The invention relates to 2-cyclσprσpylacetic acid derivatives. It concerns a compound of formula I

wherein

Ri 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, 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 Ri 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. 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,l-benzisothiazo le-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 R ₂ 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 mono- or 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

wherein

Ris 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 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

wherein

Ri is as defined above and

R _2a is optionally esterified or amidated carboxy, appropriately oxidizing a corresponding compound of formula lb

wherein Ri 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 lb as defined above, deprotecting a corresponding compound of formula II

wherein

Ri 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 -50 ^β C and about 25 ^β C, 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 0 ^β C and about 40 ^β C, 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:

Rι-CH=0 VI

R ₁ -HC=CH-CH ₂ -CH ₂ 0-Σ « ^ +

IV (Phe) ₃ P=CH-CH ₂ -CH ₂ 0-X

VII

H ₃ CCHCI2

B) V

III wherein X is an alcohol protecting group and Ri 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 phosphoniu 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 10 ^β C and about 60 ^β C, especially between about 20 ^β C and about 40 ^β C.

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 -60 ^β C and about -20 ^e C, especially between about -40 ^e C and about -30 ^e C.

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 50 ^e C and about 100 ^e C, especially between about 60 ^e C and about 80 ^e C.

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.

Kxample 1: cis-2-[2-Methylene-3-(8-{4-chloropheno∑y}octyl)cyclopropyl ] ^■ acetic acid and sodium salt

[Formula I: Rj ^s 8-(4-chlorophenoxy)octyl; R _∑ = carboxy; in free acid and sodium salt form]

[Process variant a) , oxidation]

a) Oxidation: A solution of 6.6 g cis-2-[2-Bet_.ylene-3-(8-{4-ct__oro- phenoxyloctyl)cyclopropyl]ethanol (compound of Example la) 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 Celite ^R . 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 HC1, 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.

R ^y ampie la: CJ3-2-[2-Met_tylene-3-(8-{4-chlorophenoxy)octyl)cyclopropyl] - ethanol

[Formula I: Rj, = 8-(4-chlorophenoxy)octyl; R ₂ = hydroxymethyl;

[Process variant b) , deprotection]

To a solution of 9.6 g of cis-2-I2-___thylene-3-(8-{4-chloro- phenoxyjoctyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (compound of formula II) in 100 ml of methanol/toluene 3:1 is added 1.2 g p-toluene- sulfonic 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:

¹³ C-NMR: 16.3-19.6 (2C, cyclopropyl ring); 26.0-30.6 (8C, long chain); 63.2-68.3 (2C, CH ₂ 0) ; 101.6 (1C, -CH ₂ ); 115.8-157.8 (6C, aromatic); 125.3 (1C, =C) .

The starting material is obtained as follows:

Step A) : 23.5 g of 3-{tet_a_-y^_ropyran-2-ylo y)propylpl-θsphoniua bromide

(phosphonium salt of a compound of formula VII, prepared by reaction of 3-bromo-l-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-chloropheno y)nonaldehyde (compound of formula VI, prepared by reaction of 4-chlorophenol in di ethylformamide 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 -smperature 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-l-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 -37*. This mixture is stirred at that temperature for an additional 2 hours and then allowed to warm to -5 ^β 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, <ύs-2-[2-<dιloro-2-aιethyl-3-(8-{4-chloropheι_oy}o ctyl)- cyclσprσpyl]ethyl tetrahydrqpyran-2-yl ether (compound of formula III) with a small proportion (about 5 %) of trans isomer is obtained as a pale yellow oil;

-12-

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-chlorophenox }octyl)cyclopropyl]ethyl tetrahydropyran-2-yl ether (compound of formula II) with a small proportion

(about 5 %) of trans isomer is obtained:

¹³ C-NMR: 16.6-19.6 (2C, cyclopropyl ring); 25.5-30.8 (11C, long chain + THP ring); 62.2-68.3 (3C, CH ₂ 0) ; 98.9 (1C, OCO) ; 101.4 (1C, =CH ₂ ); 115.8-157.8 (6C, aromatic); 125.3 (1C, =C) .

Example 2: cis-2-(3-Dodecyl-2-nethylenecyclopropyl)acetamide

[Formula I: Ri = dodecyl; R ₂ = C0NH ₂ ] [Amide formation]

To a solution of 165 mg of cis-2-(3-dodecyl-2-___thylene- cyclopropyl)-acetic acid (compound of Example 3) in 3 ml of ethyl acetate is added a solution of 70 mg of N-hydroxysucci__i_u.de in 3 ml of ethyl acetate, followed by the portionwise addition of 125 mg of dicyclohexyl- carbodii ide 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-hydxoxysucciiiimide 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. 59*-63 ^β ) with a small proportion (about 5 %) of trans isomer.

The following compounds of the invention (formula I) are obtained in analogous manner as indicated be

Analogously Physicochemi

Example Ri R ₂ Configuration Process variant to characteriza Mo. Ex. No. data

3

3a

3b

3c

4

5

6

7

8

9 10 10a 10b

11 11a lib lie

Analogously Physicochemica

Example Ri R ₂ Configuration Process variant to characterizati Ho. Ex. No. data

19 octyl C0NH ₂ cis racemate amide formation ₂ 4)7) NMR ^*

* ⁾ The following intermediates are predominantly formed:

Step A) : cis-hexadec-3-en-l-yl tetrahydropyran-2-yl ether (pale yellow oil) ; from tridecanaldehy 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 o

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; ^la) as under footnote ^x >, 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 sm 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;

> starting from the compound of Example 10, via the N-hydroxy3uccin_x_ide 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-ι_ethano-2,l-benzi3θtl_iazole-2 _r 2-dio__ide [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-Caπφhorsultam™ (> 99 % purity);

⁶ > starting from the corresponding alcohol (compound of formula lb);

⁷ ' together with a small proportion (about 5 %) of trans isomer; ⁸⁾ together with a small proportion of cis isomer;

' ^• H-NMR (CDCI ₃ ) : Example 10 δ 11.01 (broad,s,lH); 5.40 (d,2H); 2.58-2.36 (m,2H); 1.86-1.59 (ra,lH);

1.50-1.16 (broad,m,15H); 0.90 (t,3H);

Example 19 55.64 (broad,s,2H); 5.44-5.40 (m,2H); 2.42-2.18 (m,2H); 1.84-1.59 (m,lH)

1.50-1.15 (broad,m,15H); 0.88 (t,3H);

¹³ C-NMR: Example 23 16.3-19.5 (2C, cyclopropyl ring); 26.0-30.6 (6C, long chain); 63.2-68.3

(2C, CH ₂ 0); 101.7 (1C, =CH ₂ ); 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-chloro- phenoxy}octyl)cyclopropyl]acetic acid sodium salt (the compound of Example 1, step b) , has an ED5 ₀ 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:

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) .