IE921061A1 - Optically-active carboxylic acids, processes for the¹preparation thereof and pharmaceutical compositions¹containing them - Google Patents

Optically-active carboxylic acids, processes for the¹preparation thereof and pharmaceutical compositions¹containing them

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Publication number
IE921061A1
IE921061A1 IE106192A IE921061A IE921061A1 IE 921061 A1 IE921061 A1 IE 921061A1 IE 106192 A IE106192 A IE 106192A IE 921061 A IE921061 A IE 921061A IE 921061 A1 IE921061 A1 IE 921061A1
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Ireland
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general formula
acid
carboxylic acids
group
radical
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IE106192A
Inventor
Hans Peter Wolff
Hans-Frieder Kuehnle
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Boehringer Mannheim Gmbh
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Publication of IE921061A1 publication Critical patent/IE921061A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to R- and S-carboxylic acids of the formula I in which R1 denotes an aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl or arylamino radical, where the aryl moieties can each be substituted by one or more radicals from the group consisting of hydroxyl, halogen, C1-C8-alkyl, C1-C8-alkoxy, trifluoromethyl, cyano, nitro, amino, C1-C8-alkylamino and di-C1-C8-alkylamino, R2 denotes an aryl radical which can be substituted by one or more radicals from the group consisting of hydroxyl, halogen, C1-C8-alkyl, C1-C8-alkoxy, trifluoromethyl, cyano, nitro, amino, C1-C8-alkylamino or di-C1-C8-alkylamino, A denotes a straight-chain or branched, saturated or unsaturated aliphatic radical having 3-10 carbon atoms, which is optionally interrupted by a hetero atom, with the proviso that there should not be a hetero atom on an unsaturated aliphatic carbon atom, Y denotes the groups -S(O)n- or -O-, n denotes the numbers 0, 1 or 2 and B denotes a valency line or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1 to 5 carbon atoms, and their physiologically acceptable salts and esters. The present invention also relates to medicinal preparations containing compounds of the formula I for the treatment of diabetes, prediabetes and in particular for the treatment of adult-onset diabetes. Additionally, the substances according to the invention exhibit a pronounced hypolipodaemic action and are therefore also suitable for the treatment of disorders of fat metabolism.

Description

The present invention is concerned with new optically-active carboxylic acids, processes for the preparation thereof and pharmaceutical compositions containing them, More particularly, the present invention is concerned with R_ and S-carboxylic acids of the general formula:— *R, -A - CH - COOH 1 ' (I) Y - B - R2 wherein Rj is an aryl, aryloxy, arylthior aryl10 sulphinyl, arylsulphony1 or arylamino radical, in which the aryl moieties can, in each case, be substituted by one or more substituents of the group hydroxyl, halogen, C^-Cg-alkyl, C^-Cg-alkoxy, trifluoromethyl,. cyano, nitro, amino,. C^-Cg-alkylamino and di-C^-Cg-aIkylamino, i?2 is an aryl radical which can be substituted by one or more substituents of the group hydroxyl, halogen,. C^-Cg-alkyl, C-^-Cgalkoxy, trifluoromethyl, cyano, nitro, amino, C-^-Cgalkylamino and di-C^-Cg-alkylamino, A is a straight20 chained or branched, saturated or unsaturated aliphatic radical containing 5 to 1-0 carbon atoms which is optionally interrupted by a heteroatom,with the proviso that there is not a heteroatom on an unsaturated aliphatic carbon atom, Y is an oxygen atom or an -3(0)n~ group in which n is 0, 1 or 2 and B is a valency bond or a straight-chained or -3branched, saturated or unsaturated aliphatic radical containing; up to 5 carbon atoms, as well as the physiologically acceptable salts and esters thereof.
The present invention is also concerned with 5 pharmaceutical compositions which contain at least one compound of general formula I for the treatment of diabetes, prediabetes and especially of maturity onset diabetes. In addition, the compounds according to the present invention display an outstanding lipid-sinking action and are, therefore, suitable for the treatment of fat metabolism diseases.
In Patent Applications W0-A-87/00521 and EP-A0 279 162 are described carboxylic acids of general formula I, the examples contained in these Patent Applications referring exclusively to the preparation of racemates. The compounds described therein have, as common structural element, a substituent in the α-position to the carboxyl function. These carboxylic acids possess valuable pharmacological properties.
In particular, they are suitable for again normalising a reduced insulin sensitivity such as occurs in the case of diabetic metabolic conditions.
Surprisingly, we have now found that in the case of these sompounds, which have hitherto only been known as racemates, the action can be mainly attributed to one of the enantiomers, preferably the laevorotary form. By means of the choice of suitable optically pure R- or 3-isomers, it is possible to -4-. achieve the desired pharmacological action even at a dose which is reduced by a factor of from 4 to 100 in comparison with the less effective form. This is of great therapeutic use since, in the case of the admin5 istration of the pharmacologically-active isomer instead off of the racemate, possibly occurring side effects which can be attributed to pharmacologicallyinactive form do not arise. T^us, a distinct increase of the therapeutic margin of safety can be achieved.
T^is has the advantage that the pharmacologicallyactive isomers can be administered in considerably smaller doses in comparison with the racemates (a factor of 4- to 50 and,, in some cases,, up to a factor of 100).
The compounds according to the present invention are especially suitable for the preparation of pharmaceutical compositions for the oral treatment of diabetes mellitus and especially of type II or of type lib. It is thus possible for the first time to influence the peripheral insulin resistance in the case of type II diabetic patients. According to the present knowledge, the utilisation disturbance of insulin and glucose thereby plays a great part as one of the main causes of maturity onset diabetes. Due to this utilisation disturbance, there is brought about a hyperinsulinaemia which, in turn, is a risk factor for genesis of macroangiopathic complications.
Investigations with adipose type II diabetic patients have shown that not only the glucose but also the -5insulin level can be lowered with the compounds according to the present invention. On the basis of their special mechanism of action, the new compounds according to the present invention possess some further advantages: they do not give rise to hypoglycaemia and, since they also lower the insulin level, they lower the risk of arteriosclerosis in type II diabetic patients. Therefore, they are also suitable for the prophylaxis of arteriosclerotic diseases.
Furthermore, they possess a positive influence on increased blood pressure values and bring about a lowering of the triglyceride and cholesterol levels.
In all definitions,, aryl radicals are to be understood to be aromatic hydrocarbon radicals containing 6 to 14 carbon atoms, the phenyl and naphthyl radicals being preferred.
In all definitions,, substituted aryl radicals are to be understood to be those aromatic hydrocarbons containing 6 to 14 carbon atoms which are substituted one or more times by hydroxvl, halogen, C^-Cg-alkyl, C -Cθ-alkoxy, trif Huorometh.yl, cyano or nitro or amino optionally substituted once or twice by C-^-Cgalkyl. The aryl moieties in question preferably contain one, two or three of the above-mentioned substituents. Those alkyl moities are preferred which contain up to 6 and more preferably up to 4 carbon atoms, for example methyl, ethyl, n-propyl, -6isobutyi, tert.-butyl and neopentyl. Especially preferred aryl moities include phenyl, 4-methvlphenyl, 4- tert.-butylphenyl, 4-methoxypheny1, 2-methoxyphenyl, - trifluoromethylphenyl and 4-chlorophenyl By halogen is to be understood fluorine, chlorine, bromine and iodine and preferably fluorine, chlorine and bromine.
Unbranched aliphatic radicals A are especially the following alkylene radicals and the alkylene radicals interrupted by a heteroatom X: a) -(CH2)Q- in which o is 5 to 10 and -(CH2)p-X-COH^) - in which £ is 2 to 8 and 2 is 1 to 6, whereby o, £ and £ are whole numbers, the sum of 15 £ and £ is not greater than 10 and X is an oxygen or sulphur atom or an NH group. b) -CH2-X-(CK2)q-, -GH=CH-CH2-, -C=C-CH2-, -C=C-(CK2) -, wherein £, £ and X have the above-given meanings.
R.^ is then preferably an aryl radical.
Branched aliphatic radicals can be, for example, -CH2-CH(CH5)-CH2- or -ΟΗ^ΟζΟΕ^)-CH2~, then preferably being an aryl radical.
By an alkylene radical B there are preferably to be understood the radicals “(0Η2)Γ-, -GH2-CH=CH-, -CH2-C=C- and -GH=CH-, wherein r is a whole number of from 1 to 5.
The compounds of general formula I can be present as free acids or in the form of physiologically -7acceptable salts with weak or strong bases, which can be prepared, for example, by reaction with an aqueous solution of sodium or potassium hydroxide or of ammonia. The physiologically acceptable salts are especially alkali metal, alkaline earth metal and ammonium salts, as well as possibly . salts with blood sugar-sinking biguanides. The carboxyl group can also be esterified with lower alcohols, for example methanol, ethanol or propanol, to give the corres10 ponding physiologically acceptable esters. The esters derived from the carboxylic acids of general formula I contain, as alcohol component, a lower monohydroxy alcohol with up to 6 carbon atoms, of which methanol, ethanol and n-butanol are preferred, or a polyhydroxy alcohol with 2 to 6 carbon atoms, for example glycerol, or an alcohol with other functional groups, for example ethanolamine.
The present invention also provides processes for the preparation of the R- and S-isomers of optically20 active compounds of general formula I, wherein a) in known manner, a racemic mixture of a compound of general formula I is reacted with an opticallyactive base, for example ephedrine, and the resulting diastereomeric salts are separated by physical methods, for example fractional crystallisation or solid-liquid chromatography, whereafter the acids are again liberated, -eb) in known manner, a racemic mixture of a lower ester of a compound of general formula I is enantioselectively cleaved with an enzyme, for example an esterase or lipase, or g c) in known manner, an optically-active compound of the general formula :R1 - A - CH - COORj (χι^ X (S- or R-isomer), in which R^ and A have the abovegiven meanings and X is a group which can be split off, for example a halogen atom or a sulphonic acid ester, such as a trifluoromethylsulphonyloxy or 4-chlorophenylsulphonyloxy group, and R^ is 3 C]_“Cg-3Uiy 1 radical, is reacted with a compound of the general formula :15 H - X - B - R2 (HI) in which B and Rg have the above-given meanings and Y is a sulphur or oxygen atom, an ester obtained of the compound of general formula I is subsequently converted bv saponification into the free acid of general formula I and a derivative obtained in which Y is a sulphur atom is, if desired, converted in known manner by oxidation of the sulphur atom into a derivative in which Y is SO or SOg.
Optically-active compounds of general formula II can be prepared by -9a) hqlogenating or sulphonating an optically-active compound of the general formula :-* R, -A - CH - COOR, I 2 OH (R- or S-isomer), in which R·^, A and R^ have the 5 above-given meanings, or b) separating in known manner a racemic mixture of a compound of general formula II, in which R^ is a hydrogen atom and R^ and A have the above-given meanings, via a diasteromeric salt with an optically-active base, again liberating the acids and converting them by esterification into the optically-active esters of general formula II, Optically-active compounds of general formula IV can be obtained by a) stereoselective reduction of a co/npound of the general formula :Rx -A - CO - COOR5 (V), in which R^ , A and R^ have the above-given meanings by known processes (see H.C, Brown, 0.0, Rai and 2o P,K. Jadhav, J.A.C.S,, 106, 1531/1984) or b) by separation of a racemic mixture of a compound of general formula IV, in which R^ is a hydrogen atom and R^ and A have the above-given meanings, via diastereomeric salts with optically-active bases, subsequent liberation of the free acid and conversion of the optically-active acid of -10general formula IV into the desired ester with the above-given meaning for R^.
The preparation of racemic mixtures of compounds of general formula I is described in Patent Applic5 ations WO-A 87/00521 and EP-A-0 279 162, For the preparation of pharmaceutical compositions, the compounds of general formula I are mixed in known manner with appropriate pharmaceutical carrier materials, aroma, flavouring and colouring materials and formed, for example, as tablets or dragees, or, with the addition of appropriate adjuvant materials, suspended or dissolved in water or an oilT for example olive oil.
The compounds of general formula I can be admin15 istered orally or parenterally in liquid or solid form. As injection medium, it is preferred to use water which contains the stabilising agents, solubilising agents and/or buffers usual in the case of injection solutions. Such additives include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) and polyethylene derivatives of sorbite anhydrides.
Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, -11calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Gom-oositions suitable for oral administration can, if desired, contain flavouring and sweetening agents.
The dosage administered depends upon the age, the state of health and the weight of the recipient, the extent of the disease, the nature of further treatments possibly carried out simultaneously, the frequency of the treatment and the nature oi the desired action. The daily dose of the active compound is usually from 0.1 to 50 mg/kg of body weight. Normally, 0.5 to 40 and preferably 1.0 to 20 mg/kg/ day in one or more administrations per day are effective in order to obtain the desired results.
Preferred in the meaning of the present invention are, apart from the compounds mentioned in the Examples, the R- and S-isomers of the following compounds of general formula I, as well as the salts and esters thereof and especially the laevorotary (-)-isomers: 1. 5-(4-chlorophenyl)-2-/5-(1,1-dimethylethyl)phenoxyZ-pentanoic acid 2. 2-(4-methylphenoxy)-4-(2-phenylethoxy)-butyric acid . 4-/2-(4-chlorophenyl)-ethox27~2-A-(l,l-dimethyle thy 1)-Dhenox;y7-butyric acid -124. 4-z/2-(4-chlorophenyl)-ethylamino7-2-/5-( 1,1dimethylethyl)-phenox27-butyric acid . 5-(4-chloropheny lme thoxy )_2-(4-methylphenoxy )pentanoic acid 6. 2-/5-( 1,l-dimethylethyl)-phenox2.7-6-phenoxyhexanoic acid 7. 6-(2-chlorophenoxy)-2-(4-methylphenoxy)-hexanoic acid 8. 6-(4-chlorophenoxy)-2-(4-cyanophenoxy)-'nexanoic 10 acid 9. 6-(4-chlorophenoxy)-2-(4-dimethylaminophenoxy)hexanoic acid . 6-(4-fluorophenoxy)-2-(4-methylphenoxy)-hexanoic acid 11» 6-(4-hydroxyphenoxy)-2-(4-methylphenoxy)-hexanoic acid 12. 2-/5,(1rl-dimethylethyl)-phenylthio7-6-phenoxyhexanoic acid . 6-(4-chlorophenylthio)-2-(4-methylphenoxy)20 hexanoic acid 14. 6-(4-chlorophenylsulphonyl)-2-(4-methylphenoxy)hexanoic acid . 6-(4-chlorophenylsulphony1)-2-/5-(1,1-dimetnylethyl)-phenox2.7-dexanoic acid 16. 6-(4-chlorophenylsulphonamido)-2-/5-(1,1-dimethyl ethyl)-phenox2,7-hexanoic acid 17. 6-(4-chlorophenylamino)-2-/5-(l,1-dimethylethyl)phenox2,7-hexanoic acid -1518. 2-/^-(1,1-dimethy lethyl)-phenox27-7-phenylheptanoic acid 19. 2-/5-(1,1-dime thyle thy1)-phenox27-7-(5-me thy1phenyl)-heptanoic acid . 2-/5-(1,1-dimethylethyl)-phenox27-7-/5-(1,1dimethy1ethyl)-phenyl7-heptanoic acid 21, 7-(5-chlorophenyl)-2-(5-butylp'nenoxy )-heptanoic acid 22, 2-/3,5-bis-(l,1-dimethylethy1)-phenox27-7-(510 chlorophenyl)-heptanoic acid 23, 7-(5-chlorophenyl)-2-/5-(1,1,3,3-tetramethy1butyl)--ohenox^Z-heptanoic acid . 7-(5-chlorophenyl)-2-(3,-5-dimethy1-5-hydroxyphenoxy)-heptanoic acid . 2-(5-chlorophenoxy)-7-(5-chlorophenyl)-heptanoic acid 26. 2-/3,5-bis-( 1 ,.l-dimethylethyl)-5-hydroxyphenox277-(5-chlorophenyl)-heptanoic acid 27. 7-(5-chlorophenyl)-2-(4-methoxyphenoxy)-heptanoic acid 28. 7-(5-chloropheny1)-2-/5-(1,1-dimethylethoxy)phenox^-heptanoic acid 29. 7-(4-chloropheny1)-2-(3-trifluoromethylphenoxy)heptanoic acid . 7-(3,5-dimethyl-5-hydroxyphenyl)-2-(i-methylphenoxy)-heptanoic acid 31. 2-/5-(1,1-dime thy1ethyl)-phenoxy7-7-(3,5-dimethy1 5-hydroxyphenyl)-heptanoic acid -1432. 7-/3,5-bi9-(l,l-dimethylethyl)-+-hydroxyphenyl72-/5-(1,1-dimethylethyl)-phenoxy7-heptanoic acid 33. 2-/5-(1,1-dimethyIethy1)-Dheno 3^7-7-(3-trifluoromethylphenyl)-heptanoic acid 3+. 7-(2-dimethylaminophenyl)-2-/5-(1,1-dimethyIethy1)phenoxy_7-hep tanoic acid . 2-/5-(1,1-dimethylethyl)-phenylthio7-phenylheptanoic acid 36. 7-(+-chloropheny1)-2-/5-(lrl-dimethyIethy1)10 phenylthio7—heptanoic acid 37. 7-(+-chlorophenyl)-2-/2-(+-methylphenyl)-ethylthio7— heptanoic acid 38. 2-/5-(lrl-dimethylethyl)-phenox27-8-phenyloctanoic acid 39. 8-(+-chlorophenyl)-2-(+-methylphenoxy)-octanoic acid +0. 8-(+-chlorophenoxy)-2-(+-methylphenoxy)-octanoic acid The following Examples are given for the purpose of illustrating the present invention: Example 1. ( + )-7-(4-Chioropheny1)-2-/5-(1,1-dimethyIethy1)phenoxy7-heptanoic acid sodium salt.
A solution of 1+5 g (0.373 mol) racemic 7-(+chlorophenyl)-2-/5-(1,1-dimethyIethyl)-phenoxy725 heptanoic acid in a mixture of 50 ml ethyl acetate and 150 ml isohexane is mixed with a solution of 61.6 g (0.373 mol) (1R,2S)-(-)-ephedrine in a mixture of 50 ml ethyl acetate and 150 ml isohexane. A preIE 921061 -15cipitate slowly crystallises which is recrystallised three times from ethyl acetate. There are obtained 100.9 g (49* of theory, referred to the racemate used) (-)-7~(4-chlorophenyl)-2-/5-(1,1-diraethylethy1)5 phenox^rZ-heptanoic acid /(lR^2S)-(-)-ephedrine7 salt; D: -6.9° (c = 1>6, methanol). 100 g (0.18 mol) (-)-7-(4-chlorophenyl)-2-/5(l,l-dimethylethyl)-phenox27-heptanoic acid /ClRr2S)(-)-ephedrine7 salt are introduced, with ice cooling and stirring, into 250 ml 2N hydrochloric acid and the mixture is extracted with diethyl ether. The extracts are dried and evaporated. There are obtained 70.2 g (quantitative yield) (-)-7-(4-chlorophenyl)-2/5-( 1 ,.l-dimethylethyl)-phenox27-hept3noic acid; colourless oil; D: +13.5° (c = 1+, methanol).
A fixture of 7° S (0,18 mol) (-)-7-(4-chloropheny1)-2-/5-(1,1-dime thyle thy1)-phenox27-hep tano ic acid, 200 ml ethanol and 70 ml water is mixed dropwise, while stirring, with 90 ml 2N aqueous sodium hydroxide solution. The mixture is stirred until a clear solution is obtained, whereafter the ethanol is evaporated off. The residue is diluted with water, clarified with carbon and evaporated t o dryness. Yield: 68.6 g (93* of theory) (+)-7-(4-chlorophenyl)25 2-/5-( 1,1-dimetflJlethyl)-ohenox27-heptanoic acid sodium salt; amorphous powder; D: +11.9° (c = 1*» methanol). -16In θ manner analogous to Example 1, there are obtained from (IR,2S)-(-)-ephedrine and a) rac.-7-(2-raethoxyphenyl)-2-(4-methylphenoxy)heptanoic acid (+)-7-(2-methoxypheny1)-2-(4-methylphenoxy)heptanoic acid sodium salt: m.p, > 2?0°C (amorphous) b) rac.-6-phenoxy-2-/5-(1,1-dimethylethyl )-phenox,y7heptanoic acid (+)-6-phenoxy-2-/5-(l,1-dimethylethyl)-phenoxy710 heptanoic acid sodium salt; m.p, >3OO°C c) rac.-7-(2-methoxypheny1)-2-/5-(1,1-dimethylethy1)phenoxyZ-heptanoic acid (+)-7-(2-methoxypheny1)-2-/4-(1,1-dimethylethy1)phenox,y7-heptanoic acid sodium salt; m.p. > 270°0; D: +6.7° (c = 1λ>, methanol) d) rac,7-(2-methoxypheny1)-2-/5-(1-methylethy1)phenoxyZ-heptanoic acid (+)-7-(2-methoxypheny1)-2-/4-(1-methylethy1)phenoxy7-heptanoic acid sodium salt 20 e) rac.-5-(4-chlorophenyl)-2-/4-(l,l-dimethylethyl)phenox^Z-pentanoic acid (+)_5-(4-chloropheny1)-2-/5-(1,1-dimethylethy1)phenoxyZ-pentanoic acid sodium salt Example 2, (-)-7-(4-Chioropheny1)-2-/5-(1.l-dimethylethyl)phenoxyZ-heptanoic acid sodium salt.
A solution of 145 g (0.373 mol) racemic 7-(4chlorophenyl)-2-/5-(1,1-dimethylethyl)-phenoxy7IE 921061 -17heptanoic acid in a mixture of 50 ml ethyl acetate and 150 ml isohexane is mixed with a solution of 55 g (0.575 mol) (lS,2R)-(+)-ephedrine hemihydrate in a mixture of 50 ml ethyl acetate and 150 ml isohexane.
The resultant crystals are filtered off with suction and recrystallised three times from ethyl acetate.
There are obtained 99.8 g (48x of theory, referred to the racemate used) (-)-7-(4-chlorophenyl)-2-/£-(l,ldimethylethyl)—phenox27-heptanoic acid /ClS,2R)-( + )10 ephedrine7 salt; D: +6.8° (c = lx, methanol). 99.5 g (0.18 mol) (-)-7-(4-chlorophenyl)-2-/^(lrl-dimethylethyl)-phenox2.7“beptanoic acid /ClS,2R)(+)-ephedrine7 salt are converted with 2N hydrochloric acid into the free acid analogously to Example 1.
Yield: 69.8 g (quantitative yield) (-)-7-(4-chloropheny1)-2-/4-(1,1-dimethyIethyl)—ohenox27-heptanoic acid; colourless oil; D: -15.7° (c. = 1#, methanol). 69.8 g (0.18 mol) (-)_7-(4-chlorophenyl)-2-/T(1,1-dimethylethyl)-phenox2.7-heptanoic acid pre 20 converted into the sodium salt with 2N aqueous sodium hydroxide solution analogously to Example 1. Yield 69.9 g (95* of theory) (-)-7-(4-chlorophenyl)-2-/S( 1 ,l-dimethylethyl)-phenox2,7-beptanoic acid sodium salt amorphous powder; D: -11.5° (c = lx, methanol).
In a manner analogous to Example 2, there are obtained from (lS,2R)-(+)-ephedrine and -18a ) rac.-7-(2-methoxyphenyl)-2-(4-(methylphenoxy)heptanoic acid (-)-7-(2-methoxypheny1)-2-(4-raethylphenoxy)heptanoic acid sodium salt; m.p. 290 - 292°C; D: -6..5° (c = 1+, methanol) b) rac.-6-phenoxy-2-/5t(1,1-dimethylethyl)-phenox27heptanoic acid (-)-6-phenoxy-2-/^Γ-(1,1-dime thy lethy l)-phenox,y7~ heptanoic acid sodium salt; m.p. > 300°C; D: -2.6° (c = 1%, methanol) c ) r ac ..-7-( 2-me thoxyphenyl) -2-/5-( 1,1-dime thy le thyl) — phenoxy7-heptanoic acid (-)-7-(2-methoxyphenyl)-2-/5-(1^1-dimethylethy1)phenoxy7-heptanoic acid sodium salt; m.p. > 270°G; 15 D: -7.5° (c = 1+, methanol) d) rac.-7-(2-methoxyphenyl)-2-/5-(l-methylethyl)phenox2.7-heptanoic acid (-)-7-(2-me thoxyphenyl)-2-/5-(1-me thyle thy1)phenoxy7-heptanoic acid sodium salt; e) rac.-5-(4-chlorophenyl)-2-/5-(l,l-dimethylethyl)phenox2.7-pentanoic acid (-)-5-(4-chloropheny1)-2-/5-(1,1-dimethylethy1)phenoxy7-pentanoic acid sodium salt.
Example 3« ( + )-6-(4-Ch7orophenoxy)-2-(4-methvlphenox-7 )-hexanoic acid.
A solution of 28.5 g (82 mmol) racemic 6-(4chlorophenoxy)-2-(4-methylphenoxy)-hexanoic acid in -19165 ml ethyl acetate is mixed with a solution of 15.5 g (82 mmol) (lR12S)-(-)-ephedrine in 165 ml ethyl acetate. After seeding, crystals slowly separate out which are filtered off with suction and recrystallised three times from ethyl acetate. These crystals are introduced, while stirring and with ice cooling, into 100 ml IN hydrochloric acid and the mixture is extracted with ethyl acetate. The extracts are dried and evaporated. Yield 12.6 g (44¼ of theory, referred to the racemate used) (+)-6-(4chlorophenyl)-2-(4-methylphenoxy)-hexanoic acid; m.p. 72 - 75°G; D: +5.2° (c = ljt>, methanol).
In an analogous manner, there are obtained from: a) rac.-7-(4-chlorophenyl)-2-(4-methylphenoxy)15 heptanoic acid and (lR52S)-(-)-ephedrine (+)-7-(4-chlorophenyl)-2-(4-me thylphenoxy)heptanoic acid; m.p. 80°C; D: +15.0° (c = 1%>, methanol) b) rac.-7-(4-chlorophenyl)-2-(4-methyIphenylthio)20 heptanoic acid and (LR,2S)-(-)-ephedrine ( + )-7-(4-chlorophenyl)-2-(4-methyIpheny1thio )heptanoic acid; m.p. 58 - 60°G; D: +62.1° (c = l/o, methanol) c) rac.-5-(4-chloropheny1)-2-(4-methyIphenylsulphonyl) 4-pentynoic acid and (lR,2S)-(-)-ephedrine (+).5-(4-chlorophenyl)-2-(4-methyIphenylsulphonyl)4-pentynoic acid; m.p. 155 - 156°C; D: +21.5° (c = 1;ϊ,, methanol). -20Example 4, (-)-6-(4-Chlnrophenoxy)-2-(4-methylphenoxy)-hexanoic acid, A solution of 24.0 g (69 mmol) racemic 6-(45 chlorophenoxy)-2-(4-methylphenoxy)-hexanoic acid in 140 ml ethyl acetate is mixed with a solution of 11.4 g (69 mmol) (lS,2R)-(+)-ephedrine in 140 ml ethyl acetate. After seeding, crystals slowly separate out which are filtered off with suction and recrystallised three times from ethyl acetate. These crystals are introduced, while stirring and with ice cooling, into 100 ml IN hydrochloric acid and the mixture is extracted with ethyl acetate. The extracts are dried and evaporated. The residue is triturated under isohexane. Yield 11.1 g (46# of theory, referred to the racemate used) (-)-6-(4-chloropheny1)-2-(4-methylphenoxy)-hexanoic acid; m.p.. 72 - 74°0; D: -5.2° .(c = 1#, methanol).
In an analogous manner, there are obtained from: a) rac.-7-(4-chloropheny1)-2-(4-methylphenoxy)-heptanoic ecid and (lS,2R)-(+)-ephedrine (-)-7-(4-chloropheny1)-2-(4-methylphenoxy)-heptanoic acid; m.p. 79.5°C; D: -15.1° (c = 1#, methanol) b) rac.-7-(4-chlorophenyl)-2-(4-methylphenylthio)heptanoic acid and (lS^2R)-(+)-ephedrine (-)-7-(4-chlorophenyl)-2-(4-methylnhenylthio)heptanoic acid; m.p. 59 - 61° (c = lA, methanol) -21c) rac. -5-( 4-chlorophenyl )-2-( 4-methy lphenyl sulphonyl )4-pentynoic acid and (IS,2R)-(+)-ephedrine (-)-5-(4-chlorophenyl )-2-( 4-methy lphen.y Is ulphony 1)4-pentynoic acid; m.p. 134 - 136°C; D: -21.8° (c = 1&, methanol).
Example 5, In the following, there are described the results of pharmacological tests which demonstrated, by way of example, the different effectiveness of the enantio10 meric pairs according to the present invention.
Method.
The blood glucose-sinking action of the compounds was determined on ob/ob mice with hereditary overweight type II diabetes and existing insulin resistance The test compounds were administered to fed animals (n = 10) over the course of 5 days as suspension in a tylose solution. 0n the fifth day, the animals were sacrificed and the blood glucose concentration was determined on the blood obtained. The results are set out in the following Table 1 as percentage lowering with regard to a simultaneous control group (n = 10). -22Table 1 Bipod glucose lowering compound dose blood glucose signif- (Example No.) (mg/kg) lowering (ft) icance 1 50 17 n. s. 2 50 89 p < 0.01 5 25 5 n. s. 4 25 51 P < 0.01 5a 100 51 n. s. 4a 100 88 p < 0,01 2a 25 115 p < 0.01 2c 25 91 p < 0.01 n.s, = not significant since p >0.05.

Claims (9)

1. Patent Claims
1. R- and S-carbaxylic acids of the general formula :n R, - A - CH - COOH 1 ’ (I), Y - B - Rg wherein R^ is an aryl, aryloxy, arylthio, arylsulphiny1, 5 arylsulphonyl or arylamino radical containing 6 to 14 carbon atoms, in which the aryl moieties can be substituted by one or more substituents of the group hydroxyl, halogen, C^-Cg-alkyl, O^Gg-a lkoxy, fcrifluoromethyl, cyano, nitro, amino, C^-Cg-alkylamino 10 and di-C^-Cg-alkylamino, Rg is an aryl radical containing 6 to 14 carbon atoms which can be substituted by one or more substituents of the group hydroxyl, halogen,. C^-0g-alkyl, C^-Cg-alkoxy, trifluoromethyl, cyano, nitro, amino, C^-Cg-aIkylamino and di-C^-Cg15 alkylamino, A is a straight-chained or branched, saturated or unsaturated aliphatic radical containing 3 to 10 carbon atoms which is optionally interrupted hy an oxygen atom or the group -S(0) n ~, in which n is 0, 1 or 2, or -NH- and has a chain length of at least 20 3 carbon atoms, with the proviso that there is not a heteroatom on an unsaturated aliphatic carbon atom, Y is an oxygen atom or an -S(0) - group, n is 0, 1 or 2 and 3 is a valency bond or a straight-chained or branched, saturated or unsaturated aliphatic 25 radical containing up to 5 carbon atoms, asW«ll as the physiologically acceptable salts and esters thereof containing up to 8 carbon atoms. -242. R- and S-carboxylic acids of general formula I according to claim 1, wherein R^ is a phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl or phenylamino radical which is optionally
2. 5 substituted one or more times by halogen, hydroxyl, C^-Cg-alkyl, C^-Cg-alkoxy and trifluoromethyl. 5. R- and S-carboxylic acids of general formula I according to claim 2, wherein R^ is a 4-chlorophenyl or 2-methoxyphenyl radical. 10 4. R- and S-carboxylic acids of general formula I according to any of the preceding claims, wherein R 2 is a phenyl radical which is optionally substituted one or more times by halogen, hydroxyl, C^-Cg-alkyl, C^-Cg-alkoxy and trifLuoromethyl. 15 5. R- and S-carboxylic acids of general formula I according to claim 5, wherein R 2 is a 4-methylphenyl or 4-tert.-butylphenyl radical.
3. 6. R- and S-carboxylic acids of general formula I according to any of the preceding claims, wherein 20 A is the group -(GH 2 ) -,in which o is 3 to 10, or the group -X-(CH ? ) , in which £ is 2 to 8 and £ is 1 to 6, o, £ and £ being whole numbers and the sum of £ and £ not being greater than 10 and X being an oxygen atom, or, if R-]_ is phenyl radical as given 25 in the definition of R^, A is also one of the groups -CH 2 -X-(CH 2 ) -, -GH=GH-GH 2 -, -C=C-CH 2 -, -CH=CH-(CH 2 ) p or -C=C-(GH 2 ) -, in which £, £ and X have the abovegiven meanings. -257. R_ and S-carboxylic acids of general formula I according to any of the preceding claims, wherein B is a valency bond or a group -(0Η 2 ) ρ -, in which r is 1 to 5, -CH 2 -GH=CH-, -CH 2 -G=C- or -CH=CH-. 5 8. R- and S-carboxylic acids of general formula I according to any of the preceding claims, wherein Y is an oxygen atom.
4. 9. R- and S-carboxylic acids of general formula I according to any of the preceding claims, wherein
5. 10 Y is an oxygen atom and B is a valency bond. 10. Carboxylic acid derivatives of general formula I according to claim 1 selected from the following group of compounds: (+)-7-(4-chlorophenyl)-2-(4-methylphenylthio)15 heptanoic acid (-)-7-(4-chloropheny1)-2-(4-methylphenylthio)heptanoic acid (+ )-5-(4-chloropheny1)-2-(4-me thylphenyIsulphonyl)pentynoic acid 20 (-)-5-(4-chlorophenyl)-2-(4-methylphenyIsulphony1)pentynoic acid (-)_7-(4-chlorophenyl)-2-(4-methylphenoxy)-heptanoic acid (+)_6-(4-chlorophenoxy)-2-(4-methylphenoxy)-hexanoic 25 acid (-)_6-(4-chlorophenoxy)-2-(4-methylphenoxy)-hexanoic acid -26(-)-7-(4-chloropheny1)-2-/5-(1,1-dimethylethy1)phenoxy7“heptanoic acid (+)-2-/5-(1,1-dimethylethy1)-phenoxy7-6-phenoxyhexanoic acid 5 (-)-2-/5-(1,1-dimethylethyl)-phenoxy7-6-phenoxyhexanoic acid ( + )-7-(2-me thoxypheny1)-2-/5-(1,1-d ime thyle thy1)phenoxy7-hept3noic acid (-)-7-(2-me thoxypheny1)-2-/5-(1,1-dimethyle thy1)10 phenoxy7-heptanoic acid, as well as the physiologically acceptable salts and C^-Cg-alkyl esters thereof.
6. 11. R- and S-carboxylic acids of general formula I according to claim 1 which are hereinbefore specific ically exemplified.
7. 12. Process for the preparation of R- and Scarboxylic acids of general formula I according to any of claims 1 to 11, wherein a) in per se known manner, a racemic mixture of 20 compounds of general formula I is reacted with an optically-active base, the resultant diastereomeric salts are separated by physical methodSjfor example fractional crystallisation or solid-liquid chromatography, and the acids again 25 liberated therefrom, or b) in per se known manner, a racemic mixture of a lower ester of a compound of general formula I -27is enantioselectively cleaved with an enzyme, for example an esteras e or lipase, or c) in known manner, an optically-active compound of the general formula:-H R-. - A - CH - COOR, 5 1,3 (II) X (S- or R-isomer) in which R^ and A have the abovegiven meanings and X is a group which can be split off, for example a halogen atom or a sulphonic acid residue, is reacted with a compound of the general 10 formula:H - Y - B - R 2 (III) in which B and R 2 have the above-given meanings and Y is a sulphur or oxygen atom, and subsequently the ester obtained of a compound of general formula
8. 15 I is saponified to give a free carboxylic acid ccf general formula I, whereafter, if desired, a derivative obtained in which Y is a sulphur atom is converted by oxidation of the sulphur atom into a derivative in which Y is SO or S0 2< 20 13. Process according to claim 12 for the preparation of R- and S-carboxylic acids of general formula I according to any of claims 1 to 11, substantially as hereinbefore described and exemplified. 1+. R_ and S-carboxylic acids of general formula I 25 according to any of claims 1 to 11, whenever prepared by the process according to claim 12 or 13. -2815. Pharmaceutical compositions containing at least one R- or S-carboxylic acid of general formula I according to any of claims 1 to 11 and 14, as well as pharmaceutically conventional carrier and 5 additive materials.
9. 16. The use of R_ and S_carboxylic acids of general formula 1 according to any of claims 1 to 11 and 14 for the preparation of pharmaceutical compositions with blood sugar-sinking action. 10 17. The use of R- and S-carboxylic acids of general formula I according to any of claims 1 to 11 and 14 for the preparation of pharmaceutical compositions for the treatment of diabetes, prediabetes, maturity onset diabetes and fat metabolism diseases.
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US8329749B2 (en) 1999-06-04 2012-12-11 Metabolex, Inc. Use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of hyperuricemia
US8354448B2 (en) 1999-06-04 2013-01-15 Metabolex, Inc. Use of (−)(3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives for treatment of type 2 diabetes

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US6624194B1 (en) 1999-06-04 2003-09-23 Metabolex, Inc. Use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
US7199259B2 (en) 2003-06-20 2007-04-03 Metabolex, Inc. Resolution of α-(phenoxy)phenylacetic acid derivatives
US7714131B2 (en) 2005-09-23 2010-05-11 Metabolex, Inc. Process for the stereoselective preparation of (−)-halofenate and derivatives thereof
AU2011306397A1 (en) 2010-09-24 2013-05-02 Ranbaxy Laboratories Limited Matrix metalloproteinase inhibitors

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US3864384A (en) * 1970-05-05 1975-02-04 Rorer Inc William H Substituted phenylacetic acid compounds
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US8329749B2 (en) 1999-06-04 2012-12-11 Metabolex, Inc. Use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of hyperuricemia
US8354448B2 (en) 1999-06-04 2013-01-15 Metabolex, Inc. Use of (−)(3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives for treatment of type 2 diabetes
US8481597B2 (en) 1999-06-04 2013-07-09 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia

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