FI64350B - SAOSOM ANTIFERTILITY METHOD ANVAENDBARA OMEGA-ARYL-13-PROSTYNSYRADERIVAT - Google Patents

Description

Uο1 KU RELEASE PUBLICATION. Γ ^ * UTLÄGG N I NGSSKR1 FT 64350) c (45) Ft. Icnlti issued 13 11 1933

Fatent medcelat

V 'r ~ *' (51) Kv.lk. '^ Int.CI.3 G 07 G 177 / OC

FINLAND —FINLAND (21) Pttenttlhakemu * - P «entan * öknlng TT39J7 (22) H» Kemi * pilvS— Ansöknlngjdag 27-j. ^ - Ti (23) Alkupilvl— Glltlghettdag 27 · 12. {((41) Become public - Blivlt offentllg 28.0b.7ö

National Board of Patents and Registration (44) N * ht * vSk »i stack and date of publication— Q

Patent- oeh registerstyrelsen Ansökan utlagd och utl.skrlften published 29 · 07 "Oj (32) (33) (31) Privilege claimed — Begärd prloritet 27 12.76 USA (US) 75 ^ 157 (71) GD Searle & Co., P 0 Box 5110, Chicago, Illinois, USA (72) Paul Wad dell Collins, Deerfield, Illinois, Raphael Papoo, Skokie,

Illinois, USA (7 ^) Oy Kolster Ah (5 * 0 u) -aryl: .- 13 - Prostynic acid derivatives useful as infertility agents - Sasom antifertilitetsmedel användhara 13-Prostynic acid derivatives useful as contraceptives of formula (I) 0 ^ ch2 — y— (ch2) 3-co2ch3 JX Γ3 HO CÄC - ^ - (CIVn- ^

HO

wherein the substituents have the meanings given in claim 1.

(+ _) refers to the indicated compound and its mirror image, taking into account the stereochemical possibility at the 1-, 2- and 3-positions of the 5-membered ring, i. forms et, β'ί3 and t Af.

Halogen-containing phenyl means chlorophenyl, fluorophenyl, bromophenyl or iodophenyl.

Phenyl having an alkoxy substituent means methoxyphenyl, ethoxyphenyl, propoxyphenyl and butoxyphenyl.

Crystalline substituted phenyl and naphthyl esters of the acids of this invention, such as those described in U.S. Patent No. 3,634,062, are considered equivalent to the purposes of this invention.

Preferred compounds of formula I are those in which Y is -CH 2 -CH 2 -, and particularly preferred are those in which n is further 2 when Ar is as defined above.

The compounds of this invention are prepared by reacting a compound of formula IV

fcH2_V_ (CH2) 3— ^ 02CH3 _T UV)

HO

wherein Y is as previously defined, to react with a dimethyl- (ca-aryl-1-alkynyl) aluminum compound of formula

Si (Alk), I 3 0

Ar- (CHO) -i-CSC-AKCH,), 2 n | 3 2 ch3 wherein Ar and n are as previously defined; and Alk is alkyl of 1 to 4 carbon atoms; followed by hydrolysis of the trialkylsilyl protecting groups and subsequent chromatographic isolation of the compounds thus obtained.

Dimethyl (--aryl-1-alkynyl) Aluminum Compound The starting materials are prepared by the method shown in Scheme 1 as follows:

Ϊ1) LiC = CH OH

or T

Ar- (CH) -C-CH 2 ---> Ar- (CH) -C-C = C-H

2 n 6 2) LiC = CSiEt3 ^ followed by 3 KF / DMF treatment (Alk) SiCl

Si (Alk), 15 nit OSi (Alk)

BuLi | J

-C3C-A1 (CH3. <I-- Ar- (CH2), -C-C = 3C-H

3 2 Me A1C1 2 2 | H3 CII3

Scheme I

64350

Examples of starting materials used in the preparation of the compounds of Scheme I include ketones and aldehydes of the formula

O

I!

CH 1 -C - (CH 2) -AR

j Z n

Ar n m -chlorophenyl 2 p-fluorophenyl 2 m-trifluoromethylphenyl 2 phenyl 2 phenyl 3 phenyl 1 phenyl 4 biphenyl 2 p-methoxyphenyl 2 p-methylphenyl 2 p-ethylphenyl 2

The carboxylic acids are converted to the above-mentioned ketones and aldehydes by known methods.

Methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate and methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5- cis-enoate and the corresponding acids are known starting materials. Example 1 illustrates a preferred method for preparing the compounds of this invention.

The closest prior art is described in U.S. Patent 3,973,440, which discloses analogous PC-F 2 compounds having the formula

O

en '° 2H / - \ H0' "J - \ j CH3 oh These compounds differ from the compounds according to the invention in terms of stereochemistry at the C-11 position and in that they have the group -CH = CH- at the 3-C ^ 4 group - The 1-deoxy compounds of the invention are described in Belgian Patent 839,533, and U.S. Patent 3,978,114 also discloses related compounds.

4,64350

In the article Tetrahedron Let. 26 (1972) 2627 discloses compounds of formula

O

jl. (CH2) g - CO2CH3 ^ ^ H0-C = C -CH-C, H,.

J o JL X

OH

The compounds of this invention are particularly characterized in that the -C 1-4 state of the group has an alkyl group containing a phenyl substituent.

The contraceptive effect of the compounds of this invention is demonstrated by the following experiment:

Mature Syrian golden hamsters, 9-10 weeks old, were caged together with the dogs in the late afternoon. Vaginal samples were taken daily using a pipette between 8.15 and 10.00. The presence of sperm was considered a positive indication for breeding. The breeding date was determined as the first day of pregnancy. Pregnant females were injected daily with test compound from day one and continued for 5 days inclusive. Administration was performed either subcutaneously or intragastrically. The daily injection was usually with a volume of 0.2 ml of corn oil, although the volumes and medium may vary depending on the physical properties of the specific compound to be tested. All animals were killed on dry ice (CO 2) on the seventh day in the morning.

The genitals were completely removed and the uterus and ovaries were cleansed of foreign tissues. The total numbers of attachment sites were calculated and recorded. Based on the study, the size of the sites on day 7 was determined to be normal, and any site that was smaller and / or pale or resorbable was defined as abnormal.

A single dose of a compound was classified as active or inactive based on the percentage of attachment obtained by dividing the total number of attachment sites by the total number of luteal glands and multiplying by one hundred.

At an adhesion ratio of 50% or less, the compound was considered active.

At an adhesion ratio of 51% or greater, the compound was considered inactive.

11 5 64350

Abnormal attachment sites and luteal glands were also reported when 20% or more of the sites were abnormal or no abnormal sites at all, only when there were 50% or more abnormal luteal glands. The determination of ED, - n

do

by examination or calculation by the method of Berkson (J. Amer. Stat. Assoc. 48 (263); 565, 1953). Oestrone was used as the standard.

The relative potency was obtained from the ratio of the ED 2 Q values of oestron to the test compound.

Racemic methyl 1-7- [3β-hydroxy-2β- (3 (S) -hydroxy-3-methyl-5-phenyl-1-penty-1-yl) -5-oxocyclopenteno] - yl / heptanoate, a typical compound of the invention, was active in the fertilization contraceptive test described above at a dose of 50-200 mg per hamster.

The compounds of this invention may be combined with conventional pharmaceutical carriers. These combinations can be administered either orally or parenterally. Tablets, lozenges, capsules, dragees, pills, or powders suitable for oral administration, while aqueous solutions, non-aqueous solutions, or suspensions suitable for parenteral administration. Acceptable examples of pharmaceutical carriers are gelatiinikap-axes, sugars such as lactose or sucrose, starches such as corn starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, metyylisellu-cellulose or cellulose acetate phthalate, gelatin, talc, calcium phosphate, such as dicalcium phosphate and tricalcium phosphate, sodium rumium sulfate, calcium sulfate, polyvinylpyrrolidone, acacia, polyvinyl alcohol, stearic acid, alkaline earth metal stearates such as magnesium stearate, vegetable oils such as peanut oil, isotonic oil, agaric oil, sesame oil, olive oil, olive oil, corn oil, corn oil, corn oil, corn oil non-toxic, compatible substances.

6,64350

The invention will become more fully apparent from the following working examples.

In all examples, temperatures are expressed in degrees Celsius (° C) and amounts are by weight unless otherwise indicated. The ratio of parts by weight to parts by volume is the same as the ratio between grams and milliliters. NMR spectra were determined on a 60 or 100 MHz instrument and values are expressed in parts per million (b) -

Example 1 8 parts by volume of 2,5 molar n-butyllithium were added to a solution of 3.1 parts of triethylsilylacetylene in 20 volumes of ethyl ether at a temperature of -30 ° C. The resulting solution was allowed to warm to room temperature, then re-cooled to -30 ° C and 3 parts of benzylacetone were added. The reaction mixture was allowed to warm to room temperature and then stirred for one hour. The reaction mixture was poured into ether and dilute hydrochloric acid. The ether layer was washed with water and dried over anhydrous sodium sulfate. The ether was removed in vacuo and the residual oil was dissolved in 15 volumes of dimethylformamide with 20 parts of ground potassium fluoride. This reaction mixture was stirred and heated at 70-80 ° C for 1 hour, then diluted with water and extracted with ether. The ether layer was separated and washed with water and dried over anhydrous sodium sulfate. The ether was removed in vacuo and the residue was chromatographed on silica gel using 30% ethyl acetate / hexane as eluent to give 3-methyl-3-hydroxy-5-phenyl-1-pentine.

The hydroxyl groups were protected by treating 3.6 parts of 3-methyl-3-hydroxy-5-phenyl-1-pentine in 15 volumes of dimethylformamide successively with 3.5 parts of imidazole and 4.0 parts of triethylsilyl chloride, and this mixture was stirred for 1 hour at room temperature. . The reaction mixture was poured into ether / water and the ether layer was washed 3 times with water, dried over anhydrous sodium sulfate, then the ether was removed in vacuo. Distillation of the residual oil gave 3-methyl-5-phenyl-3-triethylsilyloxy-1-pentine.

To 7.743350 to 1.74 parts of this ether in 10 volumes of ethyl ether at -40 ° C was added 2.8 parts of 2.17 molar butyllithium. The resulting reaction mixture was allowed to stand at room temperature for 30 minutes, after which it was recooled to -40 ° C. A solution of 3.7 parts of a 15% by weight solution of dimethylaluminum in hexane was added and the reaction mixture was allowed to warm again to room temperature. The resulting reaction mixture containing dimethyl (3-methyl-5-phenyl-3-triethyl-silyloxy-1-pentyne) aluminum compound was then treated with 1 part of methyl-7- (3-hydroxy-5-oxo-1-cyclopenten-1- yl) heptanoate in 10 volumes of ethyl ether. The reaction mixture was stirred at room temperature for 1-2 hours and poured into ether and 1N hydrochloric acid. The ether layer was separated, washed with water and dried over anhydrous sodium sulfate. The ether was removed in vacuo. Purification of the residual oil by flash chromatography on silica gel using 30% ethyl acetate / hexane as eluent gave the intermediate methyl 7- [3H-hydroxy-2β- (3-methyl-3-triethylsilyloxy-5-phenyl). l-pentyn-l-yl) -5-oxocyclopent-1OT-yyliTheptanoaattia. This material was hydrolyzed overnight at room temperature using a 3: 1: 1 mixture of acetic acid, water and tetrahydrofuran. The reaction mixture was diluted with ether and washed 6 times with water, dried over anhydrous sodium sulfate, and the solvent was removed. Purification by flash chromatography on silica gel using 100% ethyl acetate as eluent gave racemic methyl 7- / 3 / G-hydroxy-2/9 - (3 (r) -hydroxy-3-methyl-5-phenyl). -penyl-1-yl) -5-oxocyclopent-1 - [(yl) / heptanoate and racemic methyl-hydroxy-2β- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyl 1-yl) -5-oxocyclopent-1-yl-7'-heptanoate and racemic NMR spectral peaks at approximately S 1.06, S 3.66 and δ 7.21.

Example 2 m-Trifluoromethylcinnamic acid was hydrogenated at room temperature at a pressure of 0.14 kp / cm using Pali dium carbon as a catalyst to give m-trifluoromethylbenzyl acid.

8 64350 21.8 parts of this acid were dissolved in 200 volumes of ether.

Then, 100 volumes of a 1.0 molar solution of methyllithium ether were added dropwise over 30 minutes at 0 ° C. After the addition was complete, the mixture was stirred at room temperature for 3-4 hours. The mixture was poured into 1N HCl, and the organic layer was washed successively with water and 5% potassium carbonate, followed by drying over anhydrous sodium sulfate. The solvent was removed to give m-trifluoromethylbenzylacetone. Following the procedure of Example 1 and exchanging the benzyl position for m-trifluoromethylbenzylacetone gave racemic methyl-7- [3β-hydroxy-2β- [3 (R) -hydroxy-3-methyl-5- (m-trifluoromethylphenyl) -1 -pentyn-1-yl / -5-oxocyclopent-10-yl] heptanoate and racemic methyl 7- [2β-hydroxy-2β- [3 (S) -hydroxy-3-methyl-5- (m- trifluoromethylphenyl) -1-pentyn-1-yl-5-oxopent-1-ex-yl / heptanoate, characterized by NMR spectral peaks at approximately cf 1.59, cf 3.68 and 4.47.

Similarly, p-fluorocinnamic acid was converted to racemic methyl 7-β-β-hydroxy-2,4-, β (S) -hydroxy-3-methyl-5- (p-fluorophenyl) -1-pentyn-1-one. yl--5-oxocyclopentyl-1-yl-heptanoate and its racemic 3R derivative; p-Bromocinnamic acid was converted to racemic methyl-7- [3β-hydroxy-2β- [3 (S) -hydroxy-3-methyl-5- (p-bromophenyl) -1-penty-1-yl] -5-oxocyclopentene -oyl-yl · · heptanoate and its racemic 3r derivative; m-Chlorocyanic acid was converted to racemic methyl-7- (3'-hydroxy-2H) (S) -hydroxy-3-methyl-5- (m-chlorophenyl) -1-methyl yl / -5-oxo-cyclopent-le <. -yl-heptanoate characterized by NMR spectral peaks at approximately δ 2.0, cf 2.84 and cf 3.67, and its racemic 3R derivative characterized by NMR spectral peaks at approximately (f 1.57, 6 3.7 and £ 4/44; p-methylcinnamic acid was converted to racemic methyl-7- [3/3 -hydroxy-2H- (3) S-hydroxy-3-methyl-5- (p-ethylphenyl) - 1-pentyn-1-yl / -5-oxo-cyclopene t-1d-yl} heptanoate and its racemic 3R derivative, p-methoxycinnamic acid was converted to racemic methyl-7-

II

9,64350 to hydroxy 2R - [3 (S) -hydroxy-3-methyl-5- (p-methoxyphenyl) -1-perityn-1-yl] -5-oxocyclopent-10 (-yl} heptanoate, which characterized by NMR spectral peaks at approximately S 1.57, cf 3.68 and <£ 4.46, and its racemic 3R derivative, and p-phenylcinnamic acid was converted to racemic methyl-7- (3/3-hydroxy-2) N- (3 (S) -hydroxy-3-methyl-5-p-biphenyl-1-pentynyl-1-yl) -5-oxocyclopent-1C * -yl] -heptanoate and its racemic 3F derivative.

4-Phenylbutyric acid was converted to racemic methyl-7- [3/3-hydroxy-2 / 3- (3 (8) -hydroxy-3-methyl-6-phenyl-1-hexyn-1-yl) -5-oxocyclopentyl]. 1 cL-γ lheheptanoate, characterized by NMR-Spectrum peaks at approximately δ 1.50, <i "2.75 and <^ 3.68, and its 3R derivative.

Example 3

Following the procedure of Example 1 and using benzyl 1-acetone and methyl 7- (3 (RS) -hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5-cis-enoate, racemic methyl 7- / 3 [3-Hydroxy-2- (3 (RS) -hydroxy-3-methyl-5-phenyl-1-penty-1-yl) -5-oxocyclopent-10-yl] -hept-5-cis-enoate, characterized by NMR-Spectrum peaks at approximately <1.58, δ 2.82 and ci "4.48.

Example 4

Following the procedure of Examples 1 and 2 and using m-chlorophenylacetone and racemic 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate, racemic acetyl 7- (3/3 - hydroxy-2 / 3- (3 (S) -hydroxy-3-methyl-4- (m-chlorophenyl) -1-butyn-1-yl-N-5-oxocyclopent-1-yl) heptanoate, characterized by NMR spectral peaks at approximately cT 1.57, <£ 2.96 and S 3.69 and its 3 (R) stereoisomer.

Example 5 Using the procedure described in Example 1 and using m-trifluoromethylbenzylacetone and methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5-cis-enoate, racemic methyl 7- (3 [3-hydroxy-2- [3 (S) -hydroxy-3-methyl-5- (m-trifluoromethylphenyl) -1-pentynyl-1-yl] -5-oxocyclopent-1-yl) hept-5 -cis-enoate / ion was characterized by NMR spectral peaks at approximately cT 1.56, <≤ * 3.65 and ci * 4.42 and its racemic 3R derivative.

10 64350

Example 6

Following the procedures of Examples 1 and 2 and using m-chlorocinnamic acid and methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) -hept-5-cis-enoate, racemic methyl 7- (3-hydroxy-2 / 3- [3 (S) -hydroxy-3-methyl-5- (m-chlorophenyl) -1-pentyn-1-yl] -5-oxocyclopent-1 ° C-yl) hept-5- cis-enoate characterized by NMR spectral peaks at approximately 1.57, δ 3.62 and cC 4.41 and its racemic and 3R derivative.

Example 7

Following the procedures of Examples 1 and 2 and using p-methoxycinnamic acid and methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5-cis-enoate, racemic methyl 7- ( 3 rt -hydroxy-2 rt - [* (S) -hydroxy-3-methyl-5- (p-methoxyphenyl) -1-pentyn-1-yl] -5-oxocyclopent-1-yl) hept-5 -cis-enoate, characterized by NMR spectral peaks at approximately <1.56, <£ 3.62 and ό 3.77 and its racemic 3R derivative.

Il

Claims (2)

11 64350 Co-aryl-13-prostynic acid derivatives useful as contraceptives of formula (I) O J 1 Hor * CHC-C- (CH 2 -Ar 2 n HO characterized in that Y is -CH 2 -CH 2 - or -CH = CH 2 -; n is 1-4; and Ar is phenyl, halogen-substituted phenyl, -alkyl substituted phenyl, phenyl substituted with N-alkoxy, p-bi-phenyl or trifluoromethylphenyl and the wavy line corresponds to the stereochemical R or S isomer. 2. Racemic methyl-7- [3,3-hydroxy-2H- [3- (S) -hydroxy-3-methyl-5-phenyl-1-penty-1-yl] -5-oxocyclopentene (Ct-yl) -heptanoate.