DE2515115A1 - 3 BETA-HYDROXY-2- (SUBSTITUTED 1-ALKENYL) -5-OXOCYCLOPENTAN-1-HEPTANIC ACIDS - Google Patents

Description

DR. J: n ^{/ a} ,; ■■ : AIR- ■: DR. '' DR. J

623 F: -: A. . '

.. WOLFF. -. . . ... 4-hüCHSf

2 K Marc

Our no. 19 8θ8

Pr / br

G.D. Searle & Co. Skokie, 111., V.St, A.

3ß-Hydroxy-2- (substituted 1-alkeny}.) -5-oxocyclopentane-1-heptanoic acids

The invention relates to 3ß-hydroxy-2- (substituted 1-alkenyl) -S-oxocyclopentane-1-heptanoic acids the general formula

0-

COOR

(D

R ^f

R "H

wherein R is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms, R ^{1 is} an alkyl radical having 1 to 7 carbon atoms and

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R "denotes a straight-chain alkyl radical with 6 to 9 carbon atoms.

Examples of alkyl radicals are methyl, ethyl, propyl, butyl, Hexyl, heptyl, octyl or nonyl.

The compounds according to the invention can be prepared by reacting an organometallic compound of the formula R " ¹ M with a ketone of the formula

COOH

where one of the two radicals R " ¹ and R""is an alkyl radical having 1 to 7 carbon atoms and the other is an alkyl radical having 6 to 9 carbon atoms, M is lithium or magnesium halogen and Z is a hydrogen atom or an alcohol protecting group. Preferred halogens are bromine, iodine or chlorine. Possible alcohol protecting groups for Z are tetrahydropyranyl or tri (lower alkyl) silyl, the lower alkyl groups containing 1 to 4 carbon atoms, and trimethylsilyl being particularly preferred. The reaction is carried out in an inert solvent, preferably one Ether such as tetrahydrofuran or diethyl ether, and the reaction is carried out at a low temperature such as in a drying oven.

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Preferably, the Schutsgruppe is introduced at Z, the indicated 'reaction carried out and then removed the protective group in a known manner. The use of protecting groups thus improves the method according to the invention.

The free carboxylic acids obtained by the process described above can optionally be converted into the corresponding ones Convert lower alkyl esters using the appropriate diazoalkane and known methods. Methyl ester, those obtained by using diazomethane are particularly preferred esters.

In cases in which a mixture of stereoisomers was obtained with the aid of the process according to the invention, can this mixture of products can be separated by standard methods known in the art, which include chromatography. The present Invention includes any racemic mixture of isomers obtained in the reaction and also any pure compounds that can be isolated from the mixtures.

The starting materials for the present invention are derived from a suitable 2-formyl-3-hydroxy-5-oxocyclopent-1-enheptanoic acid of the following formula:

COOH

CHO

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manufactured.

The 3-hydroxy function in the above compound is optionally protected by a suitable protective group, whereupon the ethylenic bond in the cyclopentane ring is reduced will. The resulting aldehyde is then treated with a triphenylacetylmethylene phosphorane of the formula

Il

«5 P = CH-C-R" "

condensed, wherein R "" has the preceding meaning. This gives the required desired starting material.

Because of their anti-fertility properties, those are according to the invention Compounds useful pharmacological agents. The present compounds are for this purpose particularly suitable as they do not exhibit many of the other effects normally associated with prostaglandin derivatives. The anti-fertility properties are demonstrated by the experiments below.

Sexually mature Syrian golden hamsters, 9 to 10 weeks old, were brought together with males in the late afternoon Cage done. Vaginal smears were taken daily in the morning using a pipette. The presence of sperm is considered positive evidence of semen transmission. The day of semen transfer is considered day 1 of gestation designated. Pregnant females were then injected daily with the test compound starting on day 1 through on day 5. The route of administration was either subcutaneous or intragastric. The daily injection became common

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carried out in a volume of 0.2 enr corn oil. All animals were sacrificed with dry ice on the morning of the 6th day. The entire reproductive tract was removed and the uterus and ovaries cleaned of external tissue. The total number of implantation sites was counted and recorded. Upon inspection, the size of the day 6 sites was determined to be normal and any sites that were smaller and / or pale or absorbent were determined to be abnormal. The total number of Corpora lutea was counted and registered. On inspection again, the red corpora were rated normal and the pale, pink, or white regressed corpora were rated abnormal. A single dose of the compound was classified as active or inactive based on the percent implantation obtained by dividing the total number of implantation sites by the total number of corpora lutea and multiplying by 100. If the implantation rate is 50 % or less, the test result is considered active. A ED_ _Q can then be determined. The compounds according to the invention were found to be active in this method.

The following examples serve to further illustrate the invention. The amounts of material are given in parts by weight unless otherwise noted.

Example A.

A solution of 2 parts of 7- (2-formyl-3-hydroxy-5-oxocyclopentl-ene) heptanoic acid and 1 part by volume of dihydropyran in 6.7 parts of methylene chloride was treated with a solution of 0.02 part of p-toluenesulfonic acid added in 0.18 part of tetrahydrofuran.

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A rapid exothermic reaction took place. After this reaction subsided, the mixture became 400 parts Diluted methylene chloride, then washed with aqueous sodium sulfate and dried over aqueous sodium sulfate. Concentration of this dry mixture under reduced pressure gave 7- / 2-formyl-3- (tetrahydropyran-2-yloxy) -5-oxocyclopent-1-ene-7heptanoic acid as a pale yellow oil.

32 parts by volume of chromium (II) sulfate solution were added to the last-named crude product added, made from chromium III sulfate, as described in Organic Synthesis, Vol. 49, p. 98. The resulting reaction mixture was stirred under nitrogen for 30 minutes, after which time 3 parts of ammonium sulfate and 25 parts of sucrose were added and the mixture was finally added by adding 1M aqueous citric acid has been acidified. This mixture was extracted with ether and the ether extract separated, one after the other washed with saturated ammonium chloride and saturated sodium chloride, then over anhydrous sodium sulfate dried and concentrated under reduced pressure, whereby 7- / 2ß-pormyl-3- (tetrahydropyran-2-yloxy) -5-oxocyclopentan7-laC-heptanoic acid originated.

A solution containing 2.2 parts of 7- / 2 "ß-formyl-3- (tetrahydropyran-2-yloxy) -5-oxocyclopentane7-10C-heptanoic acid and 5 parts of triphenyl-n-heptanoylmethylene phosphorane contained in 101 parts of benzene, was heated to reflux temperature for 4 hours, then cooled, left to stand at room temperature for about 4 hours, successively with aqueous citric acid and aqueous sodium chloride, then dried over anhydrous sodium sulfate and chromatographed on a silicon column. Elution of the column with 152 strength ethyl acetate

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in benzene gave 7 - \ / 3cXr (tetrahydropyran-2-yloxy) -2β- (3-oxol-nonenyl) -5-oxocyelopentane7-lo £ -heptanoic acid and then (7- / 5β-tetrahydropyran-2-yloxy) -2β- (3-oxo-1-noneny1) «5-oxocyclopentane7-lc £ -heptanoic acid.

When the final step of the above procedure using triphenyl-n-octanoylmethylene phosphorane and Triphenylnonanoylmethylene phosphorane instead of triphenyln-heptanoylmethylene phosphorane repeated, the products obtained were 7- / 3ß- (tetrahydropyran-2-yloxy) -2ß- (3-oxol-decenyDS-oxocyclopentarjT-lx-heptanoic acid or 7- / 3β- (tetrahydropyran-2-yloxy) -2β- (3-oxo-1-undecylenyl) -5 * "oxocyclopentane-1-oct-heptanoic acid.

Example B.

A solution of 8.3 parts of 7- (2-formyl-3-hydroxy-5-oxocyclopent-1-ene) heptanoic acid in 150 parts by volume of 50% aqueous acetic acid solution was mixed with 15 parts of zinc powder at 0 to 5 ° C. for about 2 hours touched. At the end of this time the mixture was filtered and the filtrate was diluted with about 200 parts by volume of saturated aqueous sodium chloride solution. The mixture was extracted with ether and the resulting organic solution was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was mixed with triphenyl-n-heptanoylmethylene phosphorane, obtained from 30 parts of triphenyl-n-heptanoylmethylphosphonium chloride, and dissolved in 530 parts of benzene. The resulting mixture was left to stand ^{at 25 ° C. for 5 days}

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then concentrated under reduced pressure to an "The resulting residue was extracted with Kther- and Ktherextrairt with cold hydrochloric acid and then with cold ¥ gewasü assar;! & 2i _s before about sp Natriasseilfat dried. The Löaungsmit.fc-sl was evaporated under reduced pressure and the resulting residue on silicic acid chi'oi.: Atographed, the solvents were prepared by: uan 330 parts of hexane, 880 parts of benzene, 400 parts of methanol and 200 parts of water together shook. The resulting lower layer was used as the stationary phase and the upper layer as the eluent. The elution of the column first gave 7- / 3ß-hydroxy-2ß- (3-oxo-l-nonenyl) -5-oxocyclopentane7-l <x-heptanoic acid and then 7- / J ^! X ~ Hydroxy-2β- (S-oxo-1-noneny 1) -5-oxocyclopentane7-lc £ -h "eptanoic acid.

example 1

A solution containing 2.2 parts of 7-A3ß- (tetrahydropyran-2-yloxy) -2ß- (3-oxo-l-nonenyl) -5-oxocyclopentan7-lc6-heptanoic acid, dissolved in 89 parts of tetrahydrofuran ^ contained, was with 5 volumes of a 3M essential methyl magnesium bromide solution are added. The addition was made in a more nitrogen atmosphere performed at about -78 ° C, and after completion the addition was stirred at this temperature for about another 0.5 hour. At the end of this reaction period the reaction mixture poured into cold aqueous citric acid and this acidic mixture extracted with ether. The ether extract was washed with dilute aqueous sodium chloride, dried over aqueous sodium sulfate, evaporated to dryness and the residues of a silica column chromatographed.

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Benzene / methanol was used as the upper phase and aqueous methanol was used as the lower phase. The product obtained was 7- / 3β- (Tetrahydropyran-2-yloxy) -2β- (3-hydroxy-3-methyl-inonenyl) -5-oxocyclopentane-7-lcc-heptanoic acid. This material was made up in 70 parts by volume of a 20:10:30 solution of acetic acid : Water: Tetrahydrofuran dissolved, and this solution was allowed to stand at room temperature for about 24 hours. At the end of this time, the solvent was distilled off under reduced pressure and the residue on a silica column adsorbed, then eluted with ethyl acetate and a benzene mixture. In this way 7 - / 3ß-hydroxy-2ß- (3-hydroxy-3-methyl-1-nonenyl) -5-oxocyclopentane7-jK3> was obtained heptanoic acid; Melting point about 85 to 87 ° C .; NMR maxima in deuteromethanol at δι, 33, δ4.33 and 65.77.

Example 2

A solution of 15 parts of 7 -. / 3.beta.-hydroxy-2ß- (3-oxo-l-nonenyl) -5-oxocycIopentan7-lo6-heptanoic acid and 22 parts by volume of bis (trimethylsilyDacetamid in 27 parts of tetrahydrofuran was allowed at 25 ⁰ C 2k hours to give a solution of 7- / 3ß-trimethylsilyloxy-2ß- (3-oxo-1-nonenyl) -5-oxocyclopentan7-1X-heptanoic acid, which was then diluted with 1,335 parts of tetrahydrofuran to -78 cooled ⁰ C and ethereal with 500 parts by volume of 3M methyl magnesium bromide-treated for 20 minutes at -70 ⁰ C. the cold reaction mixture was then poured into cold aqueous 3? citric acid solution and the mixture extracted resultant with ether. the ether extract was washed with lOJSiger ammonium chloride solution, dried over sodium sulfate and concentrated.

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Purified chromatography on silica. The solvent system was made by adding 13 parts of benzene, 4 parts Methanol and 2 parts of water shook. The lower layer was called the stationary phase and the upper layer was called the mobile Phase used. The crystalline product obtained after chromatography was treated with heptane, which is a small amount Containing ethyl acetate, saturated and then filtered, whereby 7-73ß-Hydroxy-2ß- (3-hydroxy-3-methyl-1-nonenyl) -5-oxocyclopentanZ-lot-heptanoic acid received; Melting point about 85 to 87 ° C.

Example 3

If 7- / 3ß- (tetrahydropyran-2-yloxy) -2ß- (3-oxo-1-decenyl) -5-oxocyclopentane7-lC6-heptanoic acid was reacted with methyl magnesium bromide according to the procedure of Example 1, the end product was 7 ~ / 3β ^< -Hydroxy-2β- (3-hydroxy-3-methyl-1-decenyl) -S-oxoeyclopentanZ-1Cfe-heptanoic acid.

In a similar manner, the reaction of 7 »/ Jβ-Cfe-trahydrogyran-2-yloxy) -2β- (3-oxorl-undecylenyl) -5« oKocyclopentan7-lct-heptanoic acid with methyliaagnesiumbroniide gave 7-j £ as the end product 3ß-Hydroxy-2ß- (3-hydroxy-3-methyl-1 »» undecylenyl} ~ 5
heptanoic acid.

Example 4

A mixture of 7 parts of potassium hydroxide dissolved in 13 parts of water and 100 parts by volume of ether was mixed with 6 parts of N-nitrosomethyl urea offset. The resulting mixture

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was stirred until most of the solid was dissolved and the yellow ethereal solution in a solution of 1 part 7- / 3ß-hydroxy-2ß- (3-hydroxy-3-methyl-1-nonenyl) -5-oxocyclopentan7-laE-heptanoic acid and 35 parts of ether decanted. After standing for several hours, the mixture was washed through dropwise

the

Treated addition of glacial acetic acid to destroy / excess reactants. The colorless essential solution was washed sequentially with cold water, cold dilute sodium bicarbonate and cold water, then over dried anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residual crude product was adsorbed on a silica chromatography column, then eluted with ethyl acetate in benzene and gave methyl 7- / 3ßhydroxy-2ß- (3-hydroxy-3-methy1-1-noneny1) -5-oxocyclopentane7-ΙΟέ-heptanoate.

Example 5

The compounds according to the invention are generally white solids which are light-stable at 5 ° C., but are not Acid (pH 1), base (pH 9) or heat are unstable. The compounds of formula (I) are in customary organic Solvents such as chloroform, ethyl acetate, methanol and acetone are soluble and insoluble in water.

Below are typical orally administrable pharmaceutical formulations containing the compound of the present invention included, described. Other pharmaceutical forms suitable for the oral administration of these compounds, are lozenges, coated tablets, pills, powders, solutions, suspensions, syrups and emulsions.

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Tablets

Component quantity / tablet

A compound of the formula (I)
(e.g. 7- / 3ß-Hydroxy-2ß- (3-hydroxy-T-methyl-1-nonenyl) -5-
oxocyclopentany-icoheptanoic acid) 10 mg

Lactose. l60 mg

Corn starch l60 mg

Polyvinylpyrrolidone 16 mg

Magnesium stearate "3 mg

The active ingredient was dissolved in ethanol and distributed on lactose. The mixture was air dried and passed through a sieve with a clear mesh size of 420 u. The corn starch and the polyvinylpyrrolidone were added to the mixture added, mixed carefully and passed through a sieve with a mesh size of 420 u. The mixture was then granulated with ethanol, sprayed onto plates and dried at 49 ° C for 16 hours. This dry granulate was then sifted. The granules were carefully mixed with magnesium stearate and the mixture into tablets pressed.

Capsules quantity / capsule

A compound of the formula (I)
(e.g. 7 - /. 3ß-Hydroxy-2ß- (3-hydroxy-3- ^> methyl-1-nonenyl) -5-oxocyclopentane7-1; X-heptanoic acid) 4 mg

Corn starch 120 mg

Lactose 120 mg

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The active ingredient was dissolved in ethanol and distributed on lactose. The mixture was air dried and passed through a sieve given with a mesh size of 42Ou. The cornstarch was added to the mixture, mixed thoroughly, sieved and mixed again. The mixture was packed in hard gelatin capsules No. 2 filled by hand or machine using 244 mg filler per capsule.

Other pharmaceutically acceptable carriers for the use of the formulations described above are, for example, sugars, such as lactose, sucrose, mannitol and sorbitol; Starches such as corn, tapioca, and potato starch; Cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose or
Methyl cellulose; Gelatin; Calcium phosphates such as dicalcium phosphate and tricalcium phosphate; Sodium sulfate; Calcium sulfate; Polyvinyl pyrrolidone; Polyvinyl alcohol; Stearic acid; Alkaline earth metal stearates such as magnesium stearate; vegetable oils derived from ^stearic acid such as peanut oil, cottonseed oil, sesame oil, olive oil or corn oil; surfactants (nonionic, cationic, anionic); Ethylene glycol polymers; β-cyclodextrin; Fatty alcohols; hydrolyzed grain solids as well as other non-toxic compatible fillers, binders, disintegrants and lubricants commonly used in pharmaceutical formulations.

In the formulations of the type described above, the novel compounds of formula (I) are present in an amount which is believed to produce the desired effect. Although 10 mg per dosage unit is often appropriate,
substantially more or less active ingredient can optionally be incorporated into each dosage unit. The daily

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Dose of these compounds depends on various factors, such as the particular compound used, the purpose for which which the compound is to be administered and the individual sensitivity of the patient. Typical Doses for use as an anti-fertility agent vary between 5 and 20 mg daily for up to 5 days when taken orally Administration.

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Claims (1)

Patent claims: 3ß-Hydroxy-2- (substituted 1-alkenyD-5-oxocyclopentane-1-heptanoic acids the general formula COOR where R is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms, R ^{f is} an alkyl radical having 1 to 7 carbon atoms and R ″ is a straight-chain alkyl radical having 6 to 9 carbon atoms. 2. Compounds according to claim 1, wherein R is a hydrogen atom and R ^{1 is} a methyl radical. 3. 7- / Jβ-Hydroxy-2β- (3-hydroxy-3-methyl-1-nonenyl) -5-oxocyclopentane 7-1 -heptanoic acid. 1}. Process for the preparation of one of the compounds of claims 1 to 3 »characterized in that an organometallic compound of the formula R" ¹ M is mixed with a ketone of the general formula COOH 509842/1019 wherein one of the two radicals R " ¹ and R""is an alkyl radical with 1 to 7 carbon atoms and the other is a straight-chain alkyl radical with 6 to 9 carbon atoms, ₃ M is lithium or magnesium halogen and Z is a hydrogen atom or an alcohol protecting group , the protective group ^, if present, removed and, if appropriate, the carboxylic acid then esterified. 5. The method according to claim ¹ I for the preparation of the compound of claim 3, characterized in that 7- £ 5 & - (tetrahydropyran-2-yloxy) -2ß- (3-oxo-l-nonenyl) -5 ~ oxocyclopentan7-l -heptanoic acid is reacted with methylmagnesium bromide and the tetrahydropyranyl group is removed. 6. The method according to claim ¹ I for the preparation of the compound of claim 3, characterized in that 7 ** / 3 "ß-trimethylsilyloxy-2ß- (3-oxo-l-nonenyl) -5-oxocyclopentan7-1 -heptanoic acid with Reacts methylmagnesium bromide and the ^ ritnethylsilylgruppe removed. 7. Pharmaceutical or veterinary agent containing one or more of the compounds of claims 1 to 3. For: G. D. Searle & Co. Skofcie * ! &., V.St.A. Dr.H.J.Wolff Attorney at Law 509842/1019