, 3H); 1.44 (s, 9H); 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 (wide s, 1H).

Example 1-9

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

[image]

A solution of 192 mg (0.380 mmol) tert-butyl 3-(4-[[(2-(2,4-dimethyl-phenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2, of 2-dimethyl-propionate (Example I-1) in 1 ml of dichloromethane was treated with 1 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure, the residue was taken up in ethyl acetate and the organic phase was washed 2x with water, 1x with 20% sodium acetate solution, 1x with water and 1x sat. NaCl solution, dried over sodium sulfate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (dichloromethane → dichloromethane/methanol 20:1) yielded 150 mg (88%) of 3(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl) amino]-methyl}phenyl)-2,2-dimethylpropionic acid.

1H-NMR (200 MHz, CDCl3): 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 (wide s, 1H).

Example 1-10

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

[image]

Similar to the procedure from Examples 1-9, 170 mg (0.318 mmol) of tert-butyl 3-(4{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)-amino ]methyl}phenyl)-2,2-dimethylpropionate (Example 1-2) was reacted with 1 ml of trifluoroacetic acid in 1 ml of dichloromethane, which gave 133 mg (87 %) of 3-(4-{[(2-(4-methoxy -2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionic acid.

1H-NMR (200 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, 3H); 3.76 (s, 2H); 6.39 (d, 2H); 6.87 (s, 1H); 7.12 (d, 2H); 7.28 (d, 2H); 7.30 (with, IH); 7.61 (s, 1H); 9.02 (wide s, 1H); 12.18 (wide with, 1H).

Example 1-11

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

[image]

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

1H-NMR (200 MHz, CDCl3): 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 15(m, 2H); 7.67 (d, 1H); 8.08 (wide 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

[image]

Similar to the procedure from Examples 1-9, 61 mg (0.115 mmol) of tert-butyl 3-(4{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenyl -amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-4) was reacted with 1 ml of trifluoroacetic acid in 2 ml of dichloromethane, resulting in 46 mg (85 %) of 3-(4-{[N-(2 -(4-Methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionic acid.

1H-NMR (200 MHz, CDCl): 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 (wide s, 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

[image]

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

1H-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, 2H); 7.13 (s, 2H); 7.17 (d, 2H); 7.68 (d, 1H); 8.19 (wide s, 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 acid

[image]

Similar to the procedure from Examples 1-9, 40 mg (0.073 mmol) of tert-butyl 3-(4{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-( 4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-6) was reacted with 1 ml of trifluoroacetic acid in 2 ml of dichloromethane, resulting in 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 acid.

1H-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 (wide s, 1H).

Example 1-15

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

[image]

Similar to the procedure from Example 1-9, 170 mg (0.374 mmol) tert-butyl 2-(4{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}-phenoxy)-2-methylpropionate (Example 1-7) was reacted with 0.72 ml (9.35 mmol) of trifluoroacetic acid in 3 ml of dichloromethane, resulting in 113 mg (72 %) of 2-(4-{[(1-{[(2,4-dimethylphenyl)amino) ]-carbonyl)propyl)amino]methyl}phenoxy)-2-methylpropionic acid.

1H-NMR (300 MHz, CDCl): δ =1.01 (t, 3H); 1.53 (d, 6H); 1.95 (m, 2H); 2.10 (s, 3H); 2.23 (s, 3H); 3.67 (wide 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 (wide s, 1H).

Example 1-16

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

[image]

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

1H-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 (wide s, 1H).

Source materials II

Example II-1

1,1-dimethylethyl 2-[(4-bromophenyl)thio]-2-methyl-propanoate

4-Bromothiophenol (100 g) and tert-butyl 2-bromoisobutyrate (118 g) were dissolved in 1 l of ethanol and treated with 29 g of KOH. The mixture was stirred under reflux for 2 h and cooled, and the KBr was filtered off. The filtrate was concentrated and the residue was recrystallized from n-hexane. This resulted in 93.6 g of a colorless solid.

1H-NMR (200 MHz, CDCl3): 1.48 (s, 15H); 7.38 (m, 4H).

Example II-2

1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate

1.0 g of 1,1-dimethylethyl 2-[(4-bromophenyl)thio]-2-methyl-propanoate was dissolved in 20 ml of THF and treated with 189 ml (3.02 mmol, 1 eq) of a solution of n-butyllithium in hexane. Immediately after that, 0.46 ml of dimethylformamide was added and the mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of 1 ml of 1 N HCl, the mixture was concentrated and the residue was taken up in ethyl acetate. The mixture was extracted sat. NaHCO3 solution and NaCl solution and dried (MgSO4). Chromatographic purification (dichloromethane) gave 550 mg of a pale yellow oil.

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

Example II-3

1,1-dimethylethyl2-[[4-[[(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

First, 550 mg of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 381 mg of furfurylamine were placed in 100 ml of methanol and treated with 1 ml of glacial acetic acid. The mixture was stirred at room temperature for 15 min, briefly brought to a boil and then, at 0°C, little by little mixed with 493 mg of sodium cyanoborohydride. The mixture was stirred overnight at room temperature and then treated with 1 N HCl and stirred for 30 min. The mixture was then alkalized using a Na2CO3 solution and extracted 2x with ethyl acetate. The organic phase was washed (saturated NaCl solution) and dried (MgSO-i). Concentration and chromatographic purification (dichloromethane/ethyl acetate 10+1) yielded 430 mg of a colorless oil.

1H-NMR (300 MHz, CDCl3): 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

1,1-dimethylethyl2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoate

5.4 g of 1,1-dimethylethyl 2-[[4-[[(2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoate was dissolved in 270 ml of tetrahydrofuran and treated with 2.27 g of triethylamine and 3.74 g ethyl bromoacetate and 14.85 g of tetra-n-butylammonium iodide. The mixture was stirred at 90 °C for 48 h, cooled and mixed with water and ethyl acetate. The organic phase was separated and washed twice with sat. NaCl solution. The mixture was dried (MgSO4) and concentrated, and the residue was purified by chromatography (cyclohexane/ethyl acetate 5+1), which gave 6.4 g of a colorless oil.

1H-NMR (CDCl 3 , 200 MHz): 1.28 (t, 3H, 3=8.7 Hz); 1.40 (s, 9H); 1.42 (s, 6H); 3.32 (s, 2H); 3.78 (s, 2H); 3.84 (s, 2H); 4.15 (q, J=8.7 Hz); 6.17 (m, 1H); 6.30 (m, 1H); 7.25-7.45 (m, 5H).

Example II-5

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

First, 192 mg of 1,1-dimethylethyl 2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]methyl]phenyl]-thio]-2-methyl-propanoate was placed in 5 ml of ethanol and treated with 0.4 ml of 1 N NaOH. The mixture was stirred at 80 °C for 1 h. The mixture was examined by TLC (CH2Cl2/methanol = 10+1) and then cooled and concentrated, and the residue was dissolved in a little water. The mixture was acidified with 1 N HCl and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and twice with sat. NaCl solution and dried over MgSO4. The mixture was concentrated, applied to silica gel and purified by vacuum chromatography using CH2Cl2 → CH2Cl2/methanol 50+1 → 25+1. This gave 132 mg of a colorless oil which solidified under high vacuum.

1H-NMR (DMSO, 200 MHz): 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 (wide with, 1H).

Example II-6

1,1-dimethylethyl2-[[4-[2-[(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate

4.0 g of 1,1-dimethylethyl 2-[[4-(2-aminoethyl)phenyl]thio]-2-methyl-propanoate [(PJ. Brown et al., J. Med. Chem. 42, 3785-88) was dissolved (1999)] in 100 ml of methanol and the mixture was treated with 2.6 g of furfural. 9.3 ml of glacial acetic acid was added and the mixture was boiled briefly (10 min). Then the mixture was cooled to 0 °C, and 4.25 g of sodium cyanoborohydride. The mixture was then stirred at room temperature overnight. 1 N HCl was added until the mixture became acidic, and the mixture was stirred for 30 min. The mixture was slightly concentrated and basified using saturated NaHCO3 solution. The mixture was then extracted for two times with ethyl acetate and the extracts were washed (saturated NaCl solution) and dried and concentrated.Chromatographic purification (dichloromethane/methanol 15+1) afforded 2.4 g of the title compound as a colorless oil.

Rf (dichloromethane/methanol 10+1) = 0.57.

Example II-7

1,1-dimethylethyl 2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate

2.4 g of 1,1-dimethylethyl 2-[[4-[2-[(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2methyl-propanoate, 1.5 g of ethyl bromoacetate, 0.97 g of triethylamine and 7.08 g of tetra -n-butylammonium iodide in 100 ml of tetrahydrofuran, and heated under reflux overnight. Ethyl acetate and water were added, and the mixture was extracted with water and sat. NaCl solution. Concentration and chromatography (petroleum ether/ethyl acetate 10+1) yielded 1.38 g of the title compound.

1H-NMR (DMSO, 200 MHz): 1.18 (t, 3H, 3=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=9.6 Hz); 7.32 (d, 2H, J=9.6 Hz); 7.58 (m, 1H).

Example II-8

1,1-dimethylethyl2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]ethyl]-phenyl]thio]-2-methyl-propanoate

1.0 g of 1,1-dimethylethyl 2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate was treated with 6.5 ml 1 N NaOH in 10 ml of ethanol. The mixture was stirred at 80 °C for 1 h, concentrated, dissolved in water and acidified with 1N HCl. After three extractions with ethyl acetate and chromatography (dichloromethane/methanol 5+1), 744 mg was obtained in the form of a colorless oil.

1H-NMR (DMSO, 200 MHz): 1.36 (s, 15H); 2.75 (m, 4H); 3.20 (s, 2H); 3.72 (s, 2H); 6.18 (mf 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-dimethylethyl2-[[4-[[(2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

First, 7.9 g of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 4.23 g of methoxyethylamine were placed in 100 ml of methanol and mixed with 19 ml of acetic acid. The mixture was stirred at RT for 15 min, boiled briefly and then, at 0 °C, it was mixed little by little with 8.9 g of sodium cyanoborohydride. The mixture was stirred at room temperature overnight and then mixed with 1 N HCl and stirred for 30 min. The mixture was then alkalized using a sodium carbonate solution and extracted 2x with ethyl acetate. The organic phase was washed with sat. sodium chloride solution and dried over magnesium sulfate. Concentration and chromatographic purification yielded 5.6 g (58 %) of a colorless oil.

1H-NMR (200 MHz, CDCl3): δ = 1.38 (s, 6H), 1.42 (s, 9H), 2.45 (m, 3H, CH2 + NH), 3.37 (s, 3H), 3.88 (s, 2H) , 7.25-7.52 (m, 4H).

Example II-10

1,1-dimethylethyl2-[[4-[[(2-(5-methylfuranmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

First, 8.0 g of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 6.3 g of 5-methyl-2-furanmethanamine were placed in 100 ml of methanol and treated with 16 ml of acetic acid. The mixture was stirred at RT for 15 min, boiled briefly, and then, at 0 °C, it was mixed little by little with 5.7 g of sodium cyanoborohydride. The mixture was stirred at room temperature overnight and then mixed with 1 N HCL and stirred for 30 min. The mixture was then alkalized using a sodium carbonate solution and extracted 2x with ethyl acetate. The organic phase was washed with sat. sodium chloride solution and dried over sodium sulfate. Concentration and chromatographic purification yielded 4.8 g (45%) of a colorless oil prone to decomposition, which was stored at -25°C.

Example II-10

1,1-dimethylethyl2-[[4-[[(2-(5-methylfuranmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

First, 8.0 g of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 6.3 g of 5-methyl-2-furanmethanamine were placed in 100 ml of methanol and treated with 16 ml of acetic acid. The mixture was stirred at RT for 15 min, boiled briefly, and then, at 0 °C, it was mixed little by little with 5.7 g of sodium cyanoborohydride. The mixture was stirred at room temperature overnight and then mixed with 1 N HCl and stirred for 30 min. The mixture was then alkalized using a sodium carbonate solution and extracted 2x with ethyl acetate. The organic phase was washed with sat. sodium chloride solution and dried over sodium sulfate. Concentration and chromatographic purification yielded 4.8 g (45%) of a colorless oil prone to decomposition, which was stored at -25°C.

1H-NMR (200 MHz, CDCl3): 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, 1H), 7.28 (dd, 2H, J=11Hz), 7.45 (m, 2H, J=11Hz).

Example II-11

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

117 g of triethylamine and 140 g of 2,4-dimethylaniline were dissolved in 2 l ml of methylene chloride, and a solution of 233 g of alpha-bromoacetyl bromide in 400 ml of methylene chloride was added with ice cooling to a maximum of 15 °C within 30 min. After a reaction time of 30 min, the precipitate was filtered off with suction, the residue was dissolved in 3 l of methylene chloride and combined with the filtrate and washed twice with 2 l of water and 2 l of sat. sodium chloride solution. The mixture was dried over sodium sulfate, filtered off with suction and concentrated, and the residue was recrystallized from ethanol. This gave 193 g of the title compound.

Example II-12

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

This compound was prepared similarly to Example 11-11 from 4.2 g of 2,4-dichloroaniline and 5.76 g of bromoacetyl bromide and 2.89 g of triethylamine in methylene chloride. This gave 5.9 g (80.4 %) of the title compound.

Rf (dichloromethane): 0.38

MS (EI pos.): M+ = 283.

Working examples 2

Example 2-1

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

Method a):

250 mg of 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-1,1-dimethylethyl propanoate, 89 mg of hydroxybenzotriazole, 249 ml of triethylamine were dissolved , 82 mg of 2,4-dimethylaniline and 131 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 25+1). This resulted in 200 mg of viscous oil.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 4.87 min ([M+H]+ = 523).

Method b):

1.5 g of 1,1-dimethylethyl 2-[[4-[[(2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoate (Example II-3) and 1.1 g of 2-bromo- of N-(2,4-dimethylphenyl)acetamide (Example II-9) in 20 ml of DMF and treated with 0.4 g of sodium bicarbonate. The mixture was heated to 90 °C overnight, concentrated and purified by chromatography (dichloromethane/ethyl acetate 10:1 and 5:1). This gave 2.1 g of the title compound.

Example 2-2

tert-butyl 2-[[4-[[[2-[(2,4/6-trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

250 mg of 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-1,1-dimethylethyl propanate, 90 mg of hydroxybenzotriazole, 250 ml were dissolved triethylamine, 80 mg of 2,4,6-trimethylaniline and 130 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 25+1). This resulted in 210 mg of viscous oil.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 5.32 min ([M+H]+ = 537).

Example 2-3

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

250 mg of 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)-amino]ethyl]phenyl]thio]-2-methyl-1,1-dimethylethyl propanoate, 90 mg of hydroxybenzotriazole, 250 ml of triethylamine were dissolved , 80 mg of 2,5-dimethyl-4-methoxyaniline and 130 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 25+1). This resulted in 190 mg of viscous oil.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt= 4.90 min ([M+H]+ = 552).

Example 2-4

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

250 mg of 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)-amino]-ethyl]-phenyl]thio]-2-methyl-1,1-dimethylethyl propanoate, 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mg of 2-methyl-4-methoxylaniline and 130 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiinide hydrochloride in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 25+1). This resulted in 190 mg of viscous oil.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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-methyl-propanoic acid

[image]

90 mg of tert-butyl 2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl was dissolved -propanoate in 5 ml of dichloromethane and reacted with 0.1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 4 h and then concentrated and purified by chromatography (dichloromethane/methanol 100+1). This gave 80 mg of the title compound as a solid foam. Rf (dichloromethane/methanol 10+1) = 0.3

1H-NMR (400 MHz, D6-DMSO): δ = 1.34 (s, 6H, CH3), 2.16 (s, 3H, CH3), 2.23 (s, 3H, CH3), 3.24 (s, 2H, CH2), 3.76 (s, 2H, CH2), 3.78 (s, 2H, CH2), 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, 1H7 furanyl-H), 9.14 (s, 1H, NH).

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

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 3.76 min ([M+H]+= 467).

Example 2-5a

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

[image]

500 mg of 2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoic acid was dissolved (Example 2-5) in 500 mg of acetonitrile and 194 mg of dicyclohexylamine was added. Water was added, part of the acetonitrile was distilled off until the mixture became turbid and the mixture was lyophilized. This resulted in 445 mg of powder.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 3.76 min ([M+H] + = 467).

Example 2-5b

2-[[4-[[[2-[(2r4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propanoic acid hydrochloride

[image]

1.20 g of 2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl]-(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoyl was dissolved acid (Example 2-5) in 100 ml of ethyl acetate and mixed with 1N HCl/diethylether until the mixture becomes turbid. The resulting crystals were filtered off with suction and washed with dry ether. This gave 1 g of the title compound.

Melting point: 158°C (from ethanol/diethyl ether).

Example 2-6

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

[image]

210 mg of tert-butyl 2-[[4-[[[2-[(2,4-/6-trimethylphenyl)-amino]-2-oxoethyl](2-furanylmethyl)amino]methIII]phenyl]thio] was dissolved -2-methyl-propanoate in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 4 h and then concentrated and purified by chromatography (dichloromethane/ethyl acetate 50+1). This gave 187 mg of the title compound as a solid foam.

1H-NMR (DMSO, 200 MHz): 1.42 (s, 6H); 2.04 (s, 6H); 2.23 (s, 3H); 3.58 (broad 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 (wide with, 1H).

Example 2-7

2-[[4-[[[2-[(2f5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoic acid

[image]

190 mg of tert-butyl 2-[[4-[[[2-[(2,5-dimethyl-4-methoxy-phenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl] was dissolved of phenyl]-thio]-2-methyl-propanoate in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 h and then concentrated and purified by chromatography (dichloromethane/methanol 50+1). This gave 166 mg of the title compound as a solid foam.

1H-NMR (DMSO, 200 MHz): 1.39 (s, 6H); 2.08 (s, 3H); 2.11 (s, 3H); 3.7 (s, 3H); 4.00 (broadcast, 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, (wide s, 1H); 12.65 (wide with, 1H).

Example 2-8

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

[image]

200 mg of tert-butyl 2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)-amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]- was dissolved of 2-methyl-propanoate in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 h and then concentrated and purified by chromatography (dichloromethane/methanol 50+1). This gave 174 mg of the title compound as a solid foam.

1H-NMR (DMSO, 200 MHz): 1.38 (s, 6H); 2.12 (s, 3H); 3.7 (s, 3H); 3.80 (broad s, 2H); 4.00 (wide with, 2H); 6.45 (m, 1H); 6.55 (m, 1H); 6.65 (m, 1H); 6.78 (m, 1H); 7.25 (m, 1H); 7.48 (m, 4H); 7.71

(m, 1H); 9.37 (wide s, 1H); 12.65 (wide with, 1H).

Example 2-9

tert-butyl 2-[[4-[2-[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate

104 mg of 1,1-dimethylethyl 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate, 36 mg of hydroxybenzotriazole, 0.1 ml of triethylamine, 29 mg of 2,4-dimethylaniline and 53 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 5+1). This resulted in 190 mg of viscous oil.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 5.3 min ([M+KT = 537).

1H-NMR (CDCl 3 , 200 MHz): 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), including: (m, 1H); 7.79 (m, 1H); 8.95 (wide s, 1H); 12.60 (wide s, 1H).

Example 2-10

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

98 mg of 1,1-dimethylethyl 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate, 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 in 5 ml of dichloromethane. The mixture was stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases were dried (MgSO4) and purified by chromatography (dichloromethane/ethyl acetate 5+1). This resulted in 48 mg of viscous oil.

TLC: Rf=0.65 (dichloromethane/ethyl acetate = 10+1).

Example 2-11

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

[image]

38 mg of tert-butyl 2-[[4-[2-[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]ethyl]phenyl]thio]-2 was dissolved -methyl-propanoate in 5 ml of dichloromethane and treated with 0.27 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 24 h and co-evaporated with toluene, and the residue was chromatographed (dichloromethane/methanol 10+1). This gave 33 mg of colorless oil. LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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 acid

[image]

30 mg of tert-butyl 2-[[4-[2-[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]ethyl] was dissolved of phenyl]thio]-2-methyl-propanoate in 5 ml of dichloromethane and treated with 0.20 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 24 h and co-evaporated with toluene, and the residue was chromatographed (dichloromethane/methanol 10+1). This resulted in 27 mg of oil that darkens when exposed to the atmosphere.

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 3.78 min ([M+H]+= 511).

1H-NMR (DMSO, 200 MHz): 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), including: (m, 1H); 7.62 (m, 1H); 8.88 (broad s, 1H); 12.55 (wide with, 1H).

The following examples of compounds are prepared in a similar way:

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

[image]

Yield: 343 mg (68 %).

1H-NMR: (200 MHz, CDCl3): δ = 1.50 (s, 6H, 2xCH3), 2.19 (s, 3H, CH3), 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, Ar-H), 9.68 (s, 1H, NH). LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 3.42 min ([M+H]+ = 521)

Example 2-14

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

[image]

Yield: 90 mg (36%)

1H-NMR (200 MHz, CDCl): δ =1.53 (s, 6H, 2xCH3), 2.29 (s, 3H, CH3), 3.75 (s, 2H, CH2), 4.25 (s, 2H, CH2), 4.28 ( s, 2H7 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 HCl/water (gradient): Rt = 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

[image]

Yield: 46 mg (26%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 183 mg (41%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 149 mg (67%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 63 mg (22%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 24 mg (18%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 2.59 min

([M+H]+ = 497)

Example 2-20

2-[[4-[[[2-[(2,5-dimethyl-4-methoxy-phenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl- propionic acid

[image]

Utilization: 60 mg (60%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 16 mg (20%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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 ] methyl]phenyl]thio]-propanoic acid

[image]

Yield: 89 mg (81%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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

[image]

Yield: 22 mg (34%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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-methyl-propanoate acid

[image]

Yield: 26 mg (20%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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-methyl-propanoic acid

[image]

Yield: 61 mg (27 %).

1H-NMR (300 MHz, CDCl3): δ = 1.38 (s, 6H, 2xCH3), 2.82 (m, 2H, CH2), 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 HCl/water (gradient): Rt = 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-methyl-propanoic acid

[image]

Yield: 50 mg (75%)

1H-NMR (200 MHz, CDCl): δ =1.50 (s, 6H, 2xCH3), 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, CH2), 4.32 (s, 2H, CH2), 5.40 (s, 1H, COOH), 7.00 (m, 2H, Ar -H), 7.32-7.52 (m, 7H, ArH), 9.00 (s, 1H, NH).

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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 ]tio]-

propanoic acid

[image]

Yield: 200 mg (99%)

1H-NMR (300 MHz, CDCl): δ =1.50 (s, 6H, 2xCH3), 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 HCl/water (gradient): Rt =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 acid

[image]

Utilization: 80 mg (98%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 3.56 min ([M+H]+ = 606).

Example 2-29

2-methyl-2-[[4-[[[(2-thiophenyl)methyl][2-oxo-2-[(2-methyl-4-methoxy-phenyl)amino]ethyl]amino]methyl]phenyl]thio ]-propanoic acid

[image]

Yield: 83 mg (83%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 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]-propanoate acid

[image]

Yield: 75 mg (60%)

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 4.19 min ([M+H]+ = 499).

Example 2-31

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

[image]

Utilization: 65% of the theoretical

1H-NMR (300 MHz, CDCl3): 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-methyl-propanoic acid

[image]

Utilization: 89% of the theoretical

1H-NMR (300 MHz, CDCl3): 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, 2H); 6.87 (s, 2H); 7.39 (d, 2H); 7.53 (d, 2H); 8.82 (No. 1H).

Source materials III

Example III-1

tert-butyl (4-formylphenoxy)acetate

[image]

At room temperature, 31.60 g (281.48 mmol) of potassium fert-butoxide and 52.70 g (270.22 mmol) of tert-butyl bromoacetate were added to a solution of 27.50 g (225.18 mmol) of 4-hydroxybenzaldehyde in 200 ml of dioxane, and the mixture was heated to boiling over night. 1 l of water was added, and the mixture was then extracted with diethyl ether, washed with 1 N sodium hydroxide solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off. By vacuum chromatography on silica gel (cyclohexane → cyclohexane/ethyl acetate 20:1 → 10:1 → 5:1), after recrystallization from pentane, the target compound was obtained. Yield: 31 % Melting point: 58 - 60 °C

Example III-2

tert-butyl 2-(4-formylphenoxy)-2-methylpropanoate

[image]

24.42 g (200 mmol) of 4-hydroxybenzaldehyde was 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 tert-butyl α-bromolzobutyrate was added drop by drop. The mixture was stirred for another hour, a further 200 mmol of lead potassium carbonate and 240 mmol of tert-butyl a-bromoisobutyrate were added, and after 4 hours at 100 °C, 1 l of water was added. After extraction with diethyl ether, washing with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off and the residue was purified by vacuum chromatography on silica gel (cyclohexane → cyclohexane/ethyl acetate 20:1 → 10:1 →5: 1) and dried under reduced pressure. The target compound was obtained in the form of colorless crystals with a yield of 42%.

1H-NMR (200 MHz, CDCl): δ =1.40 (S, 9 H), 1.62 (s, 6 H), 6.91 (d, 2 H), 7.79 (d, 2 H), 9.88 (s, 1H) . MS (ESI): 265 [M+H] + .

The following compounds were obtained similarly to the procedure from Example III-2:

Example III-3

ethyl 2-(4-formylphenoxy)-2-methylbutanoate

[image]

Utilization: 11.71 %

1H-NMR (200 MHz, CDCl3): 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] + , 273 [M+Na] + .

Example III-4

tert-butyl 2-[(3-bromophenyl)sulfanyl]-2-methylpropanoate

[image]

Utilization: 87 %

1H-NMR (200 MHz 7 CDCl 3 ): δ = 1.43 (s, 9H), 1.45 (s, 6H), 7.14 - 7.28 (m, 1H)7 7.39 - 7.53 (m, 2H), 7.67 (t, 1H).

MS (DCI/NH3): 348 [M+NH4+].

Example III-5

tert -butyl 2-(3-formylphenoxy)-2-methylpropanoate

[image]

Utilization: 35%

1H-NMR (300 MHz, CDCl): δ =1.44 (s, 9H), 1.61 (s, 6H), 7.14 (dd, IH), 7.317.35 (m, 1H), 7.41 (t, 1H), 7.45 - 7.52 (m, 1H).

MS (DCI/NHs): 282 [M+NH4+].

Example III-6

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

[image]

Utilization: 21 %

1H-NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 1.56 (s, 6H), 6.74 - 6.83 (m, 1H), 7.00 - 7.04 (m, 1H), 7.06 - 7.11 (m, 2H).

MS (DCI/NH3): 332 [M+NH4+].

Example III-7

tert-butyl 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenoxy]-2-methylpropanoate

[image]

Yield: 24 % Melting point: 142 - 143 °C

Example III-8

tert-butyl 2-[(3-formylphenyl)sulfanyl]-2-methylpropanoate

[image]

At -78°C, 30.00 g (90.56 mmol) of the compound from Example III-4 was dissolved in tetrahydrofuran and treated with 36.2 ml of a 2.5 M solution of n-butyllithium in hexane. Then 13.94 ml (181.12 mmol) of N,N-dimethylformamide was added. After 30 minutes, the mixture was warmed to room temperature and stirred for 1 hour. 30 ml of 1 N hydrochloric acid was added, the solvent was distilled off, the residue was extracted with ethyl acetate and the extract was washed with a saturated solution of sodium bicarbonate and sodium chloride, and then dried over magnesium sulfate. After vacuum chromatography on silica gel (dichloromethane), the target compound was purified by NP-HPLC (cyclohexane/ethyl acetate) and obtained in 10% yield. 1H-NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H)7 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). MS (DCI/NH3): 298 [M+NH4+].

Example III-9

tert-butyl 2-{3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-phenoxy}-2methyl-propanoate

[image]

14.93 g (47.37 mmol) of the compound from Example III-6, 10.25 g (59.21 mmol) of vinylphthalimide, 0.39 g (1.27 mmol) of tris-o-tolylphosphine, 0.07 g (0.32 mmol) of [lacuna] and 21.78 g ( 215.23 mmol) of triethylamine at 130°C. Water/methanol was added and the precipitate was then filtered off with suction and recrystallized from cyclohexane/ethyl acetate.

Utilization: 66%.

1H-NMR (200 MHz, CDCl3): δ = 1.40 (s, 9H), 1.50 (s, 6H), 6.73 (dd, IH), 6.86 - 6.93 (m, 1H), 7.16 (t, 1H), 7.21 -7.34 (m, 2H), 7.43 (d, 1H), 7.80 - 8.00 (m, 4H).

MS (DCI/NH3): 425 [M+NH4+].

Example III-10

tert-butyl 2-{3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-phenoxy}-2methyl-propanoate

[image]

15.00 g (36.81 mmol) of the compound from Example IH-9 was dissolved in 200 ml of tetrahydrofuran and stirred overnight in a hydrogen atmosphere under atmospheric pressure in the presence of a suspension of 2.00 g (2.16 mmol) of Wilkinson's catalyst in 40 ml of ethanol. Two vacuum chromatographies on silica gel (cyclohexane/dichloromethane 10:1 → cyclohexane/ethyl acetate 10:1 → 5:1 and cyclohexane → cyclohexane/dichloromethane → dichloromethane) gave the title compound in 64% yield.

1H-NMR (200 MHz, CDCl3): δ = 1.45 (s, 9H), 1.52 (s, 6H), 2.85 - 3.00 (m, 2H), 3.82-3.95 (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 III-11

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

[image]

18.88 g (49.50 mmol) of the compound from Example III-7 was dissolved in 25 ml of ethanol, and heated to boiling with 12.04 ml (247.49 mmol) of hydrazine hydrate for 2 hours and then stirred at room temperature for 12 hours. The precipitate was separated and washed with ethanol, and 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 magnesium sulfate. The solvent was removed to give the title compound in 87% yield. Melting point: 87 - 88°C.

The following compound was obtained similarly to the procedure from Example III-11:

Example III-12

tert-butyl 2-[3-(2-aminoethyl)phenoxy]-2-methylpropanoate

[image]

Utilization: 70 %

1H-NMR (200 MHz, CDCl): δ =1.31 (broad s, 2H), 1.44 (s, 9H), 1.56 (s, 6H), 2.69 (t, 2H), 2.94 (t, 2H), 6.64 - 6.75 (m, 2H), 6.81 (d, 1H), 7.15 (t, 1H).

MS (EI): 279 [M+].

Example III-13

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

[image]

20.00 g (75.67 mmol) of the compound from Example III-2 and 7.35 g (75.67 mmol) of 2-furfurylamine were mixed at room temperature with 24.06 g (113.50 mmol) of sodium triacetoxyborohydride in 350 ml of 1,2-dichloroethane for 5 hours. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The organic phase was dried over magnesium sulfate and the solvent was distilled off, and the residue was then purified by vacuum chromatography on silica gel (cyclohexane → cyclohexane/ethyl acetate 10:1 →• 2:1). The target compound was obtained with a yield of 72%.

1H-NMR (200 MHz, CDCl): δ =1.61 (broad 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), 7.32-7AO (m, 1H). MS (ESI): 346 [M+H] + .

Example III-14

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

[image]

4.79 g (19.06 mmol) of the compound from Example III-11 and 1.83 g (19.06 mmol) of furfural were dissolved in 80 ml of 1,2-dichloroethane, and in the presence of 6.06 g (28.59 mmol) of sodium triacetoxyborohydride, they were mixed at room temperature for 5 hours. . Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution. The organic phase was dried over magnesium sulfate and the solvent was distilled off, and the residue was then purified by vacuum chromatography on silica gel (cyclohexane → cyclohexane/ethyl acetate 10:1 → 2:1) and by NP-HPLC (cyclohexane/ethyl acetate 10:1). The target compound was obtained with a yield of 79%.

1H-NMR (200 MHz, CDCl): δ =1.46 (s, 9H), 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/NH3): 332 [M+H+], 349 [M+NH4+].

Example III-15

tert-butyl 2-[4-[[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]methyl]-phenoxy]-2-methyl-propanoate

[image]

First, 18.14 g (52.50 mmol) of the compound from Example III-13, 11 ml of triethylamine and 1.10 g (2.97 mmol) of tetra-n-butylammonium iodide were placed in 200 ml of tetrahydrofuran and treated with 8.77 ml (78.75 mmol) of ethyl bromoacetate, and the mixture was mixed at room temperature for 1 hour and at 60°C for 2 hours. Water and ethyl acetate were then added to the mixture and the mixture was washed with saturated sodium chloride solution and dried over magnesium sulfate, and after removing the solvent, the residue was purified by vacuum chromatography on silica gel (cyclohexane/dichloromethane 4:1 → cyclohexane/ethyl acetate 10:1 → 5: 1). The recovery of the target compound was quantitative.

1H-NMR (300 MHz, CDCl3): δ = 1.26 (t, 3H), 1.43 (s, 9H), 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 - 6.85 (m, 2H), 7.22 (d, 2H), 7.35-7.41 (m, 1H ). MS (ESI): 432 [M+H] + .

Example III-16

tert-butyl 2-[4-[[(carboxymethyl)(2-furanylmethyl)amino]methyl]phenoxy]-methyl-propanoate

[image]

22.01 g (51.00 mmol) of the compound from Example III-15 was mixed at 80 °C in 785 ml of ethanol in the presence of 6.12 g (153.00 mmol) of sodium hydroxide for 1 hour. The solvent was distilled off and water was added, and the mixture was then acidified using 1 N hydrochloric acid and extracted with ethyl acetate. The extract was then washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The amount of solvent was reduced and the product was then filtered off with suction and dried to give the target compound in 74% yield. Melting point: 152 - 155°C

Example III-17

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

[image]

First, 50 g (246.06 mmol) of 4-isopropyl-2-(trifluoromethyl)aniline and 27.39 g (270.66 mmol) of triethylamine were placed in 1000 ml of dichloromethane. At 0°-5°C, 54.63 g (270.66 mmol) of bromoacetyl bromide dissolved in 200 ml of dichloromethane was added drop by drop. The mixture was stirred at room temperature for 20 hours. The reaction mixture was then extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography. The product was recrystallized from cyclohexane/n-pentane, filtered off with suction and dried under reduced pressure at 40 °C for 20 hours. This gave 32.45 g (41% of theory) of the title compound.

1H-NMR (300 MHz, CDCl): 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 (no. 1H).

Example III-18

2-Bromo-N-(4-tert-butyl-2-methylphenyl)acetamide

[image]

First, 5.5 g (33.69 mmol) of 4-tert-butyl-2-methylaniline and 3.75 g (37.06 mmol) of triethylamine were placed in 150 ml of dichloromethane. At 0 °C -5 °C, 7.48 g (37.06 mmol) of bromoacetyl bromide dissolved in 90 ml of dichloromethane was added drop by drop, and a light brown precipitate was formed. The mixture was stirred at room temperature overnight. Then 150 ml of ethyl acetate was added to the reaction mixture, which was successively extracted with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue was purified by chromatography. The product was recrystallized from ethyl acetate and n-pentane, filtered off with suction and dried under reduced pressure at 40 °G. This gave 6.53 g (68% of theory) of the title compound.

1H-NMR (400 MHz, CDCl3): δ = 1.3 (s, 9H); 2.3 (s, 3H); 4.06 (s, 2H); 7.20-7.23 (m, 1H); 7.25 (d, 1H); 7.7 (d, 1H); 8.05 (No. 1H).

Example III-19

2-Bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide

[image]

Utilization: 41.0 % of the theoretical

1H-NMR (200 MHz, CDCl): 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 (No. 1H).

Example III-20

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

[image]

Utilization: 95.6% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (No. 1H).

Example III-21

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

[image]

Utilization: 80.5% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (no. 1H).

Example III-22

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

[image]

Utilization: 77.9 % of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 3.99 (s, 2H); 6.88 (d, 1H); 7.06 (dd, 1H); 7.21-7.36 (m, 2H); 7.38-7.57 (m, 2H); 7.68-7.79 (m, 1H); 7.80-7.95 (m, 2H); 8.51 (d, 1H); 8.85 (no. 1H).

Example III-23

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

[image]

Utilization: 28% of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 4.10 (s, 2H); 7.80-7.91 (m, 2H); 8.50 (d, 1H); 8.80 (brs, 1 H).

Example III-24

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

[image]

Utilization: 24% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example III-25

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

[image]

Utilization: 16% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (brs, 1H).

Example III-26

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

[image]

Utilization: 84.0 % of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 2.35 (s, 3H); 4.08 (s, 2H); 7.18 (s, 1H); 8.05-8.20 (m, 2H).

Example III-27

4-methyl-1,3-oxazole-5-carbaldehydedoxime

[image]

First, 0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde [prepared from the corresponding alcohol (Chem. Ber. 1961, 1248) by Swern oxidation (Tetrahedron 34. 1651 (1978))] was added. in 3 ml of water and treated with 0.66 g (9.45 mmol) of hydroxylamine hydrochloride in 2 ml of water. Then 0.68 g (4.95 mmol) of potassium carbonate was added. After 2 h, the mixture was filtered with suction and the product was washed with water and dried at room temperature. The yield was 0.41 g (72.2 % of the theoretical).

1H-NMR (200 MHz, DMSO): 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

[image]

First, 4.00 g (31.72 mmol) of 4-methyl-1,3-oxazole-5-carbaldehydedoxime was placed in 70 ml of acetic acid. At room temperature, 47.70 g (729.50 mmol) of zinc powder was added in small portions. The mixture was stirred at room temperature for 2 hours and the zinc powder was then filtered off with suction and washed twice with 50 ml of acetic acid. The filtrate was freed from the solvent under reduced pressure. The residue was treated with a 20% aqueous solution of sodium hydroxide until a pH of 11 was reached. White crystals precipitated during the addition. They were triturated with ethyl acetate and filtered off with suction. The combined filtrates were freed from the solvent under reduced pressure, and the residue was then purified by chromatography. This gave 1.34 g (38% of theory) of the title compound.

1H-NMR (300 MHz, CDCl3): δ = 1.5 (s, 2H); 2.15 (s, 3H); 3.83 (s, 2H); 7.73 (s, 1H).

Example III-29

1,1-dimethylethyl 2-[(4-bromophenyl)thio]-2-ethyl-butanoate

[image]

The synthesis was carried out similarly to Example II-1 from 4-bromothiophenol and 1,1-dimethylethyl 2-bromo-2-ethyl-butanoate [preparation, for example, similar to Liebigs Ann. Chem. 725. 106-115 (1969); J. Am. Chem. Soc. ZZ, 946-947 (1955), and bromination with N-bromosuccinimide or bromine, for example similar to Tetrahedron Lett. 1970, 3431; 3. Org. Chem. 40, 3420 (1975)].

Utilization: 15.9 % of the theoretical

1H-NMR (300 MHz, CDCl): 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

1,1-dimethylethyl2-ethyl-2-[(4-formylphenyl)thio]-butanoate

[image]

The synthesis was carried out similarly to Example 11-2 using the compound from Example III-29 as starting material.

Utilization: 70.4 % of the theoretical

1H-NMR (300 MHz, CDCl3): δ = 0.96 (t, 6H); 1.64-1.87 (m, 4H); 7.60 (d, 2H); 7.78 (d, 2H); 10.1 (s, 1H).

Example III-31

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

[image]

The synthesis was carried out similarly to Example 111-13, using the compound from Example III-30 and furfurylamine as starting materials.

Utilization: 83.1 % of the theoretical

1H-NMR (300 MHz, CDCl): 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]amino}-methyl)phenoxy]-propanoate

[image]

First, 1.25 g (4.73 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropanoate (Example 1-4) and 0.64 g (5.67 mmol) of (4-methyl-1,3-oxazol-5-ll )methylamine (Example III-28) together in 1,2-dichloroethane. At room temperature, 1.50 g (7.09 mmol) of sodium triacetoxyborohydride was added. The reaction mixture was stirred at room temperature for 4 hours and then mixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane/methanol 30:1) and then dried under reduced pressure. This gave 1,104 g (65% of theory) of the title compound.

1H-NMR (200 MHz, CDCl): δ =1.45 (s, 9H); 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 (no. 1H).

The following compounds were obtained similarly to the procedure from Example III-32:

Example III-33

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

[image]

Utilization: 92.8 % of the theoretical

1H-NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H); 1.55 (s, 6H); 2.48 (number s, 1H); 2.83 (t, 2H); 3.35 (s, 3H); 3.54 (t, 2H); 3.77 (s, 2H); 6.75-6.86 (m, 2H); 7.19 (d, 2H).

Example III-34

tert-butyl 2-methyl-2-[4-(([(5-methyl-2-furyl)methyl]amino}methyl)-phenoxypropanoate

[image]

Utilization: 55.1 % of the theoretical

1H-NMR (300 MHz, CDCl3): 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-methyl-propanoate

[image]

4.00 g (14.27 mmol) of tert-butyl 2-[(4-formylphenyl)-sulfanyl]-2-methylpropanoate (Example II-2) and 1.07 g (14.27 mmol) of 2-methoxyethylamine were dissolved in 80 ml of 1,2-dichloroethane. , and after 30 min and after 10 hours it was mixed with 4.54 g (21.40 mmol) of sodium triacetoxyborohydride. The reaction was tested by TLC, and then ethyl acetate and a saturated solution of sodium bicarbonate were added, and the product was extracted with ethyl acetate. The organic phase was washed with 1 N HCl and dried over magnesium sulfate, and the product, after removing the solvent by distillation, was purified by silica gel chromatography (ethyl acetate/cyclohexane 1:1). Yield: 2.69 g (55.6 % of theoretical)

1H-NMR (300 MHz, CDCl3): δ = 1.45 (s, 15 H); 2.96 (t, 2H); 3.37 (s, 3H); 3.72 (t, 2H); 4.13 (s, 2H); 7.52 (s, 4H).

The following compound was obtained similarly to the procedure from Example III-35:

Example III-36

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

[image]

Utilization: 68.8 % of the theoretical

1H-NMR (200 MHz, CDCl3): 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).

Working examples 3

Example 3-1

tert-butyl 2-[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoate

[image]

0.50 g (1.25 mmol) of the compound from Example III-16, 0.23 g (1.88 mmol) of 2,4-dimethylaniline, 0.22 g (1.63 mmol) of 1-hydroxy-1H-benzotriazole, 0.31 g (1.63 mmol) of EDCxHCl, 0.38 g (3.75 mmol) of 4-methylmorpholine l 0.01 g (0.08 mmol) of 4-dimethylamino-pyridine in 30 ml of N,N-dimethylformamide at 0 °C for 2 hours and then at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate, and the organic phases were then washed with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by vacuum chromatography on silica gel. (cyclohexane/dichloroethane 2:1 → cyclohexane/ethyl acetate 10:1 → 4:1). The target compound was obtained by recrystallization from n-heptane with a yield of 78%.

Melting point: 90 - 91 °C.

Example 3-2

tert-butyl 2-[4-[[[2-[(2,4-dimethylphenyl)methylamino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoate

[image]

At 0 °C, 0.51 g (1.00 mmol) of the compound from Example 3-1 and 0.04 g (1.10 mmol) of sodium hydride were mixed for 30 min and then mixed with 0.07 ml (1.10 mmol) of iodomethane and with water. The mixture was extracted with ethyl acetate, the extract was washed with water and saturated sodium chloride solution and dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by vacuum chromatography on silica gel (cyclohexane/dichloromethane 3:1 → dichloromethane → dichloromethane/ethyl acetate 15:1). The target compound was obtained by recrystallization from n-pentane in a yield of 51%.

Melting point: 80 - 81 °C.

Example 3-3

tert-butyl 2-[4-[[[2-[(2,4-dimethylphenyl)amino]ethyl](2-furanylmethyl)-aminolmethyl]phenoxy]-2-methyl-propanoate

[image]

In 5 ml of toluene, 0.25 g (0.50 mmol) of the compound from Example 3-1 was treated with 0.30 ml of a 2 M solution of borane-dimethylsulfide in tetrahydrofuran and the mixture was heated with boiling for 2 hours. The mixture was then stirred in the presence of 5 ml of 2 N sodium carbonate solution for 1 hour and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was distilled off, and the residue was then purified using silica gel vacuum chromatography (cyclohexane/dichloromethane 3:1 → cyclohexane/ethyl acetate 10:1). This gave the target compound with a yield of 37%.

1H-NMR (200 MHz, CDCl3): δ = 1.43 (s, 9 H), 1.55 (s, 6 H), 2.15 (s, 3 H), 2.22 (s, 3H), 2.73 - 2.87 (m, 2H ), 3.09 - 3.22 (m, 2H); 3.57 (sf 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), 7.34 - 7.40 (m, 1H).

MS (ESI): 493 [M+H] + , 985 [2M+H] + .

Example 3-4

2-[4-[[[2-[(2,4-dimethylphenyl)amino-2-oxoethyl](2-furanylmethyl)-aminomethylphenoxyl-2-methyl-propionic acid

[image]

7.09 g (14.00 mmol) of the compound from Example 3-1 and 35 ml of trifluoroacetic acid were mixed at room temperature in 35 ml of dichloromethane for 2 hours. The solvent was distilled off and the residue was then dissolved in ethyl acetate, washed with water, 20% sodium acetate solution and saturated sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed and the residue was then purified by vacuum chromatography on silica gel (dichloromethane → dichloromethane/ethyl acetate 5:1 → 2:1 → 1:1). This gave the target compound with a yield of 82%.

1H-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 (wide s, 1H), 9.09 (s, 1H). MS (ESI): 451 [M+H] + , 901 [2M+H] + .

The following compounds were obtained similarly to the procedure from Examples 3-4:

Example 3-5

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

[image]

Utilization: 85 %

1H-NMR (200 MHz, CDCl3): δ =1.46 (s, 6H), 1.92 (s, 3H), 2.24 (s, 3H), 2.73 (q, 2H), 3.00 (s, 3H), 3.30 (broad s, 1 H), 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-methyl-propionic acid

[image]

Utilization: 60%

1H-NMR (200 MHz, DMSO-d6): δ = 1.49 (s, 6H), 2.01 (s, 3H), 2.12 (s, 3H), 2.55 - 2.72 (broad m, 2H), 2.97 - 3.20 (broad m, 2H), 3.46 - 3.78 (m, 4H), 4.40 (broad 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 (wide s, 1H).

MS (ESI): 437 [M+H] + , 873 [2M+H] + .

Example 3-7

1,1-dimethylethyl2-[4-[[(2-methoxyethyl)[2-[[4-(1-methylethyl)-2-(trifluoro-methyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy ]-2-methyl-propionate

[image]

First, 0.533 g (1.65 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) was placed in 6 ml of dimethylformamide. At room temperature, 0.588 g (1.81 mmol) of 2-bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]-acetamide (Example III-17) and 0.152 g (1.81 mmol) of sodium bicarbonate were added. The mixture was left at 90 °C for 2 hours. The reaction mixture was then allowed to cool, and water was added. The mixture was extracted once with ethyl acetate and the organic phase was washed three times with water and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and freed from the solvent under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) and the product was then dried under reduced pressure. This gave 0.885 g (95% of theory) of the title compound.

1H-NMR (400 MHz, CDCl): 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 (No. 1H).

Example 3-8

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

[image]

First, 0.842 g (1.49 mmol) of the compound from Examples 3-7 was placed in 10 ml of dichloromethane. At room temperature, 10 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure using a rotary evaporator. The residue was taken up in ethyl acetate and washed with water, 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The product was purified by chromatography on silica gel (dichloromethane/methanol 30:1) and then dried under reduced pressure. This gave 0.648 g (85% of theory) of the title compound.

1H-NMR (200 MHz, CDCl3): 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, 2H); 7.35-7.49 (m, 2H); 8.12 (d, 1H); 9.62 (No. 1H).

Example 3-9

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

[image]

xHCl

0.4 g (0.78 mmol) of the compound from Examples 3-7 was dissolved in 4 ml of ethyl acetate. At 40 °C, first 8 ml of 1 N hydrochloric acid (in diethyl ether) and then 12 ml of diethyl ether were added. The mixture was left to stand at 4 °C for one hour. The precipitated crystals were filtered off with suction, washed with a mixture of ethyl acetate and diethyl ether (ratio 1:1) and then dried at 40 °C under reduced pressure for 20 hours. This gave 0.362 g (84.5% of theory) of the title compound.

1H-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 (no. s, 1H); 13.18 (no. 1H).

Example 3-10

1,1-dimethylethyl2-[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2-methyl-propionate

[image]

First, 0.303 g (0.94 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl)phenoxy)-2-methylpropanoate (Example III-33) was placed in 5 ml of dimethylformamide. At room temperature, 0.319 g (1.03 mmol) of 2-bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide (Example HI-19) and 0.086 g (1.03 mmol) of sodium bicarbonate were added. The mixture was stirred at 90 °C for 2 hours. The reaction mixture was then allowed to cool, and water was added. The mixture was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and freed from the solvent under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 3:1) and the product was dried under reduced pressure. This gave 0.464 g (90% of theory) of the title compound.

1H-NMR (300 MHz, CDCl3): δ = 1.20-1.45 (m, 14H); 1.50 (s, 6H); 1.70-1.90 (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 (m, 2H); 7.85 (d, 1H); 9.25 (No. 1H).

Example 3-11

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

[image]

First, 0.398 g (0.72 mmol) of the compound from Example 3-10 was placed in 5 ml of dichloromethane. At room temperature, 5 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure using a rotary evaporator. The residue was taken up in ethyl acetate and washed with water, 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The product was purified by chromatography on silica gel (dichloromethane/methanol 30:1). With heating, the residue was dissolved in dichloromethane, 1N hydrochloric acid in diethyl ether and n-heptane were added dropwise until the mixture became slightly cloudy. The product was filtered off with suction, washed with diethyl ether and dried at 40 °C under reduced pressure. This gave 0.187 g (49% of theory) of the title compound.

1H-NMR (300 MHz, CDCl3): δ = 1.15-1.47 (m, 5H); 1.55 (s, 6H); 1.68-1.90 (m, 5H); 2.25 (s, 3H); 2.36-2.49 (m, 1H); 2.85 (t, 2H); 3.28 (s, 3H); 3.30 (s, 2H); 3.52 (t, 2H); 3.72 (s, 2H); 6.87 (d, 2H); 6.99-7. 10 (m, 2H); 7.25 (d, 2H); 7.80 (d, 1H); 9.25 (No. 1 H).

The following compounds were obtained similarly to the procedure from Examples 3-7 and 3-10:

Example 3-12

1,1-dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl] phenoxy)-2-methyl-propionate.

[image]

Utilization: 88% of the theoretical

1H-NMR (300 MHz, CDCl): 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, 1H); 7.35 (s, 1H); 8.57 (d, 1H); 9.85 (no. 1H).

Example 3-13

1,1-dimethylethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)-phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl) methyl]amino]methyl]-phenyl]thio]-2-methyl-propionoate

[image]

Utilization: 80.2 % of the theoretical

1H-NMR (300 MHz, CDCl3): δ =1.40 (s, 9H); 1.41 (s, 6H); 2.14 (s, 3H); 2.29 (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

1,1-dimethyl-ethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)-phenyl]amino]-2-oxoethyl](2-furanylmethyl)amino]methyl ] phenyl]thio]-2-methylpropionate

[image]

Utilization: 85.1 % of the theoretical

1H-NMR (300 MHz, CDCl3): δ = 1.39 (s, 9H); 1.41 (s, 6H); 2.30 (s, 3H); 3.31 (s, 2H); 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

1,1-dimethylethyl2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-ethyl-butanoate

[image]

Utilization: 73.4 % of the theoretical

1H-NMR (200 MHz, CDCl): δ =0.95 (t7 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 (mf 2H); 7.28 (d, 2H); 7.35-7.50 (m, 3H); 7.75-7.88 (m, 1H); 9.05 (s, 1H).

Example 3-16

1,1-dimethylethyl2-[[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl- propionoate

[image]

Utilization: 81.9 % of the theoretical

1H-NMR (200 MHz, CDCl3): 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

1,1-dimethylethyl2-[[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxy-ethyl)amino]methyl]phenyl ]thio]-2-methyl-propionate

[image]

Utilization: 82.9 % of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-18

1,1-dimethylethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)-phenyl]amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]

phenyl]thio]-2-ethyl-butanoate

[image]

Utilization: 86.8 % of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 0.94 (t, 6H); 1.41 (sr. 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, 1H); 7.26 (d, 2H); 7.36 (d, 1H); 7.44 (d, 2H); 8.31 (s, 1H); 9.19 (s, 1H).

Example 3-19

1,1-dimethylethyl 2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)-phenyl]amino]-2-oxoethyl] (2-methoxyethyl)amino]methyl] phenyl]thio]-2-methyl-propionate

[image]

Utilization: 57.4 % of the theoretical

1H-NMR (300 MHz, CDCl3): 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

1,1-dimethylethyl2-methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)-phenyl]amino]-2-oxoethyl3[(5-methyl-2- furanyl)methyl]amino]methyl]-phenoxypropionate

[image]

Utilization: 94% of the theoretical

1H-NMR (400 MHz, CDCl): 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

1,1-dimethylethyl2-[4-[[[2-[(2-ethoxy-1-naphthalenyl)amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl]phenoxy] -2-methyl-propionate

[image]

Utilization: 95% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (No. 1H).

Example 3-22

1,1-dimethylethyl2-methyl-2-[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(5,6,7,8-tetrahydro-1-naphthalenyl) amino]ethyl]amino]methyl]phenoxy]-propionate

[image]

Utilization: 91% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-23

1,1-dimethylethyl2-[4-[[[2-[(2,4-dichlorophenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]-phenoxy]-2-methyl-propionate

[image]

Utilization: 87% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-24

1,1-dimethylethyl2-[4-[[(2-methoxyethyl)[2-[[4-(1-naphthalenyloxy)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy]- 2-methyl-propionate

[image]

Utilization: 95.5% of the theoretical

1H-NMR (300 MHz, CDCl3): 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); 7.13-7.25 (m, 3H); 7.34 (d, 1H); 7.40 (t, 1H); 7.47-7.58 (m, 2H); 7.66 (d, 1H); 7.89 (dd, 1H); 8.07-8.21 (m, 2H); 9.68 (No. 1H).

Example 3-25

1,1-dimethylethyl2-[4-[[[2-[[5-[(ethylsulfonyl)methyl]-1-naphthalenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2- methyl propionate

[image]

Utilization: 91% of the theoretical

1H-NMR (200 MHz, CDCl): 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 (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 (No. 1H).

Example 3-26

1,1-dimethylethyl2-methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)-phenyl]amino]-2-oxoethyl][(4-methyl-5 -oxazolyl)methyl]amino]methyl]-phenoxy-propionate

[image]

Utilization: 83.5% of the theoretical

1H-NMR (300 MHz, CDCl3): δ =1.25 (d, 6H); 1.40 (s, 9H); 1.55 (s, 6H); 2.10 (s, 3H); 2.85-3.00 (September, 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 (No. 1H).

Example 3-27

1,1-dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)-methyl]amino]methyl] phenoxy]-2-methyl-propionate

[image]

Utilization: 79.5% of the theoretical

1H-NMR (300 MHz, CDCl): 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 (brs, 1H).

Example 3-28

1,1-dimethylethyl2-[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxy-ethyl)amino]methyl]phenoxy] -2-methyl-propionate

[image]

Utilization: 81% of the theoretical

1H-NMR (300 MHz, CDCl): 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); 7.15-7.25 (m, 4H); 7.78 (d, 1H); 9.30 (no. 1H).

Example 3-29

1,1-dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino)-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl- propionate

[image]

Utilization: 80% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-30

1,1-dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenoxy]-2-methyl- propionate

[image]

Utilization: 84% of the theoretical

1H-NMR (300 MHz, CDCl3): δ = 1.40 (s7 9H); 1.55 (s, 6H); 3.30 (s, 2H); 3.65 (s, 2H); 3.75 (s, 2H); 6.20-6.30 (m, 1H); 6.30-6.38 (m, 1H); 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 (no. 1H).

Example 3-31

1,1-dimethylethyl2-[[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2 -methyl-propionate

[image]

Utilization: 92% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (no. 1H).

The following compounds were obtained similarly to the procedure from Examples 3-8:

Example 3-32

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

[image]

Utilization: 83.4 % of the theoretical

1H-NMR (300 MHz, CDCl3): 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); 7.20-7.35 (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][(4-methyl-5-oxazolyl)methyl]amino]methyl ] phenyl]thio]-2-methyl-propionic acid

[image]

Utilization: 62.8 % of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 1.47 (s, 6H); 2.11 (s, 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, 2H); 7.80 (s, 1H); 8.28 (s, 1H); 9.04 (s, 1H).

Example 3-34

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

[image]

Utilization: 90.9% of the theoretical

1H-NMR (300 MHz, CDCl3): 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

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

[image]

Utilization: 96.6% of the theoretical

1H-NMR (300 MHz, CDCl3): 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-butanoic acid

[image]

Utilization: 90.9% of the theoretical

1H-NMR (300 MHz, CDCl): δ =0.96 (t, 6 H); 1.58-1.87 (m, 4H); 2.28 (s, 3H); 3.31 (s, 2H); 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).

Example 3-37

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

[image]

Utilization: 83.9 % of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (no. s, 1H); 7.31 (g, 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

[image]

Utilization: 91% of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 1.25 (d, 61^); 1.55 (s, 6H); 2.17 (s, 3H); 2.91 (Sept., 1H); 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 (No. 1H).

Example 3-39

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

[image]

Utilization: 64% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 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]methyl]phenoxy]-propionic acid

[image]

Utilization: 76% of the theoretical

1H-NMR (300 MHz, CDCl): 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).

Example 3-41

2-[4-[[[2-[(2,4-dichlorophenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl-propionic acid

[image]

Utilization: 69% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-42

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

[image]

Utilization: 74% of the theoretical

1H-NMR (300 MHz, DMSO): δ = 1.45 (s, 6H); 2.72 (t, 2H); 3.18 (s, 3H); 3.25 (s, 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 (No. 1H).

Example 3-43

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

[image]

Utilization: 40.5% of the theoretical

1H-NMR (400 MHz, CD2Cl2): 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); 4.72 (s, 2H); 6.83 (d, 2H); 7.31 (d, 2H); 7.46-7.65 (m, 3H); 7.90 (d, 1H); 8.04-8.20 (m, 2H); 10.10 (No. 1H).

Example 3-44

2-methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl3amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino] methyl] phenoxy]-propionic acid

[image]

Utilization: 69% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (no. 1H).

Example 3-45

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

[image]

Utilization: 76% of the theoretical

1H-NMR (200 MHz, CDCl): 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, 1H); 9.68 (No. 1H).

Example 3-46

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

[image]

Utilization: 77% of the theoretical *

1H-NMR (300 MHz, CDCl3): 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, 1H); 7.88 (s, 1H); 8.59 (d, 1H); 9.91 (No. 1H).

Example 3-47

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

[image]

Utilization: 91% of the theoretical

1H-NMR (300 MHz, GDCl3): 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); 7.75 (d, 1H); 7.86 (s, 1H); 8.56 (d, 1H); 9.80 (brs, 1H).

Example 3-48

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

[image]

Utilization: 91% of the theoretical

1H-NMR (300 MHz, CDCl3): 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); 8.59 (d, 1H); 9.78 10(number s, 1H).

The following compounds were obtained similarly to the procedure from 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-methyl-propionic acid hydrochloride

[image]

Utilization: 53.3 % of the theoretical

1H-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 (number s, 2H); 3.74 (number s, 2H); 4.12 (no. s, 2H); 4.51 (no. s, 2H); 7.02 (d, 2H); 7.16-7.30 (br s, 1H); 7.46-7.68 (m, 4H); 9.93 (no. s, 1H); 10.36 (no. s, 1H); 12.74 (no. 1H).

Example 3-50

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

[image]

Utilization: 85.3% of the theoretical

1H-NMR (300 MHz, CDCl): 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, 1H); 9.26 (s, 1H).

Example 3-51

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

[image]

Utilization: 99% of theoretical

1H-NMR (300 MHz, DMSO): δ = 1.20 (d, 6H); 1.50 (s, 6H); 2.27 (number s, 3H); 2.963.05 (Sept., 1H); 3.95 (no. s, 2H); 4.31 (no. 4H); 6.17 (no. s, 1H); 6.63 (no. s, 1H); 6.85 (d, 2H); 7.46-7.57 (m, 5H); 10.23 (no. s, 1H); 10.55 (no. s, 1H); 13.15 (no. 1H).

Example 3-52

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

[image]

Utilization: 54% of the theoretical

LC-MS: 470 [M+]

Example 3-53

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

[image]

0.015 g (0.03 mmol) of the compound from Example 3-4 was dissolved in 0.5 ml of ethanol and treated with 0.3 ml of 1N aqueous sodium hydroxide solution. The reaction mixture was stirred for another 5 min and then concentrated using a rotary evaporator. The residue was taken up in a little toluene and the solvent was removed under reduced pressure. The product was then dried under reduced pressure for 20 hours. This gave 0.015 g (95.5% of theory) of the title compound.

1H-NMR (200 MHz, CDCl3): 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 (No. 1H).

The following compounds were obtained similarly to the procedure from Examples 3-7 and 3-10:

Example 3-54

1,1-dimethylethyl2-[[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]-amino]-2-oxoethyl](2-methoxyethyl)amino]methyl] phenyl ]thio]-2-methyl-propionate

[image]

Utilization: 61% of the theoretical

1H-NMR (200 MHz, CDCl): 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 (brs, 1H).

Example 3-55

1,1-dimethylethyl2-methyl-2-[[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxo-ethyl][(4-methyl -5-oxazolyl)methyl]amino]methyl]-phenyl]thio]propionate

[image]

Utilization: 66% of the theoretical

1H-NMR (300 MHz, CDCl3): δ =1.25 (d, 6H); 1.40 (s, 9H); 1.43 (s, 6H); 2.10 (s, 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 (no. 1H).

Example 3-56

1,1-dimethylethyl2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazoyl)-methyl]amino]methyl]phenyl ]tiO3-2-methyl-propionate

[image]

Utilization: 86% of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (brs, 1H).

Example 3-57

1,1-dimethylethyl2-[[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl] phenyl]thio]-2-methyl-propionate

[image]

Utilization: 84% of the theoretical

1H-NMR (200 MHz, CDCl3): 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, 1H); 8.57 (d, 1H); 9.67 (brs, 1H).

Example 3-58

1,1-dimethylethH2-[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazolyl)-methyl]amino]methyl]phenoxy] -2-methyl-propionate

[image]

Utilization: 54.8 % of the theoretical

1H-NMR (200 MHz, CDCl3): δ = 1.30-1.46 (m, 14H); 1.55 (s, 6H); 1.62-1.94 (m, 6H); 2.12 (s, 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); 8.96 (No. 1H).

Example 3-59

1,1-dimethyl-ethyl2-[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl ]amino]methyl]phenoxy]-2-methyl-propionate

[image]

Utilization: 64.7 % of the theoretical

1H-NMR (200 MHz, CDCl3): 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 (no. 1H).

Example 3-60

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

[image]

First, 0.248 g (0.43 mmol) of the compound from Example 3-54 was placed in 5 ml of dichloromethane. At room temperature, 5 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure using a rotary evaporator. The residue was taken up in ethyl acetate and extracted with water, 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The product was purified by chromatography on silica gel (dichloromethane, dichloromethane/methanol 30:1) and then dried under reduced pressure. This gave 197 mg (88% of theory) of the title compound.

1H-NMR (200 MHz, CDCl3): δ = 1.25 (d, 6H); 1.49 (s, 6H); 2.80 (t, 2H); 2.85-3.00 (m, 1H); 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, 1H); 9.58 (no. 1H).

The following compounds were obtained similarly to the procedure from Example 3-60:

Example 3-61

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

[image]

Utilization: 81% of the theoretical

1H-NMR (300 MHz, CDCl3): S = 1.25 (d, 6H); 1.50 (s, 6H); 2.07 (s, 3H); 2.85-3.00 (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 (no. 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 acid

[image]

Utilization: 84% of the theoretical

1H-NMR (200 MHz, CDCl): δ =1.51 (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 (No. 1H).

Example 3-63

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

[image]

Utilization: 76% of the theoretical

1H-NMR (300 MHz, CDCl3): 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 (No. 1H).

Example 3-64

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

[image]

Utilization: 80% of the theoretical

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 2.64 min

([M+H]+ = 534).

Example 3-65

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

[image]

Utilization: 80% of the theoretical

LC-MS: acetonitrile/30% aqueous HCl/water (gradient): Rt = 2.43 min

([M+H]+ = 508).

Working examples 4

Example 4-1

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

[image]

Step a)

Wang's resin (from Rapp Polvmere, Order No. H 1011) (48.0 g, 14.06 mmol of reactive groups) was suspended in dichloromethane. 2-(4-formylphenoxy)-2-methylpropionic acid [GJ. Ellymes, C. Glavnis, J. Chem. Soc. Perkin Trans. 2, 1993, 43-48] (8.78 g, 42.18 mmol), diisopropylcarbodiimide (10.65 g, 84.35 mmol) and DMAP (3.44 g, 28.12 mmol) and the mixture was then stirred at room temperature for 18 h. The mixture was then filtered and the resin was washed with dichloromethane, DMF and methanol to give resin A.

Step b)

Resin A (2.50 g, 0.72 mmol of reactive groups) and 2-furfurylamine (352 mg, 3.62 mmol) were suspended in 20 ml of trimethyl orthoformate. The mixture was shaken at room temperature for 20 h and then filtered, and the resin was washed with DMF. The resin was then suspended in 20 ml of DMF, tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid (0.42 ml, 7.25 mmol) were added, and the mixture was shaken at room temperature for 7 h. The mixture was then filtered and the resin was washed with dichloromethane, DMF and methanol to give resin B1.

step e)

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

Step d)

Resin C1 (2.5 g, 0.72 mmol of reactive groups) was suspended in 20 ml DM F 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 mixture was shaken at room temperature for 18 h and then filtered, and the resin was washed with dichloromethane, DMF and methanol. The resin was then suspended in a mixture of dichloromethane and trifluoroacetic acid. The mixture was shaken at room temperature for 30 min and then filtered and evaporated. The target compound was obtained as a colorless film.

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

[Method: Symmetry C18 column (VVaters), flow rate: 0.5 ml/min, temp. furnace 40°C, pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10% B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90% B. A: CH3CN + 0.1% HCOOH; B: H2O +0.1 % HCOOH].

1H-NMR (d6-DMSO): δ = 1.4 (s, 6H), 2.3 (s, 3H), 2.4 (s, 3H), 3.3 (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]-methyl]phenoxy]-2-methyl-propanoic acid

[image]

Resin C1 from Example 4-1 step c) (2.5 g, 0.72 mmol of reactive groups) was suspended in 20 ml of DMF and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38 g, 3.63 mmol) and 2.5 -dimethyl-4-methoxyaniline (756 mg, 5.08 mmol). The mixture was shaken at room temperature for 18 h and then filtered, and the resin was washed with dichloromethane, DMF and methanol. The resin was then suspended in a mixture of dichloromethane and trifluoroacetic acid. The mixture was shaken at room temperature for 30 min and then filtered and evaporated. The target compound was obtained as a colorless film. LC-MS: Rt = 3.48 min; [M+H]+ = 481.226 (100 %), (M-H]+ = 479.226 (100 %)

[Method: Svmmeterv C18 column (Waters), flow rate: 0.5 ml/min, temp. furnace 40°C, pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10% B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90% B. A: CH3CN + 0.1% HCOOH; B: H2O +0.1% HCOOH].

Example 4-3

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

[image]

Step a)

Resin A from Example 4-1 step a) (2.50 g, 0.72 mmol of reactive groups) and 2-aminomethylthiophene (409 mg, 3.62 mmol) were suspended in 20 ml of trimethyl orthoformate. The mixture was shaken at room temperature overnight and then filtered, and the resin was washed with DMF. The resin was then suspended in 20 ml of DMF, treated with tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid (0.42 ml, 7.25 mmol), and shaken at room temperature for 7 h. The mixture was then filtered and the resin was washed with dichloromethane, DMF and methanol to give resin 62.

Step b)

Resin B2 (2.5 g, 0.72 mmol of reactive groups) was suspended in 40 ml of dioxane and treated with triethylamine (3.03 ml, 21.75 mmol) and trimethylsilyl bromoacetate (2.38 ml, 14.5 mmol). The mixture was shaken at 60 °C overnight. The mixture was then filtered and the resin was washed with dichloromethane, DMF and methanol. The silyl protecting group was removed by suspending the resin in 25 ml of dioxane and treating with tetrabutylammonium fluoride solution (1 M in THF, 1 ml). The mixture was shaken at room temperature for 1 h and then filtered. The resin was then washed with dichloromethane, DMF and methanol to give resin C2.

Step c)

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

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

[Method: Symmetry C18 column (Waters)/ flow rate: 0.5 ml]min, temp. furnace 40°C, pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10% B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90% B. A: CH3CN + 0.1% HCOOH; B: H2O +0.1% HCOOH].

1H-NMR (d6-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).

The following compound was obtained in a similar way:

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 acid

[image]

LC-MS: Rt= 2.76 min; [M+H]+ = 495 (100%), [M-H]+ = 493 (100%) [Method: Symmetry C18 column (Waters), flow rate: 0.5 ml/min, temp. furnace 40°C, pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10% B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90% B. A: CH3CN + 0.1% HCOOH; B: H2O +0.1 % HCOOH].

Example A

Cellular transactivation analysis:

Principle of the test:

Cellular analysis is used to identify the activator of peroxisome proliferator-activated receptor alpha (PPAR-alpha).

Since mammalian cells contain different endogenous nuclear receptors that can complicate the unequivocal interpretation of the results, an established chimeric system is applied in which the ligand binding domain of the human PPARa receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. The resulting GAL4-PPARα chimera was cotransfected and stably expressed in CHO cells carrying the reporter construct.

Cloning:

The GAL4-PPARα expression construct contains the ligand binding domains from PPARα (amino acids 167-468), which was PCR-amplified and cloned into the pcDNAB.l vector. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the pFC2-dbd vector (Stratagene). The reporter construct, which contains five copies of GAL4 binding sites upstream of the thymidine kinase promoter, expresses firefly (Photinus pyralis) luciferase upon activation and binding of GAL4-PPARa.

Transactivation analysis (luciferase reporter):

CHO (Chinese hamster ovary) cells were seeded in DMEM/F12 medium (BioWVhittaker), supplemented with 10% fetal calf serum, 1% penicillin/streptomycin (GIBCO), with a cell density of 2 x 103 cells per well in plate with 384 cavities (Greiner). The cells were cultured at 37°C for 48 h and then stimulated. Test substances were then taken up in CHO-A-SFM medium (GIBCO), supplemented with 10% fetal calf serum, 1% penicillin/streptomycin (GIBCO) and added to the cells. After a stimulation period of 24 hours, luciferase activity was measured using a video camera. The measured relative light units give, as a function of substrate concentration, a sigmoidal stimulation curve. EC50 values were calculated using the computer program GraphPad PRISM (Version 3.02).

In this test, the compounds according to the invention from Examples 3-4, 3-6, 3-60, 1-9, 2-7 and 2-12 had EC50 values from 0.04 to 200 nM.

Example B

Determination of fibrinogen:

To determine the effect on plasma fibrinogen concentration, male VVistar rats were treated with the test substance for a period of 4-9 days, either by gavage or by mixing the substance with food. Under terminal anesthesia, citrated blood was then obtained by cardiac puncture. Plasma fibrinogen levels were determined using the Clauss method [Clauss A., Acta Haematol. 17, 237-46 (1957)], by measuring thrombin time using human fibrinogen as a standard. In some cases, parallel determinations were carried out using the turbidimetric method [Becker U., Bartl K., VVahlefeld A. W., Thrombosis Res. 35, 475-84 (1984)] where batroxobin was used instead of thrombin.

Example C

Description of the test for finding pharmacologically active substances that increase the concentrations of apoprotein A1 (ApoA1) and HDL cholesterol (HDL-C) in the serum of transgenic mice transfected with the human ApoA1 gene (hApoA1):

Substances tested for in vivo HDL-C raising activity were administered orally to male transgenic hApoA1 mice. One day before the start of the experiment, the animals were randomly divided into groups with the same number of animals, generally n = 7-10. Throughout the experiment, the animals had drinking water and food ad libitum. The substances were administered orally once a day for 7 days. For this purpose, the test substances were dissolved in a solution of Solutol HS 15 + ethanol + physiological solution (0.9%) in a ratio of 1+1+8 or in a solution of Solutol HS 15 + physiological solution (0.9%) in a ratio of 2+8. Dissolved substances were administered in a volume of 10 ml/kg of body weight using a gastric tube. Animals treated in exactly the same way, but given only the solvent (10 ml/kg body weight) without the test substance, served as a control group.

Before the first administration of the substance, blood samples of each mouse were taken by puncture of the retroorbital venous plexus, for the determination of ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG) (zero value). Then, using a stomach tube, the test substance was given to the animals for the first time. 24 hours after the last administration of the substance (day 8 after the start of treatment), a second blood sample was taken from each animal by puncturing the retroorbital venous plexus to determine the same parameters. Blood samples were centrifuged and after obtaining serum, cholesterol and TG were determined photometrically using EPOS Analyzer 5060 (Eppendorf-Geratebau, Netheler & Hinz GmbH, Hamburg). Said determinations were carried out using commercial enzyme tests (Boehringer Mannheim, Mannheim).

To determine HDL-C, the non-HDL-C fraction was precipitated using 20% PEG 8000 in 0.2 M glycine buffer pH 10. Cholesterol was determined from the supernatant by UV-photometry (BIO-TEK Instruments Inc. USA) in a 96-well plate, using a commercial reagent (Ecoline 25, Merck, Darmstadt).

Human mouse ApoA1 was determined using the Sandwich ELISA method using polyclonal antihuman ApoA1 and monoclonal antihuman ApoA1 antibodies (Biodesign International, USA). Quantification was performed UV-photometrically (BIO-TEK Instruments, USA) using peroxidase-coupled anti-mouse-IGG antibodies (KPL, USA) and peroxidase substrate (KPL, USA).

The effect of test substances on HDL-C concentration is determined by subtracting the value measured for the first blood sample (zero value) from the value measured for the second blood sample (after treatment). The mean value of the differences of all HDL-C values of one group was determined and compared with the mean value of the differences of the control group.

Statistical evaluation was performed using the student's test, after examining the homogeneity of variances.

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

Claims (16)

1. Compounds of general formula (I) [image] indicated by that A represents a bond or represents a group –CH2- or –CH2CH2-, X represents O, S or CH2, R1, R2 and R3 are identical or different and independently of each other represent hydrogen, (C1-C6-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C6)-alkoxy, (C6-C10)-aryloxy, halogen, trifluoromethyl, trifluoro-methoxy, (C1-C6)alkylamino-sulfonyl, nitro or cyano, or R1 and R2 are connected to two adjacent carbon atoms and together with them form a fused cyclohexane or benzene ring, whereby the latter can optionally be substituted by a (C1-C4)-alkylsulfonylmethyl group, R3 has the meaning defined above, R4 represents hydrogen or (C1-C6)-alkyl, R5 and R6 represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group, R7 represents hydrogen, (C1-6)-alkyl, phenyl or benzyl, where the mentioned aromatic radicals can in any case be mono- to tri-substituted with identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1 -C6)-Alkoxy, hydroxyl and halogen, R8 represents hydrogen, (C6-C10)-aryl or represents (C1-4)-alkyl, which in turn can be substituted by hydroxyl, trifluoromethoxy, (C1-C4)-alkoxy or phenoxy groups, which in turn are optionally substituted by trifluoromethyl , or (C6-C10 aryl or 5- or 6-membered heteroaryl with up to three heteroatoms from the group consisting of N, O and S, where all mentioned aryl and heteroaryl rings can in turn be mono- to trisubstituted with identical or different substituents from the group which consists of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6) alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino, R9 and R10 are identical or different and independently of each other each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen, R11 and R12 are identical or different and independently of each other each represents hydrogen or (C1-C6)-alkyl or together with the carbon atom to which they are attached form a (C4-C7)-cycloalkyl ring, and R13 represents hydrogen or represents a group that can be hydrolyzed and decomposed to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates. 2. Compounds of the general formula (I), indicated by the fact that in it A represents a bond or represents a group -CH2- or -CH2CH2-, X represents O, S or CH2, R 1 , R 2 and R 3 are identical or different and independently of each other each represents hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano, R4 represents hydrogen or (C1-C4)-alkyl, R5 and R6 each represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group, R7 represents hydrogen, (C1-6)-alkyl, phenyl or benzyl, in which the mentioned aromatic radical can in any case be mono- to tri-substituted by the same or different substituents from the group consisting of (C1-C6)-alkyl, ( C1-C6)-Alkoxy, hydroxyl or halogen, R8 represents hydrogen, (C6-C10)-aryl or (C1-C4)-alkyl, which in turn is optionally substituted with (C6-C10)-aryl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, whereby all mentioned ring systems can in any case be mono- to tri-substituted with identical or different substituents from the group consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6 )-Alkoxy, trifluoromethyl, trifluoro-methoxy, cyano, nitro and amino, R9 and R10 are the same or different and independently of each other each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoro-methoxy or halogen, R11 and R12 are the same or different and each independently represents hydrogen or (C1-C6)-alkyl, or together with the carbon atom to which they are attached form a (C4-C7)-cycloalkyl ring, R13 represents hydrogen or a group that can hydrolyze and decompose to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates. 3. Compounds of the general formula (I) according to claims 1 or 2, characterized by the fact that in them A represents the group -CH2- or -CH2CH2-, X represents O, S or CH2, R 1 , R 2 and R 3 are identical or different and independently of each other each represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano, R4 represents hydrogen or methyl, R5 and R6 each represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group, R7 represents hydrogen, (C1-C4)-alkyl or benzyl, R8 represents hydrogen, phenyl, benzyl or 5-membered heteroarylmethyl with up to two heteroatoms from the group consisting of N, O and S, whereby the mentioned aromatic ring systems can in any case be mono- to tri-substituted with identical or different substituents from the group consisting of chlorine, fluorine, bromine, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl and amino, R9 and R10 are the same or different and independently of each other represent hydrogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, trifluoromethyl, fluorine or chlorine, R11 and R12 are identical or different and independently of each other each represents hydrogen, methyl or ethyl, or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring, and R13 represents hydrogen or represents a group that can hydrolyze and degrade to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates. 4. Compounds of the general formula (I) according to claims 1, 2 or 3, characterized by the fact that in them A represents the group -CH2- or -CH2CH2-, X represents O, S or CH2, R1 represents hydrogen, methyl or methoxy, R2 and R3 are the same or different and each independently represents methyl, trifluoromethyl, methoxy, trifluoro-methoxy, chlorine or fluorine, R4 represents hydrogen, R5 and R6 together with the carbon atom to which they are attached form a carbonyl group, R7 represents methyl, ethyl, n-propyl or preferably hydrogen, R8 represents phenyl, furanylmethyl or thienylmethyl, whereby the mentioned ring systems can in any case be mono- or disubstituted by the same or different substituents from the group consisting of methyl and ethyl, R9 and R10 are the same or different and each represents hydrogen or methyl, preferably hydrogen, R11 and R12 are the same or different and each represents hydrogen or methyl, preferably methyl, and R13 represents a group that can be hydrolyzed and decomposed to the corresponding carboxylic acid, or preferably represents hydrogen, and their pharmaceutically acceptable salts, hydrates and solvates. 5. Compounds of formula (Ia) [image] indicated by that A represents the group -CH2- or -CH2CH2-, X represents O or S, R1 represents hydrogen, methyl or methoxy, R2 and R3 are the same or different and each independently represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine, and R8 represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, where the mentioned ring systems can in any case be mono- or disubstituted by methyl, or represents 2-methoxyethyl. 6. Compounds of formula (I) according to claims 1 to 5, characterized in that they serve for the prophylaxis and treatment of diseases. 7. Medicines, characterized in that they contain at least one compound of formula (I) according to claim 1 and inert, non-toxic, pharmaceutically acceptable carriers, excipients, solvents, transporters, emulsifiers and/or dispersants. 8. Application of compounds of formula (I) and drugs according to claims 1 to 7, characterized by the fact that they serve for prophylaxis and treatment of diseases. 9. Application of compounds of formula (I) according to claims 1 to 6, characterized in that they serve for the preparation of medicines. 10. Use of compounds of formula (I) according to claims 1 to 6, characterized in that they serve for the preparation of drugs for the treatment of arteriosclerosis. 11. Method of disease prophylaxis and treatment, characterized in that the compounds of formula (I) according to claim 1 are allowed to act on living beings. 12. Method for the preparation of medicines, characterized in that at least one compound of the formula (I) according to claim 1 is converted into an administration form using excipients and/or carriers. 13. Process for preparing compounds of formula (I) according to claim 1, characterized in that [A] compounds of general formula (II) [image] where A, X, R7, R8, R9, R10, R11 and R12 are all as defined above and T represents benzyl, (C1-C6)-alkyl or a polymeric support suitable for synthesis on a solid phase, first, with the activation of the carboxylic acid group in (II), they react with compounds of the general formula (III) [image] where R1, R2 and R3 all have the meaning defined above, which results in compounds of the general formula (Ia) [image] where A, X, T, R1, R2, R3, R7, R8, R9, R10, R11 and R12 all have the meaning defined above, or [B] compounds of general formula (IV) [image] where A, X, T, R8, R9, R10, R11 and R12 have the above meaning, react in the presence of a base with compounds of the general formula (V) [image] where R1, R2, R3 and R7 all have the above meaning, and Q is a suitable leaving group, for example halogen, mesylate or tosylate, preferably bromine or iodine, also to compounds of the general formula (Ia). Compounds of the general formula (Ia) are, if appropriate, converted into compounds of the general formula (Ib) in accordance with known methods of amide alkylation or amide reduction [image] where A, X, T, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the meaning given above, then converted with acids or bases into corresponding carboxylic acids of the general formula (Ic) where R1, R2, R3 and R7 all have the above meaning, and Q is a suitable leaving group, for example halogen, mesylate or tosylate, preferably bromine or iodine, also to compounds of the general formula (Ia). 14. Compounds of the general formula (Ia) are, if appropriate, converted into compounds of the general formula (Ib) in accordance with known methods of amide alkylation or amide reduction [image] where A, X, T, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the meaning given above, then converted with acids or bases into corresponding carboxylic acids of the general formula (Ic) LDL level in cases of arteriosclerosis and/or hypercholesterolemia. 15. Use of compounds of formula (I) according to claim 1, characterized in that they serve as agonists of the peroxisome proliferatively activated receptor. 16. Compounds of formula (II) [image] indicated by the fact that in it A, X, R7, R8, R9, R10, R11 and R12 have the meaning given in claims 1 to 5 and T represents benzyl, (C1-C6)-alkyl or a polymeric support suitable for solid phase synthesis.