CZ2003964A3 - Propionic acid derivatives, process of their preparation, medicaments in which the derivatives are comprised, their use and intermediates for their preparation - Google Patents

Abstract

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

Description

Technical field

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

BACKGROUND OF THE INVENTION

Despite many successes in therapy, coronary heart disease (KHK) remains a serious public health problem. While treatment of statins with HMG-CoA reductase inhibition has been very successful both in plasma LDL-cholesterol concentration and in mortality of risk patients, today there is no convincing treatment strategy for the treatment of patients with poor HDL / LDL-cholesterol ratio or hypertriglyceridemia.

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

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

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

SUMMARY OF THE INVENTION

It has now been found that compounds of the formula I are propionic acid derivatives

in which

A represents a bond or a group -CH ₂ - or -CH ₇ CH ₂ -

X is oxygen, sulfur or CH ₂ ,

R, R and R ³ are identical or different and independently of each brand or hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3-7 carbon atoms, hydroxy, alkoxy having from 1 IU to 6 carbon, atoms, (C až-Cry) aryloxy group, halogen, trifluoromethyl, trifluoromethoxy, α-quinolaminosulfonyl, nitro or cyano.

.-2 ..-.

or

^_ R and R are bonded to two adjacent carbon atoms and together with these form a fused cyclohexane or benzene ring, the latter being optionally substituted alkylsulfony1 methyl group having 1 to 4 carbon atoms and □

R is as defined above, denotes a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

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

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

R ^ represents a hydrogen atom, an aryl group having 6 to 10 carbon atoms or an alkyl group having 1 to 4 carbon atoms which may itself be substituted by hydroxy, trifluoromethoxy, alkoxy having 1 to 4 carbon atoms or phenoxy, which themselves are optionally once to twice substituted with a trifluoromethyl group, or it may be substituted with an aryl group of 6 to 10 carbon atoms or a five to six membered heteroaryl group with up to three heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur, all of said aryl and heteroaryl rings alone be one to three times the same or differently substituted by halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino, RIA are the same or different and each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group or a halogen atom,

Ί 17

R a are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and r 13 represents a hydrogen atom or a hydrolyzable a group which can be degraded to the corresponding carboxylic acid L ine, as well as their pharmaceutically acceptable salts, hydrates and solvates, fulfill this task and have a pharmacological effect and can be used as medicaments or in the manufacture of medicament preparations.

3

Within the scope of the present invention, in the definition of R, a hydrolyzable group refers to a group which, particularly in the body, results in the conversion of the -C (O) OR group into the corresponding carboxylic acid (R-hydrogen). Such groups are exemplified and desirable: benzyl, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl which are optionally mono- or polysubstituted, equally or differently substituted by halogen, hydroxy, amino, C 1 -C 6 alkoxy. (C1-C6) -alkoxy, (C1-C6) -alkoxycarbonyl, (C1-C6) -alkoxycarbonylamino or (C1-C6) -alkanoyloxy or, in particular, (C1-C4) -alkyl; is optionally one or more times, equally or differently substituted with halogen, hydroxy, amino, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonylamino or alkoxy another C 1 -C 4 carbon atoms.

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

An aryl group having 6 to 1 (1 carbon atoms) denotes an aromatic radical having 6 to 10 carbon atoms in the context of the present invention, for example and preferably an aryl radical of the phenyl group.

φφφ • φ

6 ···

C 3 -C 8 -cycloalkyl and C 4 -C 7 -cycloalkyl are C 3 -C 8 or C 4 -C 7 cycloalkyl radicals in the context of the present invention, examples being preferably cyclobutyl, cyclopentyl and cyclohexyl .

C 1 -C 6 alkoxy in the context of the present invention denotes a straight or branched alkoxy radical having 1 to 6 carbon atoms, with a straight or branched alkoxy radical having 1 to 4 carbon atoms being preferred. Examples which may be mentioned are preferably methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

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

C1-C6alkoxycarbonyl denotes, in the context of the present invention, a straight or branched alkoxy radical having 1 to 6 carbon atoms attached via a carbonyl group, with a straight or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in alkoxy being preferred. By way of example and preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and arb-butoxycarbonyl are mentioned.

The C 1 -C 6 alkoxycarbonylamino group in the present invention denotes a straight or branched chain alkoxycarbonyl amino group. having 1 to 6 carbon atoms ·

and is attached via a carbonyl group, an alkoxycarbonylamino radical having 1 to 4 carbon atoms in the alkoxy group is preferred. Examples which may be mentioned are preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino.

In the context of the present invention, a C 1 -C 6 alkanoyloxy group denotes a straight or branched C 1 -C 6 alkyl radical which carries in the 1-position a double-bonded oxygen atom and in the 1-position is attached via another oxygen atom. Examples which may be mentioned are preferably acetoxy, propionoxy, n-butyloxy, i-butyloxy, pivaloyloxy and n-hexanoyloxy.

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

In the context of the present invention, halogen represents fluorine, chlorine, thunder and iodine, chlorine or fluorine being preferred.

In the context of the present invention, a 5- to 6-membered heteroaryl group having up to 3 heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen denotes a monocyclic heteroaromate which is connected via a ring carbon atom and optionally via a ring nitrogen atom of a heteroaromatic.

here. Furanyl may be mentioned by way of example and preferably. a pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl and pyridazinil groups, with furanyl, thienyl and oxazolyl groups being preferred.

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

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

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

Physiologically acceptable salts may be salts of the compounds of the present invention with inorganic or organic acids. Preferred are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, acid citric acid, tartaric acid, lactic acid, kvass «4 · · •» ··

9 '

benzoic acid or methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

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

The compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.

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

A denotes a bond or a group -Cl 2 - or denotes oxygen, sulfur or a group CH 2, i → α

R, R- and are the same or different and independently of one another are hydrogen, C1-C6alkyl, hydroxy, C1-C6alkoxy, halogen, trifluoromethyl, trifluoromethoxy, nitro or nitro; 4,444 • 4

- an quanos of a group, denotes a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

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

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

O

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

R 6a are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or halogen, 12 and R ^iZ are identical or different and independently of one another represent hydrogen or alkyl having 1-6 carbon atoms or together with the carbon atom to which they are bonded form a cycloalkyl ring of 4-7 carbon atoms, Ar 13 denotes a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid liner, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

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

A denotes -CH 2 - or -CH 2 CH 2 -, denotes oxygen, sulfur or CH 2,

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

R ⁴ represents a hydrogen atom or a methyl group.

R and R denote a hydrogen atom or together with a carbon atom;

a moiety to which they are attached, a carbonyl group,

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

O

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

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

12 and R are the same or different and independently of one another represent a hydrogen atom or a methyl or ethyl group or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring denotes a hydrogen atom or a hydrolysable group which can be degraded to the corresponding carboxyl group and the pharmaceutically acceptable salts, hydrates and solvates thereof.

• ** 99 · · ····

- · 5 5 ·

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

AND indicates -CH ₉ - or, X indicates oxygen, sulfur CH or _O, R ¹ indicates hydrogen atom , methyl, or methoxy group

o 3

R 1 and R 2 are the same or different and independently of one another are methyl, trifluoromethyl, methoxy, trifluoromethoxy or chlorine or fluorine,

R 6 denotes a hydrogen atom,

R 1 and R 2 together with the carbon atom to which they are attached denote a carbonyl group,

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

Q

R represents a phenyl group, a furanylmethyl group or a thienylmethyl group, wherein said ring systems themselves may be mono- or polysubstituted by methyl or ethyl,

R 6a are the same or different and independently of one another denotes a hydrogen atom or a methyl group, and in particular a hydrogen atom, ^ * »β β β β β β β β β φ φ

R are the same or different and independently of one another denotes a hydrogen atom or a methyl group, and in particular a methyl group and denotes a hydrogen atom or a hydrolyzable group , which can be degraded to the corresponding carboxylic acid.

as well as their pharmaceutically acceptable salts, hydrates and salts.

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

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

Of particular interest are the propionic acid derivatives of formula (1) in which R ^ represents a hydrogen atom.

Furthermore, propionic acid derivatives of the general formula I in which R1 and R2 together with the carbon atom to which they are attached form a carbonyl group are particularly important.

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

R is hydrogen, methyl or methoxy-

»Fl fl fl a a fl fl fl a fl

- a group and

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

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

R 0 represents a phenyl group, furanylmethyl group, thienylmethyl group or oxazolylmethyl group, wherein said ring systems themselves may be substituted once or twice with methyl group, or represents 2-methoxyethyl group.

Particularly important propionic compounds of formula IA are acid derivatives

(IA) in which

AND

X

R ¹ denotes -CH ₉ - or -CifyCl 2 -, denotes oxygen or sulfur, denotes hydrogen atom, methyl group or methoxy-

group

R 'and R' 'are the same or different and independently of one another denote methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy or chlorine or fluorine and denote phenyl, furanylmethyl, thienylmethyl or an oxazolylmethyl group, wherein said ring systems themselves may be mono- or di-substituted by a methyl group, or represent a 2-methoxyethyl group.

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

(Π),

Wherein A, X, R, R, are as defined above and

R10 above indicates a benzyl group, an alkyl group having 1 to 6 carbon atoms, or a polymeric carrier suitable for solid phase synthesis, first by activating the carboxyl group of formula II with other III--0NH, LLL),

7 in which they have. R, ^_ and R as defined above, to sloučeninv formula Ia

0-T

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

above in which they have. A, X, T, ^{R8, 9th} In the presence of a base with compounds of formula (V)

(V), in which they have R

R '

Ί 7

R ^{@ 1} and R @ 2 are as defined above and denote a suitable leaving group, such as halogen, mesylate or tosylate, preferably bromine or iodine, also to compounds of formula Ia, then compounds of formula Ia optionally by known methods by amid alkylation or amide -reduction. are converted to compounds of formula Ib

wherein A, X, T, R ⁷ , and R are as defined above.

R ^2, R ^3,

R ⁷ , R ⁸

R ⁹ , R ¹⁰ , R ^{11 are} then converted by acids or bases to the corresponding carboxylic acids of formula Ic

(c) in which A, X, R ', R₁, R₁ defined above, and these mod ifi strike while I or a known reaction with compounds of the methods of esterification of Formula VI below wherein R _r! 3 ( VI) is as defined above

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

The process of the present invention is carried out generally under normal pressure. However, it is also possible to operate at elevated or reduced pressure, for example in the range 0.05 to 0.5 MPa.

Suitable solvents for the process are the customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloromethane, dichloromethane. or chlorobenzene and give 20

Ethyl acetate, pyridine, dimethylsulfoxide, dimethylformamide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidine (NMP), acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned.

Preferred solvents for the process step are dichloromethane and dimethylformamide. For IV + V - > Ia is dimethylformamide.

II + III -> method step

Ia

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

As the amide-forming auxiliaries in process step II + III -> a, conventional condensing agents such as carbodiimide, for example Ν, N-diethylcarbodiimide, Ν, N-dipropylcarbodiimide, Ν, N'-diisopropylcarbodiimide, Ν, N 'are preferably used. -dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) hydrochloride, 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-isoxazole-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) -Ν, Ν, N-tetramethyluronium hexafluorophosphate (HETU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,1,3,3-tetrafluoroethyl .transformate fluoride (TPTV). or 0- (7-azabenzothiazol-1-yl) -N, N, N ', N'-tetramethyluroniumΜ «« 4 · · 4 4 4 4 ·

4 4 4 4 44

V 44444 4 4 • 4 ·

4444 »4 ·· <44

4 4 *

-hexafluorophosphate (HATU), optionally in combination with other excipients such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, as well as bases with alkali metal carbonates, for example sodium or potassium carbonate or bicarbonate, or organic bases such as three alkylamines, for example, triethylamine, N-methylImorpholine, N-methylpiperidine or diisopropylethylamine. Particularly preferred is a combination of EDC, N-methylmorpholine and 1-hydroxybenzotriazole, EDC, triethylamine and 1-hydroxybenzotriazole or HATU and diisopropylethylamine.

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

The carboxylic acid ester hydroxyls in process step 1a and 2, respectively. 1b -> 1c is carried out by conventional methods by treating with inert bases in inert solvents, whereby the resulting salts are converted into carboxylic acids by treatment with acids. In the case of tert-butyl esters, hydrolysis is preferably carried out using acids.

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

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

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

In the case of compounds of formula Ia or Ib, respectively, bound to a polymeric support via a carboxylic acid group produced by solid phase synthesis, cleavage from the resin to compounds of formula Ic is also carried out by the conventional methods for hydrolyzing carboxylic acid esters described above. Trifluoroacetic acid is preferably used herein.

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

* * * * * * · · · Φ φ φ φ 1 1 1 1 · 1 · 1 ·

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

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

(VH), I know a

B represents a bond or a methylene group, in the presence of a suitable reducing agent, with compounds of formula VIIT

R ¹⁴ -NH, (VIII) in which

J. ii

R ¹ - [a-1] has the meaning given above for R or a-2] means a group of formula 15 θ

R 'wherein R is as defined above and

R ¹⁵ represents an alkyl group having 1 to 4 carbon atoms or a trimethylsilyl group.

to compounds of formula IX-14 I-. x

0-Ί

CT in which Β, X, T, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{14 are} as defined above, are then reacted in the presence of a base with compounds of formula X

R ¹⁶ -Y

In the case of process variant [a1], R @ ² denotes a group of the formula

O

wherein R ² and R 2 are as defined above or, in the case of process variant [a-2], have the above meaning

O meaning for R a

Y represents a leaving group such as a halogen atom, a mesylate or a tosvlate. preferably a bromine or iodine atom to the compounds of the general formula (XI)

(XI).

i '' 'η YT η8 ρ9 plO pil R1 - η R 1 in which Β, X, 1, R, Κ, Κ, Κ, Κ, κ and κ are as defined above, and finally the group is selectively hydrolyzed in these compounds of a carboxylic acid ester -COOR2 to a carboxylic acid, or [b] a compound of formula XII

(XH), where they are

A, X, T, R ⁹ , R ¹⁰ , are reacted in the presence of a suitable reducing agent with compounds of formula XT II

R ¹⁷ - CHO (XIII), in which it represents a hydrogen atom, an aryl group of 6 to 10 in

carbon atoms, a 5- to 6-membered heteroaralkyl having up to three heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur, or an alkyl group having from 1 to 3 carbon atoms which may itself be substituted by hydroxy, trifluoromethoxy, alkoxy having 1 to 4 carbon atoms; phenoxy, which themselves are optionally mono- or di-substituted by trifluoromethyl, or may be substituted by an aryl group having 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group having up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all of said aryl and the heteroaryl rings themselves may be substituted one to three times, equally or differently, by halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano nitro or amino to the compounds of formula XIV

in which A has a meaning,

X, T, ^R9, R ^UJ, R ^11, R ¹² and R ¹⁷ above uvetvto the presence of a base and reacted with compounds of formula XV ta · ···

Wherein R, R and Y are as defined above for compounds of formula XVI

-T (xvi), 'λ γ τ d 7 n9 ρίθ η 11- d-12 η 1 5 pi7 in which A, X, 1, R, K, R, R, R, R and R are as defined above, and in these compounds, the carboxylic acid ester group -COOR ^{33 is} selectively hydrolyzed to the carboxylic acid L-lineate.

The whole process can also be performed as solid phase synthesis. In this case, the compounds of formula (VII) or (XII) are coupled as a carboxylic acid ester to a suitable carrier resin, further reactions are carried out on a solid phase, and the target compound is then cleaved from the resin. Solid phase synthesis as well as resin bonding and resin cleavage are common standard techniques.

As exemplified in extensive literature, reference is made to Linkers for Solid Phase Organic Synthesis, Lan V. James, Tetrahedron 55, 4855-4946 (1999).

The reaction of VII + VIII -> IX or XII - XIII -> XIV is carried out in the reductive amination of the customary and inert reaction solvents, optionally in the presence of an acid. These solvents include, for example, water, dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane or alcohols such as methanol, ethanol, propanol, isopropyl alcohol or butyl alcohol. It is also possible to use mixtures of the solvents mentioned. Methanol and ethyl alcohol with the addition of acetic acid are preferred.

Suitable reducing agents for reaction VII + VIII -> IX or XII + XIII -> XIV are complex aluminum hydrides or borohydrides, such as diisobutylaluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or tetrabutylammonium borohydride, or catalytic hydrogenation can also be carried out based on transition metals such as palladium, platinum, rhodium or Raney nickel. Preferred reducing agents are sodium cyanoborohydride, sodium acetoxyborohydride and tetrabutylammonium borohydride.

Reactions VII + VIII -> IX or XII + XIII ->

XIV is generally carried out at a temperature in the range of 0 ° C to 40 ° C.

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

Suitable bases for the reaction of IX + X -> XI or XIV + XV -> XVI are customary inorganic or organic bases, preferably triethylamine.

Reaction IX + X -> XI, or XIV + XV -> XVI with ·· «· • ·· *

generally carried out in a temperature range from 0 ^tJ C to 100 ° C

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

As a base for reaction XI -> II or XVI ->

II are suitable in the case of hydrolysis of a conventional inorganic base. Lithium, potassium and sodium hydroxide are preferred. In case of cleavage of the silyl ester, tetrabutylammonium iumfluoride is preferred.

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

The compounds of the formula IV correspond to the compounds of the formulas IX and XIV, respectively, and can be prepared as described above.

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

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

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

Preferred are compounds of the present invention of formula T for the treatment of arteriosclerosis and hypercholesterolemia, for increasing the disease-lowered level of HDL, as well as for lowering the elevated levels of triglycerides, fibrinogen and LDL. In addition, they can be used for the treatment of obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and high blood pressure due to insulin resistance), liver fibrosis and cancer.

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

The in vivo potency of the compounds of the present invention can be tested, for example, in the tests described herein.

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

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

For this purpose, the active compounds can be converted into customary preparations by known methods. This is accomplished using inert, nontoxic, pharmaceutically acceptable carriers, excipients, solvents, vehicles, emulsifiers and / or dispersing agents.

Excipients include, for example: water, nontoxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethyl alcohol and glycerol), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flours (e.g. talc or silicate), sugar (e.g. milk sugar), emulsifying agents, dispersing agents (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).

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

For oral administration, mg / kg to 5 mg / kg, preferably 24 hours weight.

a dosage of 0.005 mg / kg to about 0.001 mg / kg is dispensed

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

The following examples are used in the following examples

abbreviations. which means: Ac acetyl Bu butyl DC thin layer chromatography DCI direct chemical ionization (in MS) DCM di chloromethane DIC diisopropylcarbodiimide DMAP 4-N, N-dimethylaminopyrrolidine DMF N, N-di methylformamide DMSO dimethylsulfoxide EDC N '- (3-di-methylamino-propyl) -N-ethylcarbodiimide id hydrochloride El electron bombardment ionization (for MS) ESI electrosprey-ionization (for MS) Et ethyl ges. saturated HATU O- (7-azabenzothiazol-1-yl) -N, N, N ', N'-te tramethyluronium hexafluorophosphate HOBt 1-hydroxy-1H-benzotriazole x H ₂ 0 HPLC high pressure, high performance liquid chromato graf ie LC-MS liquid chromatography-double mass spectrometry Me me thy1 MS mass spectroscopy NMR nuclear resonance spectroscopy RF back flow R _f retention index (at DC) RT room temperature

fcfcfc · fcfcfcfc fcfcfc fcfcfc fcfcfc fcfcfc fcfcfc fcfc fcfc

^R t retention time (HPLC) TBAF tetrabutylammoniumfluorid TBAI tet rabutvlamon i umj by id TFA trifluoroacetic acid THF te trahvdrofuran Ex k1 adv Embodiments of the present invention

Starting compounds I

Example 1-1

Tert-Butyl-2-methylpropionate O

A solution of 73.0 g (0.985 mol) of tert-butanol, 190 g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750 ml of dichloromethane is mixed with a solution of 100 g (0.939 rm). of butyric acid chloride in 150 ml of dichloromethane and after mixing the reaction mixture is stirred overnight. Then, 500 ml of 2M hydrochloric acid is added, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. After distillation of the crude product by distillation, 65.5 g (48%) of tert-butyl 1-2-methyl-1-propionate are obtained.

¹ H-NMR (200 MHz, CDCl ₃ ); β = 1.11 2.42 (sept, 1H).

(d, 6H), 1.44 (s, 9H).

·· • ♦ * φ • * φ φ φφφ

Example 1-2

Tert-Butyl 1-3- (4-bromophenyl) -2,2-dimethylpropionate

To a solution of 10.0 g (69.34 mmol) of tert-butyl 2-methylpropionate (Example 1-1) in 100 mL of tetrahydrofuran at -78 ° C was slowly added dropwise 34.7 mL (69.4 mmol) of 2. M lithium diisopropylamide solution. After the addition was complete, the reaction mixture was stirred for one hour at -78 ° C, then 15.76 g (63.04 mmol) of 4-benzyl bromide in 10 ml of tetrahydrofuran was added and stirred for one hour at temperatures.

The reaction mixture is then allowed to come to room temperature, poured into 100 ml of 1 N hydrochloric acid, the phases are separated and the aqueous phase is extracted three times with diethyl ether. The combined organic phases were washed with sodium bicarbonate solution, dried over anhydrous sodium sulphate and the solvent was removed in vacuo. After evaporative purification of the residue under vacuum from an oil pump, 16.75 g (85%) of tert-butyl (4-bromophenyl) -2,2-dimethylpropionate are obtained.

¹ H-NMR (200 MHz, DMSO): δ - 1.06 (s, 6H), 1.38 (s, 9H),

2.74 (s, 2H), 7.10 (d, 2H), 7.47 (d, 2H).

1-3

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

O'

φφ ♦ · · · • · ·

Φ φ * * · · · · · · · • • • <<<· <® ® ®

A solution of 6.00 g (19.16 mmol ·) of tert-butyl 3- (4-bromophenyl) -2,2-dimethylpropionate (Example 1-2) in 80 mL of tetrahydrofuran at -75 ° C 13.5 ml (22.98 mmol) of a 1.7 M solution of tert-butyllithium in pentane are slowly added while maintaining the temperature below -60 ° C. The reaction mixture was stirred for 15 minutes, then 1.82 g (24.90 mmol) of Ν, Ν-dimethylformamide was added and the mixture was stirred for an additional 4 hours at -75 ° C. It is then slowly warmed to -20 ° C, mixed with 20 ml of water with vigorous stirring and then warmed to room temperature. The aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried over a mixture of sodium sulphate and sodium carbonate and the solvent is removed in vacuo. Distillation of the residue in an oil pump vacuum gave 2.54 g (51%) of tert-butyl 3- (4-formylphenyl) -2,2-dimethylpropionate.

¹ H-NMR (300 MHz, CDC1 _3): 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 1-4

Target. Butyl 2- (4-formylphenoxy) -2-methylpropionate

O

A solution of 4-hydroxybenzaldehyde (24.4 g, 200 mmol) in dimethylformamide (100 mL) was treated with cesium carbonate (97.75 g, 300 mmol) and stirred at 90 ° C for 1 h. A solution of 66.93 g (300 mmol) of tert-butyl 2-bromo-isobutyrate in 100 ml of dimethylformamide is then added dropwise.

·· * <· • 3 «

• 4 ·· ·· ···

4 ^U ··

The amide was then stirred overnight at 90 DEG C. After the dimethylformamide had been distilled off in vacuo, the residue was taken up in ethyl acetate, washed twice with water, twice with 1N sodium hydroxide solution and once with saturated sodium chloride solution and dried over anhydrous sulfate. sodium sulfate and the solvent was removed in vacuo. 16.6 g (31%) of tert-butyl 2- (4-formylphenoxy) -2-methylpropionate are obtained.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.63 (s, 6H), 6.90 (d, 2H), 7.78 (d, 2H), 9.88 (s, 1 H).

Example 1-5

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

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 furylamine in 10 ml The reaction mixture was stirred at room temperature for 30 minutes, treated with 1.21 g (5.72 mmol) of sodium triacetoxyborohydride and stirred at room temperature for 22 hours. 6 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate are added, the phases are separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined and dried over anhydrous sodium sulphate. After removal of the solvent in vacuo, chromatographic purification on silica gel (cyclohexane -> cyclohexane / ethyl acetate 10: 1 -> 2: 1) yielded 720 mg (55%) of tert-butyl 3- (4 - {[(2-furmethylmeth37)]. hydroxy) phenyl} -2,2-dimethylpropionates.

@ ¹ H-NMR (300 MHz, CDCl3): .delta. = 1.11 (s, 6H), 1.42 (s, 9H),

1.62 (breites s, 1 H), 2.70 (s, 2 H), 3.76 (s, 2 H). 3.60 (s, 2H); 6.18 (d, 1H); 6.32 (dd, 1H); 7.10 (d, 2H); 7.20 (d, 1H);

2H), 7.35 (d, IH).

Example 1-6

Tert-Butyl-3- [4- (anilinomethyl) phenyl] -2,2-dimethylpropionate

Analogously to Example 1-5, 200 mg (0.762 mmol) of tert-butyl 1-3- (4-formylphenyl) -2,2-dimethylpropionate (Example 1-3), 71 mg (0.762 mmol) of aniline are reacted and 210 mg (0.991 mmol) of sodium acetoxyborohydride in 2 ml of dichloroethane per 223 mg (86%) of tert-butyl 3- [4- (nor Linomethyl) phenyl] -2,2-dimethylpropionates.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.11 (s, 6H), 1.42 (s, 9H),

2.81 (s, 2H), 3.98 (breites s, 1H), 4.29 (s, 2H), 6.64 (d, 2H), 6.71 (t, 1H), 7.12 (d, 2H) 7.17 (t, 2H); 7.25 (d, 2H).

Example 1-7

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

Analogously to 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) were reacted. mmol) of toluidine and 210 mg (0.991 mmol) of sodium acetoxyborohydride in 2 ml of dichloroethane to 206 mg (76%) of tert-butyl-2,2-dimethyl-3- (4 - {[(4-methylphenyl) amino] methyl} phenyl) propionate.

@ ¹ H-NMR (400 MHz, CDCl3): .delta. = 1.11 (s, 6H), 1.42 (s, 9H),

2.23 (s, 3H), 2.81 (s, 2H), 3.87 (breites s, 1H), 4.27 (s, 2H), 6.57 (d, 2H), 6.98 (s) d, 2H), 7.12 (d, 2H), 7.25 (d, 2H).

Example 1-8

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

Analogously to Example 1-5, 1.20 g (4.54 mmol) of tert-butyl 2- (4-formylphenoxy) -2-methylpropionate (Example 1-4) were reacted, 0.70 g ( 4.54 mmol) of DL-2-aminobutyrate, 0.92 g (9.08 mmol) of triethylamine and 1.44 g (6.81 mmol) of sodium acetoxyborohydride at room temperature in 10 ml of dichloroethane. After a further addition of 0.9 g (4.25 mmol) of sodium acetoxyborohydride * and 0.35 g (2.27 mmol) of methyl acid ester

DL-2-aminobutyric and heated at 40 ° C for 3 hours to give 1.47 g (89%) of methyl 2 - {[4- (2-tert-butoxy-1,1-dimethyl- 2-oxoethoxy) benzyl] amino} butyrate.

@ 1 H-NMR (300 MHz, DMSO): .delta. = 0.84 (t, 1H), 1.38 (s, 9H),

1.47 (s, 6H) 1.57 (dt, 2H), 2 29 (s, 1H) , 3.08 (t 1H), 3.47 (d, 1H), 3.62 (s, 3H) 3.65 (d, 1H); 73 (d, 2H), 7.18 (d, 2H). Ex d 1 and d 1-9

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

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

1 H-NMR (400 MHz, CDCl _3; 1: δ = 1.11 (p. , 6H) 1.27 (t, 3H); 1.42 (with , 9H), 2.80 (s, 2H). , 3.31 (with, 2H), 3.76 (s, 2H). 3.84 (with (2H), 4.17 (q. 2H) _; , 6.20 (d, 1H), 6.32 (dd, IH), 7.10 (d (2H), 7.25 (d, 2H), , 7.38 (d, 1H). At to lad 1-10

Tert-Butyl 3- (4 - {[N- (2-ethoxy-2-oxo) ethyl-N-pheny] amino] methyl} phenyl) -2,2-dimethylpropionate

Analogously to that described in Example 1-9, from tert-butyl 3- [4- (anilinomethyl) phenyl] -2,2-dimethylpropionate (Example 1-6), 198 mg (0.583 mmol), 108 mg (0.292) were obtained. mmol) of tetra-n-butylammonium iodide, two times each of 89 mg (0.875 mmol) of triethylamine and three times the dose of 146 mg (0.875 mmol) of ethyl bromoacetate in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide 191 mg (77%). 3- (4 - ([(2-ethoxy-2-oxoethyl) (2-phenyl) amino] methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (200 MHz, cdci ₃ ; 1: δ = 1.11 (s , 6H) , 1.25 (t, 3H) 1.42 (s , 9H) , 2.70 (s, 2H), . 4.05 (s, 2H), 4.20 (q-2H), 4.62 (s , 2H) , 6.69 (d, 2H), 6.73 (t, 1H), 7.07 7.25 (m

6H)

Example 1-11

Tert-Butyl-3- (4 - {[N- (2-ethoxy-2-oxo) ethyl] -N- (4-methylphenyl) amino] methyl} phenyl) -2,2- d ime thy 1 propionate

Analogously to Example 1-9, tert-butyl-2,2-dimethyl-3- (4 - {[4- (methylphenyl) amino] methyl} phenyl) propionate (181 mg (0.512 mmol)) was obtained ( Example 1-7), 95 mg (0.256 mmol) of tetra-n-butylammonium iodide, two portions of 78 mg (0.768 mmol) of triethylamine each and three portions of 128 mg (0.768 mmol) of ethyl bromoacetate each in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide 176 mg (78%) tert-butyl-3- (4 - {[N- (2-ethoxy-2-oxo) ethyl-N- (4-methyl} phenyl) amino] methyl} phenyl) - 2,2-Dimethyl Lp crude ionate.

¹ H-NMR (200 MHz, CDC1 _3): δ = 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 Lad 1-12

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

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

@ 1 H-NMR (200 MHz, DMSO): .delta. = 1.06 (s, 6H), 1.37 (s, 9H), 2.74 (s, 2H); 3.24 (s, 2H); 3.76 (with, 2H), 3.84 (with, 2H), 6.32 (m, 1H); 6.41 (m, 1H); 7.11 (d, 2H), 7.26 (d, 2H), 7.63 (d, 1H), 12.20 (breites with, 1H).

Example 1-13

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

HIM

'0

• · ·

Analogous to that described in Example 1-12, the title compound was obtained from 175 mg (0.411 mmol). - Butyl 3- (4 - {[(2-ethoxy-2-oxoethyl) (2-phenyl) amino] methyl} phenyl) -2,2-dimethylproplonate (Example 1-10) and 1 23 ml (1.23 mmol) of 1 N sodium hydroxide in 3 ml of ethanol 162 mg (99%) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N -phenylglycine.

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

12.53 (breites s, 1 H),

Example 1-14

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

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

¹ H-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),. · · · · «- čL4 _ * ··· ·· ··

6.48 (d, 2H), 6.90 (d, 2H), 7.08 (d, 2H), 7.18 (d, 2H),

12.48 (breites s, 1 H).

Example 1-15

2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)] -

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

@ 1 H-NMR (300 MHz, DMSO): .delta. = 0.91 (t, 3H), 1.40 (s, 9H),

1.51 (s, 6H), 1.84 (m, 2H), 3.25 (breites with, 1H), 3.57 (t, 1H), 3.99 (s, 2H), 6.81 ( d, 2H), 7.38 (d, 2H).

Implementing examples

Example 1-1

Tert-Butyl 3- (4 - {[(2- (2,4-dimethylphenyl) amino-2-oxoethyl) (2-fluoromethyl) amine] methyl} phenyl) -2,2-dimethylpropionate fl *

To a solution of 200 mg (0.498 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (2-fluoromethyl) glycine (Example 1-12) and 91 mg (0.747 mmol) of 2,4-dimethylaniline in 8 ml of dimethylformamide was added at 0 ° C 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3- (3-dimethylamino) petroleum carbamide, 151 mg (1.444 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine were added and the reaction mixture was stirred at room temperature for 1 hour. It is stirred for 9 hours at room temperature and then mixed with 10 ml of water. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. After chromatographic purification of the residue obtained on silica gel (cyclohexane / ethyl acetate 10: 1 -> 3: 1),

228 mg (91%) tert-butyl-3- (4 - {[(2- (2,4-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl} phenyl) -2,2- dimethyl 1-propionate.

@ ¹ H-NMR (200 MHz, CDC1 ₃ ) : δ = = 1.10 (s . 6H) , 1.40 (with. , 9H) 2.26 (s, 2H) , 2.28 (s, 3H), 2.80 (s, 2H), 3.29 (with, 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, IH) . 9.12 (b re i tes 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-di. methylpropionate

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

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

Example 1-3

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

Analogously to Example 1-1, 65 mg (0.164 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N-phenylglycine was reacted (Example 1-13), mg (0.245 mmol) 2,4-dimethylaniline, 29 mg (0.213 mmol)

1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) of 1-ethyl] -3- (3-dimethylamino) propylcarbodiimide hydrochloride, 50 mg (0.491 mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of 4-dimethylaminopyridine in 2 ml of dimethylformamide to 65 mg (79%) of tert-butyl-3- (4 - {[N-2,4-dimethylphenyl) amino-2-oxo) ethyl] -N-phenylamino] methyl} phenyl -2,2-dimethylpropionate.

¹ H-NMR (200 MHz, CDC1 _3): 6 = 1.10 (s, 6H), 1.41 (s, 9H),

1.90 (s, 3H), 2.26 (s, 3H), 2.79 (s, 2H), 4.09 (s, 2H),

4.66 (s, 2H), 6.80-6.95 (m, 4H), 6.98 (d, 1H), 7.12 (s,

4H), 7.27 (m, 2H), 7.67 (d, 1H), 8.11 (breites, 1H).

Example 1-4

Tert-Butyl-3- (4 - {[N- (2- (4-methoxy-2,5-dimethylphenyl) amino-2-oxo) ethyl-N-phenylaminolomethyl} phenyl) -2,2-dimethylpropionate onát

N

H • ♦

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

¹ H-NMR (200 MHz, CDCl 3)] 1: δ = 1.11 (with. , 6H) , 1.42 (with, , 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 (with, IH), 6.83 (dd _; , IH) 6.89 (d, 2H); 7.13 (s, 4H), , 7.24 (d, 2H), 7.34 (m. IH), 7.94 (breites, 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 -dimethy1-

Analogously to Example 1-1, 50 mg (0.121 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- (4-methoxybenzyl) was reacted. -methylphenyl) glycine (Example 1-14), 22 mg (0.182 mmol) 2,4-dimethylaniline, 21 mg (0.158 mmol) of 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) mmol) hydrochloride of 1-ethyl-3- (3-dimethylamino) propylcarbamide, 37 mg (0.364 mmol) of N-methylmorpholine and 0.1 mg (0.001 mmol) of 4-dimethylaminopyridine in 2 ml dimethylformamide per 40 mg (64%) tert-butyl-3- (4 - {[N- (2- (2,4-dimethylphenyl) amino-2-oxoethyl)) -N- (4-methylphenyl) (amino) methyl} phenyl) 2,2-dimethylpropionate.

¹ H-NMR (300 MHz, CDCl 3)? ): δ = 1.10 (with , 6H) , 1.40 (with , 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 (with, 1H), 6.98 (d, 1H), 7.06 (d, 2H). 7.11 (d, 2H), , 7.13 (d, 2H), 7.67 (d. 1H), 8.18 (breites s, 1H). Example 1-6

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

Analogously to Example 1-1, 50 mg (0.121 mmol) of N- [4- (3-tert-butoxy-2,2-dimethyl-3-oxopropyl) benzyl] -N- was reacted. (4-methylphenyl) glycine (Example 1-14), 28 mg (0.182 mmol) 4-methoxy-2,5-dimethylaniline, 21 mg (0.158 mmol) 1-hydroxy---benzotriazole, 30 mg (0.158 mmol) 1-ethyl-3- (3-dimethylamino) propylcarbodiimide, 37 mg (0.364 mmol) N-methylmorpholine and 0.1 mg (0.001 mmol) 4-dimethylaminopyridine in 2 ml d ime thy 1 fo rm * · * * * * * * *

amide to 58 mg (88%) of tert-butyl-3- (4 - {[N- (2- (4-methoxy-2,5-dimethyl-phenyl) -amino-2-oxo-ethyl)) -N - (4-Methylphenylamino) methyl} phenyl) -2,2-dimethylpropionate.

¹ H-NMR (300 MHz, CDCl ₃ ) : 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); 2H), 7.10 (d, 2H), 7.13 (d, 2H), 7.37 (s, 1H); 8.01 (breites s, 1H).

Example 1-7

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

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

^LH-NMR (200 MHz, CDC1 _3): 5 = 0.99 (t, 3H), 1.43 (s, 9H),

1.56 (s, 6H), 1.74 (m, 2H), 2.21 (s, 3H), 2.28 (s, 3H), H

φφ · <··

1H), 6.83 (d, 2H),

2H), 7.93 (d, IH),

3.22 (dd, 1Η), 3.69 (d, 1Η), 3.82 (d 6.98 (s, 1Η), 7.02 (d, 1Η), 7.18 (d,

9.32 (breites s, 1 H).

Example 1-8

Tert-Butyl 2- (4 - {[(1 - {[(4-methoxy-2 carbonyl} propyl) aminolmethyl} phenoxy) -2-methylpropionate, 5-dimethylphenyl) amino

Analogously to Example 1-1, 320 mg (0.90 mmol) of 2 - {[4- (2-tert-butoxy-1,1-dimethyl-2-oxoethoxy) benzyl] amino} was reacted. butyric acid (Example 1-15), 210 mg (1.36 mmol) of 4-methoxy-2,5-dimethylaniline,

160 mg (1.18 mmol) of 1-hydroxy-1H-benzotriazole, 230 mg (1.18 mmol) of 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 per 130 mg (30%) of tert-butyl-2- (4 - {[(1 - {[(4-methoxy-2,5- dimethylphenyl) amino] carbonyl} propyl) amino] methyl} phenoxy) -2-methylpropionate.

¹ H-NMR (200 MHz, CDCl ₃ ) and; = 0.99 (i.e. , 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, 1 H), 6.83 (d, 2H), 7.19 (d, 2H), 7.65 (s. 1H),

9.13 (breites s, 1 H).

this • it to ·· «• to · · · ·

to »»· ·

Example 1-9

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

A solution of 192 mg (0.380 mmol) of tert-butyl 3 - {[(2- (2,4-dimethylphenyl) amino-2-oxoethyl) (2-furylmethyl) amino] methyl] phenyl) -2,2-dimethylpropionate (example 1-1) in 1 ml of dichloromethane is mixed with 1 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. Then the reaction mixture is concentrated in vacuo, taken up in ethyl acetate, the organic phase is washed twice with water, once with 20% sodium acetate solution, once with water and once with saturated sodium chloride solution, dried over sodium sulphate and freed from solvent in vacuo. . Purification of the residue by chromatography on silica gel (dichloromethane → dichloromethane / methanol 20: 1) afforded 150 mg (88%) of 3- (4 - {[(2- (2,4-dimethylphenyl) amino-2)). oxoethyl) (2-fluoromethyl) amino] methyl} phenyl) -2,2-dimethylpropionic acid.

¹ H-NMR (200 MHz, CDC1 _3): δ = 1.16 (with, 6H) , 2.26 (with. , 3H) 2.28 (s, 3H); 2.87 (s, 2H); 3.30 (s, 2H) 3.71 (with. 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); 9.12 (broad t, 1H). 7.37 (d. 1H), 7.83 (d. 1H),

- · φ * φ • Φ φφφφ • · φ φφ φ * φφφφ

Example 1-10

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

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

¹ H-NMR (200MHz, 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, IH), 7, 12 (d, 211), 7.28 (d, 2H), 7.30 (s, IH) , 7.61 (s, IH), 9.02 (bre i tes, IH) 12.18 (bre i tes s, IH).

Example 1-11

3- (4 - {[N - (2- (2,4-Dimethyl-phenyl) -amino-2-oxo) -ethyl] -sulfanylamino] -methyl} -phenyl) -2,2-dimethyl-propionic acid

O

OH

N * 99 · V * V V V V V V V V V V V V V V V V V V V

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

¹ H-NMR (200 MHz, CDC1 _3): δ = 1.19 (s, 6H), 1.90 (s, 3H);

2.26 (s, 3H), 2.87 (s, 2H), 4.08 (s, 2H), 4.66 (s, 2H),

6.80 - 6.95 (m, 4H), 6.98 (d, 1H), 7.14 (s, 4H), 7.27 (m,

2H), 7.67 (d, 1H), 8.08 (breites with, 1H).

Example 1-12

Acid for 3- (4 - {[N- (2- (4-methoxy-2,5-dimethyphenyl) amino) -1-oxoethyl] -N-phenylamino methyl} phenyl 1) - 2,2 - dimethyl - propionate

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

· 4 * 4 * 4 4 * • 4 44 44 44 4 44 fl fl

- - · 3 · ·

- 20 · · fl «20 20 fl fl fl fl 20 fl fl fl fl

¹ H-NMR (200 MHz, CDC1 ₃ ): δ 1 19 (s, 6H) 1.94 (with, 3H) (s, 3H) 2.86 (with, 2H), 3 , 77 (s, 3H), 4.08 (s, 2H), , 4, 6 6 2H), 6.56 (s, 1H) , 6.83 (dd, 1H), 6.88 (d, 2H) , 7. , 13 (with 4H), 7.24 (d, 2H) , 7.34 (m, 1H), 7.93 (breites s, 1H) Example 1-13

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

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

¹ H-NMR (200 MHz, CDCl ₃ ); δ 1.17 (s, (SH), 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 (breites s, 1H), this · this • to this • it to this * * to «« • to 4 · to · to · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 1-14 acid

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

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

NMR (200 MHz, CDCl ₃ ): δ 1 , 18 (s, 6H), 1, 96 (s. 3H) , 2.15 (with, 3H), 2.26 (s, 3H) 2.86 (with, 2H), 3.76 ( s, 3H), 4, 03 (p. 2H) . 4.61 (s. 2H), 6.57 (s, 1H). , 6.80 (dd, 2H), 7.07 (4, 2H) , 7.14 (s, 4H), 7.36 (s, 1H), , 8.02 (brei tes, 1H) Ex d 1 and d 1-15

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

··· ·

OH

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

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.01 (t, 3H), 1.53 (d, 6H), 1.95 (m, 2H), 2.10 (s, 3H), 2 23 (s, 3H), 3.67 (breites s, 1H),

4.02 (m, 1 H), 4.55 (m, 1 H), 6.61 (d, 2 H), 6.82 (d, 1 H), 6.89 (s, 1 H), 7.10 (d) 2 H, 7.11 (s, 1 H), 9.53 (breites, 1 H).

Example 1-16

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

OH

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

¹ H-NMR (300 MHz, CDC1 ₃₎ ): δ = 1.05 (t , 3H) 1.55 (d, 6H) 1.97 (m (2H), 2.10 (s, 6H) , 3.75 (s, 3H), 3.78 (m, IH), 4.08 (m (2H), 4.50 (m, 2H) , 6.50 (s, 1H), 6.64 (d, 2 H), 6.94 (s (1H), 7.14 (d, 2H) , 7.65 (s, 1H), 9.38 (breites 1H). Default compounds TI Ex ice II-1

2 - [(4-bromophenyl) thio] -2-methyl-L-propanoic acid 1,1-dimethylethyl ester

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

¹ H-NMR (200 MHz, CDCl ₃ ): 1.48 (s, 15H), 7.38 (τη, 4H).

Example II-2

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

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

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

Example I 2 - [[4 - [[(2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid T-3,1-dimethylethyl ester

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

¹ H-NMR (300 MHz, CDCl ₃ ): 1.42 (s, 15H), 3.79 (s, 2H), 3.80 (s, 2H), 6.15 (m, 1H). 6.28 (m, 1H); 7.25-7.45 (m, 5H).

Example II-4

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

5.4 g of 2 - [[4 - [[furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester is dissolved in 270 ml of tetrahydrofuran and mixed with 2.27 g of triethylamine, 3.74 g of ethyl bromoacetate and 14.85 g of tetra-n-butylammonium iodide. The reaction mixture was stirred at 90 ° C for 48 hours, cooled and treated with water and ethyl acetate. The organic phase was separated and washed twice with saturated sodium chloride solution.

After drying over anhydrous magnesium sulfate, concentrating and chromatographic purification (cyclohexane / ethyl acetate 5 + 1), 6.4 g of a colorless oil are obtained.

¹ H-NMR (CDCl ₃ , 200 MHz): 1.28 (t, 3H, J = 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-propanoic acid 1,1-dimethylethyl ester

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

¹ H-NMR (DMSO, 200 MHz): 1.32 (s, 9H), 1.39 (s, 6H), 3.18 (s,

3.22 (s, 7.34 (d,

2H), 3.23 (s, 2H), 6.27 (m, 1H), 6.40 (m, 2H, J = 9.0 Hz), 7.50 (d, 2H, J = 9.0 Hz),

7.59 (m, 1H); 12.38 (breites s, 1H).

Example I I - 6

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

4.0 g of 2 [[4- (2-amino62 ethyl) phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ethyl ester [(PJ Brown et al., J Med. Chem. 42. 3785- 88 (1999)] is dissolved in 100 ml of methanol and mixed with 2.6 g of fural, after which 9.3 ml of glacial acetic acid is added and boiled briefly (10 minutes), after which the mixture is cooled to 0 ° C, 4.25 g of sodium cyanoborohydride in portions, stirred overnight, treated with 1N hydrochloric acid until acidic, and stirred for 30 minutes, then concentrated, basified with saturated sodium bicarbonate solution, extracted twice with ethyl acetate. Chromatographic purification (dichloromethane / methanol 15 + 1) gave the title compound as a colorless oil (2.4 g).

Rf (dichloromethane / methyl alcohol 10 + 1) = 0.57.

Example 11 - 7

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

2.4 g of 2 - [[4- [2 - [(carboxymethyl) - (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester were dissolved in 1.5 g. g of ethyl bromoacetate, 0.97 g of triethylamine and 7.8 g of tetra-n-butylammonium iodide in 100 ml of tetrahydrofuran and were refluxed overnight. The reaction mixture was then treated with ethyl acetate and water and shaken with water and saturated sodium chloride solution.

Concentration and chromatography of the residue (petroleum ether / ethyl acetate 10 + 1) gave 1.38 g of the title compound.

¹ H-NMR (DMSO, 200 MHz): 1.18 (t (s, 15H), 2.77 (m, 4H), 3.32 (s 2H), J = 7) 8 Hz), 6.21 (m, 1H), = 9.6 Hz), 7.32 (d, 2H, J = 9.6

Example 11 - 8

3H, t, J = 7. , 8 Hz) , 1.37 2H), . 3.81 (s. , 2H), 4.06 (q. 6.34 (m, 1 H), 7.16 (d, 2H, J) Hz), 7.58 (m, 1H).

Acid 1,1-dimethylethyl ester

2 - [[4- [2 - [(carboxymethyl) (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropane

1.0 g of 2 - [[4- [2 - [(2-ethoxy-2-oxoethyl) (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethylethyl ester was mixed with 6 5 ml of 1 N sodium hydroxide in 10 ml of ethanol, stirred for one hour at 80 DEG C., concentrated, the residue is dissolved in water and acidified with 1N hydrochloric acid. Extraction three times with ethyl acetate and chromatography (dichloromethane / methanol 5 + 1) afforded 744 mg of the product as a colorless oil.

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

Example II-9

2 - [[4 - [[(2-methoxyethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ethyl ester

7.9 g of 2 - [(4-formylphenyl) thio] -2-methylpropanoic acid 1,1-dimethyl ester are introduced with 4.23 g of methoxethylamine in 100 ml of methanol and mixed with 19 ml of acid.

4 4 4 acetic. The reaction mixture was stirred for 15 minutes at room temperature, boiled briefly, and then treated portionwise at 0 ° C with 8.9 g of sodium cyanoborohydride. After stirring overnight at room temperature, it is treated with 1 N hydrochloric acid and allowed to stir for 30 minutes, then made alkaline with sodium carbonate solution and extracted twice with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration and chromatographic purification gave 5.6 g (58%) of the product as a colorless oil.

¹ H-NMR (200 MHz, CDC1 _3): 5 = 1.36 (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 11 -10

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

8.0 g of 2 - [(formylphenyl) thio] -2-methylpropanoic acid 1,1-dimethyl ester are introduced with 6.3 g of 5-methyl-2-furanmethylamine in 100 ml of methanol and mixed with 16 ml. acetic acid, stirred for 15 minutes at room temperature, boiled briefly and then treated portionwise at 0 ° C with 5.7 g of sodium cyanoborohydride. After stirring overnight at room temperature, the reaction mixture was treated with 1 N hydrochloric acid and allowed to stir for 30 minutes, then basified with sodium carbonate solution and extracted twice with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration and chromatographic purification, 4.8 g (45%) of the product are obtained as a colorless oil which destroys decomposition and is stored at -25 ° C.

¹ H-NMR (200 MHz, CDC1 _3): 5 = 1.42 (s, 15H), 1.72 (s, 1H,

NH), 2.28 s, 3H), 3.79 (s, 2H), 3.78 (s, 2H), 5.88 (m, 1H), 6.03 (m, 3H), 7, 28 (dd, 2H, J = 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 are dissolved in 2 l of methylene chloride and mixed with a solution of 233 g of .alpha.-bromoacetyl bromide in 400 ml of methylene chloride at a maximum of 15 DEG C. for 15 minutes under ice cooling. After 30 minutes of reaction time, the precipitate formed is filtered off with suction, the residue is taken up in 3 l of methylene chloride, combined with the filtrate and washed twice with 2 l of water and 2 l of saturated sodium chloride solution. It is dried over sodium sulphate, filtered off with suction and the residue is crystallized from ethanol. 193 g of the title compound are obtained.

Example 11-12

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

This compound was prepared in analogy to Example 11-11 from 4.2 g of 2,4-dichloroaniline, 5.76 g of bromoacetyl bromide and 2.89 g of triethylamine in methylene chloride.

5.9 g (80.4%) of the title compound are obtained.

Rf (dichloromethane): 0.38 · · ·

MS (EI pos.): M ⁺ = 238.

Production examples 2

Example 2-1

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

Method a)

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

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient):

R _t = 4.87 min ([M + H] ⁺ = 523)

Method b)

1.5 g of 2 - [[4 - [[(2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester (Example II-3) and 1.1 g of 2- of bromo-N- (2,4-dimethylphenyl) -acetamide (Example II-9) is dissolved in 20 ml of dimethylformamide and mixed with &lt; tb &gt;

-67 φφφ «

and Hφ with 0.4 g of sodium bicarbonate, whereupon the reaction mixture is heated at 90 ° C overnight, concentrated and purified by chromatography (dichloromethane / ethyl acetate 10: 1 and 5: 1). 2.1 g of the title compound are obtained.

Example 2-2

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

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

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 5.32 min ([M + H] ⁴ = 537).

Example 2-3

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

250 mg of 2 - [[4- [2 - [(carboxymethyl) (2-fluoromethyl) amino] methyl] phenyl] thio-2-methyl-1,1-dimethyl ester • 4 4 · · 4 ··· ·

4 4 4

4 «4 · 445

443 · 4 4 4

4 4 4 4

4444 44 44 4-methylpropanoic acid are mixed together with 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mg of 2,5-dimethyl-4-methoxyaniline and 130 mg of Ν'- (3-dimethylaminopropyl) -N- hydrochloride. ethylcarbodiimide and dissolved in 5 ml of dichloromethane. The reaction mixture was stirred for 20 hours at room temperature and extracted with 1 N sodium hydroxide, 1 N hydrochloric acid, water and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous magnesium sulfate and chromatographed (dichloromethane / ethyl acetate 25 + 1) to give 190 mg of a viscous oil.

LC-MS: acetone / tri 1/30% aqueous hydrochloric acid / water (gradient); R ^. = 4.90 min ([M + H] ⁺ = 552)

Example 2-4

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

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

LC-MS: acetone! tril./30% aqueous hydrochloric acid / water φ * ·· φ φ * φ ··· φ

- 69 (gradient): R _t = 4.69 min ([M + H] ⁺ = 538)

Example 2-5

2 - [[4 - [[[2 - [(2,4-Dimethylphenyl) amino] -2-hexyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid

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

Rf (dichloromethane / methanol 10 + 1) = 0.3 ¹ H-NMR (400 MHz, D 6 -DMSO): δ = 1.34 (s, 6H, CH ₃ ), 2.16 (s, 3H, CH ₃₎ ), 2.23 (s, 3H, CH-j), 3.24 (s, 2H, _CH2), 3.76 (s, 2H _CH2), 3.78 (s, 2H, _CH2); 6.38-6.40 (m, 2H, 2 x furanyl-H) 6.93-6.95 (d, 2H, Ar-H); 7.0 (s, 1H, Ar-H); 38-7.51 (m, 4H, Ar-H). 7.60-7.61 (m, 1H, furanyl-H); 9.14 (s, 1H,

NH).

MS (EI pos.): M ⁺ = 467 ([M + H] &lt; + ^&gt; ), m / z = 489 ([M &lt; ⁺ &^gt; Na] ^&lt; ^{+ &gt;} ) * · · · · · · · ·

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

LC-MS: acetonitrile 1/30% aqueous hydrochloric acid / water (gradient): R _t = 3.76 min ([M + H] ⁺ = 467).

Example 2-5-a

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

500 mg of 2 - [[4 - [[2 - [(2,4-dimethylphenyl.) Amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid (ex. 2-5) was dissolved in 500 mg acetonitrile and 194 mg dicyclohexylamine was added. Water is then added, part of the acetonitrile is distilled off until cloudy and lyophilized. 445 mg of a powder is obtained.

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

Example 2-5b

2 - [[4 - [[[2 - [(2,4-Dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid hydrochloride ··· · Β β β

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

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

Example 2-6

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

210 mu 2-tert-butyl ester of 2 - [[4 - [[2 - [(2,4,6 0 0 · · 4)]

Μ ·· • 4 0 0 0

0 0 0 · 0000 * 0 000 000 000 000

0000 ·· 00 000 ·· 00

Trimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methylpropanoic acid was dissolved in 5 ml of dichloromethane and treated with 1 ml. trifluoroacetic acid. After stirring at room temperature for 4 hours, concentrating and chromatographic purification (dichloromethane / ethyl acetate 50 + 1), 187 mg of the title compound is obtained as a foamy solid.

1 H-NMR (DMSO, 200 MHz): 1.42 (s, 6H), 2.04 (s, 6H), 2.23 (s 3H), 3.58 (breites s, 2H), 4.05 (s, 2H), 4.12 (s, 2H), 6.55 (m, 2H), 6.87 (s, 2H), 7.48 (d, 2H, J = 9.0 Hz), 7 51 (d, 2H, J = 9.0 Hz), 7.72 (m, 1H), 9.40 (breites with, 1H).

Example 2-7

2 - [[4 - [[[2 - [(2,5-dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-methyl 1. - Propane

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

¹ H-NMR (DMSO, 200 MHz): 1.39 (s, 6H), 2.08 (s, 3H), 2.11 (3H), 3.7 (s, 3H), 4.00 (breites s, 4H), 6.48 (m, 1H), 6.51 (m, 1H), 6.76 (s, 1H), 7.08 (s, 1H), 7.48 (m, 4H) 7.72 (m 1H), 9.35 (breites s, 1H), 12.65 (breites s, 1H).

Example 2-8

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

200 mg of 2 - [[4 - [[[2 - [(2-methyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenyl] thio] -2-tert-butyl ester methyl-propanoic acid is dissolved in 5 ml of dichloromethane and treated with 1 ml of trifluoroacetic acid. After stirring at room temperature for 20 hours, concentration and chromatographic purification (dichloromethane / methyl alcohol 50 + 1), the title compound was obtained as a solid foam. ¹ H-NMR (DMSO, 200 MHz): 1.38 (s,

3H), 3.80 (brei tes s, 2 Η), 4.00 1H), 6.55 (m, 1H), 6.65 (m. , 1H) 1H), 7.48 (m, 4H), 7.71 (m, , 1H)

174 mg of the title compound.

6H), 2.12 (s, 3H), 3.7 (s, 2H), 6.45 (m,

6.78 (m, 1H); 7.25 (m, 9.37 (breites s, 1H));

12,6? (breites s, 1 H).

Example 2-9

2 - [[4- [2 - [[2 - [(2,4-Dimethylphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] ethyl] phenyl] thlo] - tert -butyl ester - 2-methyl-propane

104 mg of 2 - [[4- [2 - [(carboxymethyl) (2-furanylmethyl) amino] ethyl] phenyl] thio] -2-methylpropanoic acid 1,1-dimethyl ester is mixed with 36 mg of hydroxybenzotriazole,

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

190 mg of a viscous oil are obtained.

LC-MS: acetonitrile 1/30% aqueous hydrochloric acid / water (gradient): R _t = 5.3 min ([M + H] ⁺ = 537).

¹ H-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, 2), 3.78 (s, 2H), 6.22 (m, 1H), 6.95 (m, 1H), 7.00 (m, 1H) 7.05 (d, 2H,

J = 10.0 Hz), 7.35 (d, 2H, J = 10.0 Hz), (m, 1H), 7.79 (m, 1H), 8.95 (breites with, 1H), 12.60 (breites, 1H)

Example 2-10

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

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

Example 2-11

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

mg of 2 - [[4- [2 - [[2 - [(2,4-dimethyl-phenyl) amino] -2-oxoethyl]] - (2-furanylmethyl) amino] - tert-butyl ester -

ethyl · phenyl] thio] -3-methylpropanoic acid was dissolved in 5 ml of dichloromethane and treated with 0.27 ml of trifluoroacetic acid. The reaction mixture is stirred for 24 hours at room temperature, taken up in toluene and the residue is purified by chromatography (dichloromethane / methanol 10 + 1). 33 mg of product are obtained in the form of a colorless oil.

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

Example 2-12

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

mg of 2 - [[4- [2 - [[2 - [(2,5-di-methyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-furanylmethyl) amino] tert-butyl ester] ethyl] phenyl] thio] -2-methylpropanoic acid is dissolved in 5 ml of dichloromethane and treated with 0.20 ml of trifluoroacetic acid. The reaction mixture is stirred for 24 hours at room temperature, taken up in toluene and the residue is purified by chromatography (dichloromethane / methylalcohol 10 + 1).

27 mg of product are obtained in the form of an air-darkening oil.

LC-MS: Acetonitrile / 30% aqueous HCI / water (gradient): R _t = 3.78 min ([M + H] ⁺ = 511).

φ «···· φφ ·· φφφφ φφφφ

¹ H-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 (with, 2H), 6 33 (m, 2H), 6.72 (m. IH), 7.15 (d, 2H) .1-9 , 8 Hz), 7.24 (d , 2H, J = 9.8 Hz), (m, lH) , 7.62 (m, 1H), 8.88 (bre ites s, IH) 12.55 (BRE s tes s, 1H).

The following exemplary compounds are obtained in an analogous manner:

Example 2-13

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

Yield: 343 mg (68%) ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.50 (s, 6H, 2 x CH ₃ ), 2.19 (with 3H, CH ₃ ). 3.38 (s, 2H, _CH2), 3.78 (s, 2H, _CH2), 3.83 (s, 2H _CH?), 4.30 (s, br, COOH), 5, 85 (m, 1H, furanyl-H), 6.16 (tri, 1Η, fused 1-H), 7.18-7.49 (m, 6H, Ar-H), 8.30 (m, 1H ,

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

LC-MS: acetonitrile 1/30% aqueous hydrochloric acid / water (gradient): = 3.42 min ([M + H] ⁺ = 521).

• · «4 ··· 4 4

4 4 4 • 4444

Example 2-14

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

Yield: 90 mg (36%) ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.53 (s, 6H, 2 x CH ₃ ), 2.29 (s, 3H, CH ₃ ), 3, 75 (s, 2H, _CH2), 4.25 (s, 2H, _CH2), 4.28 (s, 2H, _CH2), 5.95 (m, 1H, furanyl-H), 6.49 (m, 1H, furanyl-H), 7.35 (s, 2H, Ar-H), 7.38-7.51 (m, 4H, Ar-H), 9.51 (s, 1H, NH) .

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 3.05 min ([M + H] ⁺ = 555).

Example 2-15

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

φ · φ · · · φ ·

Yield: 46 mg (26%).

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

Example 2-16

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(2,4-dimethylphenyl) amino] ethyl] amino] methyl] phenyl 11thio] - Propane

Yield: 183 mg (41%)

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

Example 1 ad 2-17

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(2,5-dimethyl-4-methoxyphenyl) amino] ethyl] amino no] methyl] phenyl] thio] propanoic acid

Yield: 149 mg (67%).

LC-MS: acetonitrile 11/30% aqueous hydrochloric acid / water (gradient): R t = 4.10 min ([M + H] ⁺ = 511).

Example 2-18

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(4-chloro-2-trifluoromethylphenyl) amino] ethyl] amine] no] methyl] phenyl] thio] propanoic acid

Yield: 63 mg (22%).

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

Example 2-19

2-Methyl-2 - [[4 - [[[(5-methyl-2-furanyl) methyl] - [2-oxo-2 - [(4-methoxy-2-methylphenyl) amino]] Ethyl] amino] methyl] phenyl] thio] -propane

Yield: 24 mg (18%)

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water · 000 * 00 0 (gradient): R t = 2.59 min ([M + H] ⁺ - 497).

EXAMPLE 2-20

2 - [[4 - [[[2 - [(2,5-Dimethyl-4-methoxyphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] - 2-methyl-1-propanoate

Yield: 60 mg (60%).

LC-MS: acetonitrile 1/30% aqueous hydrochloric acid / water (gradient): R t = 2.15 min ([M + H] ⁺ = 475).

Example 2-21

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

Yield: 16 mg (20%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): Rt ₌ 3.59 min ([M + H] ⁺ = 89).

• it to it **

Λ

Example 2-22

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

Yield: 89 mg (81%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R f. = 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 lamino] methyl] phenyl thio] propanoate

Yield: 22 mg (34%).

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

• 9 9

Example 2-24

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

Yield: 26 mg (20%).

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

Example 2-25

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

OH

mg (27 %) MHz , cdci ₃ ) : δ = 1.38 (with, 6H, 2 x _CH3), 2.82 (m 23 (with, 3H, OMe), 3.32 (s, 2H, _CH2), 3.50 (m, [0100] 2H s, 2H, ch ₂ ) , 5.28 (s, 1H, COOH), 7.15-7.48 (m

6H. Ar-H), 8.35 (m, 1H, Ar-H), 9.90 (s, 1H, NH).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R _t = 2.76 min ([M + H] = 485).

Example 2-26

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

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

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

Example 2-27

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

ΌΗ · * ·· 00 0000 00 »*« · * · * 0 * 0 ♦ «• · * 0 0 0 0 0000 * _on - * · ·» ·· 0 "0 0 *

00 * · * · · 0000 * ··· 0 »<0 000 00 00

Yield: 200 mg (99%) ^I H-NMR (300 MHz, CDC1 _3): δ = 1.50 (s. 6H, 2 x _CH3), 2.20 (s, 3H, Me), 3.61 ( s, 2H, _CH2), 4.20 (s, 2H, _CH2), 4.48 (s, 2H. _CH2), 5.60 (s, 1H, COOH), 7.00 (m, 2H , Ar-H), 7.02-7.17 (m, 3H, Ar-H and thienyl-H), 7.36 (m, 3H, Ar-H), 7.50 (m, 2H, Ar- H), 8.00 (s, 1H, Ar-H), 8.88 (s, 1H, NH),

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): = 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] phenyl] thio] -propanová

Yield: 80 mg (98%).

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

Example 2-29

2-Methyl-2 - [[4 - [[[(2-thiophenyl) methyl] -2-oxo-2 - [(2-methyl-4-methoxyphenyl) amino] ethyl] amino] methyl] bitches 1] th io] -p petroleum »♦ 4« «·

LC-MS: acetonitrile 1/30% aqueous hydrochloric acid / water (gradient): R t = 2.74 min ([M + H] ⁺ = 498).

Example 2-30

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

Yield: 75 mg (60%).

LC-MS: acetonitrile / 30% aqueous hydrochloric acid / water (gradient): R t = 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 L-propanoic acid

- 8 '• φφ · · · · · · φφ φφ Φφφ

Yield: 63% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.51 (s

3.34 (s, 3H), 3.37-3.45 (m, 2H), 3 (s, 3H), 3.89 (s, 2H), 4.34 (s, 2H),

7.35-7.44 (m, 3H), 7.52 (d, 2H), 9

6H), 2.18 (s, 3H),

3.75 (m, 2H), 3.77, 6.67-6.78 (m, 2H), (s, 1H).

and d 2-32

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

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

2.25 (s, 3H), 3.35 (s, 3H), 3.38-3.54 (m, 2H), 3.65-3.77 (m, 2H), 3.85-3, 94 (m, 2H), 4.30-4.45 (m, 2H), 6.87 (s, 2H), 7.39 (d, 2H), 7.53 (d, 2H), 8.82 (br s, 1 H).

Starting compounds III

- 38 Example III-1

Tert-Barium (4-formylphenoxy) acetate

ΓΊ

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

Yield: 31% t, bp: 58-60 ° C

Example III-2

Tert-Butyl 2- (4-formylphenoxy) -2-methylpropanoate (200 mmol)

4-Hydroxybenzaldehyde (mmol) was added in 250 ml of N, N-dimethylformamide and mixed with potassium carbonate. Dissolve 24.42 g at a temperature of 27.64 g (200 100 ° C) dropwise.

* ···

89.59 g (240 mmol) of α-bromoisobutyric acid tert-butyl ester, stirred for one hour, an additional 200 mmol of potassium carbonate and 240 mmol of t-butyl α-bromoisobutyrate are added and after 4 hours at 100 DEG C. ° C, the reaction mixture was mixed with water. After washing with 1 N sodium hydroxide and saturated sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane -> cyclohexane / ethyl acetate 20: 1 -> 10: 1 -> 5 : 1) and dried in vacuo. The title compound is obtained in the form of a colorless crystalline substance.

Yield: 42%.

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.62 (s, 6H), 6.91 (d, 2H), 7.79 (d, 2H), 9.88 (s, 1 H).

MS (ESI): 265 [M + H] &lt; + ^&gt; .

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

Example ITI-3

Ethyl 2- (4-formylphenoxy) -2-methylbutanoate

Yield: 11.71% ¹ H-NMR (200 MHz, CDCl ₃ ): δ - 1.00 (t, 3H), 1.22 (t, 3H),

1.61 (s, 3H), 1.90-2.20 (m, 2H), 4.24 (q, 2H), 6.90 (d, 2H), 7.80 (d, 2H), 9.85 (s, 1 H).

MS (EST): 251 [M + H] &lt; + &^gt;, 273 [M + Na] &lt; + ^&gt; .

·· ·· ··· * * · · · · ♦

Example III-4

Target. Butyl 2 - [(3-bromophenyl) sulfanyl] -2-methylpropanoate

Yield: 87%

1 H-NMR (200 MHz, CDCl 3): δ = 1.43 (s, 9H), 1.45 (s, 6H) 7.14-7.28 (m, 1H), 7.39-7, 53 (m, 2H); 7.67 (t, 1H). MS (DCI / NH ₃ ): 348 [M + NH ₄ ⁺ ],

Example 111-5

Tert-Butyl 2- (3-formylphenoxy) -2-methylpropanoate

Yield: 35% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.44 (s, 9H), 1.61 (s, 6H)

7.14 (dd, 1H), 7.31-7.35 (m, 1H), 7.41 (ΐ, 1H), 7.45 5.52 (m, 1H).

MS (DCI / NH ₃ ): 282 [M + NH ₄ ⁺ ].

Example IIT-6

Tert-Butyl-2- (3-bromophenoxy) -2-methylpropanoate φ ··· φ φ φ · φ φ • φφφ

Yield; 21% ¹ H-NMR (300 MHz, CDCl ₃ ): 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 / NH ₃ ); 332 [M + NH ₄ ^+].

Example III-7

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

Yield:

T. t. : 142-143 ° C

Example I 11 - 8

Tert-Butyl 1-2 - [(3-formylphenyl) sulfanyl] -2-methylpropanoate

Dissolve 30.00 g (90.56 mmol) at -78 ° C * · ·· · ♦ ··

The compound of Example III-4 in tetrahydrofuran was treated with 36.2 mL of a 2.5 M solution of n-butyllithium in hexane, and then 13.94 mL (181.12 mmol) of Ν, N-dimethylformamide was added. After 30 minutes, warm the reaction mixture to room temperature and stir for one hour. 30 ml of 1N hydrochloric acid are then added, the solvent is distilled off, the residue is extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After flash chromatography on silica gel (dichloromethane), the title compound is purified by NP-HPLC (cyclohexane / ethyl acetate) to give a yield of 10%.

HNMR (300 MHz, CDC1 _3): δ = 1.43 (s, 9H), 1.46 (s, 6H),

7.50 (t, 1H), 7.77-7.80 (m, 1H), 7.87 (d, 1H), 7.98-8.05 (m, 1H), 10.00 (s, 1H).

MS (DCI / _NH3): 298 [M + NH ₄ ^+]

Example III-9

Target. Butyl-2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethenyl] phenoxy} -2-methylpropanoate

14.93 g (47.37 mmol) of the compound of Example III-6, 10.25 g (59.21 mmol) in vinyl phthalimide, 0.39 g (1.27 mmol) are heated in an autoclave at 130 ° C. ) tr is - o-tol lf osf i ··· 4 ta

93 nu, 0.07 g (0.32 mmol) and 21.78 g (215.23 mmol) of tetriethylanetine. After addition of a mixture of water and methanol, the precipitate is filtered off with suction and crystallized from a mixture of cyclohexane and ethyl acetate.

Yield: 66% ¹ H-NMR (200 MHz, CDCl ₃ ); δ = 1.40 (s, 9H), 1.50 (s, 6H), 6.73 (dd, 1H), 6.86-6.93 (m, 1H), 7.16 (t, 1H) 7.21, 7.34 (m, 2H), 7.43 (d, 1H), 7.80-8.00 (m, 4H).

MS (DCI / NH ₃ ): 425 [M + NH ₄ ⁺ ].

Example III-10

Tert-Butyl 2- {3- [2- (1,3-dioxo-1,3-dihydro-2H-indol-2-yl) ethyl] phenoxy} -2-methylpropanoate

15.00 g (36.81 mmol) of the compound of Example II-1-9 are dissolved in 200 ml of tetrahydrofuran and stirred overnight under a hydrogen atmosphere at normal pressure in the presence of a suspension of 2.00 g (2.16 mmol) of the Vilkinson catalyst in 40 ml. ml of ethyl alcohol. After two flash chromatography on silica gel (cyclohexane / dichloromethane 10: 1 -> cyclohexane / ethyl acetate 10: 1 -> 5: 1 cyclohexane -> cyclohexane / dichloromethane -> dichloromethane) the title compound is obtained in 64% yield.

¹ H-NMR (200 MHz, CDCl ₃ ): 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) )

· Φφφφ • · φ φ · ···

····

7.77 - 7.89 (m, 2Η).

MS (ESI): 432 [M + Na &lt; + & gt ^; ], 841 [2M + Na] ^&lt; ^{+ &gt;.}

Example 111-11

Target. Butyl 2- (4-aminophenoxy) -2-methylpropanoate h ₂ n

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

T. t. : 87-88 ° C

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

Example 111-12

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

O

· * ··· • ·

- 95 Yield: 70% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.31 (breites s, 2H), 1.44 (s, 9H), 1.56 (s, 6H), 2 69 (t, 2H), 2.94 (t, 2H), 6.64-6.75 (m, 2H), 6.81 (d, 1H), 7.15 (t, 1H).

MS (ESI): 279 [M ^& lt ^{; +} & gt ^; ].

EXAMPLE 1 III-13

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

20.00 g (75.67 mmol) of the compound of Example III-2 and 7.35 g (75.67 mmol) are stirred in 350 ml of 1,2-dichloromethane.

2-furylamine with 24.06 g (113.50 mmol) of sodium acetoxyborohydride for 5 hours at room temperature. The reaction mixture is then treated with a saturated sodium bicarbonate solution and ethyl acetate, and after drying the organic phase with magnesium sulfate and distilling off the solvent, the residue is purified by flash chromatography on silica gel (cyclohexane → cyclohexane (ethyl acetate 10; 1 → 10)). 2: 1) The title compound is obtained in 72% yield.

⁴ h- NMR (200 MHz, CDC1 3) ^: δ = 1.61 (breites s, 1H) , 1 , 44 (p 9Η) , 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); 18 (d, 2H) , 7.32 - 7.40 (m, 1H)

* · ♦ ·

96 MS (ESI): 346 [M + H] &lt; + ^&gt; .

Example 11 I - 14

Tert-Butyl 1- 2- {4 - [(2-furylmethyl) amino] phenoxy} -2-methylpropanoate

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

@ 1 H-NMR (200 MHz, CDCl3): .delta. = 1.46 (s, 9H), 1.48 (s, 6H),

3.80 (breites s, 1H), 4.26 (s, 2H), 6.21 (d, 1H), 6.25 6.35 (m, 1H), 6.50-6.61 (m, 2H), 6.72-6.86 (m, 2H), 7.30-7.39 (m, 1H).

MS (DCI / _NH3): 332 [M + H] ^+, 349 [M + NH ₄ ⁺ b

Example ad-15

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

97 amino] methyl] phenoxy] -2-methylpropanoate

In 200 ml of tetrahydrofuran, 18.14 g (52.50 mmol) of the compound of Example III-13, 11 ml of triethylamine and 1.10 g (2.97 mmol) of tetra-n-butylammonium iodide with 8.77 ml (78, 75 mmol) of ethyl bromoacetates and the reaction mixture is stirred for 1 hour at room temperature and for 2 hours at 60 ° C. It is then treated with water and ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and, after evaporation of the solvent, the residue is purified by flash chromatography on silica gel (cyclohexane / dichloromethane 4: 1 -> cyclohexane / ethyl acetate). 10: 1

-> 5: 1) The yield is quantitative.

¹ H-NMR (300 MHz, CDC1 _3): 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, 1H); 2H), 7.35-7.41 (m, 1H).

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

Example 111-16

Tert-Butyl 2- [4 - [[(carboxymethyl) (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoate · ΦΦΦ ΦΦΦ · «t t «» ► · · · · ·

I · Φ

I φ Φ «•« φ φ

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

mp: 152-155 ° C

Example

III-17

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

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

44444 4 44 «« 3

445 445 * 0 · * ·· * 44 * 4 · 4 * 44

99% saturated sodium bicarbonate solution and water, the organic phase is dried over anhydrous sodium sulphate and the solvent is evaporated off under vacuum. The residue is purified by chromatography, the product is crystallized from a mixture of cyclohexane and n-pentane, filtered off with suction and dried at 40 DEG C. for 20 hours under vacuum. 32.45 g (41% of theory) of the title compound are obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 2.95 (sept.,

1H), 4.05 (s, 2H), 7.45 (d, 1H), 7.49 (s, 1H), 8.02 (d, 1H);

1H), 8.50 (brs, 1H).

Example 111-18

2-bromo-N- [4-tert-butyl-2-methylphenyl) acetamide d

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

4 4 * ·

4) of the title compound.

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

8.05 (brs, 1H).

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

You full of heaviness: 41.0 ^T H-NMR (200 MHz, CDC1 _3): δ = 1.20 1.95 (m, 5H), 2.28 (s, 3H), 2.35 2H), 7.00 - 7.13 (m, 2H), 7.69 (d,

1.50 (m, 5H), 2.55 (m, 1H), 1H), 8.05 (br

1.65 4.07 (s, s, 1H).

Example III-20

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

Br

Yield: 95.6% ¹ H-NMR (200 MHz, CDCl 3): δ = 1.70-1.90 (m, 4H), 2.55 2.70 (m, 2H), 2.75-2.85 (m, 2H), 4.08 (s, 2H), 6.95 (d, 1H), 7.14 (t, 1H), 7.69 (d, 1H), 8.09 (br s, 1H) ).

• · • t ·

- 101

Example 111-21

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

Yield: 80.5% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 4.08 (s, 2H), 7.01 (d, 1H),

7.18 (dd, 1H), 7.30-7.62 (m, 4H), 7.70 (d, 1H), 7.85 8.17 (m, 3H), 8.47 (br s, 1H).

Example 111-22

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

Yield: 77.9% ¹ H-NMR (200 MHz, CDCl ₃ ): 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); 51 (d, 1H); 8.85 (br s, 1H).

• 4 • 4 • 4 • 4

Π ^Λ _ · · · 4 4> 4 4 4 4 4 4 4 4 4 4 4 4

Example 111-23

Ν- [2,4-Bis (trifluoromethyl) phenyl] -2-bromoacetamide

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

Example III-24

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

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

7.87 (m, 3H); 8.07 (br s, 1H).

Example 111-2 5

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

103 at · ·· ··· ·· a

Br

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

Example III-26

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

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

7.18 (s, 1H); 8.05-8.20 (m, 2H).

Example 111 - 2 7

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

104

•

• o

OH

0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde [made from the corresponding alcohol (Chem. Ber. 1961, 1248)] by Swern oxidation (Tetrahedron 34, 1651) is introduced in 3 ml of water. (1978)] 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 is added, after 2 hours it is filtered off with suction, washed The residue was dried at room temperature to give 0.41 g (72.2% of theory).

¹ H-NMR (200 MHz, DMSO): δ = 2.21 (s, 3H), 8.20 (s, 1H),

8.33 (s, 1H); 11.48 (s, 1H).

Example TII-28 (4-methyl-1,3-oxazol-5-yl) methylamine

CH

4.00 g (31.72 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde are added in 70 ml of acetic acid and 47.70 g (729.50 mmol) are added in small portions at room temperature. zinc powder. The reaction mixture is left stirring at room temperature for 2 hours, after which the zinc powder is filtered off with suction and washed twice more with 50 ml of acetic acid. The filtrate is freed from the solvent in vacuo and the residue is stirred with 20% sodium hydroxide until a pH of 11 is reached. The white crystalline precipitate formed is stirred with ethyl acetate and filtered off with suction. Spo • «

The 105 filtrates are freed from the solvent in vacuo and the residue is purified by chromatography. 1.34 g (38% of theory) of the title compound are obtained.

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

3.83 (s, 2H); 7.73 (s, 1H).

Example III-29,1-Dimethyl-2 - [(4-bromophenyl) thio] -2-ethyl-butanoic acid ester

/ O

The synthesis is carried out analogously to Example II - 1 from 4-bromothiophenol and 2-bromo-2-ethyl-butanoic acid 1,1-dimethyl ester [prepared, for example, by Liebigs Ann. Chem. 725,106-115 (1969); J. Am. Soc. 77, 946-947 (1955) and bromination with N-bromosuccinimide or thunder, for example, according to Tetrahedron Lett. 1970, 3431; J. Org. Chem. 40, 3420 (1975)].

Yield: 15.9%

1 H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.58-1.74 (m, 4H), 7.28-7.35 (m, 2H), 7 39-7.46 (m, 2H).

Example III-30

2-ethyl-2 - [(4-formylphenyl) thio] butanoic acid 1,1-dimethyl ester • to · ♦

· Tot tot oto oto to to to to to to to to to to to to to to to to to to to to

The synthesis is carried out analogously to Example II-2, starting from the compound of Example II-29. Yield: 70.4% of theory ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.64-1.87 (m, 4H), 7.60 (d, 2H), 7.78 (d, 2H), 10.1 (s, 1H).

Example 111-31

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

The synthesis is carried out analogously to Example I11-13, starting from the compound of Example 111-30,

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

Example 111 - 3 2

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

Methyl 4-amino} methyl) phenoxy] propanoate

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- are added together. 1,3-oxazol-5-yl) methylamine (Example II-28) in 1,2-dichloromethane and treated at room temperature with 1.50 g (7.09 mmol) of sodium acetoxyborohydride. The reaction mixture was stirred for 4 hours at room temperature, then treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. The residue obtained is purified by chromatography on silica gel (dichloromethane / methanol 30: 1) and then dried in vacuo. It is obtained as follows

1.104 g (65% of theory) of the title compound.

¹ H-NMR (200 MHz, CDC1 _3): 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 (br s, 1H).

The following compounds are obtained analogously to Example I 11-32:

Example III-33

Target. Butyl L-2- (4 - {[(2-methoxyethyl) amino] methyl-phenoxy) -2-methylpropanoate • 4 * 444

4 4

• 4

4

4 4 4 4

4 · 4 * 4

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

Example 111-34

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

Yield: 55.1% ¹H-NMR (300 MHz, CDC1 _3): δ = 1.44 (s, 9H), 1.55 (s, 6H),

2.27 (s, 3H), 3.71 (s, 4H), 5.83-5.92 (m, 1H), 6.00-6.08 (m, 1H), 6.75-6, 88 (m, 2H); 7.12-7.24 (m, 2H).

Example 111-35

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

H * φ

- 109

4.0 g (14.27 mmol) of tert-butyl 2 - [(4-formylphenyl) sulfanyl] -2-methylpropanoate (Example 11-2) and 1.07 are dissolved in 80 ml of 1,2-dichloroethane. g (14.27 mmol) of 2-methoxyethylamine, and after 30 minutes and 10 hours, 4.54 g (21.40 mmol) of sodium acetoxyborohydride are added. After DC-control, ethyl acetate and saturated sodium bicarbonate solution were added and the product was extracted with ethyl acetate. The organic phase is washed with 1 N hydrochloric acid, dried over anhydrous magnesium sulphate and, after distilling off the solvent, it is purified by chromatography on silica gel (ethyl acetate / cyclohexane 1: 1).

Yield: 2.69 g (55.6%) ¹H-NMR (300 MHz, CDC1 _3): δ = 1.45 (s, 15H), 2.96 (t, 2H), 3.37 (s, 3H), 3.72 (t, 2H), 4.13 (s, 2H), 7.52 (s, 4H).

Analogously to Example II-1-35, the following compound is obtained:

Example 111-36

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

Yield: 68.8% ¹H-NMR (200 MHz, CDC1 _3): delta = 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.

- 110

2H), 7.75 (s, 1H).

EXAMPLES 3

Example 3-1

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

0.50 g (1.25 mmol) of the compound of Example III-16 is stirred in 30 ml of N, N-dimethylformamide with 0.23 g (1.88 mmol).

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

0 «

0 0

- 111

T. 90-91 C. C.

Example 3-2

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

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

Mp 80-81 ° C

Example 3-3

Tert-Butyl 1-2- [4 - [[[2 - [(2,4-dimethylphenyl) amino] ethyl] - (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoate ··> «·· _Ί -t -ί · ··· · · β

- 1 χ 4 »· ··· ··· ♦ ·· ··

0.25 g (0.50 mmol) of the compound of Example 3-1 was treated with 0.50 ml of a 2M solution of borane-dimethylsulfide in tetrahydrofuran in 5 ml of toluene and heated to boiling for 2 hours.

It is then stirred for one hour in the presence of 5 ml of 2 N sodium carbonate solution and the organic phase is washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and distilling off the solvent, the residue obtained is purified by flash chromatography on silica gel (cyclohexane / dichloromethane 3: 1 -> cyclohexane / ethyl acetate 10: 1). The title compound is obtained in a yield of 37%.

¹ H-NMR (200 MHz, CDCl ₃ ): δ - 1.43 (s, 9H), 1.55 (s, 6H),

2.15 (s, 3H), 2.22 (s, 3H), 2.73-2.87 (m, 2H), 3.09-3.22 (m, 2H), 3.57 (s, 2H), 3.63 (s, 2H), 6.12-6.19 (m, 1H), 6.28-6.35 (m, 1H), 6.47 (d, 1H), 6.73 6.95 (m, 4H), 7.20 (d, 1H), 7.34-7.40 (m, 1H).

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

Example 3-4

2- [4 - [[[2 - [(2,4-Dimethylphenyl) amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid * 9 9 9

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

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.57 (s, 6H), 2.24 (s, 3H),

2.27 (s, 3H), 3.31 (s, 2H), 3.67 (s, 2H), 3.75 (s, 2H), 6.22-6.36 (m, 2H), 6 88 (d, 2H), 6.93-7.03 (m, 2H), 7.23 (d, 2H), 7.34-7.40 (m, 1H), 7.78 (d, 1H) ), 8.00 (breites with,

1H), 9.09 (s, 1H).

MS (ESI): 451 [M + H] &lt; + &^gt;, 901 [2M + H] ^&lt; ^{+ &gt;} .

Analogously to Example 3-4, the following compounds were obtained;

Example 3-5

2 - 14 - [[[2 - [(2,4-dimethylphenyl) methylamino] -2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

Yield:%

H-NMR (200 MHz, CDC1 _3): 5 = 1.46 (s, 6H), 1.92 (s, 3H); 2.24 (s, 3H). 2.73 (q, 2H), 3.00 (s, 3H), 3.30 (breites with, 1H), 3.63 (d, 2H), 3.78 (d, 2H), 6.19 (d, 1H), 6.30-6.40 (m, 1H), 6.74 (d, 2H), 6.80-7.10 (m, 5H), 7.52-7.57 (m 1H). MS (ESI) 466 [M + H] ⁺ , 487 [M + Na] &lt; + ^&gt; . Example 3-6

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

x 2 CF ₃ COOH

Yield; ^L 60% H-NMR (200 MHz, DMSO-d ₆₎

2.12 (s, 3H), 2.55 - 2.72 (bre i tes m, 2H), 3.46 - 3 6.20 - 6,50 (m, 3H) 6.68 2H), 7,56 - 7.68 (m, 1H),

_δ = 1.49 (s, 6H), 2.01 (s, 3H), (breites m, 211), 2.97-3.20 78 (m, 4H), 4.40 ^ breites s, 1H) 6.88 (m, 4H), 7.12-7.30 (m, 13.00 (breites s, 1H)).

«Φφφ

115 ·· β · φ · φ · φ

• · »<<<

MS (ESI); 437 [Μ + Η] ^+, 873 [2Μ + Η] ^+,

Example 3-7

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

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

0.885 g (95% of theory) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ); Δ = 1.25 (d, 6H), 1.42 (s, 9H),

1.55 (s, 6H). 2.80 (t, 2H), 2.93 (sept, 1H), 3.28 3.30 (s, 2H), 3.54 (t, 2H), 3.70 (s, 2H), 6 80 (d.

(s, 3H), 2 H),

116 · * ··

7.20 (d, 2H), 7.39 (dd, 1H), 7.45 (d, 1H), 8.17 (d, 1H), 9.65 (br s, 1H).

Example 3-8

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

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

¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.26 (d, 6H), 1.55 (s, 6H),

2.81 (t, 2H), 2.91 (sept, 1H), 3.28 (s, 3H), 3.31 (s, 2H), 3.55 (t, 2H), 3.72 (s) s, 2H), 6.90 (d, 2H), 7.25 (d, 2H), 7.35-7.49 (m, 2H), 8.12 (d, 1H), 9.62 (br s, 1H).

- 118 • · · «

«4«

Example 3-9

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

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

@ 1 H-NMR (200 MHz, DMSO): .delta. = 1-3.08 (m, 1H), 3.28 (s, 3H),

3.80 (m, 2H), 4.00-4.20 (tn, (d, 2H), 7.20-7.70 (m, 5H), 1H).

(d, 6H), 1.55 (s, 6H), 2.94 3.30-3.40 (m, 2H), 3.60 2H), 4.30-4.50 (m, 2H), 6.86 10.25 (br s, 1H), 13.18 (br s,

Example 3-10

2- [4 - [[[2 - [(4-Cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] 1,1-dimethyl ethyl ester -

0.303 g (0.94 mmol) of tert-butyl 2- (4 - {[(2-methoxyethyl) amino] methyl} phenoxy) -2-methylpropanoate (Example 111-33) are introduced in 5 ml of dimethylformamide and 0.319 g (1.03 mmol) of 2-bromo-N- (4-cyclohexyl-2-methylphenyl) acetamide (Example III-19) and 0.086 g (1.03 mmol) of sodium bicarbonate are added at room temperature. The mixture was stirred at 90 ° C for 2 hours, allowed to cool and water was added. The mixture is extracted with ethyl acetate, the organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent in vacuo. The residue obtained is purified by chromatography on silica gel (cyclohexane / ethyl acetate 3: 1) and the product is dried in vacuo to give 0.464 g (90% of theory) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): 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 0.06 (m, 2H), 7.15-7.25 (m, 2H), 7.85 (d, 1H), 9.25 (br s, 1H).

Example 3-11

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

- 119

HIM /

0.398 g (0.72 mmol) of the compound of Example 3-10 is introduced in 5 ml of dichloromethane, 5 ml of trifluoroacetic acid are added at room temperature and the reaction mixture is stirred for 2 hours at room temperature. It is then concentrated in vacuo, the residue is taken up in ethyl acetate, washed with water, 20% sodium acetate solution, water and saturated sodium chloride solution, the organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The product is purified by chromatography on silica gel (dichloromethane / methanol 30; 1). The resulting residue was dissolved in dichloromethane with heating, 1 N hydrochloric acid in diethyl ether was added and n-heptane was added dropwise until light turbidity. The product was filtered off with suction, washed with diethyl ether and dried in vacuo at 40 ° C. 0.187 g (49% of theory) of the title compound is obtained.

¹ H-NMR (300 MHz, CDC1 _3): δ = 1.15 to 1.47 (m, 5H), 1.55 (s, 6H), 1.68 to 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 (br s, 1H).

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

120 r

Example 3-12: 2- [4 - [[[2 - [[2,4-Bis (trifluoromethyl) phenyl] amino] -2-oxoethyl]] - [(5-methyl-2- furanyl) methyl] aminomethyl] phenoxy] -2-methylpropionic acid

Yield: 88% teor i e ¹ H-NMR (300 MHz, CDC1 _3): δ = 1.40 (s. , 9H). , 1.55 (s , 6H), 2.15 (s, 3H). 3.30 (s, 2H); 3.65 (s. 4H), 5.85 (m, 1H), 6 (d, 1H), 6.81 (m, 2H); 7.20 (m, 2H); 7.25 (m, 1 H), 7.35 ( 1H), 8.57 (d, 1H), 9.85 (br s, 1H). Example 3-13

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

F

- 121 • ta ta ta ta ta

Yield: 80.2% H-NMR (300 MHz, CDC1 _3): 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, IH) 7.23 - 7.31 (m, 2H), 7.49 (d, 2H), 7.78 (s, 1H). 8.30 (s, IH), 9.05 (s, 1H). Example 3-14

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

Yield: 85.1% 1 H-NMR (300 MHz, CDCl ₃ ): 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); 19 (s, 1H)

Example 3-15

2 - [[4 - [[[2 - [(2,4-dimethylphenyl) amino] -2-oxoethyl]] - (2-furanylmethyl) amino] methyl] phenyl] thio] 1,1-dimethylethyl ester - 2-ethyl-butane • Λ

Hlt <·· ·

- 122

Yield: 73.4% @ 1 H-NMR (200 MHz, CDCl3): .delta. = 0.95 (t, 6H), 1.41 (s, 9H),

1.55-1.78 (m, 4H), 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s,

2H), 3.73 (s, 2H), 3.74 (s, 2H), 6.20-6.38 (m, 2H), 6.90 7.08 (m, 2H), 7.28 (s) d, 2H), 7.35-7.50 (m, 3H), 7.75-7.88 (m, 1H), 9.05 (s, 1H).

Example 3-16

2 - [[4 - [[[2 - [(4-cyclohexyl-2-methylphenyl) amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenyl] thio] -2-dimethylethyl ester methyl propionic

Yield: 81.9% ^X H-NMR (200 MHz, CDC1 _3): δ = 1.31 to 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) ).

• · • 0 • ♦

- 123

- ♦ ···

Example 3-17

2 - [[4 - [[[2 - [[4- (1,17-dimethylethyl) -2-methylphenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] 1,1-dimethylethyl ester phenyl] thio] -2-methylpropionic

Yield: 82.9%

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

Example 3-18

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

Yield: 86.8%

H-NMR (200 MHz, CDC1 _3): δ = 0.94 (ΐ, 6H), 1.41 (s, 9H), and • * ♦ • 9 · · • «» *

- 124

1.55-1.75 (m, 4H), 2.30 (s, 3H), 3.31 (s, 2H), 3173 (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);

1H).

Example 3-19

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

Yield: 57.4% ¹ H-NMR (300 MHz, CDCl 3): δ = 1.40 (s, 9H), 1.41 (s, 6H),

2.29 (s, 3H), 2.83 (t, 2H), 3.27 (s, 3H), 3.29 (s, 2H), 3.51 (t, 2H), 3.77 (s 2 H, 7.11 (s, 1 H), 7.30 (d, 2 H), 7.46 (d, 2 H), 8.29 (s, 1 H), 9.44 (s, 1 H).

Example 3-20

2-methyl-2- [4 - [[[2 - [[4- (L-methylmethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] 1,1-dimethylethyl] [( 5-methyl-2-furanyl) methyl] amino] methyl] phenoxy] propionic acid

·· · »· ♦

4 «44

Yield: 94% ¹H-NMR (400 MHz, CDC1 _3): δ

1.55 (s, 6H), 2.17 (s, 3H)

3.15 (m, 4H), 5.85 (m, 1H) (d, 2H), 7.35 (m, 1H), 7.4 1H).

Example 3-21

2- [4 - [[[2 - [(2-ethoxy-1-naphthalenyl) amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] 1,1-dimethylethyl ester J phenoxy] -2-methylpropionic = 1.25 (d, 6H), 1.40 (s, 9H),

2.88 (sept, 1H), 3.25 (s, 2H), 6.10 (d, 1H), 6.81 (d, 2H). 7.21 (m, 1H); 8.15 (d, 1H); 9.67 (s,

Yield: 95%

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.30 (t, 3H), 1.43 (s, 9H), 1.54 (s, 6H), 2.25 (s, 3H), 3 44 (s, 2H), 3.78-3.82 (ni, 4H), 4.15 (q, 2H), 5.89-5.94 (m, 1H), 6.15-6.18 (m, 1H) 6.84 (d, 2 H). 7.20-7.38 (m, 4H), 7.45 (ΐ, 1H), 7.65 (d, 1H), 7.75-7.85 (m, 2H), 9.05 (br s) , 1H).

Example 3-22

2-Methyl-2- [4 - [[[(5-methyl-2-furanyl) methyl]] - [2-oxo-2 - [(5,6,7,8-tetrahydro-2-oxo-2 - [[1,1-dimethylethyl] ethyl] 1,1-dimethylethyl ester) rahydro44

- 126

MM »»

4 ··· 4 4 ·

4 4 ₄

4 4 4 4 · «• · 445 · · · ·

-1-naphthylene 1) amino] ethyl] amino] methyl] phenoxy] propionic

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

1.70-1.95 (m, 4H), 2.20 (s, 3H), 2.65-2.82 (m, 4H), 3.24 (s, 2H), 3.67 (s, 4H), 5.86-5.90 (m, 1H), 6.10-6.14 (d, 1H), 6.78-6.93 (m, 3H), 7.08 (t, 1H) 7.22 (d, 2H); 7.89 (d, 1H); 9.20 (br s, 1H).

Example 3-23

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

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

2.81 (t, 2H), 3.24 (s, 3H), 3.29 (s, 2H), 3.51 (t, 2H), 3.70 (s, 2H), 6.80 (m 2H, 7.10-7.30 (m, 3H), 7.38 (d, 1H), 8.42 (d, 1H), 9.93 (br s, 1H).

4 4 4444

- 127 • «« ·

Μ ·

4

4 4 0 «

4 0 4 • 00 • 44

Example 3-24

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

Yield; 95.5% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.41 (s, 9H), 1.55 (s, 6H),

2.80 (t, 2H), 3.28 (s, 3H), 3.30 (s, 2H), 3.54 (ΐ, 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);

1H), 7.89 (dd, 1H), 8.07-8.21 (nt, 2H), 9.68 (br s, 1H).

Example 3-25

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

O

S = 0 in ° /

... · »·············································· ·

- 128 • · · • · · · · · • · · · · »· · Yield: 91% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.20 - 1.37 (m, 12H) , 1.55 (s 6H), 2.83 - 2, 94 (m, 4H); 3.22 (s. 3H), 3.39 (with, 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 (brs, 1H) • Example L a d 3-26

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

Yield: 83.5% 1 H-NMR (300 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.40 (s, 9H),

1.55 (s, OH), 2.10 (s, 3H), 2.85-3.00 (sept., 1H), 3.28 (s, 2H), 3.66 (s, 2H), 3.75 (s, 2H), 6.82 (d, 2H), 7.20 (d, 2H), 7.38 (dd, 1H), 7.40-7.45 (m, 1H), 7 75 (s, 1H); 8.14 (d, 1H); 9.45 (br s, 1H).

Example 3-27

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

129

Yield : 79,5 % ¹ H-NMR (300 MHz, CDCl-1 L: 5 = 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, IH) 8.56 (d , IH), 9.71 (b r s, 1H). Ex lad 3-28

2- [4 - [[[2 - [[4- (1,1-Dimethyl-ethyl) -2-methyl-phenyl] -amino] -2-oxo-ethyl] (2-methoxy-ethyl) -amino] 1,1-dimethyl-ethyl ester] methyl] phenoxy] -2-methylpropionic

Yield: 81% ¹ H-NMR (300 MHz, CDCl ₃ ): δ - 1.30 (s, 9H), 1.40 (s, 9H),

1.55 (s, 6H), 2.38 (s, 3H), 2.80 (t, 2H), 3.29 (s, 5H), 3.50 (ΐ, 2H), 3.70 (s) 2H), 6.80 (d, 2H), 7.15-7.25 (m, 4H), 7.78 (d, 1H), 9.30 (br s, 1H).

Example 3-29

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] 1,1-dimethylethyl ester] ( 2 - me thoxve t hy 1) am i.

130 methyl] phenoxy] -2-methylpropionic

Yield: 80% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.39 (s, 9H), 1.55 (s, 6H),

2.82 (t, 2H), 3.28 (s, 3H), 3.33 (s, 2H), 3.52 (t, 2H), 3.71 (s, 2H), 6.80 (d 2H, 7.18 (d, 2H), 7.78 (d, 1H), 7.84 (s, 1H), 8.60 (d, 1H), 9.98 (br s, 1H).

Example

3-30

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

Yield: 84% ^R H-NMR (300 MHz, CDCl _3): δ = 1.40 (s, 9H), 1.55 (s, 6H),

3.30 (s, 2H), 3.65 (s, 2H), 3.75 (s, 2H), 6.20-6.30 (m, 1H), 6.20-6.30 (m, 1H), 6.30-6.38 (m, 1H), 6.82 (d, 2H)

0 «« 0

00 0

131

0 0

7.18 (d, 2H), 7.36-7.39 (m, 1H), 7.75 (d, 1H), 7.90 (s, 1H), 8.60 (d, 1H), 9 82 (br s, 1H).

Example 3-31

2 - [[4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl] amino] -2-oxoethyl] - (2-furanylmethyl) amino] methyl] 1,1-dimethylethyl ester] phenyl] thio] -2-methylpropionate

Yield: 92% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.45 (s, 6H),

3.31 (s, 2H), 3.74-3.80 (m, 4H), 6.25 (d, 1H), 6.30-6.38 (m, 1H), 7.22-7, 40 (m, 3H), 7.50 (d, 2H), 7.78 (d, 1H), 7.90 (s, 1H), 8.61 (d, 1H), 9.78 (br s, 1H),

Example 3-32

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

• ·

131 * · · *

Yield: δ 3.4% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.56 (s, 6H), 2.15 (s, 3H),

3.29 (s, 2H). 3.69 (with. 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, 1 H), 7.86 (s, 1H), 8.56 (d, IH), 9.79 (s, 1 H).

Example 3-33

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

Yield: 62.8% ¹ H-NMR (200 MHz, CDCl ₃ ): 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, 1 H), 9.04 (s, 1 H).

Example 3-34

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

- 133 • to to - to to • to to · to • to * to • to this to • tototo to tototo • totototo to to ··· «* · to · · * to«

Yield: 90.9% ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.32 (s, 2H), 3.75 (s, 4H)

7.29 (d, 2H); 7.36 (d, 1H) (s, 1H).

1.46 (s, 6H); 6.30 (dd, 2H); 7.48 (d, 2H);

2.28 (s, 3H).

7.10 (s, 1 H),

8.27 (s, 1H); 9.16

Example 3-35

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

Yield; 96.6% ¹ H-NMR (300 MHz, CDC1 _3); δ = 0.97 (t, 6H), 1.60-1.90 (m, 4H), 2.25 (s, 3H), 2.28 (s, 3H), 3.31 (s, 2H), 3 73 (s, 2H), 3.74 (s, 2H), 6.26 (d, 1H), 6.29-6.35 (m, 1H), 6.95-7.05 (m, 2H) 7.29 (d, 2H), 7.37 (d, 1H), 7.46 (d, 2H), 7.80 (d, 1H), 9.03 (s, 1H).

«3 ·· ♦ ·

- 134 ·· ·· »3 4 ·

4 * * 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Example 3-36

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

Yield: 90.9% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.96 (t, 6H), 1.58-1.87 (m, 4H), 2.28 (s, 3H) 3.31 (s, 2), 3.73 (s, 2H), 3.76 (s, 2H), 6.26 (d, 1H), 6.30-6.36 (m, 1H), 7 10 (s, 1H); 7.27 (d, 2H); 7.34-7.40 (m, 1H); 7.45 (d, 2H); 8.28 (s, 1H); 16 (s, 1 H).

Example 3-37

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

Yield: 83.9% ¹ H-NMR (200 MHz

CDCl ₃ ): δ

1.46 (s, 6H), 2.27 (s, 3H), to * ·· * ·

- 13;

* This to this this to this this

2.84 (t, 2H), 3.27 (s, 3H), 3.31 (s, 2H), 3.50 (t, 2H), 3.77 (s, 2H), 7.10 (br s, 1H), 7.31 (d, 2H), 7.48 (d, 2H), 8.24 (s, 1H), 9.43 (s, 1H).

Example 3-38

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

Yield; 91% ¹ H-NMR (200 MHz, CDCl ₃ ): δ - 1.25 (d, 6H), 1.55 (s, 6H),

2.17 (s, 3H), 2.91 (sept, 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); 1H), 9.55 (brs, 1H).

Example 3-39

2- [4 - [[[2 - [(2-ethoxy-1-naphthalenyl) amino] -2-oxoethyl] [(5-methyl-2-furanyl) methyl] amino] methyl] phenoxy] -2 -me thy1 -propionic

Yield: 64%

136 ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.25-1.32 (2, 3H), 1.60 (s, 3H), 2.25 (s, 3H), 3.45 ( s, 2H), 3.82 (s, 4H), 4.15 (quart., 2H), 5.94 (m, 1H), 6.17 (d, 1H), 6.90 - 7.00 ( m, 2H), 7.23 7.46 (m, 5H), 7.60-7.70 (m, 1H), 7.75-7.80 (m, 2H), 9.05 (br s, 1H).

Example 3-40

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

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

4H), 2.20 (s, 3H), 2.36 (t, 2H), 2.78 (t, 2H), 3.30 (s, 2H), 3.69 (s, 4H), 5.89 (m, 1H), 6.12 (d, 1H), 6.83-6.94 (m, 4H), 7.09 (t, 1H), 7.20-7.32 (m, 1H), 7.85 (d, 1 H), 9.15 (s, 1 H).

Example 3-41

2- [4 - [[[2 - [(2,4-dichlorophenyl) amino] -2-oxoethyl] (2-methylthio) amino] methyl] phenoxy] -2-methyl - oil

2.82 (t, 2H).

3.75 (s, 2H), 6.90 * · · · ·

4Λ7 .. • · φ · φ · φ · φ φφφ φφφφ

Yield: 69% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.55 (s, 6H)

3.28 (s, 3H), 3.00 (s, 2H), 3.54 (t, 2H), (m, 2H), 7.18-7.36 (m, 3H), 7.39 (s) d, 1H), 8.40 (d, 1H), 9.90 (br s, 1H).

Example 3-42

2- [4 - [[(2-methoxyethyl) [2 - [[4- (1-naphthalenyloxy) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] amino] methyl] phenoxy] -2-methic acid thy1-propionate

Yield: 74%

@ ¹ H-NMR (300 MHz, DMSO): .delta 1.45 (s, 6H); 2.72 (i.e. 2H) > 3.18 (s, 3H). 3.25 (s, 2H). 3.47 (t, 2 H), 3.68 (with. 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 (t, 2H), 9.66 (br s, 1H), .80 (d, 1H) , 90 (d (1H), 8.05

Example 3-43

2- [4 - [[[2 - [[5 - [(ethylsulfonyl) methyl] -L-naphthalenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] methyl] phenoxy] -2- methyl-propionic • 0 »0

I 0> 00 0 *

000 · 5 »3 8 · · -

Yield: 40.5%

1 H-NMR (400 MHz, CD ₂ Cl ₂ ): δ = 1.34 (t, 3H), 1.46 (s, 6H), 2.83-3.04 (m, 4H), 3.24 ( s, 3H), 3.37 (s, 2H), 3.32-3.64 (m, 2H), 3.78 (s, 2H), 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 (br s, 1 H).

Example 3-44

2-Methyl-2- [4 - [[[2 - [[4- (1-methyl-ethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl]] ((4-methyl-5-yl) -acetic acid) oxazolyl) methyl] amino] methyl] phenoxy] propionic acid

Yield: 69%

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.25 (d, 6H), 1.58 (s, 6H),

2.09 (s, 3H, 2.82-3.04 (sept, 1H), 3.30 (s, 2H), 3.66 (s 2H), 3.76 (s, 2H), 6, 90 (d, 2H), 7.25 (d, 2H), 7.35-7.48 (m, 2H), 7.80 (s, 1H), 8.11 (d, 1H), 9.40 (br s, 1 H).

Example 3-45

2- [4 - [[[2 - [[2,4-bis (trifluoromethyl) feny1) amino] * »• • φ · · · φ *« _• Λ · · ·> · · * '· ·

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

Yield: 76% ¹ H-NMR (200 MHz, CDCl 3): δ = 1.60 (s, 6H), 2.10 (s, 3H),

3.32 (s, 2H), 3.70 (s, 2H), 3.77 (s, 2H), 6.90 (d, 2H), 7.21 (d, 2H), 7.73-7 90 (m, 3H), 8.55 (d, 1 H), 9.68 (br s, 1 H).

Example 3-46

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

Yield; 77% 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 (br s, 1H).

Example 3-47

2 - [4 - [[[2 - [[2,4-bis (trifluoromethyl) phenyl)] amino]]

.40

-2-oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropionic

Yield; 91% ¹H-NMR (300 MHz, CDC1 _3): δ - 1.57 (s, 6H), 3.30 (s, 3.70 (s, 2H), 3.77 (s, 2H), 6, 30 (dd, 2H), 6.88 (d 7.20-7.35 (m, 2H), 7.37-7.42 (m, 1H), 7.75 (d,

2H),

2H),

1H), 7.86 (s, 1H), 8.56 (d, 1H), 9.80 (br s, 1H).

Example 3-48

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

Yield; 91% ¹ H-NMR (300 MHz, CDCl 3): g = 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, IH), 7.90 (s, 1H), 8.59 (d, 1H), 9.78 (brs, 1H).

jmi ·· -:

US The icing compounds are obtained analogously to 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-acid hydrochloride -methy1-propionic

Yield: 53.3% ¹ H-NMR (300 MHz, DMSO): δ = 1.20-1.48 (m, 12H), 1.62 1.87 (m, 5H), 2.14 (s, 3H), 3.27 (s, 3H), 3.51 (s, 2H), 3.74 (s, 2H), 4.12 (s, 2H), 4.51 (s, 2H) 7.02 (d 2H), 7.16-7.30 (br s, 1H), 7.46-7.68 (m, 4H), 9.93 (br s, 1H), 10.36 (br s, 1H), 12.74 (br s, 1H).

Example 3-50

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

xHc:

• 444

4 · 4 4 •• 4 «•« 4445 4 «4 4 4

4444 44 44 444

- 140 ·· * ·

Yield: 85.3% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.29 (s, 9H), 1.56 (s, 6H),

2.26 (s, 3H), 2.86 (t, 2H), 3.29 (s, 3H), 3.35 (s, 2H), 3.53 (t, 2H), 3.74 (s) 2H, 6.88 (d, 2H), 7.15-7.26 (m, 4H), 7.79 (d, 1H), 9.26 (s, 1H),

Example 3-51

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

Yields k: 99 % ¹ H-NMR (300 MHz, DMSO): 5 = 1, 20 ( d, 6H), 1.50 (with, 6H), 2.27 (br s, 3H), 2.96 - 3. , 05 (sep., 1H) , 3 , 95 (br s, 2H) , 4, 31 (br s, 4H), 6.17 (br s, 1H) , 63 (br s, 1H) , 85 (d, 2H), 7.46 - 7.57 (m, 5H), 10 23 (br s, 1H) , 10 , 55 (b r s, 1H) 13.15 (br p , 1H) At k 1 a d 3 -52

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

Ο

χ HCi

Yield: 54%

LC-MS: 470 [M ^& lt ^{; +} & gt ^; ]

Example 3-53

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

The reaction mixture was dissolved in 0.5 ml of ethanol, treated with 0.3 ml of 1 N sodium hydroxide, stirred for 5 minutes and the reaction mixture was evaporated. The residue is taken up in a small amount of toluene and the solvent is evaporated off under vacuum, after which the product is dried under vacuum for 20 hours. 0.15 was obtained

g (95.5 % theory) in the title listed compounds. ¹ H-NMR (200 MHz, CDC1 _3): δ = 1.21 (s, 6H) 2.10 - 2,20 6H) 3 16 (i i, 2H), 3.58 - 3.64 (m , 4H), 6.18 - 6.25 (m 6.73 - 6.82 (m, 2H), 7.09 - 7.35 (m, 3H) 7.71 (d, 1 H) (br s, 1H).

The following compounds are obtained in an analogous manner to that of

• φ · · · · · · · · ·

144 described in Examples 3-7 and 3-10

Example 3-54

2 - [[4 - [[[2 - [[4- (1-methylethyl) -2- (trifluoromethyl) phenyl] amino] -2-oxoethyl] (2-methoxyethyl) amino] 1,1-dimethyl ethyl ester [methyl] phenyl] thio] -2-methylpropionic

Yield: 61% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.24 (d, 6H), 1.39 (s, 9H), 1.42 (s, 6H), 2.80 (t 2H, 2.90-3.1 (m, 1H), 3.28 (s, 3H), 3.32 (s, 2H), 3.53 (t, 2H), 3.78 (s, 2H) 2H), 7.25-7.50 (m, 6H), 8.14 (d, 1H), 9.62 (br s, 1H).

Example 3-55

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

N • φ · φ · φ · ·

145 ··· φ • φ φ

Yield: 66% ¹ H-NMR (300 MHz, CDCl 3): δ = 1.25 (d, 6H), 1.40 (s, 9H), 1.43 (s, 6H), 2.10 ( s, 3H), 2.90-3.10 (m, 1H), 3.29 (s, 2H), 3.70-3.80 (tn, 4H), 7.30-7.55 (m, 6H), 7.77 (s, 1H), 8.13 (d, 1H), 9.40 (br s, 1H).

Example 3-56

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

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

Example 3-57

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

Yield: 84% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.40 (s, 9H), 1.42 (s, 6H), 2.11 (s, 3H), 3.32 (s (2H), 3.74-3.82 (m, 4H), 7.29 (d, 2H), 7.49 (d, 2H), 7.70-7.85 (m, 2H), 7, 87 (s, 1H); 8.57 (d, 1H); 9.67 (br s, 1H).

Example 3-58

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

Yield : 54.8 % ¹ H-NMR (200 MHz, CDC1 ₃ j l: 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 (with , 2H), 3.74 (s, 2H); 6.82 (d, 2H), 6.98 - 7.08 (m , 2H), 7, 18 (d, 2H), 7.77 (s, 1H), 7.8 3 (d, 1 H), 8.96 (br s, 1H).

·· • <

• · · · · · ·

- 1ΑΪ

Example 3-59

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

Yield: 64.7% ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.29 (s, 9H), 1.41 (s, 9H),

1.55 (s, 6H), 2.12 (s, 3H), 2.28 (s, 3H), 3.29 (s, 2H), 3.65 (s, 2H) 3.75 (s, 2H) 6.82 (d, 2H); 7.10-7.30 (m, 4H); 7.77 (s, IH), 7.85 (d, 1H), 8.98 (brs, 1H). Example 1 and d 3-60

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

0.248 g (0.43 mmol) of the compound of Example 3-54 are introduced in 5 ml of dichloromethane, 5 ml of trifluoroacetic acid are added at room temperature and the reaction mixture is stirred for

148 hours at room temperature, then evaporated in vacuo. The residue is taken up in ethyl acetate and extracted with water. 20% sodium acetate solution, water and saturated sodium chloride solution. The organic phase is dried with anhydrous magnesium sulfate and freed from solvent in vacuo. The product is purified by chromatography on silica gel (dichloromethane / methanol 30: 1) and dried in vacuo. 197 mg (88% of theory) of the title compound are obtained.

¹ H-NMR (200 MHz, CDC1 _3): 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 (br s, 1H).

The following compounds were obtained in analogy to 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

HIM'

Yield: 81%

4 * «4 - «4 • 4 4 4 44 * 4 - · * · ·· «· <«. ⁵ · »•:::: • 4 4 • · 4 • »4 • * * 4 · »44 ¹ H-NMR (300 MHz, CDC1 _3): δ = 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 (brs, 1H) Example 3-62

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

Yield: 84% ¹ H-NMR (200 MHz, CDCl ₃ ): 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 (br s, 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-methylproplon-4-yl

4

4 * 4 • 4

• 4

4 4 4 4 · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 444 444 444 44 44 # 44

Yield: 76% ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.49 (s, 6H), 2.09 (s, 3H), 3.35 (s, 2H), 3.74-3 80 (τη, 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 (br s, 1H).

Example 3-64

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

Yield: 80%

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

Example 3-65

2- [4 - [[[2 - [[4- (1,1-dimethylethyl) -2-methylphenyl] 151] ** ** amino] -2-oxoethyl] [(4-methyl-5-oxazolyl)] methyl] amino] methyl] phenoxy] -2-methyl-propionic acid

Yield: 80%

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

EXAMPLES 4

Example 4-1

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

Step a)

Vang resin (Rapp Polymere, Best.-Nr.

H 1011) (48.0 g, 14.06 mmol of reactive groups) was suspended in dichloromethane. After addition of 2- (4-formylphenoxy) -2-methylpropionic acid [G. J, E1.1 ymes, C. Glynis, J. Chem. Soc. Perkin Trans. 2, 1993, 43-48] (8.78 g, 42.18 mmol), di

- 152 isopropylcarbodiimide (10.65 g, 84.35 mmol) and DAMP (3.44 g, 28.12 mmol) are shaken for 18 hours at room temperature, then filtered, the resin 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-furylamine (352 mg, 3.62 mmol) are suspended in 20 mL of trimethylorthoformate, shaken for 20 h at room temperature, filtered and the resin was washed with dimethylformamide. The resin was then suspended in 20 mL of dimethylformamide, treated with tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid (0.42 mL, 7.52 mmol) and shaken for 7 hours at room temperature. The mixture was then filtered, the resin was washed with dichloromethane, dimethylformamide and methanol to give resin B1.

Step c)

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 mL). The reaction mixture was shaken overnight at 60 ° C, then filtered and the resin was washed with dichloromethane, dimethylformamide and methanol. 1 M in THF, 1 mL). The reaction mixture was shaken for one hour at room temperature, filtered, and the resin was washed with dichloromethane, dimethyl153, formamide and methanol to give resin C1.

Step d)

Resin C1 (2.5 g, 0.72 mmol of the reactive groups) was suspended in 20 mL of dimethylformamide and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38 g, 3.63 mmol) and 2 mL. 5-dimethylaniline (615 mg, 5.08 mmol). The reaction mixture was shaken for 18 hours at room temperature, filtered and the resin was washed with dichloromethane, dimethylformamide and methanol. The resin is then suspended in a mixture of dichloromethane and trifluoroacetic acid, shaken for 30 minutes at room temperature, then filtered and evaporated. The title compound is obtained in the form of a colorless film.

1C-MS: R _t = 3.68 min; [M + H] ⁺ = 451.3 (100%), [MH] ⁺ =

449.3 (100%).

[methoda: Symmetry C18 Saule (Vaters), flow: 0.5 mL / min, heating temperature 40 ° C, pressure 40 MPa, gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90% A, 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B

A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH].

¹ H-NMR (d ₆ -DMSO): δ = 1.4 (s, 6H), 2.3 (s, 3H), 2.4 (s, 3H), 3.33 (s, 2H), 3 7 (s, 2H), 3.8 (s, 2H), 6.3 (d, 1H), 6.4 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H); 2H), 7.05 (d, 1H), 7.2 (m, 2H),

7.4 (s, 1 H), 7.8 (s, 1 H).

Example 4-2

2 - [4 - [[[2 - [(4-methoxy-2,5-dimethylphenyl) amino] -2] -

- 154

oxoethyl] (2-furanylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid

The resin of Example 4-1, step c) (2.5 g, 0.72 mmol of the reactive groups) was suspended in 20 mL of dimethylformamide and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU (1.38). g, 3.63 mmol) and 2,5-dimethyl-4-methoxyaniline (756 mg, 5.08 mmol), the reaction mixture was shaken for 18 hours at room temperature, filtered and the resin was washed with dichloromethane, dimethylformamide and methanol. . The resin was then suspended in a mixture of dichloromethane and trifluoroacetic acid, shaken for 30 minutes at room temperature, filtered and evaporated.

The title compound is obtained in the form of a colorless film.

LC-MS: R t = 3.48 min; [M + H] ⁺ = 481.226 [MH] ⁺ = 479.226 (100%), [Method: Symmetry 08 Saule (Vaters), (100%), Flow: 0.5 mL / min, Heating Temperature 40 ° C, Pressure 40 MPa, gradient: t = 0 min% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90 20% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A,% B. A: CH ₃ CN + 0.1% HCO ₃ H; Β: Η _? 0 + 0.1% HCOOH].

% A,

Example

4-3

2- [4 - [[[2 - [(4-methoxy-2,5-dimethylphenyl) amino] -2-oxoethyl] (2-thienylmethyl) amino] methyl] phenoxy] -2-methyl 15ο

propane

0Η 'Ν

Η

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) was suspended in 20 ml of trimethylformate, shaken overnight at room temperature, filtered and the resin was washed with dimethylformamide. The resin was then suspended in 20 mL of dimethylformamide, treated with tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid (0.42 mL, 7.25 mmol) and shaken for 7 hours at room temperature. Then the mixture was filtered, the resin was washed with dichloromethane, dimethylformamide and methanol to give resin B2.

Step b)

Resin B2 (2.5 g, 0.72 mmol of reactive groups) was suspended in 40 mL of dioxane, treated with triethylamine (6 mL, 6 mL, 4 mmol) and trimethylsilyl bromoacetate (2.38 mL, 14 mL). 5 mmol) and the reaction mixture was shaken overnight at 60 ° C. The mixture was then filtered and the resin was washed with dichloromethane, dimethylformamide and methanol. The silica protecting groups are removed by suspending the resin in 25 ml of dioxane, mixing with a solution of tetrabutvlammonium fluoride (1 M in tetrahydrofuran, 1 ml). 4 4 • 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 for one hour at room temperature and then filtered. The resin was washed with dichloromethane, dimethylformamide and methanol to give resin C2.

Step c)

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

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

[methoda: Symmetry C18 Saule (Vaters), flow: 0.5 mL / min, heating temperature 40 ° C, pressure 40 MPa, gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90% A,% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; B: H ₂ O + 0.1% HCOOH], ¹ H-NMR (d 6 -DMSO): δ = 1.5 (s, 6H), 2.1 (s, 3H), 2.2 (s, 3H) )

3.3 (s, 2H), 3.7 (s, 2H), 3.8 (s, 3H), 4.0 (s, 2H), 6.8 7.5 (m, 9H).

Analogously obtained:

fc · »

157

Example 4-4

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

O.

OH

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

[methoda: Symmetry C18 Saule (Vaters), flow: 0.5 mL / min, heating temperature 40 ° C, pressure 40 MPa, gradient: t = 0 min: 10% A, 90% B; t = 4.0 min: 90% A, 10% B; t = 6.0 min: 90% A,% B; t = 6.1 min: 10% A, 90% B; t = 7.5 min: 10% A, 90% B. A: CH ₃ CN + 0.1% HCOOH; Β: Η _? 0 + 0.1% HCOOH].

Example A

Cellular transactivation experiment

Test principle:

Cellular experiment is used to identify peroxisome-proliferator-activating alpha (PPAR-α) activators.

Since mammalian cells contain various endogenous nuclear receptors that could complicate: unambiguous interpretation of the results, an established chimer-system in which the ligand binding domains are

158

of human PPARα receptors fused to the DNA-binding domains of yeast xrancription factor GAL4. The GAL4-PPARα chimeras thus combusted are co-transfected and stably expressed in CHO cells with a reporter construct.

Cloning:

The GAL4-PPARα-expression construct contains ligand binding domains of PPARα (amino acids 167-468) that are PCR-amplified and cloned into the pcDNA3.1 vector. This vector already contains the GAL4-DNA-binding domains (amino acids 1-147) of the vector pFC2-dbd (stratagens). The reporter construct, which contains five copies of the GAL4-binding site upstream of the thymidine kinase promoter, results in the expression of firefly-luciferase ((Photinus pyralis) upon activation and binding of GAL4-PPARα).

Transactivation experiment (luciferase-reporter):

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

The compounds of the present invention of Examples 3-4;

- 159

3-6, 3-60, 1-9, 2-7 and 2-12 show EC ₅₀ values of 0.04 to 200 nM in this assay.

Example B

Determination of fibrinogen

To determine the effect on plasma fibrinogen concentration, male Vistar rats are treated for 4 to 9 days with the test substance using an oesophageal probe or food admixture. Citric blood is then obtained by terminal puncture in terminal anesthesia. Plasma fibrinogen levels are determined using the Clauss method [Clauss A., Acta Haematol. 17,

237-46 (1957)] by measuring thrombin time with human fibrinogen as a standard. In some cases, a parallel determination is performed using the turbidometric method [Becker

U., Bartl K., Vahlefeld A.V., Thrombosis Res. 35, 475-84 (1984)] using batroxobin instead of thrombin.

Example C

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

The substances to be tested for their HDL-C enhancing effect in vivo are orally administered by male transgene to hApoA1-mice. Throughout the experiment, animals are provided with water and feed ad libitum. The substances are applied once a day for 7 days. For this purpose, the test substances are dissolved in a solution of HS 15 solutol + ethanol + sodium chloride solution (0,9%) in a ratio of 1 + 1 + 8 or in a solution of:

160 solutol of HS 15 + sodium chloride solution (0.9%) in a ratio of 2 + 8. Application of the dissolved substances is carried out in a volume of 10 ml / kg body weight by means of an esophagus probe. As a control group, animals were treated with the same treatment but only with solvent (10 ml / kg body weight) without the test substance.

Prior to the first administration of the substance, each mouse for blood determination of ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG) was bled by retro-orbital venenplexus puncture (precedence). Thereafter, the animals are first dosed with the test substance via an oesophageal tube. 24 hours after the last application (day 8 after the start of treatment), each animal is bled again by retro-orbital venenplexus puncture to determine the same parameters. Blood samples are centrifuged and, after obtaining serum, cholesterol and TG are determined photometrically using an EPOS Analyzer 5060 (Eppendorf-Geratbau, Nethler & Hinz GmbH, Hamburg). The assay is performed with a commercially available enzyme assay (Boehringer Mannheim, Mannheim).

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

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

- 161 • «4

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

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

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

Claims (16)

PATENT CLAIMS Claims 1. Propionic acid derivatives of the general formula I in which: A represents a bond or a group -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen, sulfur or CH ₂ , R ¹ , R ² and R ² are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, hydroxy, C 1 -C 6 alkoxy, aryloxy 6 to 10 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, alkylaminosulfonyl, nitro or cyano, or 1 9 R and R are attached to two adjacent carbon atoms and together with them form a fused cyclohexane or benzene ring, the latter being optionally substituted with an alkylsulfonylmethyl group of 1 to 4; 163 carbon atoms and as defined above, R @ ⁴ denotes a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and R @ 4 denotes a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group; denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or benzyl group, said aromatics alone being one to three times the same or differently substituted by an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxy group or halogen atom, R @ 6 denotes a hydrogen atom, a (C6 -C10) aryl group or a (C1 -C4) alkyl group which may itself be substituted by hydroxy, trifluoromethoxy, (C1 -C4) alkoxy or phenoxy, which themselves are optionally once to twice substituted with a trifluoromethyl group, or it may be substituted with an aryl group of 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, all said aryl and heteroaryl rings alone being one to three times equally or differently substituted by halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms - 164 - ··· atoms, trifluoromethyl, trifluoromethoxy, cyano, nitro or amino, R ⁹ and R ¹⁰ are the same or different and independently of one another represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group or a halogen atom, R ¹¹ and R ¹² are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and R @ ³ denotes a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof. Propionic acid derivatives of the general formula I, in which »» AND indicates a bond or a group or -CH 2 CH 2 -, J X indicates oxygen, sulfur or CH 2, R ¹ , R ² and R ³ are the same or different and independently of one another denotes a hydrogen atom, an alkyl group having 1 to 6 carbon, hydroxy, 1 to 10 alkoxy - 165 6 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano, R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 and R 2 denote a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group, R? denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl or benzyl group, said aromatics alone being one to three times the same or differently substituted by an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxy group or halogen atom, R &lt; 6 &gt; denotes a hydrogen atom, an aryl group having 6 to 10 carbon atoms or an alkyl group having 1 to 4 carbon atoms which may itself be substituted by an aryl group having 6 to 10 carbon atoms or a 5- to 6-membered heteroaryl group with up to three heteroatoms from nitrogen , oxygen and / or sulfur, all of said ring systems alone being one to three times equally or differently substituted with halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano , nitro or amino, R 6 and R 10 are the same or different and independently of one another 166 a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group or a halogen atom, R ¹ ! and are the same or different and independently of one another represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or together with the carbon atom to which they are attached form a cycloalkyl ring having 4 to 7 carbon atoms and denote a hydrogen atom or a hydrolysable group which may be degraded to the corresponding carboxylic acid, as well as pharmaceutically acceptable salts, hydrates and solvates thereof. Propionic acid derivatives according to claim 1 or 2, in which A is -Cl · ^ - or, X is oxygen, sulfur or CH 2, R 1, and they are the same or different and independently of one another are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro or fluoro, trifluoromethyl , trifluoromethoxy, nitro or cyano, R ⁴ represents hydrogen or methyl, - and R· denotes a hydrogen atom or, together with the carbon atom to which they are attached, a carbonyl group, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ⁸ represents a hydrogen atom, a phenyl group, a benzyl group or a five-membered heteroarylmethyl group with up to two heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur, said ring systems alone being one to three times same or differently substituted by chlorine, fluorine or bromine , hydroxy, (C1-C4) -alkyl, (C1-C4) -alkoxy, trifluoromethyl or amino, R ⁹ and R ¹⁰ are the same or different and independently of one another are hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, or fluorine or chlorine, R ^x and R ^z are the same or different and independently of one another represent a hydrogen atom or a methyl or ethyl group or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring R ^J represents a hydrogen atom or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, as well as their pharmaceutically acceptable salts, hydrates - 168 ·· ···· and solvates. Propionic acid derivatives according to claim 1, 2 or 3 of the general formula I, in which A is -CH ₂ - or -CH ₂ CH ₂ -, X is oxygen, sulfur or CH ₂ , R ⁴ represents a hydrogen atom, a methyl group or a methoxy group R1 _and R3 are the same or different and independently of one another are methyl, trifluoromethyl, methoxy, trifluoromethoxy or chlorine or fluorine, R ⁴ represents hydrogen, R 1 and R 2 together with the carbon atom to which they are attached denote a carbonyl group, R is methyl, ethyl, n-propyl or especially hydrogen, R 6 represents a phenyl group, a furanylmethyl group or a thienylmethyl group, wherein said ring systems themselves may be mono- or di-substituted in the same way or differently by a methyl or ethyl group, R ⁹ and R ¹⁰ are the same or different and independently of one another denote a hydrogen atom or a methyl group and in particular 169 hydrogen atom, R ^11a are the same or different and independently of one another denotes a hydrogen atom or a methyl group and in particular a methyl group and denotes a hydrolysable group which can be degraded to the corresponding carboxylic acid, or in particular a hydrogen atom, and pharmaceutically acceptable salts, hydrates and solvates. 5. Propionic acid derivatives of the general formula ΙΑ in which A represents a group or -CH 2 CH 2 -, X is oxygen or sulfur, R1 represents a hydrogen atom, a methyl group or a methoxy group 9 -1 _v , R and R are the same or different and independently of one another are methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy. · Φ · φφ • Φ • · φ A chlorine or fluorine group or atom, and R @ 2 denotes phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, wherein said ring systems may themselves be substituted once or twice by methyl, or denotes 2-methoxyethyl. 6. Propionic acid derivatives of the formula I as defined in claims 1 to 5 for preventing and treating diseases. A medicament comprising at least one propionic acid derivative of the formula I as defined in claim 1 and inert, nontoxic, pharmaceutically acceptable carriers, excipients, solvents, vehicles, emulsifiers and / or dispersing agents. 8. Use of propionic acid derivatives of the general formula And medicaments as defined in claims 1 to 7 for preventing and treating diseases. Use of propionic acid derivatives of the general formula 1 as defined in claims 1 to 6 for the manufacture of medicaments. Use of the propionic acid derivatives of the formula I as defined in claims 1 to 6 for the manufacture of a medicament for the treatment of arteriosclerosis. 11. A method for the prevention and treatment of diseases, characterized in that the compounds of the formula I as defined in claim 1 are allowed to act. - 171 ···· 4 · 44 · 9 4 · 9 4 • 9 9 · 4 4 «· ·» to animals. A process for the manufacture of medicaments, characterized in that at least one compound of the formula I as defined in claim 1 is converted into a dosage form together with excipients and / or carriers. A process for the preparation of propionic acid derivatives of the formula I as defined in claim 1, characterized in that the compounds of the formula II are reacted with [A]. HOOC (H), wherein A, X, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, and T represents a benzyl group, an alkyl group having 1 to 6 carbon atoms, or a polymeric carrier suitable for solid phase synthesis, first by activating the carboxyl group with the compounds of formula II in formula II. R \ R '(ΠΙ) _; 172 wherein R ¹ , R ² and R ^{3 are} as defined above for compounds of formula Ia 0-kterém in which A, X, T, R ² , R ² , R ³ , R ² , R ⁸ , R ⁹ , R ² , R I? and R are as defined above, or [B] are reacted with compounds of formula IV (IV) wherein A, X, T, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} as defined above, presence of a base with compounds of formula V Q R (V) wherein R ² , R ² , R ³ and R ^{2 are} as defined above and 173 Q denotes a suitable leaving group, also to compounds of formula Ia, then compounds of formula I by amide-alkylation, optionally to compounds of formula Ib rIa, optionally known by amide reduction, are converted (Ib) in which A, X, T, R ^1, R ^2, R ^{3, R7, R8, R9,} Rl, ^R11 and R as defined above, then converted with acids or bases into the corresponding carboxylic acid of formula Ic in which a, X, R @ ¹ , R @ ² , R @ ³ , R @ ⁷ , R @ ⁸ , R @ ⁹ , R @ ¹⁰ , R @ ¹¹ and R @ ^{12 are} as defined above. 174 are modified by reaction with compounds of formula VI R ¹³ - Z (VI), Wherein R is as defined above and Z denotes a suitable leaving group or denotes a hydroxyl group. Řs Use according to claim 9 for the manufacture of a medicament for the treatment of arteriosclerosis, for increasing a disease-reduced level of HDL to reduce an elevated level of triglycerides and IDL in arterio sclerosis and / or hypercholesterolemia. Use of the compounds of formula I as defined in claim 1 as peroxisome-proliferator-activated receptor agonists. 16. Compounds of formula II OT (Π) in which A, X, R ^7, R ^8, R ^9, R ^10, R ¹¹ and R ¹² as defined above and T represents a benzyl group, an alkyl group having 1 to 6 carbon atoms, or a polymeric carrier suitable for solid phase synthesis.