WO1992001447A1 - 2-cyclopropylacetic acid derivatives - Google Patents

2-cyclopropylacetic acid derivatives Download PDF

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Publication number
WO1992001447A1
WO1992001447A1 PCT/EP1991/001331 EP9101331W WO9201447A1 WO 1992001447 A1 WO1992001447 A1 WO 1992001447A1 EP 9101331 W EP9101331 W EP 9101331W WO 9201447 A1 WO9201447 A1 WO 9201447A1
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Prior art keywords
formula
compound
cis
carbon atoms
appropriate
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PCT/EP1991/001331
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French (fr)
Inventor
Laszlo Revesz
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Sandoz Ltd.
Sandoz-Patent-Gmbh
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Publication of WO1992001447A1 publication Critical patent/WO1992001447A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/10—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/05—Alcohols containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/26—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing rings other than 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
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention relates to 2-cyclopropylacetic acid derivatives. It concerns a compound of formula I
  • R 1 is a straight-chained alkyl group of 6 to 20 carbon atoms, a phenylalkyl group wherein the alkylene moiety is straight-chained and is of 3 to 15 carbon atoms, or a phenoxyalkyl or phenylthioalkyl group wherein the alkylene moiety is straight-chained and is of 2 to 14 carbon atoms, whereby any phenyl moiety optionally is monosubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35,
  • R 2 is hydroxymethyl or optionally esterified or amidated carboxy
  • a compound of the invention can be in cis or trans geometrical isomer form.
  • the cis form i.e. the form wherein R 1 and the -CH 2 -R 2 moiety are on the same side of the plane formed by the cyclopropyl moiety, is preferred.
  • Each geometrical isomer form can be in racemic or optically active form.
  • the compound of, e.g., Example 11 is a cis racemate; it can be in the 3R,4S (compound of Example 11a) or the 3S,4R (compound of Example lib) optically active form.
  • Individual geometrical isomers are obtained in conventional manner, e.g. either by physical separation such as distillation or, preferably, from corresponding isomeric starting
  • Individual enantiomers are obtained in conventional manner from corresponding optically active starting materials or by separation of the corresponding racemates, e.g. by high pressure liquid chromatography or, preferably, Dupont 500TM liquid chromatography of an amide of the racemic acid with an optically active amine such as L-phenylglycine or, preferably, (+)-hexahydro-8, 8-dimethyl-3H-3a, 6-methano-2, 1-benzisothiazole-2, 2-dioxide [i.e. (+)-10,2-CamphorsultamTM, Fluka Chemicals], followed by hydrolysis of the resultant optically active amide.
  • an optically active amine such as L-phenylglycine or, preferably, (+)-hexahydro-8, 8-dimethyl-3H-3a, 6-methano-2, 1-benzisothiazole-2, 2-dioxide [i.e. (+)-10,2-CamphorsultamTM, Fluka Chemicals], followed by hydro
  • a compound of formula I preferably is in free acid or salt, especially in salt, particularly sodium salt form.
  • a salt preferably is a pharmaceutically acceptable, particularly a metal salt such as the sodium or potassium, especially the sodium salt.
  • An esterified carboxy group R 2 preferably is esterified with a pharmaceutically acceptable and physiologically hydrolyzable ester moiety.
  • An esterified carboxy group R 2 preferably is alkoxycarbonyl.
  • amidated carboxy group preferably is amidated with a
  • An amidated carboxy group R 2 preferably is aminocarbonyl optionally monoor disubstituted by alkyl of 1 to 4 carbon atoms, phenyl or
  • Straight-chained alkyl of 6 to 20 carbon atoms preferably is of 8 to 16, especially of 10 to 13, particularly of 12 carbon atoms.
  • the alkylene moiety of phenylalkyl preferably is of 5 to 12, especially of 8 to 10 carbon atoms.
  • phenylthioalkyl preferably is of 5 to 12, especially of 8 to 10 carbon atoms.
  • a phenyl moiety may be unsubstituted.
  • When it is substituted it preferably is substituted in the 4 position, preferably by halogen, especially chlorine.
  • Alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms preferably are methyl and, respectively, methoxy.
  • Halogen preferably is fluorine or chlorine, especially chlorine.
  • a subgroup of compounds of the invention is the compounds of formula Is
  • R 1s is a straight-chained alkyl group of 6 to 15 carbon atoms or a
  • phenoxyalkyl group wherein the alkylene moiety is straight-chained and is of 4 to 10 carbon atoms, whereby the phenyl moiety optionally is substituted in the 4 position by chlorine, and
  • R 2a is hydroxymethyl or carboxy optionally amidated in the form of an
  • a compound of the invention can be obtained by a process which comprises
  • R 1 is as defined above and
  • R 2a is optionally esterified or amidated carboxy
  • R 1 is as defined above; and optionally esterifying or amidating the carboxy group in the resultant carboxylic acid; and b) for the preparation of a compound of formula Ib as defined above, deprotecting a corresponding compound of formula II
  • R 1 is as defined above and
  • X is an alcohol protecting group, and recovering the resultant compound of formula I in free form or salt form as appropriate.
  • the process of the invention can be effected in conventional manner.
  • Process variant a) is an oxidation of an alcohol to the carboxylic acid. It is effected in conventional manner.
  • the reaction is effected with a selective oxidizing agent, namely any oxidizing agent capable of oxidizing an alcohol to an acid without oxidizing the 2-methylene double bond, such as pyridinium dichromate in dimethylformamide or, preferably, chromic acid (Jones reagent).
  • the reaction preferably is effected in an inert organic solvent, preferably a ketone, especially acetone.
  • the temperature preferably is between about -50oC and about 25oC, especially about -20°C and about -5°C.
  • the optional amidation or esterification of the carboxyl group is also effected in conventional manner, e.g.
  • Esters can be prepared by reacting the acid with an alcohol in the presence of an ester-forming reagent such as dicyclohexylcarbodiimide, or by reacting a reactive derivative of the acid such as the acid chloride with the alcohol.
  • Amides can be obtained by reacting a reactive derivative such as the N-hydroxysuccinimide ester of the acid with an amine.
  • Process variant b) is conveniently carried out by deprotecting a compound of formula II with an acid such as p-toluenesulfonic acid, preferably in an inert solvent such as an aliphatic or aromatic
  • hydrocarbon e.g. toluene or a lower alcohol, e.g. methanol.
  • X preferably is a conventional protecting group such as tetrahydropyran-2-yl.
  • the temperature preferably is between about 0oC and about 40oC, preferably between about 15°C and about 30°C.
  • a compound of the invention can be isolated from the reaction mixture by conventional techniques, e.g. chromatography and/or
  • Salts can e.g. be prepared by reacting the acid with a reactive form of a cation, such as sodium or potassium hydroxide or methoxide.
  • a reactive form of a cation such as sodium or potassium hydroxide or methoxide.
  • a compound of formula II can be prepared e.g. in accordance with the following reaction scheme:
  • Step A) is a Wittig reaction. It is carried out e.g. by reacting an aldehyde of formula VI with a hydroxy-protected triphenylphosphorane of formula VII or a corresponding phosphonium salt such as phosphonium bromide, conveniently in an inert solvent such as an aliphatic or aromatic hydrocarbon or an ether, e.g. toluene or tetrahydrofuran, in the presence of a base.
  • an inert solvent such as an aliphatic or aromatic hydrocarbon or an ether, e.g. toluene or tetrahydrofuran
  • the relative proportions of geometrical isomers formed can be varied depending on the base selected. With e.g. potassium
  • the temperature is preferably between about 10oC and about 60oC, especially between about 20oC and about 40oC.
  • Step B) is preferably carried out in an inert solvent in the presence of butyl lithium.
  • the inert solvent is preferably an aliphatic or aromatic hydrocarbon such as hexane, or an ether such as diethyl ether.
  • the temperature is preferably between about -60oC and about -20oC, especially between about -40oC and about -30oC.
  • Step C) is preferably carried out in an inert solvent with a dehydrohalogenating agent such as potassium t-butoxide.
  • the inert solvent is preferably polar, such as t-butanol, especially dimethylsulfoxide.
  • the temperature preferably is between about 50oC and about 100oC, especially between about 60oC and about 80oC.
  • a compound used as a starting material is known or can be prepared by known methods starting from known compounds, e.g. as described in the Examples.
  • the predominantly cis or predominantly trans isomer obtained according to step A) above can, if desired or indicated, be further purified e.g. by physical means such as chromatography or distillation at any stage in the process after step A).
  • Example 1 cis-2-[2-Methylene-3-(8- ⁇ 4-chlorophenoxy ⁇ octyl)cyclopropyl]- acetic acid and sodium salt
  • Example 1a cis-2-[2-Methylene-3-(8- ⁇ 4-chlorophenoxy ⁇ octyl)cyclopropyl]- ethanol
  • the starting material is obtained as follows:
  • Step A) 23.5 g of 3- ⁇ tetrahydropyran-2-yloxy)propylphosphonium bromide
  • triphenylphosphine in acetonitrile is suspended in 200 ml of anhydrous tetrahydrofuran and to this suspension is slowly added at room temperature 80 ml of a 0.675 M solution of potassium bis(trimethylsilyl) amide. The mixture is allowed to warm to about 30° and the dark orange solution obtained is stirred at room temperature for 2 hours.
  • Step B) A solution of 12.4 g of the ether of step A) above in 13 ml of diethyl ether and 6.6 ml of 1,1-dichloroethane (compound of formula V) is cooled to -37° and 45 ml of 1.6 M n-butyl lithium in hexane is added dropwise over a period of 7.5 hours at a temperature of -37o. This mixture is stirred at that temperature for an additional 2 hours and then allowed to warm to -5o over 12 hours. To the mixture is added 20 ml of water; the aqueous phase is then extracted twice with diethyl ether. The extracts are combined, dried over magnesium sulfate and then evaporated to dryness.
  • Step C) A solution of 14.2 g of the crude ether of step B) above in 75 ml of anhydrous dimethylsulfoxide is heated to 70° and 5.8 g potassium t-butoxide is added over a period of 10 minutes. This mixture is heated at
  • Step A) cis-hexadec-3-en-1-yl tetrahydropyran-2-yl ether (pale yellow oil); from tridecanaldehyde, compound of formula VI);
  • Step B) cis-2-[(2-chloro-2-methyl-3-dodecyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (pale yellow oil);
  • Step C) cis-2-(3-dodecyl-2-methylenecyclopropyl)ethyl tetrahydropyran-2-yl ether (pale yellow oil;
  • step A) lithium bromide and phenyllithium in place of potassium
  • fractionation is effected by Dupont 500TM liquid chromatography of the amide with (-)-hexahydro-8,8-di- methyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide [i.e. (-)-10,2-CamphorsultamTM, Fluka Chemicals] followed by hydrolysis with 1 N lithium hydroxide in tetrahydrofuran, resulting in pure enantiomer (> 99 % purity);
  • Example 19 ⁇ 5.64 (broad, s,2H); 5.44-5.40 (m,2H); 2.42-2.18 (m,2H); 1.84-1.59 (m,1H);
  • the compounds of the invention in free acid form or in the form of a pharmaceutically acceptable salt, ester or amide possess interesting pharmacological activity. They are indicated for use as pharmaceuticals.
  • This activity can be determined e.g. in the chronic hypoglycemic screen test: Male Sprague-Dawley rats, 2 to 3 months of age, weighing 200 to 220 grams, are kept in a room at a controlled ambient temperature of 22*C and a 12/12 hour light/dark cycle for one week before and during testing. The rats are fed a high fat diet ad libitum. At fed state, 40 mg of streptozotocin/kg body weight are injected via the tail vain. One week later, those rats are considered to be diabetic which have fed blood glucose of greater than 200 mg/dl and, following an overnight fast, when given an oral glucose tolerance test have blood glucose of 41 to 80 mg/dl 3 hours after the test.
  • Blood glucose is determined with a YSI Glucose Analyzer. On day 1, food is removed from rats at 9:00 a.m.; and after an initial blood glucose reading is taken via the tail vein, vehicle (control) or compound (9 rats/treatment) is administered orally. Six hours later blood glucose level is measured and immediately thereafter the rats are refed. The same rats are given either vehicle or drug once a day for 11 consecutive days. Blood glucose is then determined after a 6-hour fast post dosing on days 4, 8, and 11. The ED 50 value is the amount of compound required to produce a 50 % reduction on day 11 of the average increase in blood glucose level induced by streptozotocin.
  • the compounds are active in the above test at a dosage of from about 1 mg/kg to about 100 mg/kg per day of drug given orally.
  • the compounds are therefore indicated for use in the treatment of diabetes and in lowering blood cholesterol and triglyceride level.
  • the dosage to be employed will vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 1 mg/kg to about 100 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For the larger mammals, for example primates such as humans, the total daily dosage is from about 5 mg to about 500 mg per day.
  • Unit dosage forms comprise from about 1 mg to about 250 mg of the active compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered in a manner similar to known standards for the above uses.
  • the suitable daily dosage for a particular compound will depend on a number of factors, such as its relative potency of activity. It has for example been determined that the preferred compound of the invention, 2-[2-methylene-3-(8- ⁇ 4-chlorophenoxy ⁇ octyl)cyclopropyl] acetic acid sodium salt (the compound of
  • Example 1 has an ED 50 of approximately 13 mg/kg in the chronic hypoglycemia test.
  • An indicated daily dosage for this compound is from about 1 mg to about 100 mg, preferably from about 5 mg to about 50 mg p.o.
  • the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions or emulsions. These pharmaceutical preparations may contain up to about 90 % of the active ingredient in combination with the carrier or adjuvant.
  • Capsules containing the ingredients indicated below may be prepared by conventional techniques and are indicated for use in the above indications at a dose of one or two capsules, two to four times a day: Ingredient Weight (mg)
  • the invention thus also concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention in free form or pharmaceutically acceptable salt form as appropriate, together with a pharmaceutically acceptable carrier or diluent.
  • It further comprises a process for the preparation of a pharmaceutical composition which comprises mixing a such compound with a pharmaceutically acceptable carrier or diluent.
  • Examples 1, steps a) and b), Examples 3, 3b and 11 are preferred, particularly those in sodium salt form, especially the compound of Example 1, step b).

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Abstract

This invention concerns the compounds of formula (I) wherein R1 and R2 have various significances, in free form or salt form as appropriate. They possess antidiabetic and hypoglycemic activity and are therefore indicated for use in the treatment of diabetes and for lowering blood cholesterol and triglyceride level. They can be prepared by appropriate alcohol oxidation optionally follwed by ester or amide formation, or by deprotection.

Description

2-CYCLOPROPYLACETIC ACID DERIVATIVES
The invention relates to 2-cyclopropylacetic acid derivatives. It concerns a compound of formula I
Figure imgf000003_0001
wherein
R1 is a straight-chained alkyl group of 6 to 20 carbon atoms, a phenylalkyl group wherein the alkylene moiety is straight-chained and is of 3 to 15 carbon atoms, or a phenoxyalkyl or phenylthioalkyl group wherein the alkylene moiety is straight-chained and is of 2 to 14 carbon atoms, whereby any phenyl moiety optionally is monosubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35,
R2 is hydroxymethyl or optionally esterified or amidated carboxy,
in free form or salt form as appropriate, hereinafter briefly named "a compound of the invention". A compound of the invention can be in cis or trans geometrical isomer form. The cis form, i.e. the form wherein R1 and the -CH2-R2 moiety are on the same side of the plane formed by the cyclopropyl moiety, is preferred. Each geometrical isomer form can be in racemic or optically active form. Thus the compound of, e.g., Example 11 is a cis racemate; it can be in the 3R,4S (compound of Example 11a) or the 3S,4R (compound of Example lib) optically active form. Individual geometrical isomers are obtained in conventional manner, e.g. either by physical separation such as distillation or, preferably, from corresponding isomeric starting
materials. Individual enantiomers are obtained in conventional manner from corresponding optically active starting materials or by separation of the corresponding racemates, e.g. by high pressure liquid chromatography or, preferably, Dupont 500™ liquid chromatography of an amide of the racemic acid with an optically active amine such as L-phenylglycine or, preferably, (+)-hexahydro-8, 8-dimethyl-3H-3a, 6-methano-2, 1-benzisothiazole-2, 2-dioxide [i.e. (+)-10,2-Camphorsultam™, Fluka Chemicals], followed by hydrolysis of the resultant optically active amide.
A compound of formula I preferably is in free acid or salt, especially in salt, particularly sodium salt form.
A salt preferably is a pharmaceutically acceptable, particularly a metal salt such as the sodium or potassium, especially the sodium salt.
An esterified carboxy group R2 preferably is esterified with a pharmaceutically acceptable and physiologically hydrolyzable ester moiety. An esterified carboxy group R2 preferably is alkoxycarbonyl.
An amidated carboxy group preferably is amidated with a
pharmaceutically acceptable and physiologically hydrolyzable amino moiety. An amidated carboxy group R2 preferably is aminocarbonyl optionally monoor disubstituted by alkyl of 1 to 4 carbon atoms, phenyl or
straight-chained phenylalkyl of 1 to 4 carbon atoms in the alkylene moiety thereof, whereby any phenyl moiety optionally is monosubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35. It preferably is unsubstituted aminocarbonyl. Straight-chained alkyl of 6 to 20 carbon atoms preferably is of 8 to 16, especially of 10 to 13, particularly of 12 carbon atoms. The alkylene moiety of phenylalkyl preferably is of 5 to 12, especially of 8 to 10 carbon atoms. The alkylene moiety of phenoxyalkyl and
phenylthioalkyl preferably is of 5 to 12, especially of 8 to 10 carbon atoms. A phenyl moiety may be unsubstituted. When it is substituted it preferably is substituted in the 4 position, preferably by halogen, especially chlorine. Alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms preferably are methyl and, respectively, methoxy. Halogen preferably is fluorine or chlorine, especially chlorine.
A subgroup of compounds of the invention is the compounds of formula Is
Is
Figure imgf000005_0001
wherein
R1s is a straight-chained alkyl group of 6 to 15 carbon atoms or a
phenoxyalkyl group wherein the alkylene moiety is straight-chained and is of 4 to 10 carbon atoms, whereby the phenyl moiety optionally is substituted in the 4 position by chlorine, and
R2a is hydroxymethyl or carboxy optionally amidated in the form of an
aminocarbonyl moiety,
in free form or salt form as appropriate. A compound of the invention can be obtained by a process which comprises
a) for the preparation of a compound of formula la
Ia
Figure imgf000006_0001
wherein
R1 is as defined above and
R2a is optionally esterified or amidated carboxy,
appropriately oxidizing a corresponding compound of formula Ib
Ib
Figure imgf000006_0002
wherein R1 is as defined above; and optionally esterifying or amidating the carboxy group in the resultant carboxylic acid; and b) for the preparation of a compound of formula Ib as defined above, deprotecting a corresponding compound of formula II
II
Figure imgf000007_0001
wherein
R1 is as defined above and
X is an alcohol protecting group, and recovering the resultant compound of formula I in free form or salt form as appropriate.
The process of the invention can be effected in conventional manner.
Process variant a) is an oxidation of an alcohol to the carboxylic acid. It is effected in conventional manner. The reaction is effected with a selective oxidizing agent, namely any oxidizing agent capable of oxidizing an alcohol to an acid without oxidizing the 2-methylene double bond, such as pyridinium dichromate in dimethylformamide or, preferably, chromic acid (Jones reagent). The reaction preferably is effected in an inert organic solvent, preferably a ketone, especially acetone. The temperature preferably is between about -50ºC and about 25ºC, especially about -20°C and about -5°C. The optional amidation or esterification of the carboxyl group is also effected in conventional manner, e.g. as described hereunder or in the Examples. Esters can be prepared by reacting the acid with an alcohol in the presence of an ester-forming reagent such as dicyclohexylcarbodiimide, or by reacting a reactive derivative of the acid such as the acid chloride with the alcohol. Amides can be obtained by reacting a reactive derivative such as the N-hydroxysuccinimide ester of the acid with an amine.
Process variant b) is conveniently carried out by deprotecting a compound of formula II with an acid such as p-toluenesulfonic acid, preferably in an inert solvent such as an aliphatic or aromatic
hydrocarbon, e.g. toluene or a lower alcohol, e.g. methanol. X preferably is a conventional protecting group such as tetrahydropyran-2-yl. The temperature preferably is between about 0ºC and about 40ºC, preferably between about 15°C and about 30°C.
A compound of the invention can be isolated from the reaction mixture by conventional techniques, e.g. chromatography and/or
recrystallization.
Salts can e.g. be prepared by reacting the acid with a reactive form of a cation, such as sodium or potassium hydroxide or methoxide.
A compound of formula II can be prepared e.g. in accordance with the following reaction scheme:
Figure imgf000008_0001
Figure imgf000009_0001
wherein X is an alcohol protecting group and R1 is as defined above.
Step A) is a Wittig reaction. It is carried out e.g. by reacting an aldehyde of formula VI with a hydroxy-protected triphenylphosphorane of formula VII or a corresponding phosphonium salt such as phosphonium bromide, conveniently in an inert solvent such as an aliphatic or aromatic hydrocarbon or an ether, e.g. toluene or tetrahydrofuran, in the presence of a base. The relative proportions of geometrical isomers formed can be varied depending on the base selected. With e.g. potassium
bis (trimethylsilyl) amide, predominantly the cis isomer is formed (typically only about 5 % trans isomer is obtained). With e.g. lithium bromide and phenyllithium, predominantly the trans isomer is obtained. The temperature is preferably between about 10ºC and about 60ºC, especially between about 20ºC and about 40ºC.
Step B) is preferably carried out in an inert solvent in the presence of butyl lithium. The inert solvent is preferably an aliphatic or aromatic hydrocarbon such as hexane, or an ether such as diethyl ether. The temperature is preferably between about -60ºC and about -20ºC, especially between about -40ºC and about -30ºC.
Step C) is preferably carried out in an inert solvent with a dehydrohalogenating agent such as potassium t-butoxide. The inert solvent is preferably polar, such as t-butanol, especially dimethylsulfoxide. The temperature preferably is between about 50ºC and about 100ºC, especially between about 60ºC and about 80ºC. Insofar as its preparation is not described herein, a compound used as a starting material is known or can be prepared by known methods starting from known compounds, e.g. as described in the Examples. The predominantly cis or predominantly trans isomer obtained according to step A) above can, if desired or indicated, be further purified e.g. by physical means such as chromatography or distillation at any stage in the process after step A).
The following Examples illustrate the invention. All temperatures are in degrees Centigrade. In the NMRs the shifts are in ppm relative to trimethylsilane.
Example 1: cis-2-[2-Methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]- acetic acid and sodium salt
[Formula I: R1 = 8-(4-chlorophenoxy)octyl; R2 = carboxy;
in free acid and sodium salt form]
[Process variant a), oxidation] a) Oxidation: A solution of 6.6 g cis-2-[2-methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]ethanol (compound of Example 1a) in 80 ml of acetone is cooled to -20° and 14.7 ml of 2.67 M of Jones reagent is added dropwise with stirring over a period of 15 minutes while maintaining the temperature at less than -5°. After the addition is complete, the reaction mixture is stirred for an additional 2.5 hours at less than -5° and then 8 ml of isopropanol is added. This mixture is stirred at 0° for 20 minutes and then filtered through CeliteR. The green residue is washed with excess acetone and the combined filtrates are evaporated under vacuum. The residue (yellow oil) is dissolved in ether, extracted twice with 2 N NaOH, the aqueous phase is washed twice with ether, the water phase is acidified to pH 5 with 2 N HCl, extracted twice with tetrahydrofuran, the organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resultant yellow oil is crystallized with hexane to give the title compound in free acid fore as a white solid (M.P. 54-55°), with a small proportion (about 5 %) of trans isomer. b) Salt formation: To a solution of 1.2 g of the acid obtained under step a) above in 80 ml of ethanol is added 3.4 ml of 1 N NaOH and the resultant solution is stirred for 1 hour. The solvent is evaporated and the residue is triturated with ether to yield the title compound in sodium salt form as a white solid (M.P. 168-170°), with a small proportion
(about 5 %) of trans isomer. Example 1a: cis-2-[2-Methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]- ethanol
[Formula I: R1 = 8-(4-chlorophenoxy)octyl; R2 = hydroxymethyl;
[Process variant b), deprotection]
To a solution of 9.6 g of cis-2-[2-methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (compound of formula II) in 100 ml of methanol/toluene 3:1 is added 1.2 g p-toluenesulfonic acid. The mixture is stirred overnight at room temperature and after evaporating under reduced pressure, the residue is again dissolved in methanol/toluene and stirred for an additional 3.5 hours. To this solution is added 1.2 g of potassium carbonate and stirring is continued for an additional 1.5 hour. The mixture is filtered, evaporated under vacuum, and partitioned between 500 ml of ether and 500 ml of water. The aqueous phase is extracted twice with ether and the combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered and evaporated under reduced pressure. The crude product is purified by flash chromatography using 20 % ethyl acetate/hexane to elute the product. Evaporation of the eluant under reduced pressure yields the title compound as a yellow oil, with a small proportion (about 5 %) of trans isomer:
13C-NMR: 16.3-19.6 (2C, cyclopropyl ring); 26.0-30.6 (8C, long chain);
63.2-68.3 (2C, CH2O) ; 101.6 (1C, =CH2); 115.8-157.8
(6C, aromatic); 125.3 (1C, =C) .
The starting material is obtained as follows:
Step A) : 23.5 g of 3-{tetrahydropyran-2-yloxy)propylphosphonium bromide
(phosphonium salt of a compound of formula VII, prepared by reaction of 3-bromo-1-propanol with dihydropyran in ethanol in the presence of p-toluenesulfonic acid and reaction of the resultant product with
triphenylphosphine in acetonitrile) is suspended in 200 ml of anhydrous tetrahydrofuran and to this suspension is slowly added at room temperature 80 ml of a 0.675 M solution of potassium bis(trimethylsilyl) amide. The mixture is allowed to warm to about 30° and the dark orange solution obtained is stirred at room temperature for 2 hours. A solution of 11.8 g of 9-(4-chlorophenoxy)nonaldehyde (compound of formula VI, prepared by reaction of 4-chlorophenol in dimethylformamide with 1,9-dibromononane in the presence of potassium carbonate and reaction of the resultant product in dimethylsulfoxide with iodomethane and sodium bicarbonate) in 40 ml of tetrahydrofuran is slowly added dropwise. The solution is stirred at room temperature for 60 minutes and then evaporated under reduced pressure. The residue is partitioned between chloroform and water. After separation the aqueous phase is extracted twice with chloroform. The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue is triturated thrice with diethyl ether, filtered, evaporated to dryness under vacuum, and the oil obtained is then purified by flash chromatography using 5 % ethyl acetate/hexane to elute the desired product. After evaporation, cis-12-(4-chlorophenoxy)-dodec-3-en-1-yl tetrahydropyran-2-yl ether (compound of formula IV) with a small proportion (about 5 %) of trans isomer is obtained as a colourless oil;
Step B) : A solution of 12.4 g of the ether of step A) above in 13 ml of diethyl ether and 6.6 ml of 1,1-dichloroethane (compound of formula V) is cooled to -37° and 45 ml of 1.6 M n-butyl lithium in hexane is added dropwise over a period of 7.5 hours at a temperature of -37º. This mixture is stirred at that temperature for an additional 2 hours and then allowed to warm to -5º over 12 hours. To the mixture is added 20 ml of water; the aqueous phase is then extracted twice with diethyl ether. The extracts are combined, dried over magnesium sulfate and then evaporated to dryness. The crude product, cis-2-[2-chloro-2-methyl-3-(8-{4-chlorophenoxy}octyl)-cyclopropyl]ethyl tetrahydropyran-2-yl ether (compound of formula III) with a small proportion (about 5 %) of trans isomer is obtained as a pale yellow oil; Step C) : A solution of 14.2 g of the crude ether of step B) above in 75 ml of anhydrous dimethylsulfoxide is heated to 70° and 5.8 g potassium t-butoxide is added over a period of 10 minutes. This mixture is heated at
70* for 5 hours, 2.4 g of potassium t-butoxide are added, and after heating for 3 more hours the solution is allowed to cool to room temperature.
After adding the mixture to ice and saturated sodium chloride, the aqueous phase is extracted 3 times with ether. The combined extracts are dried over magnesium sulfate, evaporated under vacuum, and the resultant dark oil is purified by flash chromatography (5 % ethyl acetate/hexane). The product, cis-2-[2-methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (compound of formula II) with a small proportion
(about 5 %) of trans isomer is obtained:
13C-NMR: 16.6-19.6 (2C, cyclopropyl ring); 25.5-30.8 (11C, long chain +
THP ring); 62.2-68.3 (3C, CH2O) ; 98.9 (1C, OCO); 101.4 (1C, =CH2); 115.8-157.8 (6C, aromatic); 125.3 (1C, =C).
Example 2: cis-2-(3-Dodecyl-2-methylenecyclopropyl)acetamide
[Formula I: R1 = dodecyl; R2 = CONH2]
[Amide formation]
To a solution of 165 mg of cis-2-(3-dodecyl-2-methylenecyclopropyl)-acetic acid (compound of Example 3) in 3 ml of ethyl acetate is added a solution of 70 mg of N-hydroxysuccinimide in 3 ml of ethyl acetate, followed by the portionwise addition of 125 mg of dicyclohexylcarbodiimide in 3 ml of ethyl acetate. The mixture is stirred at room temperature for 20 hours; and after filtering, the solvent is evaporated off under reduced pressure. After dissolving the residue (which is the crude N-hydxoxysuccinimide ester of the compound of Example 3) in 10 ml of tetrahydrofuran, ammonia gas is bubbled through the solution for
45 minutes. The resulting mixture is filtered and the filtrate is evaporated under reduced pressure. The oil obtained is crystallized from hexane to yield the title compound (M.P. 59º-63º) with a small proportion (about 5 %) of trans isomer. The following compounds of the invention (formula I) are obtained in analogous manner as indicated below:
Analogously Physicochemical
Example R1 R2 Configuration Process variant to characterization No. Ex. No. data
3 dodecyl COOH cis racemate a) 1, step a)6)7) M.P. 34.5-35.5º
3a dodecyl COOH cis 3R,4S-enant. fractionation5a) - M.P. 34°
3b dodecyl COOH cis 3S,4R-enant. fractionation5b) - M.P. 34°
3c dodecyl COOH trans racemate a) 1, step a) 6,8) M.P. 40.5-41.5º
4 4-phenoxybutyl COOH cis racemate a) 1, step a)6)7)
5 4-(4-Cl-phenoxy)butyl COOH cis racemate a) 1, step a)6)7) M.P. 97-100º
6 6-(4-Cl-phenoxy)hexyl COOH cis racemate a) 1, step a)6)7) M.P. 80-81°
7 7-(4-Cl-phenoxy)heptyl COOH cis racemate a) 1, step a)6)7)
8 8-(4-tolyloxy)octyl COOH cis racemate a) 1, step a)6)7)
9 8-(4-methoxyphenoxy)octyl COOH cis racemate a) 1, step a)6)7)
10 octyl COOH cis racemate a) 1, step a)6)7) NMR*
10a tetradecyl COOH cis racemate a) 1, step a)6)7) M.P. 42-43° 10b tridecyl COOH cis racemate a) 1, step a)6)7) M.P. 54-54.5°
11 dodecyl COONa cis racemate salt formation 1, step b)3)7) white solid;
M.P.>200°; ** 11a dodecyl COONa cis 3R,4S-enant. salt formation 1, step b)3) [α]D 25= -10.6º
(c=0.42, MeOH) 11b dodecyl COONa cis 3S,4R-enant. salt formation 1, step b)3) [α]D 25= +9.4°
(c=0.34, MeOH) 11c dodecyl COONa trans racemate salt formation 1, step b)3)8) **
Analogously Physicochemical
Example R1 R2 Configuration Process variant to characterization No. Ex. No. data
12 4-phenoxybutyl COONa cis racemate salt formation 1, step b)3)7)
13 4-(4-Cl-phenoxy)butyl COONa cis racemate salt formation 1, step b)3)7) **
14 6-(4-Cl-phenoxy)hexyl COONa cis racemate salt formation 1, step b)3)7) **
15 7-(4-d-phenoxy)heptyl COONa cis racemate salt formation 1, step b)3)7)
16 8-(4-tolyloxy)octyl COONa cis racemate salt formation 1, step b)3)7)
17 8-(4-methoxyphenoxy)octyl COONa cis racemate salt formation 1, step b)3)7)
18 octyl COONa cis racemate salt formation 1, step b)3)7) **
18a tetradecyl COONa cis racemate salt formation 1, step b)3)7) **
18b tridecyl COONa cis racemate salt formation 1, step b)3)7) **
19 octyl CONH2 cis racemate amide formation 24)7) NMR*
20 dodecyl CH2OH cis racemate b) 1a1) M.P. 90-93°
20a dodecyl CH2OH trans racemate b) 1a1a) ***
21 4-phenoxybutyl CH2OH cis racemate b) 1a2)
22 4-(4-Cl-phenoxy)butyl CH2OH cis racemate b) 1a2) ***
23 6-(4-Cl-phenoxy)hexyl CH2OH cis racemate b) 1a2) NMR*
24 7-(4-Cl-phenoxy)heptyl CH2OH cis racemate b) 1a2)
25 8-(4-tolyloxy)octyl CH2OH cis racemate b) 1a2)
26 8-{4-methoxyphenoxy)octyl CH2OH cis racemate b) 1a2)
27 octyl CH2OH cis racemate b) 1a2) ***
27a tetradecyl CH2OH cis racemate b) 1a2) ***
27b tridecyl CH2OH cis racemate b) 1a2) ***
1) The following intermediates are predominantly formed:
Step A) : cis-hexadec-3-en-1-yl tetrahydropyran-2-yl ether (pale yellow oil); from tridecanaldehyde, compound of formula VI);
Step B) : cis-2-[(2-chloro-2-methyl-3-dodecyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (pale yellow oil);
Step C) : cis-2-(3-dodecyl-2-methylenecyclopropyl)ethyl tetrahydropyran-2-yl ether (pale yellow oil;
B.P. 117-126°/0.13 mmHg);
together with a small proportion (about 5 %) of trans isomer; the end product has a similar proportion of trans isomer;
1a)as under footnote 1), but using for step A) lithium bromide and phenyllithium in place of potassium
bis (trimethylsilyl) amide; predominantly the trans intermediates are obtained, together with a small proportion of cis isomer; the end product has a similar proportion of cis isomer;
2) starting from the corresponding compound of formula II, which is itself prepared according to steps A),
B) and C) from corresponding starting materials, initially from the following compounds of formula VI: 5-phenoxypentaldehyde;
5-(4-chlorophenoxy)pentaldehyde;
7-(4-chlorophenoxy)heptaldehyde;
8-(4-chlorophenoxy)octaldehyde;
9-(4-tolyloxy)nonaldehyde;
9-(4-methoxyphenoxy)nonaldehyde;
nonaldehyde;
pentadecaldehyde; and
tetradecaldehyde;
whereby the intermediates (and thus the end products) are predominantly formed as the cis isomer, together with a small proportion (about 5 %) of trans isomer;
3) starting from the corresponding free acid;
4) starting from the compound of Example 10, via the N-hydroxysuccinimide ester, by reaction of the ester with ammonia gas;
5a) fractionation is effected by Dupont 500™ liquid chromatography of the amide with (-)-hexahydro-8,8-di- methyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide [i.e. (-)-10,2-Camphorsultam™, Fluka Chemicals] followed by hydrolysis with 1 N lithium hydroxide in tetrahydrofuran, resulting in pure enantiomer (> 99 % purity);
5b)as under footnote 5a), using (+)-10,2-Camphorsultam™ (> 99 % purity);
6) starting from the corresponding alcohol (compound of formula Ib);
7) together with a small proportion (about 5 %) of trans isomer;
8) together with a small proportion of cis isomer; * 1H-NMR (CDCl3) : Example 10: δ 11.01 (broad,s,1H); 5.40 (d,2H); 2.58-2.36 (m,2H); 1.86-1.59 (ra,1H);
1.50-1.16 (broad,m,15H); 0.90 (t,3H);
Example 19: δ5.64 (broad, s,2H); 5.44-5.40 (m,2H); 2.42-2.18 (m,2H); 1.84-1.59 (m,1H);
1.50-1.15 (broad,m,15H); 0.88 (t,3H);
13C-NMR: Example 23: 16.3-19.5 (2C, cyclopropyl ring); 26.0-30.6 (6C, long chain); 63.2-68.3
(2C, CH2O); 101.7 (1C, =CH2); 115.8-157.8 (6C, aromatic); 125.3 (1C, =C); ** acidification gives the corresponding free acid; *** oxidation gives the corresponding free acid.
The compounds of the invention in free acid form or in the form of a pharmaceutically acceptable salt, ester or amide possess interesting pharmacological activity. They are indicated for use as pharmaceuticals.
In particular, they possess hypoglycemic and antidiabetic activity.
This activity can be determined e.g. in the chronic hypoglycemic screen test: Male Sprague-Dawley rats, 2 to 3 months of age, weighing 200 to 220 grams, are kept in a room at a controlled ambient temperature of 22*C and a 12/12 hour light/dark cycle for one week before and during testing. The rats are fed a high fat diet ad libitum. At fed state, 40 mg of streptozotocin/kg body weight are injected via the tail vain. One week later, those rats are considered to be diabetic which have fed blood glucose of greater than 200 mg/dl and, following an overnight fast, when given an oral glucose tolerance test have blood glucose of 41 to 80 mg/dl 3 hours after the test. Blood glucose is determined with a YSI Glucose Analyzer. On day 1, food is removed from rats at 9:00 a.m.; and after an initial blood glucose reading is taken via the tail vein, vehicle (control) or compound (9 rats/treatment) is administered orally. Six hours later blood glucose level is measured and immediately thereafter the rats are refed. The same rats are given either vehicle or drug once a day for 11 consecutive days. Blood glucose is then determined after a 6-hour fast post dosing on days 4, 8, and 11. The ED50 value is the amount of compound required to produce a 50 % reduction on day 11 of the average increase in blood glucose level induced by streptozotocin.
The compounds are active in the above test at a dosage of from about 1 mg/kg to about 100 mg/kg per day of drug given orally.
The compounds are therefore indicated for use in the treatment of diabetes and in lowering blood cholesterol and triglyceride level. The dosage to be employed will vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 1 mg/kg to about 100 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For the larger mammals, for example primates such as humans, the total daily dosage is from about 5 mg to about 500 mg per day. Unit dosage forms comprise from about 1 mg to about 250 mg of the active compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
The compounds of the invention may be administered in a manner similar to known standards for the above uses. The suitable daily dosage for a particular compound will depend on a number of factors, such as its relative potency of activity. It has for example been determined that the preferred compound of the invention, 2-[2-methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl] acetic acid sodium salt (the compound of
Example 1, step b), has an ED50 of approximately 13 mg/kg in the chronic hypoglycemia test. An indicated daily dosage for this compound is from about 1 mg to about 100 mg, preferably from about 5 mg to about 50 mg p.o.
For the above use the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions or emulsions. These pharmaceutical preparations may contain up to about 90 % of the active ingredient in combination with the carrier or adjuvant.
Capsules containing the ingredients indicated below may be prepared by conventional techniques and are indicated for use in the above indications at a dose of one or two capsules, two to four times a day: Ingredient Weight (mg)
Compound of Example 1b 50
Lactose 445
Colloidal silicon 50
Stearic acid 5
total: 550 mg
The invention thus also concerns a pharmaceutical composition comprising a compound of the invention in free form or pharmaceutically acceptable salt form as appropriate, together with a pharmaceutically acceptable carrier or diluent.
It further comprises a such compound for use as a pharmaceutical, particularly as an anti-diabetic and blood cholesterol and triglyceride level lowering agent.
It further comprises a process for the preparation of a pharmaceutical composition which comprises mixing a such compound with a pharmaceutically acceptable carrier or diluent.
It further comprises the use of a such compound for the manufacture of a medicament, particularly for the manufacture of a medicament for the treatment of diabetes and for lowering blood cholesterol and triglyceride level.
The compounds of Examples 1, steps a) and b), Examples 3, 3b and 11 are preferred, particularly those in sodium salt form, especially the compound of Example 1, step b).

Claims

C L A I M S
1. A compound of formula I
I
Figure imgf000022_0002
wherein
R1 is a straight-chained alkyl group of 6 to 20 carbon atoms, a phenylalkyl group wherein the alkylene moiety is straight-chained and is of 3 to 15 carbon atoms, or a phenoxyalkyl or phenylthioalkyl group wherein the alkylene moiety is straight-chained and is of 2 to 14 carbon atoms, whereby any phenyl moiety optionally is monosubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35,
R2 is hydroxymethyl or optionally esterified or amidated carboxy,
in free form or salt form as appropriate.
2. A compound according to claim 1 of formula Is
Is
Figure imgf000022_0001
wherein
R1s is a straight-chained alkyl group of 6 to 15 carbon atoms or a
phenoxyalkyl group wherein the alkylene moiety is straight-chained and is of 4 to 10 carbon atoms, whereby the phenyl moiety optionally is substituted in the 4 position by chlorine, and
R2s is hydroxymethyl or carboxy optionally amidated in the form of an
aminocarbonyl moiety,
in free form or salt form as appropriate.
3. A compound according to claim 1 which is cis-2-[2-methylene- 3-(8-{4-chlorophenoxy}octyl)cyclopropyl]acetic acid or the sodium salt thereof.
4. The compound according to claim 1 which is
either cis-2-[2-methylene-3-(8-{4-chlorophenoxy}octyl)cyclopropyl]- ethanol
or cis-2-(3-dodecyl-2-methylenecyclopropyl)acetamide, or which is of formula I and is a cis racemate and
either R1 is dodecyl, 4-phenoxybutyl, 4-(4-Cl-phenoxy)butyl,
6-(4-Cl-phenoxy)hexyl, 7-(4-Cl-phenoxy)heptyl,
8-(4-tolyloxy)octyl, 8-(4-methoxyphenoxy)octyl, octyl, tetradecyl or tridecyl and
R2 is COOH, COONa or CH2OH,
or R1 is octyl and
R2 is CONH2,
or which is of formula I and is a trans racemate and
R1 is dodecyl and
R2 is COOH, COONa or CH2OH,
or which is of formula I wherein the configuration is cis and is either
3R, 4S or 3S, 4R,
R1 is dodecyl and
R2 is COOH or COONa.
5. A process for the preparation of a compound according to claim 1 which comprises
a) for the preparation of a compound of formula Ia
Ia
Figure imgf000024_0002
wherein
R1 is as defined in claim 1 and
R2a is optionally esterified or amidated carboxy,
appropriately oxidizing a corresponding compound of formula Ib
Ib
Figure imgf000024_0001
wherein R1 is as defined in claim 1; and optionally esterifying or amidating the carboxy group in the resultant carboxylic acid; or b) for the preparation of a compound of formula Ib as defined in this claim, deprotecting a corresponding compound of formula II
II
Figure imgf000025_0001
wherein
R1 is as defined in claim 1 and
X is an alcohol protecting group, and recovering the resultant compound of formula I in free form or salt form as appropriate.
6. A pharmaceutical composition comprising a compound according to claim 1 in free form or pharmaceutically acceptable salt form as appropriate, together with a pharmaceutically acceptable carrier or diluent.
7. A compound according to claim 1 in free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical.
8. A process for the preparation of a pharmaceutical composition which comprises mixing a compound according to claim 1 in free form or
pharmaceutically acceptable salt form as appropriate, with a
pharmaceutically acceptable carrier or diluent.
9. Use of a compound according to claim 1 in free form or pharmaceutically acceptable salt form as appropriate, for the manufacture of a medicament.
10. A method of treatment of diabetes or for lowering blood cholesterol and triglyceride level which comprises administering a therapeutically effective amount of a compound according to claim 1 in free form or pharmaceutically acceptable salt form as appropriate, to a patient in need of such treatment.
PCT/EP1991/001331 1990-07-18 1991-07-16 2-cyclopropylacetic acid derivatives WO1992001447A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956077A (en) * 1958-07-07 1960-10-11 Abbott Lab Ester of methylenecyclopropane-carboxylic acid
US2956076A (en) * 1958-07-07 1960-10-11 Abbott Lab Cyclopropane-formamidomalonate intermediates and process
CH482648A (en) * 1963-11-05 1969-12-15 Whitefin Holding Sa Process for the preparation of new phenylcyclopropane compounds
EP0015604A1 (en) * 1979-03-05 1980-09-17 Shell Internationale Researchmaatschappij B.V. Compounds and compositions for use in inhibition of lipogenesis in mammals

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Publication number Priority date Publication date Assignee Title
US2956077A (en) * 1958-07-07 1960-10-11 Abbott Lab Ester of methylenecyclopropane-carboxylic acid
US2956076A (en) * 1958-07-07 1960-10-11 Abbott Lab Cyclopropane-formamidomalonate intermediates and process
CH482648A (en) * 1963-11-05 1969-12-15 Whitefin Holding Sa Process for the preparation of new phenylcyclopropane compounds
EP0015604A1 (en) * 1979-03-05 1980-09-17 Shell Internationale Researchmaatschappij B.V. Compounds and compositions for use in inhibition of lipogenesis in mammals

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Title
Chemical Abstracts, volume 99, no. 5, 1 August 1983, (Columbus, Ohio, US), Stirk, Janet H. et al. : "The effects of some short-chain fatty acids on pyruvate carboxylate activity in intact isolated rat liver mitochondria ", see page 201, abstract 34620m, & Biochem. Soc. Trans. 1983, 11( 3), 286- 28 *

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