WO1997030018A1

WO1997030018A1 - 2,2-difluoroalkane carboxylic acids, process for their preparation and medicaments containing the same

Info

Publication number: WO1997030018A1
Application number: PCT/EP1997/000725
Authority: WO
Inventors: Edgar Voss; Johannes Pill
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1996-02-16
Filing date: 1997-02-15
Publication date: 1997-08-21
Also published as: DE19605700A1; AU1790297A

Abstract

The invention concerns medicaments for treating diabetes mellitus which contain as active substance a compound of formula (I), in which A, B, A' and W have the meanings given in the claims. The invention further concerns novel compounds of formula (I) and a process for their preparation.

Description

2,2-Difluoroikanecarboxylic acids, process for their preparation and medicaments containing them

The present invention relates to 2,2-difluoroalkane carboxylic acids, processes for their preparation and medicaments which contain these compounds.

The invention relates to new 2,2-difluoroalkane carboxylic acids of the general formula I.

W A 'B A C COOH (I),

F in which

A an alkyl chain with 5-20 carbon atoms,

A 'is a valence line, a vinylene or acetylene group or an alkyl chain with 1-10 carbon atoms,

B is a valence line, a methylene group, sulfur, oxygen or the group NR ¹ ,

in which

R ^{1 can be} hydrogen, benzyl, phenyl or a C1-C4 alkyl radical, a carbonyl, sulfonamide, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR- ^ R- * group,

in which

R ^{2 is} hydrogen, a C i -C4-alkyl radical or phenyl, R3 is a C1-C4-alkyl radical, benzyl, phenyl, hydroxy or a group NR ⁴ R ⁵ ,

wherein

R ^{4 can be} hydrogen, benzyl, phenyl or a C j -C4 alkyl radical and R5 can be hydrogen or a C \ -C4 alkyl radical,

a group Y-Z-Y,

in which

Y sulfur or oxygen,

Z can be an alkyl chain (CH2) _n and n 1-5,

means, and

a halogen atom; a cyano or rhodano group, aminocarbonyl; an isopropyl or tert-butyl radical; a C3-Cg-cycloalkyl radical which can be unsubstituted or substituted by phenyl or C1-C4-alkyl; a cyclohexenyl or cyclopentenyl radical, a phenyl ring which can be substituted by one or any combination of the following substituents: -CC4-alkyl,

C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, trifluoromethyl, nitro, amino, hydroxy, cyano, mercapto, sulfonamino, acetylamino, carboxy, phenoxy, benzyloxy, phenyl, benzoyl, car - Boxy -CC-C4-alkyl, methylenedioxy, ethylenedioxy, fluorine, chlorine, bromine, iodine, Carboxymethoxy, carboxyethoxy, acetoxy, acetyl, propionyl, a group NR ° R ⁷ , where R ^{6 is} hydrogen, C * -C4-alkyl, benzyi and R ^{7 is} hydrogen, -C-C4-alkyl, benzyi, phenyl or benzoyl, the respective aromatic rings can be unsubstituted or mono- or polysubstituted by halogen, hydroxy or C 1 -C ₄ alkoxy, furthermore an α- or ß-naphthyl ring which is substituted by methyl, hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, acetyl , Chlorine or bromine may be substituted or a tetrahydronaphthyl radical,

mean,

as well as their physiologically tolerable salts or esters and substances which are hydrolyzed or metabolized in vivo to form compounds of the general formula I. If chiral compounds are formed by the substitution of the alkyl chain in I with the radicals described, both the substances with R and S conformation are the subject of the invention. C 1 -C ₄ -alkyl substituents are understood to mean straight-chain or branched alkyl radicals; methyl and ethyl substituents are preferred.

Compounds of formula I have valuable pharmacological properties. They normalize elevated glucose levels without accompanying risk of hypoglycaemia and are therefore ideal for treating diabetes mellitus

Current principles of oral antidiabetic agents such as the commonly used sulfonylureas are based on an increased release of insulin from the pancreatic β-cells, a mechanism that leads to a total exhaustion of the diabetic's own insulin production in the long term. Modern considerations of the pathobiochemistry of adult diabetes therefore emphasize the need to treat the peripheral insulin resistance that is present in this case.

Compounds of formula I effect the improvement of glucose utilization z. B. in the muscle, by increasing insulin sensitivity, they reduce hyperinsulinemia and thus correspond exactly to the required therapy concept. Diabetics often suffer from a general derailment of the entire metabolic situation, characterized by hyperlipidemia, increased cholestones, hypertension, obesity and hyperinsulinemia, a clinical picture which is referred to as metaboic syndrome or syndrome X and which leads to major complications. In addition to the breakdown of hyperinsulinism, compounds of the general formula I additionally bring about a reduction in triglycerides, cholesterol and fibrinogen, and are therefore outstandingly suitable for the treatment of the metabolic syndrome.

Preferred compounds of the general formula I are compounds

in which

A is an alkyl chain with 8-16, preferably 10-14 carbon atoms,

A 'a valence line, vinylene or acetylene,

B valence line, a methylene group, oxygen, sulfur, sulfoxide or sulfonyl and

W is a C3-Cg-cycloalkyl or an optionally substituted phenyl radical, in particular 4-chlorophenyl, 4-methylthiophenyl, 4-C _r C ₄ -alkylphenyl,

4-methyl-sulfonylphenyl,

mean.

The alkyl chain A or A ¹ is preferably straight-chain, but can also be branched. Halogen is to be understood as fluorine, chlorine, bromine or iodine. The C3-Cg-cycloalkyl radicals mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclopentyl and cyclohexyl are preferred.

Examples of physiologically usable salts of the compounds of the formula I are alkali metal, alkaline earth metal, ammonium and alkylammonium salts, such as the Na, K, Mg, Ca or tetramethylammonium salt.

Examples of esters are aliphatic alcohols, such as C 1 -C 6 -alkanols, in particular methyl, ethyl, propyl, butyl and isopropyl esters.

The carboxylic acid derivatives of the general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizing agents, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control or polyethylene derivatives of sorbitan hydrides. Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, finely divided silica, higher molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

The dose administered depends on the age, health and weight of the recipient, the extent of the disease, the type of other treatments which may be carried out at the same time and the type of effect desired. The daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Usually 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day to achieve the desired results.

The compounds of general formula I in which A, A ', B and W have the meanings given above are prepared by using a halogen compound of general formula II X - A - B - A '- W OD.

with esters of difluoroacetic acid in the presence of strong bases. The reaction is usually carried out in solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether or t-butyldimethyl ether at temperatures between -80 ° C. and -20 ° C. The preferred base is lithium diisopropylamide (LDA). The products are usually purified by flash chromatography on silica gel and / or recrystallization of the sodium salts from alcohols such as methanol, ethanol or isopropanol

The compounds of formula II are known from the literature or can be prepared by processes known per se. For example, the halogen compounds can be synthesized by Wittig reaction of an aromatic or aliphatic aldehyde W-CHO with the phosphonium salt of an α, ω-dihalogen compound, optionally followed by subsequent catalytic hydrogenation of the double bond formed. Alternatively, an aryl or alkyl bromide W-Br can be converted into the Grignard compound by magnesium and coupled to ct, ω-dihalogen compounds under cuprate catalysis according to Schlosser (Angew Chem 86, 50 (1974))

Halogen compounds of the general formula II in which W is an aryl, alkyl or cycloalkyl radical are obtained by converting the corresponding bromine compound W-Br into the Grignard compound using magnesium and using cuprate catalysis according to Schlosser (Angew. Chem. 86 , 50 (1974) is coupled to an α, ω-dihalogen compound.

Compounds II, in which A 'or B corresponds to an acetylene group, are reacted by reacting the acetylene compound W-CsC-H or W-A'-CsC-H with α, ω-dibromoalkanes in liquid ammonia in the presence of sodium amide or in dioxane Synthesized presence of ButylUthium. By hydrogenation of the triple bond by known methods, e.g. B. on the Lindlar catalyst, substances of formula II are accessible in which B or A 'is a vinylene group. If the compounds of the formula II are those in which B represents a sulfur atom, these are prepared by reacting the thiols W-SH or W-A'-SH with the ω-bromo-2,2-dichlorocarboxylic acid esters described in this invention. Dipolar, aprotic solvents, preferably dimethylformamide, in the presence of inorganic bases such as sodium hydride or potassium carbonate are suitable for carrying out this reaction. The thioethers obtained can be converted into the sulfoxides or sulfones in a known manner by oxidation with 3-chloroperbenzoic acid or hydrogen peroxide.

o Compounds of the general formula π in which B is oxygen or nitrogen are prepared by reacting the alcohols, phenols W-A'-OH or amines W-A'-NHR- with α, ω-dibromoalkanes, the Reaction is usually carried out in dimethylformamide or dimethyl sulfoxide in the presence of bases such as sodium hydride, potassium hydroxide, triethylamine, potassium carbonate or 5 pyridine at temperatures of 20-120 ° C.

Another process for the preparation of compounds of the general formula I is that the halogen compounds of the general formula II are converted into the Grignard compounds and reacted with oxalic acid dialkyl esters, oxalic acid 0 half-ester chlorides or oxalic acid half-ester imidazolides

R - O CO CO A B A 'W (III)

5 The α-keto esters of the general formula III obtained in this way yield

Reaction with DAST (diethylaminosulfur trifluoride) in an inert solvent such as dichloromethane or tetrahydrofuran, the corresponding difluorocarboxylic acid esters of the general formula I.

For the purposes of the present invention, in addition to the compounds mentioned in the examples, the following compounds of the formula I, which can also be present as salts or esters, are suitable:

1. 2,2-difluoro-14- (3,5-di-tert-butyl-4-hydroxyphenyi) tetradecanoic acid 2 2,2-difluoro-14- (3,5-dimethyl-4-hydroxyphenyl) tetradecanoic acid

3 12- (4-chlorophenyl) -2,2-difluoro-dodecanoic acid

4 2,2-difluoro-14- (2-methoxyphenyl) tetradecanoic acid

5 2,2-difluoro-12-phenylsulfonyldodecanoic acid

6 12- (4-chlorophenylthio) -2,2-difluoro-dodecanoic acid

7 12- (4-Carboxymethoxy-phenyl) -2,2-difluorododecanoic acid

8 14- (Cyclohex-2-enyl) -2,2-difluoro-tetradecanoic acid

9 14-Cyclohexyl-2,2-difluoro-tetradecanoic acid

10 2,2-difluoro-14-phenylsulfinyl-tetradecanoic acid

1 1 2,2-difluoro-12- (5,6,7,8-tetrahydro-napht-l-yl) -dodecanoic acid

12 14- (4-Cyano-phenyl) -2,2-difluoro-tetradecanoic acid

13 12-biphen-4-yl-2,2-difluoro-dodecanoic acid

14 10- (4-Benzyloxy-phenyl) -2,2-difluoro-decanoic acid

15 2,2-difluoro-12- (4-methylphenylsulfonylamino) dodecanoic acid

16. 2,2-difluoro-12- (4-phenoxyphenyl) dodecanoic acid

17. 14- (4-Acetylaminophenyl) -2,2-difluoro-tetradecanoic acid

18 10- (4-benzylphenyl) -2,2-difluoro-decanoic acid 19 2,2-difluoro-17, 17-dimethyl-octadecanoic acid

20 2,2-difluoro-14- (4-methylphenyl) 14-oxotetradecanoic acid

21 2,2-difluoro-14- (4-fluorophenyl) tetradecanoic acid

22 2,2-difluoro-12- (4-methylsulfonylphenyl) dodecanoic acid

23 12- (4-tert-Butylphenyl) -2,2-difluoro-dodecanoic acid

24 12- (4-tert-butylphenoxy) -2,2-difluoro-dodecanoic acid

25 2,2-difluoro-15-phenylpentadecanoic acid

26 2,2-difluoro-18-phenyloctadecanoic acid

27 2,2-difluoro-13-phenyl-tridecanoic acid

28 14-Cyclopentyl-2,2-difluoro-tetradecanoic acid

embodiments

example 1

2,2-difluoro-12-phenyl-dodecanoic acid 1 ^•

l-bromo-10-phenyl-decane 5

To a solution of 18.3 g (61.1 mmol) of 1,10-dibromodecane in 24 ml of THF, 10 ml (0.1 mmol) of 1.34 g (1.00 mmol) of CuC.2 and 0.85 g (2.00 mmol) of anhydrous lithium chloride and 100 ml of THF prepared orange-red solution of Li2CuCl4. A Grignard solution formed from 1 96 g (80.6 mmol) of magnesium and 11 5 g (73.2 mmol) of bromobenzene was then added dropwise within 1 h. The mixture was allowed to thaw, the batch turning dark and a precipitate separating out. After stirring for 20 h, 50 ml of saturated ammonium chloride solution and 100 ml of ethyl acetate were added, the phases were separated, washed twice with saturated NaCl solution, the organic phase was dried over sodium sulfate, the solution was removed on a rotary evaporator and the residue was fractionated by vacuum distillation 17 2 g ( 94%) 5, bp 130-134 ° C / 0 7mbar as a colorless liquid

2-Oxo-l 2-phenyl-dodecanoic acid ethyl ester 6

A Grignard solution prepared from 0 70 g (30 mmol) of magnesium and 7.0 g (23 mmol) of 5 in 10 ml of THF was slowly added dropwise to a solution of 20 0 g (137 mmol) of diethyl oxalate in 20 ml of THF at 0 ° C. The mixture was allowed to thaw and stir up a day at room temp. After adding 50 ml of saturated ammonium chloride solution. and 100 ml of ethyl acetate and washed twice with sat ammonium chloride solution, once with sat. NaCl solution, dried over sodium sulfate and evaporated the solution. i vac. Excess diethyl oxalate was distilled off at 90 ° C. in a high vacuum. and purified the residue by flash chromatography on silica gel (heptane / ethyl acetate 9 1). 3 5 g (48%) 6 were obtained as a colorless oil.

2,2-Difluoro-12-phenyl-dodecanoic acid ethyl ester 7 2.19 g (14.9 mmol) of diethylaminosulfur trifluoride (DAST) were added dropwise to a solution of 4.33 g (13.6 mmol) 6 in 15 ml of dichloromethane with cooling. The clear yellow-orange colored solution was left 20 Stir h and then add 30 ml of water. The mixture was extracted three times with 30 ml of dichloromethane each time, dried over sodium sulfate and the solvent was evaporated in a vacuum. 5 3 g of a yellow oil were obtained which, after flash chromatography on silica gel (mobile phase: isohexane / ethyl acetate 95: 5), gave 3.7 g (80%) 7.

5 2,2-difluoro-12-phenyldodecanoic acid 1

0.20 g (28 mmol) of lithium wire was carefully dissolved in 30 ml of water and then a solution of 3.5 g (10 mmol) of 7 in 30 ml of THF was added. After 30 minutes, 50 ml of 3N HCl and 50 ml of ethyl acetate were added, and the organic phase was washed with 3N HCl and sat. NaCl solution, dried over sodium sulfate and removed the solution. i. Vak. To

Flash chromatography on silica gel (eluent: heptane / ethyl acetate 9 1, 1% glacial acetic acid) was recrystallized from isohexane. 2.3 g (74%) 1 of melting point 53- 54 ° C.

5 Example 2

2,2-difluoro-16-phenyl-hexadecanoic acid 2:

1 -Brom-6-phenylhexane 8 0 To 34.0 g (1.40 mol) of magnesium shavings were added 50 ml of tetrahydrofuran, a solution of 188.4 g (1.20 mol) of bromobenzene in 300 ml of THF was added and the mixture was heated under reflux for 1 h. The reaction solution thus obtained. was added dropwise within 2 h at 0 ° C. to a mixture of 341.5 g (1.40 mol) of 1,6-dibromohexane dissolved in 450 ml of THF and one of 1.34 g (1.00 mmol) of CuCl2 and 0.85 g (2.00 mmol) of anhydrous 5 lithium chloride and 100 ml of THF prepared orange-red solution of Li2CuCl4. Then 25 h at room temp. stirred, decomposed with 6 N HCl, diluted with water and extracted several times with ether. It was washed with water, dried over sodium sulfate and the solution was removed. i. Vac. The 345 g of crude product obtained were passed through a Vigreux column with a column top (Reflux ratio 10 1) fractionally distilled. 80.4 g (45%) 8, bp 74-78 ° C / 0 04 mbar.

l-bromo-14-phenyl-tetradecane 9 A solution of 20.0 g (83 0 mmol) 8 in 40 ml THF was added dropwise to 2.25 g (93.0 mmol) magnesium shavings and 5 ml THF and the mixture was heated under reflux for 1 h. The solution thus obtained was added dropwise within 30 min at 0 ° C. to a mixture of 25 3 g (93.0 mmol) of 1,8-dibromoctane in 50 ml of THF and 9.3 ml (0.93 mmol) of a 0 1 M lithium cuprate solution. (so.). Then they were left at room temp. come and stirred for another 18 hours. After decomposition with ammonium chloride solution. and 6N HCl was extracted with ether. It was washed with water, dried over sodium sulfate and the solvent was removed. The 32.2 g of a colorless liquid obtained were purified by vacuum distillation, 10.5 g (36%) 8, bp. 162-165 ° C./010 mbar

Ethyl 2-oxo-16-phenylhexadecanoate 10

10 0 g (28.3 mmol) 10 dissolved in 25 ml THF were added to a mixture of 0 83 g (34 mmol) magnesium shavings and 2 ml THF and the mixture was heated under reflux for 1 h. The solution thus obtained was added dropwise at 0 ° C. to a solution of 4 97 g (34 mmol) of diethyl oxalate in 10 ml of THF. The mixture was stirred at room temperature for a further 20 h, and ammonium chloride solution was added. and 2N HCl and extracted with ether. The organic phase was washed with sat. NaCl solution. washed, dried over sodium sulfate and excess diethyl oxalate distilled off at 90 ° C. under high vacuum. Column chromatography on silica gel (mobile phase heptane / ethyl acetate 50 l) gave 2 10 g (21%) 10 as a colorless oil.

2,2-difluoro-16-phenyl-hexadecanoic acid ethyl ester 11 1.90 g (5.10 mmol) 10 were dissolved in 1.5 ml dichloromethane and 0.82 g (5.3 mmol) diethylarnosulfur trifluoride (DAST) was added under nitrogen, the batch being cooled with a little ice water. The mixture was stirred at room temperature for 6 h. poured onto 100 ml ice water and extracted with ether. After drying over sodium sulfate, the solution m. evaporated and the residue purified by column chromatography on silica gel (eluent: heptane / ethyl acetate 50: 1). 1 40 g (70%) 11.

2,2-difluoro-16-phenyl-hexadecanoic acid 2

A solution of 8.1 ml (8.1 mmol) of 1 N KOH in 8 1 ml of ethanol was added to 1.20 g (3 00 mmol) 11. The mixture was stirred at room temperature for 20 h. and then acidified with 2N HCl. After extraction with ether, the mixture was dried over sodium sulfate and the solvent was removed. After column chromatography on silica gel (mobile phase: heptane / ethyl acetate 5: 1), 0.45 g (40%) 2 of waxy consistency, dec. > 130 ° C.

Example 3

2,2-difluoro-14-phenyl-tetradecanoic acid 3

l-bromo-12-phenyl-dodedecane 12

31.0 g (128 mmol) 8 were added dropwise to 3.40 g (140.0 mmol) magnesium shavings and 120 ml THF and the mixture was heated under reflux for 1 h. The solution thus obtained was added dropwise to a mixture of 26.8 g (110 mmol) of 1,8-dibromohexane in 100 ml of THF and 20 ml (2.0 mmol) of a 0.1 M lithium cuprate solution within 1 h. (see above) with the internal temperature being kept between 0 and 5 ° C. Then allowed to room temperature. come and stirred for another 20 hours. After decomposition with ammonium chloride solution. and 6N HCl was extracted with ethyl acetate. It was washed with water, dried over sodium sulfate and the solution was removed. i vac. The 39 6 g of a colorless liquid obtained were purified by vacuum distillation, 16.8 g (47%) 12, bp. 128-132 ° C./0.03 mbar.

Ethyl 2-oxo-14-phenyl-tetradecanoate 13

10 0 g (30 7 mmol) 12 dissolved in 25 ml THF were added to a mixture of 0 80 g (33 mmol) magnesium shavings and 2 ml THF and the mixture was heated under reflux for 1 h. The solution thus obtained was added dropwise at 0 ° C. to a solution of 4 97 g (34 mmol) of diethyl oxalate in 10 ml of THF. The mixture was stirred at room temperature for a further 20 h, ammonium chloride solution was added. and 2N HCl and extracted with ether. The organic phase was washed with sat. NaCl solution. washed, dried over sodium sulfate and excess diethyl oxalate distilled off at 90 ° C. under high vacuum. Column chromatography on silica gel (mobile phase: heptane / ethyl acetate 50 l) gave 2.44 g (23%) 13 as a colorless oil

2,2-difluoro-14-phenyl-tetradecanoic acid ethyl ester 14

2.30 g (6.60 mmol) 13 were mixed under nitrogen with 1 07 g (6 60 mmol) diethylaminosulfur trifluoride (DAST), the batch being cooled with a little ice water. The mixture was stirred at room temperature for 6 h. poured onto 100 ml of ice water and extracted with ether. After drying over sodium sulfate, the solution m. evaporated and the residue (2.2 g) purified by column chromatography on silica gel (mobile phase: heptane / ethyl acetate 50 l) 0 67 g (27%) 14

2,2-difluoro-14-phenyl-tetradecanoic acid 3

A mixture of 5.3 ml (5.3 mmol) of 1 N KOH and 5.3 ml of ethanol was added dropwise to 0.650 g (1.76 mmol) of 14 at room temperature. The mixture was stirred for 50 h Room temp., Acidified with 2N HCl, extracted with ether, dried over magnesium sulfate and removed the solvent in vacuo. 0 56 g (93%) 3 were obtained as a colorless oil

For conversion into the sodium salt, 0.560 g (1.64 mmol) 3 was dissolved in some ether and a solution of 66 mg (1.64 mmol) sodium hydroxide in 3 ml ethanol was added. The precipitate obtained was washed with ether and dried in vacuo 0 42 g (70 %) 2,2-difluoro-14-phenyl-tetradecanoic acid sodium salt, decomposition from 130 ° C.

Example 4

Pharmacological test report

Homocygote ob / ob mice develop hyperglycemia, hyperinsulinemia and obesity [Herberg and Coleman, Metabolism 26, 59-99 (1977)] Die

Fatty acid synthesis is increased in the liver and adipose tissue [Hems et al, Biochem J 1950, 167-173 (1975)] The increased blood glucose is probably the result of several factors such as increased insulin resistance, changes in glucose transport and both increased gluconeogenesis and glycogenofysis [Genuth et al, Endocnology 88, 1230-1238 (1971)]. This complex of symptoms in the ob / ob mouse is very similar to type II diabetes in humans.

The tests were carried out on obese female ob / ob mice (Jackson Laboratory, USA). The allocation to the individual test groups was based on the blood glucose level before the first substance application. Care was taken to ensure homogeneous distribution in the different groups. The test substances were suspended in water after suspension Carboxymethyl cellulose (10 ml / kg) administered with a steel probe po for 5 consecutive days. To determine the blood sugar, insulin, triglycerides and free fatty acids, blood was drawn 2 hours after the last dose by opening the neck vessels. The parameters were determined using standard test kits from Boehringer Mannheim and Pharmazia. Example blood sugar "Insulin TG NEFA

% (abs.)% (abs.)%%

1 - 83 (146) -52 (92) -52 -58

2 - 61 (175) -17 (269) -35 -33

3 -101 (1 18) -91 (32) -77 -58

* Control (carboxymethyl cellulose) at the end of the test -120 = 100%,

abs .: absolute mg / 100 ml

** Check at the end of the test = 100%, abs .: μU / ml

TG: triglycerides; NEFA: non esterified fatty acids

Tab .: Effect of 2,2-difluoroalkane carboxylic acids, shown using examples 1, 2 and 3 on blood sugar, insulin, triglycerides and non-esterified fatty acids in the blood serum of diabetic ob / ob mice. The substances were dosed at 100 mg / kg / d for 5 consecutive days in carboxymethyl cellulose

Suspension administered po. The controls were treated with the same amount of vehicle (mean, n = 10 / group). The substances described led to a drastic reduction in hyperglycaemia and hyperinsulinemia. In example 3 even normoglycemia and normoinsulinemia is achieved. Reduction of hyperglycaemia while lowering insulin indicates a significant improvement in insulin resistance. As a further quality of action, these substances have clear lipid-lowering properties, shown here by a decrease in the triglycerides and the non-esterified fatty acids.

In summary, it is found that 2,2-difluoroalkane carboxylic acids as

Therapeutic for both diabetes and dyslipidemia and a combination of both, as described in the metabolic syndrome, are suitable.

Claims

New compounds of formula I.

W A 'B A C COOH (I),

in which

A an alkyl chain with 5-20 carbon atoms,

B is a valence line, a methylene group, sulfur, oxygen or the group NR-,

in which

R can be hydrogen, benzyl, phenyl or a C j -C4 alkyl radical,

a carbonyl, sulfonamide, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR- ^ R- * group,

in which R2 is hydrogen, a C i -C4 alkyl radical or phenyl,

R ^{J is} a C] -C4 alkyl group. Benzvl, phenyl, hydroxv or a Gaippe

NR ⁴ R ⁵ ,

woπn

R ^{4 can be} hydrogen, benzyl, phenyl or a C ⁴ -C ⁴ alkyl radical and R5 can be hydrogen or a C 1 -C 4 alkyl radical,

a group Y-Z-Y,

in which

Y can be sulfur or oxygen, Z can be an alkyl chain (CH2) _n and n 1-5,

means, and

W is a halogen atom, a cyano or rhodano group, aminocarbonyl, an isopropyl or tert-butyl radical, a C3-C8-

Cycloalkyl radical, which may be unsubstituted or substituted by phenyl or C 1 -C 4 -alkyl, em cyclohexenyl or cyclopentenyl radical, a phenylene radical which may be substituted by one or any combination of the following substituents C 1 -C 4 -alkyl, C 1 - C4-alkoxy, C 1-C4-alkylthio,

C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, tπfluoromethyl, nitro, amino, hydroxy, cyano, mercapto, sulfonapuno, acetylammo, carboxy, phenoxy, benzyloxy, phenyl, benzoyl, carboxy-Cι-C4-alkyl, Methylenedioxy, ethylenedioxy, fluorine, chlorine, bromine, iodine, carboxymethoxy, carboxyethoxy, acetoxy, acetyl,

Propionyl, a group NR ° R ⁷ , where R is hydrogen, -CC4-alkyl, benzyi and R ^{7 is} hydrogen -CC4-alkyl, benzyi, phenyl or benzoyl, the respective aromatic rings being unsubstituted or one or more times by halogen , Hydroxy or C 1 -C 4 -alkoxy may be substituted, furthermore an a- or β-naphthyl ring, which may be substituted by methyl, hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, acetyl, chlorine or bromine or a tetrahydronaphthyl radical,

mean,

and their physiologically acceptable salts or esters and optical isomers

New compounds according to claim 1, in which in formula I

A is an alkyl chain with 8-16, preferably 10-14

Carbon atoms,

A 'a valence line, vinylene or acetylene,

B valence line, a methylene group, oxygen, sulfur,

Sulfoxide, sulfonamide or sulfonyl and

W is a C3-Cg-cycloalkyl or an optionally substituted one

Phenyl radical, in particular 4-chlorophenyl, 4-methylthiophenyl, 4-C 1 -C 4 -alkylphenyl, 4-methylsulfonylphenyl

Use of compounds of formula I according to one of claims 1 or 2 for the manufacture of medicaments for the treatment of diabetes mellitus

Medicament containing at least one compound of formula I according to one of claims 1 or 2 in addition to conventional pharmaceutical auxiliaries and

Carrier materials. 1 ~>

5. A process for the preparation of compounds according to any one of claims 1 or 2, characterized in that a compound of Foπnel II

X - A - B - A '- W (II),

in which A, B, A 'and W have the meaning given and X is halogen l o,

reacted with difluoroacetic acid ester in the presence of strong bases or alternatively converted into Grignard compounds and converted into compounds of the formula I with dietlylaminosulfur trifluoride 15 and then, if desired, the compounds of the formula I obtained are converted into other compounds of the formula I by oxidation, hydrogenation or saponification and optionally free acid converted into esters or salts.