NO774465L - PROCEDURE FOR PREPARING OMEGA-ARYL-13 PROSTYNIC ACID DERIVATIVES - Google Patents

Description

(JU-aryl-13-prpstynoic acid derivatives and methods for their preparation.

The present invention relates to compounds with the following formula

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

Y is -CH2-CH2- or CH=CH-} R», R" and R"' are each hydrogen or methyl; n is 0-3} and Ar is phenyl, halogen-substituted phenyl, lower alkyl-substituted phenyl where the latter lower alkyl group can contain from 1-4 carbon atoms, lower alkoxy-substituted phenyl where said lower alkoxy group can contain from 1-4 carbon atoms, g-biphenyl or trifluoromethyl-substituted phenyl , and where the wavy line represents R or S stereochemistry.

(+) refers to the shown compound and its mirror image with respect to stereochemistry around the 2 and 3-sides of the 5-membered ring, i.e. a,p,|3and|3,a,a.

By lower alkyl groups with from 1-7 carbon atoms are meant methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl radicals and branched isomers of these groups.

By lower alkyl-substituted phenyl is meant 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 according to the present invention of the type described in US patent 3,894,062 are considered equivalent for the present purposes.

Compounds with the following formula:

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

where R and Ar are as defined above.

Compounds according to the present invention can be prepared by reacting a compound with the formula

where R and Y are as defined above, with a dimethyl-(\JJ -aryl-1-alkynyl)aluminum compound of the following formula

where Ar, R', R", R"' and n are as defined above, and where Alk is an alkyl group with from 1 to k carbon atoms, after which one

hydrolyzes the trialkylsilyl protecting group and then chromatographically separates the compounds produced.

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

Reaction scheme I Starting compounds for the preparation 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»973»440 where there are PGE 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^yC2. k instead of -C=C-, 11-deoxy compounds according to the present invention are described in Belgian patent no. 839,533 and US patent 3,978,114 which also describe related compounds.

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 -C-H.,-.

o11

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 together with males in the late afternoon. Vaginal smears were taken daily between 8:15 and 10:00

in the morning using a pipette. Presence of sperm was an-

seen to be 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 cc of corn oil, but the volume and liquid will depend on the particular compound being tested. All animals were killed with dry ice (COg)

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 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 percentage 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 was considered inactive.

Abnormal implantation sites and abnormal number of corpora lutea were also reported when 20$ or more sites were abnormal or if there were no abnormal sites but only 50$ or more abnormal corpora lutea. ^ V^ q "^0r an ^ordinance was judged from inspection or calculated by the method indicated by Berkson ("JgrAmeaK. Stat. Assoc. 48 (263), 565, 1953). Estrone was used as a standard A relative potency was obtained by comparing the ratio of EDj.fø for estrone to the corresponding ratio for the test compound.

Racemic methyl 7-β-hydroxy-2β-(3(s)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl7-heptanoate which is a representative compound according to the present invention is active in the aforementioned test of antifertility activity in a dose of 50-200 mg per hamster.

Compounds according to the present invention can be combined with common pharmaceutical 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 pharmaceutical 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, pblyvinyl alcohol, stearic acid, alkaline earth metal stearates such as magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil or theobroma, water, agar, alginic acid, benzyl alcohol, isotonic saline and isotonic phosphate buffer solutions such as well as other known non-toxic carriers.

The following examples illustrate the invention. In the following examples, temperatures are given in °C and amounts 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 reported in parts per million (S).

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 prepared.

The hydroxyl group was protected by treating 3.6 parts of 3-methyl-3-hydroxy-5-phenyl-l-pentyne 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-triethylsilyloxy-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 by weight of a 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- cyclopenten-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 residual oil by low-pressure liquid chromatography on silica gel using 30% ethyl acetate/hexane as eluent gave the intermediate methyl-7-^3P-hydroxy-28-(3-methyl-3-triethylsilyloxy-5-phenyl- 1-pentyn-1-yl)-5-oxocyclopent-la-yl 7-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-β36-hydroxy-2B-(3(R)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-la-yl 7-heptanoate and racemic methyl 7-[3|3-hydroxy-26-(3(S)-hydroxy-3-methyl-5-phenyl-1-pentyn-l-yl)-5- oxocyclo-pent-la-yl7heptanoate, and the latter compound: is characterized by nuclear magnetic resonance spectrum peaks at approx. S1.56.8 3.66 and $7.21.

Example 2

m-trifluoromethylcinnamic acid was hydrogenated at room temperature at approx. 1.3 kg/cm o 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 1 N 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-7-38-hydroxy-28-^3(r)-hydroxy-3-methyl-5- (m-trifluoromethylphenyl)-1-pentyn-1-yl7-5-oxo-cyclopent-loc-yl^ heptanoate and racemic methyl-7-£3B-hydroxy-28-^3(S)-hydroxy-3-methyl- 5-(m-trifluoromethylphenyl)-1-pentyn-1-yl7-5-oxocyclopent-1-yl-3-heptanoate, which is characterized by nuclear magnetic resonance spectrum peaks at approx. S1.59,

3.68 and 54.47.

In a similar manner, p-fluorocinnamic acid was converted to racemic methyl-7-£38-hydroxy-28-^3(s)-hydroxy-3-inethyl-5-(g-fluorophenyl)-1-pentyn-1-yl7-5 -oxocyclopent-la-yl"^ heptanoate and its racemic JR derivative} p-bromocinnamic acid was converted to racemic methyl-7-£^B-hydroxy-2B-^3(s)-hydroxy-3-methyl-5-(g -bromophenyl)-l-pentyn-l-yl7-5-oxocyclopent-la-yl3heptanoate and its racemic JR derivative, m-chlorocinnamic acid were converted to racemic methyl-7- ^38-hydroxy-28-/^3(S)- hydroxy-3-methyl-5-(m-chlorophenyl)-l-pentyl-l-yl7-5-oxocyclopent-la-ylJjheptanoate characterized by nuclear magnetic resonance spectrum peaks at ca.S2.0, &2.84 and 83»67 and its racemic JR derivative characterized at nuclear magnetic resonance spectrum peaks at about Sl.57, $3.7 and

fe4.44; p-Methylcinnamic acid was converted to racemic methyl-7-■f3S-byhydroxy-28-^3(s)-hydroxy-3-methyl-5-(g-methylphenyl)-1-pentyn-1-yl7-5-oxocyclopent- la-yl3 heptanoate and its racemic 3R derivative, g-ethylcinnamic acid were converted to racemic methyl-7-£36-hydroxy-2B<->^3(<s>)-hydroxy-3-methyl-5-(g-< (ε>tylphenyl)-1-pentyn-1-yl7-5-oxocyclopent-1-yl3-heptanoate and its racemic 3R derivative; g-Methoxycinnamic acid was converted to racemic methyl-7-£38-hydroxy-28-/3(s)-hydroxy-3-methyl-5-(p-methoxy-phenyl)-1-pentyn-1-yl7-5- oxo-cyclopent-la-yl3heptanoate characterized by nuclear magnetic resonance spectrum peaks at approx. 8l.57» £>3»68 and & 4.46, and its racemic 3R derivative; p-Phenyl-cinnamic acid was converted to racemic methyl-7-(38-hydroxy-28-(3(s)-hydroxy-3-methyl-5-p-biphenyl-1-pentyn-1-yl)-5-oxocyclo -pent-la-yl 7-heptanoate and its racemic 3 R derivative.

4-Phenylbutyric acid was converted to racemic methyl 7-^38-hydroxy-28-(3(S)-hydroxy-3-methyl-6-phenyl-1-hexyn-1-yl)-5-oxocyclopent-1a-yl7heptanoate characterized at nuclear magnetic resonance spectrum peaks at approx. Sl,50, 82,75»and&3,68

and its 3R deriv.

Example 3

By replacing benzylacetone with benzyldimethylacetaldehyde and using the method from example 1, racemic methyl-7-^38-hydroxy-28-(3(R)<->hydroxy-4,4-dimethyl) was produced -5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl 7-heptanoate and racemic methyl 7-β38-hydroxy-28-(3(s)-hydroxy-4,4-dimethyl- 5-phenyl-1-pentyl-1-yl)-5-oxocyclopent-la-yl)heptanoate.

Example 4

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. then racemic methyl-7-β38-hydroxy-28-(3(RS)-hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl7hept-5 was prepared - cis-enoate characterized by nuclear magnetic resonance spectrum peaks at approx. 1.58, 62.82 and<&>4.48.

Example 5

By using the methods from examples 1 and 2 and using m-chlorophenylacetone and racemic 7-(3-hydroxy-5-oxo-1-cyclopenten-1-y1)heptanoate, racemic methyl-7-£38-hydroxy- 26-^3(S)-hydroxy-3-methyl-4-(m-chlorophenyl)-1-butyn-1-yl7-5-oxocyclopent-1a-yl^heptanoate characterized by nuclear magnetic resonance spectrum peaks at ca. &1.57»&2»96 °g &3»69 and its 3(R) stereoisomer.

Example 6

Using 7-(3-nydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid, ethyl 7-(3-nydroxy-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 used in Example 1,

and then using the same procedure as stated in this example, the following compounds were prepared: racemic 7-β38-hydroxy-28-(3(s)-hydroxy-3-niethyl-5-phenyl-1-pentyn-1- yl )-5-oxocyclopent-la-yl7heptanoic acid and its racemic JR derivative racemic ethyl-7-^38-hydroxy-28-(3(s)-hydroxy-3-methyl-5-phenyl-l-pentyn-l-yl )-5-6xocyclopent-la-yl 7-heptanoate and its racemic 3R derivative, and racemic heptyl-7-[38-hydroxy-28-(3(s)-hydroxy-3-methyl-5-phenyl-1-pentyn- 1-yl)-5-oxocyclopent-la-yl 7-heptanoate and its racemic JR derivative.

Example 7

Using the procedure from Example 1 and using m-trifluoromethylbenzylacetone and methyl 7-(3-nydroxy-5-oxo-1-cyclopenten-1-yl)hept-5-cis-enoate. racemic methyl-7-38-hydroxy-28-3(s)-hydroxy-3-methyl-5-(m-trifluoromethylphenyl)-1-pentyn-1-yl7-5-oxocyclopent -la-yi^hept-5-cis-enoate and its racemic JR derivative.

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, we got one prepared racemic methyl-7-β38-hydroxy<y-28->^3(s)-hydroxy-3~methyl-5-(m-chlorophenyl)-1-pentyn-1-yl7-5-oxocyclopent- la-yljrhept-5- ci' al-

enoate and its racemic JR derivative.

Example 9

By using the procedure from examples 1 and 2 and using g-methoxycinnamic acid and methyl 7-(3-hydroxy-5-oxo-1-cyclo-pentenl-1-yl)hept-5-cis-enoate, racemic methyl-7-[3B]-hydroxy-26-[3(S)-hydroxy-3-methyl-5-(p-methoxyphenyl)-1-pentyn-1-yl]-5-oxocyclopent-la-y^hept -5- cis -enoate and its racemic JR derivative.

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-/36- hydroxy-28-(3(s)-hydroxy-3-methyl-7-phenyl-1-heptyn-1-yl)-5-oxocyclopent-1a-yl7beptanoate and its racemic 3** deriv.

Claims (8)

1. Process for the preparation of compounds with the following formula where R is hydrogen or lower alkyl having from 1 to 7 carbon atoms; Y is -CH2 -CH2 - or -CH=CH-; R <*> , R" and R"' are individually hydro- gen or methyl; n is from 0-3" and Ar is phenylhalogen-substituted phenyl, lower alkyl-substituted phenyl where said lower alkyl group can have from 1-4 carbon atoms, lower alkoxy-substituted phenyl where said lower alkoxy group can contain from 1-4 carbon atoms, p-biphenyl or trifluoromethyl-substituted phenyl, and where the wavy line represents R or S stereochemistry, characterized by reacting a compound with the formula where R and Y are as defined above, with a dimethyl- -aryl- l« alkynyl)aluminum compound2.see with the formula where Ar, R <*> , R" and R"' and n are as defined above, and where Alk is an alkyl group with from 1 to k carbon atoms, after which the trialkylsilyl protecting group is hydrolysed and the compounds produced are separated chromatographically. 2. Process according to claim 1, characterized in that methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)heptanoate is reacted with dimethyl (3-methyl-5-phenyl-3-tri-ethylsilyloxy -1-pentyne)aluminum, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the racemic methyl-7-(3-hydroxy-23-(3(S)-hydroxy-3-methyl-5- phenyl-1-pentyn-1-yl)-5-oxocyclo-pent-la-yl 7-heptanoate. 3» Method according to claim 1, characterized in that methyl 7-(3-hydroxyl-5-oxo-1-cyclopenten-1-yl)-heptanoate is reacted with dimethyl 3-methyl-3-triethylsilyl- oxy-5-(m-trifluoromethylphenyl)-1-pentyne)aluminum, hydrolyzes the produced product to remove the triethylsilyl protecting group, after which the racemic methyl-7-£-38-hydroxy-28-/ 3( S )-Hydroxy-3-methyl-5-(m-trifluoromethylphenyl)-1-pentyn-1-yl7-5-oxocyclopent-la-yl3'-heptanoate. 4. Process according to claim 1, characterized in that methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate is reacted with dimethyl/3-(m-chlorophenyl)-3-methyl-3 -triethylsilyloxy-1-pentyne7aluminum, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the racemic methyl-7-$3P-hydroxy-28-^3(S)-hydroxy-3-methyl-5- (m-chlorophenyl)-1-pentyn-1-yl7-5-oxocyclopent-1-yl3heptanoate and racemic methyl-7-£36-nydr,oxy-26-^3(R)-hydroxy-3-methyl-5- (m-Chlorophenyl)-1-pentyn-1-<yl>7-5-oxocyclopent-1-yl-3-heptanoate. 5. Method according to claim 1, characterized in that methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate is reacted with dimethyl/3-(p-methoxyphenyl)-3-methyl- 3-triethylsilyloxy-1-pentyne)aluminum, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the prepared racemic methyl-7-£38-hydroxy-2(3-/3(s)-hydroxy-3- methyl 5-(p-meth-oxyphenyl)-1-pentyn-1-yl)-5-oxocyclopent-1-yl-3-heptanoate. 6. Process according to claim 1, characterized in that methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate is reacted with dimethyl (3-methyl-6-phenyl-3-tri- ethylsilyloxy-l-hexyne)aluminium, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the racemic methyl-7-(38-hydroxy-26-(3-(s)-hydroxy-3-methyl-6) prepared -phenyl-1-hexyn-1-yl)-5-oxocyclopent-la-yl 7-heptanoate. 7. Process according to claim 1, characterized in that methyl 7-(3-nydroxy-5-oxo-1-cyclopenten-1-yl)-hept-5-cis-enoate is reacted with dimethyl (3-methyl-5- phenyl-3-triethylsilyloxy-1-pentyne)aluminum, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the prepared racemic methyl-7-β-hydroxy-28-(3(RS)-hydroxy-3- *methyl-5-phenyl-1-pentyn-1-yl)-5-oxocyclopent-la-yl7hept-5-£ is~ enoa' t» 8. Process according to claim 1, characterized in that methyl 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoate is reacted with dimethyl N-(m-chlorophenyl)-3-methyl -3-triethylsilyloxy-1-butyne7aluminum, hydrolyzes the product prepared to remove the triethylsilyl protecting group and then chromatographically separates the racemic methyl-7-£38-hydroxy-2p-^3(s)-hydroxy-3-methyl- 4-(m-Chlorophenyl)-1-butyn-1-yl7-5-oxocyclopent-loc-yl3-heptanoate.