NO148333B - OEMGA-ARYL-13-PROSTYNIC ACID DERIVATIVES WITH FERTILIZING PREVENTION EFFECT. - Google Patents

Description

The present invention relates to compounds with an antifertility effect with the following formula:

where R is hydrogen or alkyl with 1-7 carbon atoms, Y is

-CH2-CH2- or CH=CH-; R<1>, R" and R"' are each hydrogen or methyl; n is 0-3; and Ar is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl where the latter alkyl group contains

holds 1-4 carbon atoms, alkoxy-substituted phenyl where alkoxy-

the group contains 1-4 carbon atoms, p_-biphenyl or trifluoromethyl-substituted phenyl, and where the wavy line represents

ters R or S stereochemistry.

(±) refers to the shown compound and its mirror

image with regard to stereochemistry around the 2 and 3 positions in the 5-atom ring, i.e. a,0,3 and 3,a,a.

Alkyl groups with 1-7 carbon atoms mean methyl, ethyl,

propyl, butyl, pentyl, hexyl, heptyl radicals and branched isomers of these groups.

Alkyl-substituted phenyl means tolyl, phenethyl, p_-tertiary

butylphenyl, p_-propylphenyl and the like.

Halogen-substituted phenyl means chlorophenyl, fluorophenyl,

bromophenyl and iodophenyl.

Alkoxy substituted phenyl refers to methoxyphenyl,

ethoxyphenyl, propoxyphenyl and butoxyphenyl.

Crystalline substituted phenyl and naphthyl esters of acids

related to those in the present invention are described in US patent 3,894,062.

Compounds of the following formula: where R, R<1>, R", R"1, n and Ar are as defined above are preferred. Particularly preferred are compounds with the following formula:

where Ar is phenyl or trifluoromethylphenyl.

Compounds according to the present invention can be prepared by reacting a compound of the formula: where R and Y are as defined above, with a dimethyl-(c-aryl-1-alkynyl) aluminum compound of the following formula:

where Ar, R', R", R"<1> and n are as defined above, and where Alk is an alkyl group with from 1 to 4 carbon atoms, after which the trialkylsilyl protecting group is hydrolysed and the compounds produced are then chromatographically separated.

Said dimethyl (c-aryl-1-alkynyl) aluminum compounds can be prepared by means of the method indicated in the following reaction scheme I as indicated in the following:

Reaction nucleus I

Starting compounds for the production of compounds indicated in reaction scheme I can be exemplified by ketones and aldehydes with the formula:

Carboxylic acids can be converted to the above-mentioned ketones and aldehydes in a well-known manner.

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 well-known starting compounds. Example 1 illustrates a preferred method for producing compounds according to the present invention.

The closest previously known compounds seem to be those described in US patent 3.9 73,440 where there are PGE2 analogues with the following formula:

These compounds differ from compounds according to the present invention in the stereochemistry at C-11 and in that they have a -CH=CH at C;13-c-14 instead of -C=C-. Furthermore, compounds related to those in the present invention are also described in Belgian Patent No. 839,533 and US Patent No. 3,978,114.

Tetrahedron Let. 26, page 2627 (1972) describes compounds of the formula:

Compounds according to the present invention clearly stand out from these in that there is a phenyl-substituted alkyl radical instead of the aforementioned -C5H^^~-

The present compounds have antifertility effects, which can be shown by the following test:

Sexually mature female Syrian golden hamsters 9-10 weeks old,

were caged with males late in the afternoon. Vaginal smears were taken daily between 8:15 and 10:00 in the morning using a pipette. The presence of sperm was considered a positive sign of insemination. The day of insemination was designated as the 1st day of pregnancy. Pregnant females were injected daily with the test compound starting on day 1 and continuing through day 5. The delivery route was either subcutaneous or through the stomach. The daily injection was usually in a volume of 0.2 cm 3 of corn oil, but the volume and liquid will depend on the particular compound being tested. All animals were killed with dry ice (CC^) on the 6th day of pregnancy.

All reproductive organs were removed, and the uterus and ovaries were cleaned of extra tissue. The total number of implantation sites was counted and noted. Usual 6-day sites were termed normal, and any other sites that were either smaller and/or pale or resorbed were termed abnormal.

The total number of corpora lutea was counted and noted. By this observation, red corpora were considered to be normal, while pale, pink and white and otherwise reabsorbed corpora were considered to be abnormal.

A single dose of the compound was considered to be active or inactive on the basis of percent implantation which was calculated by dividing the total number of implantation sites by the total number of corpora lutea and multiplying the total by 100.

50% or less implantation was considered active.

51% or more were considered inactive.

Abnormal implantation sites and abnormal number of corpora

lutea was also reported when 20% or more sites were abnormal or if there were no abnormal sites but only 50% or more abnormal corpora lutea. ED5Q for a prior bond was judged from inspection or calculated using the method indicated by Berkson (J. Amer. Stat. Assoc. 48 (263), 565, 1953). Estrone was used as a standard. A relative potency was obtained by comparing the ratio of ED^q for estrone to the corresponding ratio for the test compound.

Racemic methyl 7-[33-hydroxy-23-(3(S)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl]-heptanoate which is a representative compound according to the present invention, is active in the above described test of antifertility activity in a dose of 50-200 mg per hamster.

Compounds according to the present invention can be combined with usual carriers or diluents. These preparations can then be administered either orally or parenterally. For oral administration, tablets, capsules, coated tablets, pills or powders are suitable, while aqueous solutions, non-aqueous solutions or suspensions are suitable and well suited for parenteral administration. Acceptable carriers and diluents can be exemplified by gelatin capsules, sugars such as lactose or sucrose, starches such as corn starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose or cellulose acetate phthalate, gelatin, talc, calcium phosphate such as dicalcium phosphate or tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinylpyrrolidone, acacia, polyvinyl alcohol, stearic acid, alkaline earth stearates such as magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil or theo-broma, water, agar, alginic acid, benzyl alcohol, isotonic saline solution and isotonic phosphate buffer solutions as well like other known non-toxic carriers.

The following examples illustrate the invention, and amounts are given in parts by weight if nothing else is stated. The relationship between parts by weight and parts by volume is the same as that between grams and milliliters. Nuclear magnetic resonance spectra were determined using a 60- or 100-mega Hertz instrument and indicated in parts per million (6).

Example 1

8 parts by volume of 2.5 molar n-butyllithium was added to a solution of 3.1 parts of triethylsilylacetylene in 20 parts by volume of ethyl ether at -30°C. The resulting solution was allowed to warm to room temperature and was then cooled again to -30°C whereupon 3 parts of benzylacetone were added. The reaction mixture was allowed to warm to room temperature and was then stirred for 1 hour. The 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 under reduced pressure, and the remaining oil dissolved in 15 parts by volume of dimethylformamide containing 2 parts of powdered potassium fluoride. This reaction mixture was stirred and kept at 70-80°C for 1 hour and 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 under reduced pressure, and the residue was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent, whereby 3-methyl-3-hydroxy-5-phenyl-1-pentyne was produced.

The hydroxyl group was protected by treating 3.6 parts of 3-methyl-3-hydroxy-5-phenyl-l-pentryne in 15 parts by volume of dimethylformamide with 3.5 parts of imidazole and 4.0 parts of triethylsilyl chloride and stirring the mixture for 1 hour at room temperature. The reaction mixture was poured into ether/water, and the ether layer was washed with water three times, dried over anhydrous sodium sulfate, after which the ether was removed under reduced pressure. Distillation of the remaining oil gave 3-methyl-5-phenyl-3-triethyl-silyloxy-1-pentyne.

1.74 parts of this ether in 10 parts by volume of ethyl ether at -40°C

2.8 parts by volume of 2.17 molar butyllithium were added. The reaction mixture was left at room temperature for half an hour and then cooled again to -40°C. A solution of 3.7 parts of a 15% by weight solution of dimethylaluminum chloride in hexane was then added, and the reaction mixture was again allowed to warm to room temperature. The resulting reaction mixture containing dimethyl-(3-methyl-5-phenyl-3-triethylsilyloxy-1-pentyne)-aluminum was treated with 1 part of methyl-7-(3-hydroxy-5-oxo-1-cyclopentene-1- yl)heptanoate in 10 parts by volume of ethyl ether. The reaction mixture was stirred at room temperature for 1 to 2 hours and poured into ether and 1 N hydrochloric acid. The ether layer was separated, washed with water and dried over anhydrous sodium sulfate.

The ether was removed under reduced pressure. Purification of the remaining oil by low-pressure liquid chromatography on silica gel using 30% ethyl acetate/hexane as eluent gave the intermediate methyl-7-[33-hydroxy-23~ (3-methyl-3-triethyl-silyloxy-5-phenyl-1- pentyn-1-yl)-5-oxocyclopent-la-yl]heptanoate. This compound was hydrolyzed overnight at room temperature using a 3:1:1 acetic acid:water:tetrahydrofuran mixture. The reaction mixture was then diluted with ether and washed six times with water and dried over sodium sulfate and the solvent was then removed. Low pressure liquid chromatography on silica gel using 100% ethyl acetate as eluent gave racemic methyl-7-[30-hydroxy-20-(3(R)-hydroxy-3-methyl-5-phenyl-l-pentyn-l-yl )-5-oxo-cyclopent-la-yl ] heptanoate and racemic methyl 7-[30-hydroxy-23-(3(S)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclo-pent-la-yl] heptanoate, and the latter compound is characterized by nuclear magnetic resonance spectrum peaks at approx. 61.56, 63.55 and 67.21.

Example 2

m-trifluoromethylcinnamic acid was hydrogenated at room temperature at approx. 1.3 kg/cm 2 using palladium-p-carbon as catalyst, and m-trifluoromethylbenzylacetic acid was produced. 21.8 parts of this acid were dissolved in 200 parts by volume of ether. Then 100 parts by volume of 1.0 molar methyllithium in ether were added dropwise over 30 minutes at 0°C. After addition, the mixture was stirred at room temperature for 3 to 4 hours. The mixture was then poured into 1N HCl, the organic layer

washed successively with water and 5% potassium carbonate and then dried over anhydrous sodium sulfate. The solvent was removed to give m-trifluoromethylbenzylacetone. By using the method indicated in example 1, but by replacing benzylacetone with m-trifluoromethylbenzylacetone, racemic methyl-7-{33-hydroxy-23-[3(R)-hydroxy-3-methyl-5 -(m-trifluoromethylphenyl)-1-pentyn-1-yl]-5-oxo-cyclopent-la-yl}heptanoate and racemic methyl-7-{ 33~hydroxy-23- [ 3 (S)-hydroxy-3- methyl 5-(m-trifluoromethylphenyl)-1-pentyn-1-yl]-5-oxocyclopent-la-yl}heptanoate, which is characterized by nuclear magnetic resonance spectrum peaks at ca. 61.59,

63.68 and 64.47.

In a similar manner, p_-fluorocinnamic acid was converted to racemic methyl-7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(p_-fluorophenyl)-1-pentyn-1-yl]- 5-oxocyclopent-la-yl}heptanoate and its racemic 3R derivative; p-Bromocinnamic acid was converted to racemic methyl-7-{33-hydroxy-20-[3(S)-hydroxy-3-methyl-5-(£-bromophenyl)-1-pentyn-1-yl]-5-oxocyclopent -la-yl}heptanoate and its racemic 3R derivative, m-chlorocinnamic acid were converted to racemic methyl-7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(m-chlorophenyl)- 1-pentyl-1-yl]-5-oxocyclopent-la-yl}heptanoate characterized by nuclear magnetic resonance spectrum peaks at approx. 62.0, 62.84 and 63.67 and its racemic 3R derivative characterized by nuclear magnetic resonance spectrum peaks at ca. 61.57, 63, 7 and 64 .44; p_-Methylcinnamic acid was converted to racemic methyl-7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(p_-methylphenyl)-1-pentyn-1-yl]-5- oxocyclopent-la-yl}heptanoate and its racemic 3R derivative, p_-ethylcinnamic acid were converted to racemic methyl-7-{33-hydroxy-23~[3(S)-hydroxy-3-methyl-5-(p-ethylphenyl) -1-pentyn-1-yl]-5-oxocyclopent-la-yl}heptanoate and its racemic 3R derivative; p_-Methoxycinnamic acid was re-

formed to racemic methyl-7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(p_-methoxy phenyl)-pentyn-1-yl]-5-oxo-cyclopent-la- yl }-heptanoate characterized by nuclear magnetic resonance spectrum

peaks at approx. 61.57, 63.68 and 64.46, and its racemic 3R derivative; p_-Phenylcinnamic acid was converted to racemic methyl-7-[3|3-hydroxy-2|3-(3(S)-hydroxy-3-methyl-5-p_-biphenyl-1-pentyn-1-yl)-5 -oxocyclopent-la-yl]heptanoate and its racemic 3 R deriv.

4-Phenylbutyric acid was converted to racemic methyl-7-[3B-hydroxy-2(3-(3 (S)-hydroxy-3-methyl-6-phenyl-1-hexyn-1-yl)-5-oxocyclopent -la-yl ] heptanoate characterized by nuclear magnetic resonance spectrum peaks at about 61.50, 62.75 and 63.68 and its 3R deriv.

Example 3

By replacing benzylacetone with benzyldimethylacetaldehyde and using the procedure from example 1, racemic methyl-7-[3B-hydroxy-2B-(3 (R)-hydroxy-4,4-dimethyl-5-phenyl-l-pentyne was produced -1-yl)-5-oxocyclopent-la-yl]-heptanoate and racemic methyl 7-[3|3-hydroxy-2|3-(3 (S)-hydroxy-4,4-dimethyl-5-phenyl -1-pentyl-1-yl)-5-oxocyclopent-la-yl)heptanoate.

Example 4

By using the procedure from example 1 and using benzyl acetone and methyl 7-(3(RS)-hydroxy-5-oxo-1-cyclopenten-1-yl)hept-5-cis-enoate, racemic methyl- 7-[3B-hydroxy-2B-(3(RS)-hydroxy-4-methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl] hept-5-cis-enoate characterized at nuclear magnetic resonance spectrum peaks at approx. 61.58, 6 2.82 and 64.48.

Example 5

By using the procedures from examples 1 and 2 and using m-chlorophenylacetone and racemic 1-(3-hydroxy-5-oxo-1-cyclo-penten-1-yl)heptanoate, racemic methyl-7-{3B -hydroxy-26- [3 (S)-hydroxy-3-methyl-4-(m-chlorophenyl)-1-butyn-1-yl]-5-oxocyclopent-la-yl}heptanoate characterized by nuclear magnetic resonance spectrum peaks at approx. 61.57,

62.96 and 63.69 and its 3(R) stereoisomer.

Example 6

Using 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid, ethyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate and heptyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate respectively instead of said methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)heptanoate which was used in example 1,

and then using the same method as stated in this example, the following compounds were prepared: racemic 7-[3B-hydroxy-2B-(3(S)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl ) -5-oxocyclopent-la-yl]heptanoic acid and its racemic 3R derivative; racemic ethyl 7-[30-hydroxy-2B~(3(S)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl]heptanoate and its racemic 3R derivative, and racemic heptyl-7-[3B-hydroxy-23-(3(S)-hydroxy-3-methyl-5-phenyl-l-pentyn-l-yl)-5-oxocyclo-pent-la-l- yl]heptanoate and its racemic 3R deriv.

Example 7

By using the procedure from example 1 and using m-trifluoromethylbenzylacetone and methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)hept-5-cis-enoate, racemic methyl -7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(m-trifluoromethylphenyl)-1-pentyn-1-yl]-5-oxocyclopent-la-yl} hept-5-cis-enoate and its racemic 3R deriv. t

Example 8

By using the method indicated in examples 1 and 2 and using m-chlorocinnamic acid and methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)hept-5-cis-enoate, then one prepared racemic methyl-7-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(m-chlorophenyl)-1-pentyn-1-yl]-5-oxocyclopent-la-yl }hept-5-cis-enoate and its racemic 3R derivative.

Example 9

By using the procedure from 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-{33-hydroxy-23-[3(S)-hydroxy-3-methyl-5-(p_-methoxyphenyl)-1-pentyn-1-yl]-5-oxocyclopent-la-yl}hept-5- cis-enoate and its racemic 3R deriv.

Example 10

By using the procedure from examples 1 and 2 and using 5-phenylpentanoic acid and methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)heptanoate, racemic methyl-7-[3B- hydroxy-23-(3(S)-hydroxy-3-methyl-7-phenyl-1-heptyn-1-yl)-5-oxocyclopent-la-yl]heptanoate and its racemic 3R deriv.

Claims (3)

1. w-aryl-13-prostynic acid derivatives with contraceptive effect, characterized by the formula: where R is hydrogen or alkyl of 1-7 carbon atoms; Y is -CH2-CH2- or -CH=CH-; R', R" and R"' are hydrogen or methyl; n is 0-3; and Ar is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl where the alkyl group contains 1-4 carbon atoms, alkoxy-substituted phenyl where the alkoxy group contains 1-4 carbon atoms, p_-biphenyl or trifluoromethyl-substituted phenyl, and where the wavy line represents R- or S-stereochemistry. 2. Compound according to claim 1, characterized by the formula: 3. Compound according to claim 1, characterized by the formula: