WO1996011901A1

WO1996011901A1 - NOVEL α,α,α',α'-TETRACHLOROBICARBOXYLIC ACIDS, PROCESS FOR PRODUCING THEM AND MEDICAMENTS CONTAINING THEM

Info

Publication number: WO1996011901A1
Application number: PCT/EP1995/003980
Authority: WO
Inventors: Edgar Voss; Johannes Pill; Peter Freund
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1994-10-13
Filing date: 1995-10-10
Publication date: 1996-04-25
Also published as: DE4436578A1; AU3840695A

Abstract

Compound of formula (I) in which A and A' are mutually independently a straight or branched alkylene chain with 1-10 carbon atoms, B is ortho, meta or para-phenylene, 1,2, 1,3 or 1,4-cyclohexylidene, sulphur, oxygen or NR1 in which R1 may be hydrogen, benzyl, phenyl or a C1-C4 alkyl radical, a carbonyl, sulphoxide or sulphone group, an E or Z-vinylene or an acetylene group, a CR2-R3 group, R2 is hydrogen, a C1-C4 alkyl radical or phenyl, R3 is a C1-C4 alkyl radical, benzyl, phenyl, hydroxy or a NR4R5 group, R4 is hydrogen, benzyl, phenyl or a C1-C4 alkyl radical, and R5 may be a hydrogen or a C1-C4 alkyl radical, a Y-W-Y group, Y is sulphur or oxygen and W is an alkylene chain (CH2)n, and n may be 1-15, their optical isomers and their physiologically compatible salts and esters, process for producing them and medicaments containing these compounds for the treatment of metabolic syndrome.

Description

New α, α, α \ α'-tetrachlorodicarboxylic acids, processes for their preparation and medicaments containing them

The present invention relates to α, α, α ', α'-tetrachlorodicarboxylic acids, processes for their preparation and medicaments which contain these compounds.

The invention relates to α.α ^ '. Α'-tetrachlorodicarboxylic acids of the general formula I.

Cl Cl

HOOC C B A'- CO COOH

(I).

Cl Cl

in which

A and A ', depending on each other, are a straight-chain or branched alkylene chain with 1-10 carbon atoms,

B ortho-, meta- or para-phenylene, 1, 2-, 1, 3- or 1, 4-cyclohexylidene, sulfur / oxygen or NR- ^* ,

in which

R- * can be hydrogen, benzyl, phenyl or a C 1 -C 4 -alkyl radical, a carbonyl, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR2-R3 group, R2 is hydrogen, a C * | -C4 alkyl radical or phenyl,

R3 is a C1-C4-alkyl radical, benzyl, phenyl, hydroxy or a group NR4R5,

R4 is hydrogen, benzyl, phenyl or a C 1 -C 4 -alkyl radical and

R5 is hydrogen or a C * | -C4-alkyl radical can be a group Y-W-Y,

Y sulfur or oxygen,

W can be an alkylene chain (CH2) _n and n 1-5 means

as well as their physiologically tolerable salts or esters and substances which are hydrolysed or metabolized in vivo to compounds of general formula I. If chiral compounds are formed by the substitution of the alkylene chain with the radicals described, both the substances with R and S configuration are the subject of the invention.

EP-A-0 279 978 already describes α, α, α ', α'-tetrachlorodicarboxylic acids which are suitable as medicaments for the treatment of obesity, hyperlipidemia or diabetes. Compared to compounds from EP-A-0279 978, the compounds of the formula I show a strong inhibition of insulin-induced lipogenesis in vitro and are therefore suitable for the treatment of metabolic diseases. In particular, the new compounds have a significantly greater inhibition of triglyceride synthesis with comparable inhibition of cholesterol synthesis.

Compounds of the formula I normalize elevated glucose levels without an accompanying risk of hypoglycaemia and are outstandingly suitable for the therapy of diabetes mellitus.

Previous active principles of oral antidiabetic agents, e.g. B. the commonly used sulfonylureas are based on an increased release of insulin from the ß cells of the pancreas, a mechanism that leads to 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 reducing insulin sensitivity, they reduce hypersulinemia and thus correspond exactly to the required therapy concept.

Diabetics often suffer from a general derailment of the entire metabolism, characterized by hyperlipidemia. Cholesterol elevation, hypertension, obesity and hyperinsulinemia. a clinical picture, which is referred to as metabolic syndrome or syndrome X and causes late complications of the greatest extent. In addition to the breakdown of hyperinsulinism, compounds of the general formula I also bring about a reduction in triglycerides, cholesterol and fibrinogen. They are therefore ideal for the treatment of the metabolic syndrome.

Preferred compounds of the general formula I are compounds in which A and A 'are a straight-chain alkylene chain having 2-5 C atoms and B is a phenylene, acetylene or (Z) or (E) -vinylene group, an oxygen atom, a sulfur atom , an SO or Sθ2 group, an S- (CH2) 3 ~ S group or a -CH (phenyl) group. Particularly preferred compounds of the general formula I are compounds in which A and A 'is a straight-chain alkylene chain of 5 methylene groups and B is an acetylene or (Z) - or (E) -vinylene group.

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, Ca or tetramethylammonium salt.

Particularly suitable esters of compounds of the formula I are alkyl esters with 1 to 5 carbon atoms. In vivo hydrolyzable derivatives of the compounds of formula I are e.g. B. salts with pharmacologically acceptable alkali, alkaline earth or ammonium bases; Esters, especially lower alkyl esters with 1 - 6 carbon atoms. such as B. methyl, ethyl and isopropyl esters; Amides, the nitrogen atom of which may optionally be mono- or disubstituted by alkyl groups having 1-6 carbon atoms, such as. B. N-methylamide and N, N-dimethylamide.

The dicarboxylic 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

Contains injection solutions usual stabilizers, solubilizers and / or buffers. Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylene diamine tetraacetic 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, the health and the weight of the recipient, the extent of the disease, the type of further 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. Normally 0.5 to 40 and preferably 1.0 to 20 mg / kgday are effective in one or more applications per day in order to obtain the desired results.

The compounds of the general formula I in which A, A 'and B have the meanings mentioned above are prepared by using an α, ω-dihalogen compound of the general formula II

X - -ABA ¹ - X (II), with dichloroacetic acid or esters of dichloroacetic 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. 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 starting compounds of the formula II are known from the literature or can be prepared by processes known per se.

1. 7- [3- (6-Carboxy-6,6-dichloro-hexyloxy) propoxy] -2,2-dichloroheptanoic acid

2. 6- [3- (5-carboxy-5,5-dichloropentyl) phenyl] -2,2-dichlorohexanoic acid

3. 7- [4- (6-carboxy-6,6-dichlorohexyl) phenyl] -2,2-dichloroheptanoic acid

4. 7- [4- (6-carboxy-6,6-dichlorohexyl) cyclohexyl] -2,2-dichloroheptanoic acid

5. 7- (6-carboxy-6,6-dichloro-hexylamino) -2,2-dichloroheptanoic acid

6. 2,2, 14, 14-tetrachloro-8-oxopentadecanedioic acid

7. 2,2,14,14-tetrachloro-8-hydroxy-pentadecanedioic acid

8. 2,2, 10, 10-tetrachloro-6-methyl-undecanedioic acid

9. 6-Benzylamino-2,2,10,10-tetrachloro-undecanedioic acid Execution examples

Example 1 :

5-f4- (4-carboxy-4 4-dιchlorobutyl) -phenvπ-2.2-dιchlor-pentanoic acid

51 ml (0 125 mol) of a 2 45 M solution of butylthium in hexane were added dropwise to a solution of 12 7 g (17 7 ml 0 125 mol) dnsopropylamine in 30 ml THF stirred at -50 ° C. After 10 mm at -10 ° C, the mixture was cooled to -78 ° C and 8 1 g (5 2 ml, 0.62 mol) were added

Dichloroacetic acid dissolved in 5 ml of THF and stirred for a further 25 min at -78 ° C. After adding 4 95 g (15 6 mmol) of 1,4-bιs- (3-bromopropyl) benzene 11, the temperature of the initially deep orange was left , later colorless solution rise to -40 ° C. After one hour, the mixture was decomposed with 40 ml of 6N HCl and 10 ml of water were added to dissolve the concentration precipitate. The organic phase was separated off, the aqueous phase was extracted twice with 40 ml ether, concentrated the combined organic phases, took up in 100 ml ether and washed several times with a little water. Drying the ether phase over magnesium sulfate and evaporation gave 9.9 g crude product. For further purification, the mixture was washed 6 times with a little water and the part-stable product obtained (8 2 g) was stirred 5 times more with isohexane. 44 g (68%) 1 as a beige substance with a melting point of 239-240 ° C

Example 2:

5-12- (4-carboxy-4.4-dιchlor-butvπ-phenvπ-2.2-dιchlor-pentane acid

Analogously to Example 1 from 1,2-bιs- (3-bromopropyl) benzene 12 and dichloroacetic acid, yield 43% colorless oil Example 3:

2.2.14.14-tetrachloro-8-thia-pentadecane-diacid

With stirring in a nitrogen atmosphere, 24.3 g (33.6 ml, 0.240 mol) of diisopropylamine were dissolved in 100 ml of THF and 100 ml (0.240 mol) of a 2.40 M solution of butyllithium in hexane were added dropwise at -50 ° C. The mixture was allowed to come to -10 ° C. for 10 minutes, then a solution of 15.5 g (0.120 mol) of dichloroacetic acid in 20 ml of THF was added dropwise at -75 ° C., the mixture was stirred at -75 ° C. for 25 minutes and then 93.5 g ( 55.0 ml, 0.41 mol) of 1,5-dibromopentane in 50 ml of THF so that the temperature rose to -40 ° C. After 2.5 h at -40 ° C., the mixture was hydrolyzed with 10 ml of 6N HCl and the precipitate formed was dissolved with 20 ml of water. The organic phase was washed twice with a little water, dried over magnesium sulfate and the solvent was removed. in a vacuum. Flash chromatography of the residue on silica gel (mobile phase: ethyl acetate / heptane 1:10) gave 19.5 g (59%) of 7-bromo-2,2-dichlorohectanoic acid 13 as a colorless oil.

It was dissolved in 300 ml of ethanol saturated at 0 ° C. with hydrogen chloride gas and stirred for a further 5 hours at 0 ° C. After removal of the main amount of ethanol i. Vac. the residue was taken up in ether, washed with water, dried over magnesium sulfate and the solvent removed. 21.2 g (98%) of 7-bromo-2,2-dichloroheptanoic acid ethyl ester 14 were obtained as a colorless oil. 18.4 g (60.0 mmol) 14 were dissolved in 150 ml THF and a solution of 7.50 g (30.0 mmol) sodium sulfide non-hydrate in 350 ml water / THF 1: 1 was added. One dripped under nitrogen at room temp. 30 ml (60.0 mmol) of 2 N NaOH and stirred for a further 5 h at 75 ° C. After cooling, it was acidified with 2N HCl and extracted with ether. It was washed with water, dried over magnesium sulfate and the solvent was removed. 11.6 (80%) 2,2,14,14-tetrachloro-8-thia-pentadecanedioic acid 3. after stirring with isohexane crystals of mp. 84-86 ° C. Example 4:

7- (6-carboxy-6.6-dιchlor-hexyl-1-sulfιnyl) -2.2-dιchlor-heptanoic acid

6 0 g (14 mmol) 3 were dissolved in 100 ml of ethanol, cooled in an ice bath and saturated with hydrogen chloride gas at 0-5 ° C. The mixture was boiled under reflux for 1 h (TLC control with ethyl acetate / heptane 15), the main amount of ethanol was distilled on a rotary evaporator, took the residue in ether, washed with water, dried over magnesium sulfate and evaporated the solvent in vacuo from 4 9 g (72%) 2,2, 14,14-tetrachloro-8-thiapentadecanedioatediethyl ester 15, light yellow oil

53 g (3 1 mmol) of 3-chloroperbenzoic acid were dissolved in 15 ml of dichloromethane at 0 ° C. to dissolve 15 g (3 1 mmol) of 15 in 30 ml of dichloromethane. The mixture was allowed to come to room temperature within 2 h and the mixture was washed with saturated sodium bicarbonate and water, dried over magnesium sulfate and removed the solvent in vacuo 10 g (64%) colorless oil, which after flash chromatography on silica gel (mobile phase heptane / ethyl acetate / methanol 10 5 1) 0 80 g (52%) sulfoxide ester 16 as a loose oil

A mixture of 0.760 g (1 52 mmol) of sulfoxide ester, 3.2 ml of 1 N KOH and 3 2 ml of ethanol was kept at room temperature for 2 5 h. touched. TLC control (eluent ethyl acetate / heptane 1 3) indicated complete conversion. Acidified to pH 2-3 with 2 N HCl, extracted with ether, washed with water, dried over magnesium sulfate and the solvent removed 0 66 g (98%) colorless crystals, after boiling with isohexane, mp. 113-114 ° C

Example 5:

7- (6-carboxy-6.6-dichloro-hexyl-1-sulfonyl) -2.2-dichloro-heptanoic acid

100 g (2 30 mmol) of sulfide 3 were dissolved in 10 ml of glacial acetic acid and 3 ml of 30% hydrogen peroxide were added dropwise at room temperature. The mixture was stirred for 2 d at room temperature, poured into ice water and extracted with ether. The ether extract was dried over magnesium sulfate, concentrated and acetic acid removed azeotropically with toluene. 0 96 g (87%) of sulfone 5 remained as a colorless oil

Example 6:

2 2,18,18-tetrachloro-8 2-dιthιa-nonadecan-dιsaure

Under a nitrogen atmosphere, 3 80 g (12 4 mmol) of 14 in 50 ml of dimethylformamide, 2 76 g (20 mmol) of potassium carbonate and 0 67 g (6 2 mmol) of 1,3-dimercaptopropane were added. The mixture was stirred at room temperature for 12 h stirred, diluted with water and cold neutralized with dil hydrochloric acid. After extraction with ether, drying over sodium sulfate and concentration in vacuo, 2 52 g (72%) of yellow oil were obtained, purification by medium pressure chromatography on silica gel (mobile phase ethyl acetate / heptane 1 10) 18 g of colorless oil (2,2,18,18-tetrachloro-8,12-dithianonadecane-disaurediethyl ester 18)

A mixture of 1 8 g (3 2 mmol) 18, 64 ml (6 4 mmol) 1 N KOH and 7 ml ethanol was at room temp. stirred, 5 ml of ethanol added and stirring continued for 5 h until a clear solution was obtained. Dilution with 10 ml of water, extraction with ether and discarding this extract. The water phase was acidified with 2N HCl, extracted with ether, washed with water, over magnesium sulfate dried and evaporated The 1 21 g (76%) crude product obtained was purified by flash chromatography on silica gel (mobile phase. ethyl acetate / heptane / methanol 5 10.2). Colorless oil which crystallized on trituration with isohexane. 0 9 g (56%) 6, mp 61-64 ° C Example 7:

2.2.8,8-tetrachloro-5-phenyl-nonanedioic acid

Analogously to Example 1 from 1,5-dibromo-3-phenylpentane 17 and dichloroacetic acid, mobile phase: toluene / ethyl formate / methanol 10: 8: 1 + 1% formic acid. 2.53 g (38%) 7, m.p. 156 -157 ° C.

Example e:

2,2,14,14-tetrachloro-8-oxapentadecanedioic acid

Analogously to Example 1 from 5,5'-dibromodipentyl ether 18 and dichloroacetic acid, mobile phase. Ethyl acetate / heptane 1: 2, yield 32% colorless oil. An analytical sample was dissolved in ethanol and converted into the disodium salt with the calculated amount of solid sodium hydrogen carbonate. After removal of the solvent, the mixture was crystallized using ethyl acetate and isohexane. Colorless crystals, mp 61-62 ° C with decomposition.

Example 9:

2.2-15.15-tetrachloro-hexadec-8-in-diacid

110.6 ml (0.260 mol) of butyllithium (2.35 M in hexane) were added dropwise to a solution of 25.0 g (0.250 mol) of trimethylsilylacetylene (Aldrich) in 200 ml of THF under a nitrogen atmosphere at -78 ° C. The mixture was stirred for a further 45 minutes and 70.4 ml (0.520 mol) of 1,5-dibromopentane were added rapidly. After 20 min at -78 ° C, the mixture was kept at -30 ° C for 30 min, gradually allowed to room temperature. came and stirred for another 12 hours. The reaction mixture was shaken out with semi-saturated sodium chloride solution, the main amount of THF was carefully distilled off and the remaining oil was fractionated via a canned column. 36.5 g (59%) of 5-bromo-1-trimethylsilyl-1-pentyne 19, bp. 85-86 ° C./3.5 mbar, were obtained as a colorless oil. 6.25 g (25.0 mmol) 19 were dissolved in 40 ml THF and 7.84 g (30.0 mmol) tetrabutylammonium fluoride trihydrate in 20 ml THF were added. After adding 3 ml of water, the mixture was stirred at room temperature for 14 h and the main amount of THF was removed. It was taken up in isohexane and washed neutral with water. After drying over magnesium sulfate, fractionation was carried out in vacuo. 2.70 g (%) 5-bromo-1-pentin 20, bp 30-35 ° C / 3 mbar.

Under a nitrogen atmosphere, 2.70 g (15.4 mmol) 20 were dissolved in 60 ml 5: 1 dioxane-toluene and cooled to -20 ° C. In parallel, 7.20 ml (16.2 mmol) of a 2.35 M solution of butyllithium in hexane and 4.4 ml

(32 mmol) 1, 5-dibromopentane was added dropwise. The mixture was allowed to come to room temperature and heated to reflux for 22 h. After adding 10 ml of 3 N HCl. was extracted with isohexane, the organic phase washed neutral, dried over magnesium sulfate and concentrated. Fractionation of the residue by Kugelrohr distillation gave 1.00 g (25%) 1, 12-dibromo-6-dodecin 21 as a colorless oil.

Analogously to Example 1, 1.00 g (3.09 mmol) 21 were reacted with dichloroacetic acid. Purification of the crude product by flash chromatography on silica gel (mobile phase: heptane / ethyl acetate 10: 1, 1% glacial acetic acid) gave 0.40 g (26%) 9 as a colorless oil.

Example 10:

(Z 2.2-15.15-tetrachloro-8-hexadec-8-enedioic acid

200 mg of 9 were dissolved in 20 ml of THF and, after the addition of 20 mg of Lindlar catalyst, hydrogenated for 3 hours at an excess pressure of 30 mbar. The catalyst was suctioned off and the solvent was removed. 195 mg (96%) 10 as a colorless oil. Example 11

Pharmacological test report

Rat hepatocytes in culture are suitable for studies of cellular metabolism. These Pπmark cultures offer the advantage that several substances can be examined in a comparative manner in a nonproliferative system, ie, pπmar, determined by Metaboh processes

Rat hepatocytes were isolated by recirculating collagenase perfusion and cultured in slanting tubes. The ¹⁴ C-acetate assembly in Tπglycende (TG) and Cholestenn (CH) was examined in the presence and absence of test substances.

Tab 1 Effect of α, ω-dicarboxylic acids with an interrupted chain such as compounds A, B and C and in comparison with a dicarboxylic acid not interrupted chain such as compound D on the incorporation of ¹⁴ C-acetate in Tπglycende (TG) and cholestones (CH) in primary monolayer cultures of liver cells from male Sprague-Drawley rats during an incubation period of 48 hours in serum-free Dulbecco MEM. The differences from the solvent-treated controls (DMSO 0 1%, v / v) are given in percent (x + SEM, 4 culture dishes from 2 preparations)

D = 2,2,15,15-tetrachlorohexadecane-1,16-diacid from EP 0 279 978 The α, ω-dicarboxylic acids with an interrupted chain mentioned here lead to a significantly greater inhibition of the ¹⁴ C-acetate incorporation in lipids than compound D, a representative with an uninterrupted chain. This effect is particularly evident in a strong reduction in TG de novo synthesis.

The generally significantly stronger inhibition of TG synthesis represents a qualitative advantage over compound D. A reduction in the cholestyrene and triglycid synthesis leads to a reduction in the lipids in serum and in various tissues. These active substances should therefore be used in hyper and dislipidemia alone or in combination with other diseases or metabolic disorders such as e.g. Diabetes has therapeutic benefits.

Claims

claims

Compounds of formula I.

Cl Cl ι

HOOC - C B V c COOH (D,

Cl Cl

in which

A and A 'independently of one another are a straight-chain or branched alkylene chain with 1 -10 carbon atoms

B ortho-, meta- or para-phenylene 1, 2-, 1, 3- or 1, 4-cyclohexylιden, sulfur, oxygen or NR **,

in which

R *] can be hydrogen, benzyl, phenyl or a C1-C4-alkyl radical, a carbonyl, sulfoxide or sulfone group, an E or Z-vinylene or an acetylene group, a CR2-R3 group

R2 is hydrogen, a C * | -C4 alkyl radical or phenyl,

R3 is a C1-C4-alkyl radical, benzyl, phenyl, hydroxy or a group NR4R5,

R4 is hydrogen, benzyl, phenyl or a C * | -C4 alkyl radical and R5 can be hydrogen or a C ** -C4-alkyl radical, a group YWY,

Y sulfur or oxygen.

W can be an alkylene chain (CH2) _n and n 1-5 means

their optical isomers.

and their physiologically tolerable salts or esters.

2. Process for the preparation of compounds of formula I.

Cl Cl

(I).

HOOC - C A B A'- COOH

Cl Cl

in which

A and A 'independently of one another are a straight-chain or branched alkylene chain with 1-10 carbon atoms.

B ortho-, meta- or para-phenylene, 1, 2-, 1,

3- or 1, 4-cyclohexylidene, sulfur, oxygen or NR * ^* ,

in which

R * l can be hydrogen, benzyl, phenyl or a C1-C4 alkyl radical, a carbonyl, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR2-R3 group, R2 is hydrogen, a C - * - C4-alkyl radical or phenyl,

R3 is a C1-C4 alkyl radical, benzyl. Phenyl, hydroxy or a group NR4R5,

R4 is hydrogen, benzyl, phenyl or a C1 -C4-

Alkyl radical and

R5 can be hydrogen or a C 1 -C 4 -alkyl radical, a group Y-W-Y,

Y sulfur or oxygen,

W can be an alkylene chain (CH2) n and n 1-5 means

their optical isomers,

and their physiologically tolerable salts or esters,

characterized in that a compound of formula II

X B - A'-

(II).

in which A, A 'and B have the meaning given and X represents a halogen atom,

reacted with dichloroacetic acid or its ester in the presence of strong bases, and then the compounds obtained are converted into physiologically tolerable salts or esters.

Medicament containing at least one compound according to claim 1, for the treatment of the metabolic syndrome.

4. Use of compounds according to claim 1 for the manufacture I0 of medicaments for the treatment of the metabolic syndrome.