DE2758156A1 - OMEGA-ARYL-13-PROSTINE ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME - Google Patents

Description

Our No. 21 ^ 84 Ka / be

DG Searle & Co.
Skokie, 111., V.St.Α ..

jL> TAryl-13-prostinic acid derivatives, processes for their production and pharmaceutical preparations containing the same

The present invention relates to L.j-aryl-13-prostinic acid derivatives the general formula

Il Γ]

² 2 3 2 _R , _F,. (I)

! I.

HC C = CCC- (CH ₀ ) -Ar ... \ I 2 η

HO R "'

where R is a hydrogen atom or a lower alkyl radical having 17 carbon atoms, Y is a radical of the formulas -CHp-CHp- or -CH = CH-, R ^f , R "and R" ^{1 are} each a hydrogen atom or a methyl radical, η 0 to 3 and Ar is a phenyl radical, halogen-substituted phenyl radical, lower-alkyl-substituted phenyl radical, the lower alkyl radical ^{containing from 1 to 1} J carbon atoms, lower-alkoxy-substituted phenyl radical, the lower alkoxy radical containing from 1 to 4 carbon atoms, p- Biphenyl radical or trifluoromethyl-substituted phenyl radical and the wavy line R or S represents stereochemistry, processes for their production and pharmaceutical preparations and veterinary drugs containing the same.

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(O refers to the connection shown and its reflection referring to the stereochemistry at the 1-, 2- and 3-positions of the 5-linear ring, i.e. H. '.'., ic, & and B, "■ · ..,.» ..

Lower alkyl radicals with 1-7 carbon atoms mean methyl radicals, Ethy residues, PrcpyI residues, 3utyIreste, Pentyl residues, Hexylreste, Heptyl radicals and branched-chain isomers of the same.

Mied-alkyl-substituted phenyl radicals mean the Tclyl radical, Phenethyl radical, p-tert-butylphenyl radical, p-propylphenyl radical and like that.

Halogens ubiquitous phenyl radicals mean chlorophenyl radicals, fluorophenyl radicals, Bromophenyl residues and iodophenyl residues.

Alkoxy-substituted phenyl radicals refer to I-ethoxyphenyl radicals, Ethoxyphenyl residues, propoxyphenyl residues and butoxyphenyl residues.

Crystalline, substituted phenyl and naphthyl of inventive acids of the way they are described in the excess sludge PS 3 89 ¹ "062 are considered for the purposes of the present invention to be equivalent.

Compounds of the formula

^ JI ^ _i , (CH ₂ ) ₆ -CO ₂ R (+) ι ι _H , _R "

C = C — C — C - (CH ₂ ) _n - Ar OE R ^M1

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in which R, R ¹ , R ", R"', η and Ar have the meanings given above, are preferred. The compounds of the formula are particularly preferred

μ. ■ ( ^CH 2 ⁾ 6 ~ ^C0 2 ^R

2 ⁾ 6

C-CH ₂ -CH ₂ -Ar OK

wherein R and Ar are as defined above. The compounds of the invention are by reacting a Compound of formula

H ₀ -Y

(IV) HO

in which R and Y have the meaning given above, with a dimethyl-gu-aryl-1-alkynyl> aluminum compound of the formula

Si (AIk) ₃

R "0

'I I

Ar- (CH ₀ JC-CC = C-Al (CHO ₅ c- η j 5 c-

R "'

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wherein Ar, R ^1, R ", R ^1" and η are as defined above and Alk is alkyl of 1 - ¹ means I carbon atoms, followed by hydrolysis of the resulting product to remove the trialkylsilyl protecting group and subsequent
produced chromatographic separation of the compounds thus obtained.

Dimethyl- (uj-aryl-l-alkynyl) aluminum, which is used as the starting material is used is prepared by the procedures outlined in Scheme I below.

^ttf

R "0

1) LiC ^ CK

Ar- (CH ₂ ) -CCR- 2 η,

R "t

followed by

KF / DMP

j Ar- (CH ₂ ) _n -C

OK j

C = C-H

Si (AIk) ₃

R "O

Ι ·, Ar- (CH ₂ ) _n -C CC = C-Al (CH ₃ ) ₂

R ¹

^BuLi

R "OSi (Alk) ο

Il

Ar- (CHo) ₉ -C CC = CH

^{2 2} | |

Scheme I.

Examples of starting materials for preparing the compounds shown in Scheme I are the ketones and aldehydes of the formula

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■ Ζ} η

R ¹ -CC- (CK ,.) -Ar ι ^ η

R "

Ό Tl

ί "t

Phenyl 1 H K CH ₃ m-chlorophenyl 1 H H CH ₃ p-fluorophenyl 1 K H CH ₃ m-trifluoromethylphenyl 1 H H CH ₃ Phenyl 1 CH ₃ CH ₃ K Phenyl 2 H H CH ₃ Phenyl 0 CH ₃ CH ₃ H Phenyl 3 H H CH ₃ Phenyl 2 H CH ₃ CK ₃ p-methoxyphenyl 1 TT
Ii Ii CHq p-methylphenyl 1 H H CH ₃ p-ethylphenyl 1 H H CE ₃ Biphenyl 1 H H CH-.

Carboxylic acids are converted to the aforementioned ketones and aldehydes by methods known in the art.

Methyl 7- (3-hydroxy-5-oxo-l-cyclopenten-l-yl) heptanoate and Ethyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5-cis-enoate

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and the corresponding acids are known starting materials. Example 1 illustrates a preferred process for preparing the compounds of the invention.

The closest prior art is U.S. Patent 3,973
2

, Which

PGE ₀ -Anaio £ a of the formula

describes. These compounds differ from the compounds according to the invention in the stereochemistry at C atom 11 and in that they have _{a -CH = CK- at C 1} ^ -C ₁ I ₄ instead of -C = C-. 11-deoxy compounds of the present invention are described in EE-PS 839 533 and US-PS 3,978,111 also describes related compounds.

In Tetrahedron Let. 26, page 2627 (1972) are compounds of the formula

described.

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The compounds according to the invention differ in particular from these compounds in that they have a phenyl-substituted alkyl radical _{instead of -Cj-H 11 -.}

The antifertilitive effectiveness of the compounds according to the invention is illustrated by the following test:

Syrian golden hamsters aged 9-10 weeks were sexually mature locked in a cage with males in the late afternoon. A pipette was used daily between 8:15 am and 10:00 am Vaginal smears taken. The presence of sperm was considered a positive sign of insemination. The day the insemination was designated as day 1 of gestation. Pregnant females were mated daily, beginning with the test injected on day 1 through day 5. The route of administration is either subcutaneous or intragastric. The daily Injection was usually made in a volume of 0.2 ml of corn oil, but the volume and vehicle may vary will vary depending on the physical properties of the particular compound being tested. All animals were on day 6 killed with dry ice (COp) in the morning.

The entire uterine tract was removed and the uterus and ovaries were cleared of foreign tissue. The total number the implantation sites were identified and recorded. Upon observation, the 6 day size spots were found to be normal and any spots that were smaller and / or pale or absorbent were marked abnormal.

The total number of corpora lutea was determined and recorded. Upon observation, the red corpora lutea were identified as

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considered normal and the pale, pink or white regressed Corpora lutea considered abnormal.

The only dose of a compound was given on a percentage basis Implantation, which is obtained by dividing the total number of Implantation sites obtained by the total number of corpora lutea and multiplying by 100 were considered active or inactive classified.

A degree of implantation of 50 % or less was considered active.

A degree of implantation of 51 % or more was considered inactive.

Abnormal implantation sites and corpora lutea are also reported when 20 % or more sites are abnormal or, if there are no abnormal sites, only 50 % or more abnormal corpora lutea are present. The ED ^ value of a compound is approximately determined by examination or calculated according to the method of Berkson (J.Amer. Stat. Assoc. 48 (263), 565, 1953). Oestrone was used as the reference substance. From the ratio of the ED _cr . Value of oestrone to the ED _cr . Value of the

50 pO

Test compound will maintain relative potency.

Racemic methyl 7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-1 ^r A-yl7-heptanoate, a representative compound of the present invention is effective in the anti-fertility test described above at 50-200 mg per hamster.

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The compounds according to the invention can be used with conventional pharmaceutical Straps can be combined. These mixtures can be administered either orally or parenterally. For the oral Administration are tablets, troches, capsules, coated tablets, pills or powders, while aqueous solutions, non-aqueous Solutions or suspensions are suitable for parenteral administration. Acceptable pharmaceutical carriers are e.g. B. gelatin capsules, Sugars such as lactose or sucrose, starch 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 gum, polyvinyl 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, theobroma oil, water, agar, alginic acid, benzyl alcohol, isotonic saline and phosphate buffer solutions and other non-toxic compatible substances.

The following examples serve to illustrate the present invention. In these examples, the temperatures are given in ⁰ C and the amounts in parts by weight, unless parts by volume are mentioned. The ratio between parts by weight and parts by volume is the same as the existing ratio between grams and milliliters. NMR resonance spectra were performed on a 60 or 100 megahertz instrument and are reported in ppM (J).

example 1

8 parts by volume of 2.5 molar n-butyllithium were a solution of 3.1 parts of triethylsilylacetylene in 20 parts by volume of ethyl

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ether added at -30 ° C. The resulting solution was allowed to warm to room temperature and then recooled to -3O ⁰ C and treated with 3 parts of benzyl acetone. 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 ethereal layer was washed with water and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the remaining oil was dissolved in 15 parts by volume of dimethylformamide containing 2 parts of powdered sodium fluoride. The Rekationsgemisch was stirred and one hour heated to 70 - 8O ⁰ C, after which it was 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 the eluant to give 3-methyl-3-hydroxy-5-phenyl-1-pentyne.

The hydroxypropyl group was obtained by treating 3 »6 parts of 3-methyl-3-hydroxy-5-phenyl-1-pentyne in 15 parts by volume of dimethylformamide in succesive manner with 3» 5 parts of imidazole and M, 0 parts of triethylsilyl chloride and stirring this for one hour Mixture protected at room temperature. The reaction mixture was poured into ether / water and the ethereal layer was washed three times with water, dried over anhydrous sodium sulfate, and then the ether was removed under reduced pressure. The distillation of the remaining oil gave S-Kethyl-S-phenylO-triethylsilyloxy-1-pentyne.

1,7k parts of this ether in 10 volumes of ethyl ether were in -l "0 ^o C with 2.8 parts by volume of 2.17 molar butyl-lithium comparable

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puts. The resulting reaction mixture was turned off for 30 minutes at room temperature and then again - ¹ IO cooled ⁰ C. A solution of 3> 7 parts of a 15 weight percent solution of dinethylaluminum chloride in hexane was added and the reaction mixture was allowed to warm to room temperature. The resulting reaction mixture, which contained dimethyl- (3-methyl-5-phenyl-3-triethylsilyloxy-1-pentyne) aluminum, was mixed with one part of methyl-7- (3-hydroxy-5-oxo-1-cyclopentene-1 -yl) -heptanoate treated in 10 parts by volume of ethyl ether. The reaction mixture was stirred at room temperature for 1-2 hours and poured into ether and 1N hydrochloric acid. The ethereal layer was separated, washed with water and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure. After purification of the remaining oil by low pressure liquid chromatography on silica gel using 30 % ethyl acetate / hexane as the eluent, the intermediate, I-'ethyl-7- / 3ß-hydroxy-2ß- (3-methyl-3-triethylsilyloxy-5- phenyl-1-pentin-1-yl) -5-oxocyclopent-loo-yl7heptanoate. 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 six times with water and dried over anhydrous sodium sulfate. The solvent was removed. Low pressure liquid chromatography on silica gel using 100 % ethyl acetate as the eluant gave racemic methyl 7- / 3β-hydroxy-2β- (3 (R) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl ) -5-oxocyclopent-1 ^ -yi7heptanoat and racemic methyl 7- / 3 ~ ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentin-1-yl) - 5-oxocyclopent-1 "X-yl7heptanoate, which is characterized by peaks in the Ni-IR spectrum at about 11.56, - $" 3.66 and i7.21.

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Example 2

ρ m-Trifluonnethyl-cinntsäure was taking at room temperature at 0.1 ^ kg / cm using palladium on charcoal as a catalyst
Hydrogenated formation of m-trifluoromethylbenzyl acetic acid.

21.8 parts of this acid were dissolved in 200 parts by volume of ether. They were then added dropwise over a period of time
100 parts by volume of 1.0 molar methyl lithium in ether were added at 0 ^{° C. for 30 minutes.} After the addition was finished
the mixture was stirred for 3-4 hours at room temperature. The mixture was poured into 1 N HCl, the organic layer was washed sequentially with water / water and 5 percent potassium carbonate
and then dried over anhydrous sodium sulfate. The solvent was removed to give m-trifluoromethylbenzyl acetone. If the procedure described in Example 1 was followed, but the benzyl acetone was replaced by m-trifluoromethylbenzyl acetone, racemic methyl-7- {3ß-hydroxy-2ß- / 3 (R) -hydroxy-3-methyl-5- (m- trifluoromethylphenyl) -1-pentyn-1-ylT-S-oxocyclopent-1c-yljheptanoate and racemic methyl 7- _L 3ßhydroxy-2ß- / 5 (S) -hydroxy-3-methy1-5- (m-trifluoromethylphenyI) -I-pentyne -l-yl7-5-oxocyclopent-l '* - ylj heptanoate, which is characterized by peaks in the

NMR spectrum at about si, 59,) '3 »68 and ό ^, ^ Ί is obtained.

Similarly, p-fluorocinnamic acid was converted into racemic methyl-7- {3ß-hydroxy-2ß- / 3 (S) -hydroxy-3-methyl-5- (p-fluorophenyI) -l-pentyn-1-ylT- S-oxocyclopent-lji-yl] heptanoate and the racemic 3R derivative of the same, p-bromocinnamic acid in racemic methyl-7-
| 3β-hydroxy-2β- / T (S) -hydroxy-3-methyl-5- (p-bromophenyl) -l-pentinl-ylJ-S-oxocyclopent-l'Ä-yl] heptanoate and the racemic. 3R derivative of the same, m-chlorocinnamic acid in racemic methyl-7- | 3ßhydroxy-2ß- / 3 (S) -hydroxy-3-methyl-5- (m-chlorophenyl-l-pentyl-l-yl7-

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5-oxocyclopent-lj-yl> heptanoate _> which is characterized by peaks in the NMR spectrum at etv / a ^ 2.0, -.2.84 and 0.67, and the racemic 3R derivative thereof, which is indicated by peaks is marked in the NMR spectrum at about VI, 57, .3.7 and ^, ^ 4, p-methylcinnamic acid in racemic methyl-7-β-hydroxy-2β- / 3 (S) -hydroxy-3-raethyl ~ 5- (p-methylphenyl Jl-pentin-l-ylZ-S-oxocyclopent-la-ylj heptanoate and the racemic 3R derivative of the same, p-ethylcinnamic acid in racemic methyl-7- -: 3ß-hydroxy-2ß- / 5 ( S) -hydroxy-3-methyl-5- (p-ethylphenyl) -l-pentin-l-yl7-5-oxocyclopent-la-yl) heptanoate and the racemic 3R derivative of the same, p-methoxycinnamic acid in racemic methyl 7- (3β-hydroxy-2β-A5 (S) -hydroxy-3-methyl-5- (p-methoxyphenyl) -l-pentin-1-yl7-5-oxocyclopent-II-yl] -heptanoate, which is represented by peaks is marked in the NMR spectrum at about σ'1.57 »^ 3.68 and οΜ, ^ β. and the racemic 3R derivative of the same and p-phenylcinnamic acid in racemic methyl-7-A3fi> -hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-p-biphenyl-1-pentine- l-yl) ~ 5-oxocyclopent-10-yl7heptanoate and the racemic 3R derivative of the same transferred.

4-Pheny! Butyric acid was converted into racemic methyl-7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-6-phenyl-1-hexyn-1-yl) -5-oxocyclopent-10L- yl7heptanoate, which is characterized by peaks in the NMR spectrum at ο 1.50, i> 2.75 and <f3.68, and the 3R derivative of the same convicted.

Example 3

The procedure described in Example 1 was worked according but benzylacetone replaced by Benzyldimethylacetaldehyd, so were racemic Hethy 1-7 / 3.beta.-hydroxy-2ß- (3 (R) -hydroxy !, * ¹ J-dimethyl-S-phenyl -l-pentin-1-ylJ-S-oxocyclopent-ll-yl theptanoate and racemic methyl 7 ~ / 3ß-hydroxy-2ß- (3 (S) ^-hydroxy-1 », 4-diraethyl-S-phenyl-1- Pentin-1-yD-S-oxocyclopent-la-yl theptanoate .

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Example M

The procedure described in Example 1 was followed, but benzyl acetone and 1 '! Ethyl 7- (3 (R « ^c i) -hydroxy-5-oxo-1-cyclopenten-1-yl) hept-5-cis-enoate used, so was racemic ethyl-7- / 3ß-hyaroxy-2ß- (3 (RS) -hydroxy-3-methyl-5-phenyl-1-pentinl-ylJ-S-oxocyclopent-10t-ylThept-S-cis- enoate, which is characterized by peaks in the NMR spectrum at about 1.58, 02.82 and g * l, ^ 8.

Example 5

If the procedure used in Examples 1 and 2 was followed and m-chlorophenylacetone and racemic 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate were used, racemic methyl 7- pβ- hydroxy-2ß- / 3 (S) -hydroxy-3-Jaethyl- ^l l- (ia-chlorophenyl) -l-butyn-l-ylT-S-oxocyclopent-la-yl ^ -heptanoate, which is indicated by peaks in the NMR Spectrum is indicated at about Jl, 579 d2.96 and 43.69, and the 3 (R) -stereoisomer thereof is obtained.

Example 6

If the procedure described in Example 1 was followed, but instead of the ifethyl-7- (3-hydroxy-5-oxo-lcyclopenten-l-yl) -heptanoate used there 7- (3-hydroxy-5-oxo-l-cyclopentenl-yl) -heptanoic acid, ethyl-7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) -heptanoate or keptyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) -heptanoate were used, the following were used Compounds obtained: Raceric 7- / 3ß-Hydroxy-2ft- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentin-1-yl) -5-oxocyclopent-1C ^ yl7-heptanoic acid and the racemic 3R derivative of the same, racemic ethyl 7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-id-yl7 -heptanoate and the racemic 3R derivative of the same and

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racemic heptyl-7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-1 ^ -yl7-heptanoate and the racemic 3R derivative thereof.

Example 7

The procedure described in Example 1 was followed and m-trifluoromethylbenzyl acetone and methyl 7- (3 ~ hydroxy-5-oxocyclopenten-1-yl) -hept-5-cis-enoate racemic ethyl-7- {3β-hydroxy-2β- / 3 (S) -hydroxy-3-methyl-5- (mtrifluoromethylphenyD-1-pentin-1-ylT'-S-oxocyclopent-IS.-yl ^ -hept-5-cis-enoat and the racemic 3R derivative thereof.

Example 8

The procedure described in Examples 1 and 2 was followed and m-chlorocinnamic acid and methyl 7- (3-hydroxy-5-oxo-1-cyclopentene-1-yD-hept-5-cis-enoate used, racemic methyl-7- | 3ß-hydroxy-2ß- / 3 (S) -hydroxy-3-methyl-5- (mchlorphenyl) -l-pentin-1-yl7-5-oxocyclopent-ia-yl ^ -hept-5-cisenoate and the racemic 3R derivative thereof.

Example 9

The procedure described in Examples 1 and 2 was followed and p-methoxycinnamic acid and methyl 7- (3-hydroxy-5-oxol-cyclopentene-1-yD-hept-5-cis-enoate) racemic methyl 7- {3β-hydroxy-2β-A5 (S) -hydroxy-3-methyl-5- (p-methoxyphenyl) -1-pentin-1-yl7-5-oxocyclopent-1 & -yl were used *> - hept-5-cis-enoate and / racemic 3R derivative thereof.

Example 10

The procedure described in Examples 1 and 2 was followed and 5-phenylpentanoic acid and methyl-7- (3 ~

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hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate is used, so v / urden racemic methyl 7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-7-phenyl-1-heptin-1-yl) -5-oxocyclopent-1: \ - yl7-heptanoate and the racemic 3R derivative thereof.

Example 11

Typical pharmaceutical preparations which contain the compounds according to the invention are described below:

tablet

Ingredient Quantity (mg) / tablet

Compound according to the invention (e.g.

racemic methyl-7-A5ß-hydroxy-

2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-

l-pentin-l-yl) -5-oxocyclopent-lu-

y17-heptanoate) 0.001

Mannitol 36.00

Microcrystalline cellulose 10.00

Polyvinyl pyrrolidone 2.50

Thixcine 1.50

The active ingredient was dissolved in isopropyl alcohol and added to mannitol distributed. The mixture was air dried and passed through a

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Sieve driven with a mesh size of 0.42 mm. Microcrystalline Cellulose and polyvinylpyrrolidone were added to the mixture. The mixture-then carefully mixed and then driven through a sieve with a mesh size of 0.12 mm. The mixture was then made with isopropyl alcohol granulated and spread on boards and dried for M hours at room temperature. The dried granules were then sieved. The granules were carefully mixed with thixcin and the mixture compressed into tablets.

Capsules

Ingredient Quantity (mg) / capsule

Compound according to the invention (e.g. racemic methyl-7-./3ß-hydroxy-2ß-(3(S) -hydroxy-3-methyl-5-phenyl- 1-pentin-l-yl) -5-0x0x0eyelopent-lX-

yl7-heptanoate) 0.001

Mannitol 1 ^ 0.00

Microcrystalline cellulose 35.00

The active ingredient was dissolved in isopropyl alcohol and distributed on mannitol. Microcrystalline cellulose was added and the mixture was mixed thoroughly and filled by hand or machine into appropriately sized hard gelatin capsules using 175 mg of filling per capsule.

Other acceptable pharmaceutical carriers for use with

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the above formulations are, for. B. sugars such as lactose, sucrose, mannitol or sorbitol, starches such as corn starch, Tapioca starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose or methyl cellulose, Gelatin, calcium phosphates, such as dicalcium phosphate or calcium phosphate, Sodium sulfate, calcium sulfate, polyvinylpyrrolidone, polyvinyl alcohol, stearic acid, alkaline earth metal stearates, such as Magnesium stearate, stearic acid from vegetable oils such as peanut oil, Cottonseed oil, sesame oil, olive oil, corn oil, surfactants (non-ionic, cationic, anionic), ethylene glycol polymers, ß-cyclodextrin, fatty alcohols, hydrolyzed grain solids and other non-toxic compatible fillers, Binders, disintegrants and lubricants commonly used in pharmaceutical formulations.

Parenteral preparation

Be component amount (mg) / 2 cm

Connection according to the invention (e.g.

racemic methyl-7- / 5ß-hydroxy-

2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-

l-pentin-l-yl) -5-oxocyclopent-ia.-

yl7-heptanoate) 0.001

Ethanol 2.0

The active ingredient was dissolved in the ethyl alcohol, the solution was filtered and filled into ampoules, and the ampoules were sealed. The ampoules were then sterilized using appropriate procedures.

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" ^21t " 2758Ί56

Other acceptable pharmaceutical carriers for a parenteral one Product are, for example, vegetable oils such as peanut oil, corn oil, Cottonseed oil, sesame oil, benzyl alcohol, saline solution, phosphate buffer, water / water, ethylene glycol polymers, urea, dimethylacetamide, Triton, dioxolane, ethyl carbonate, ethyl lactate, glycerin formal, isopropyl myristate, surfactants (non-ionic, cationic, anionic), polyalcohols and ethanol.

In the preparations of the type described above, the compounds according to the invention are used in one to achieve the desired Effect sufficient amount available. Although 0.001 mg per unit dosage is often suitable, it may be desired also considerably more or less active ingredient in each Dosage unit to be incorporated. The daily dosage of the compounds according to the invention depends on various factors, such as the particular compound employed, the condition for which the compound is administered and the response of the individual patients.

For: G. D. Searle, & Co.

Skokie, Alll / l V.St.A.

Dr. ff. J.W ff Lawyer

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Claims (19)

Claims R ¹ R "
HO ' C = CC- C- (CH ₀ ) _n - Ar where R is a hydrogen atom or a lower alkyl radical having 1-7 carbon atoms, Y is a radical of the formulas -CH ₂ -CH ₂ - or -CH = CH-, R ¹ , R "and R ^{nt are} each hydrogen or methyl, η 0 to 3 and Ar is phenyl radicals, halogen-substituted phenyl radicals, lower-alkyl-substituted phenyl radicals, the lower alkyl radical containing from 1 to 4 carbon atoms, lower-alkoxy-substituted phenyl radicals, the lower alkoxy radical containing 1-4 carbon atoms, p-biphenyl radicals or Trifluoromethyl-substituted phenyl radicals and the wavy line R or S denote stereochemistry. 2. Racemic I>: ethyl-7- / 3ß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-la-yl7- heptanoate as a compound according to claim 1. 3. Racemic methyl 1-7- ^: 3β-hydroxy-2β- / J (S) -hydroxy-3-methy 1-S-dn-trifluoromethylphenyD-1-pentin-1-ylZ-S-oxocyclopent-lxyl jheptanoate as a compound according to Claim 1. 809827/0900 OPiOtNAL INSPECTED 4. Raceir.isches Hethyl-7- '<J>H-hyarov.i; -2Ά- / J (S ) -hydroxy-3-rcethyl-5- (m-chlorophenyl) -pentin-1-yl7-5-oxocyclopent-1: \ .- yl * heptanoate as a compound according to claim 1. 5. Raceirasches Kethyl -? - ^ 3ii-hydroxy-2ß- / 5 (R) -hydroxy-3-methyl-5- (m-chlorrhenyD-1-pentin-1-yl ^ Z-S-oxocyclopent-1 ^ -ylj Heptanoate as a compound according to claim 1. 6. Racemic r-iethyl-7- {3 [beta] -hydroxy-2 [beta ]- / 3 (S) -hydroxy-3-ir.ethyl-5- (p-methoxyphenyl) -l-pentyn-1-yl) -5-oxocyclopent -li.-yI ^ Heptanoate as a compound according to claim 1. 7. Racemic methyl 7- / Jβ-hydroxy-2β- (3 (S) -hydroxy-3-methyl-6-phenyl-1-hexyn-1-yl) -5-oxocyclopent-1-X-yl 7 Heptanoate as a compound according to claim 1. 8. Racenic methyl-7 - /. 3S-hydroxy-2β- (3 (KS) -hydroxy-3-r-ethyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-10-yl7hept -5- cis -enoate as a compound according to claim 1. 9. Racemic methyl-7- {3ß-hydroxy-2ß- / 3 (S) -hydroxy-3-methyl- 4- (m-chlorophenyD-l-butyn-l-yl ^ Z-S-oxocyclopent-l-i-y I ^ heptanoate as a compound according to claim 1. 10. Process for the preparation of a compound according to claim 1, characterized in that one is a compound of the general formula g - Y - (CH ₂ ) ₃ - CO ₂ R (IV) HO 809827/0908 wherein R and Y have the meaning given in claim i, with a dir.ethyl- (o> -aryl-1-alkynyl) -alurainiuri compound the general formula Si (AIk) ₃
R "0 i I Ar- (CH ₂ ) _n -CC R ¹ wherein Ar, R ¹ , R ", R" * and η have the meaning given in claim 1 and Alk is an alkyl radical having 1 - k carbon atoms, reacts, then subjecting the trialkylsilyl protective group to hydrolysis and the compounds thus obtained subsequently separates chromatographically. 11. The method according to claim 10, characterized in that one Methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate nit Dimethyl (3-methyl-5-phenyl-3-triethyl-silyloxy-1-pentyne) aluminum is converted, the product thus obtained for removal hydrolyzed the triethylsilyl protective group and subsequently the racemic methyl-7- / Iß-hydroxy-2ß- (3 (S) -hydroxy-3-methyl-5-phenyl-1-pentyn-1-yl) -5-oxocyclopent-li -yl7heptenoate separates chromatographically. 12. The method according to claim 10, characterized in that one Methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate with * i098? 7 / 090ft Dirr, ethyl - / _ ^ Tinethyl-3-triethyl3ilyloxy-5- (ni-trifluoromethylphenyl) -l-pentiri7 converts, the product thus obtained is hydrolyzed to remove the triethylsilylxoxy-protective group and
hereinafter the racemic ethyl-7- ^ 3ß-hydroxy-2ß- / 5 (S) -hydroxy-3-rnechyl-5- (m-trifluoromethylphenyl) -l-pentin-1-yl7-5-oxocyclopent-lx-yljheptancat separates chromatographically. 13. The method according to claim 1O _1, characterized in that i'1ethyl-7- (3 ~ hydroxy-5-oxo-l-cyclopenten-yl) heptanoate with
Dimethyl - / β- (m-chlorophenyl) -3-methyl-> triethylsilyloxy-1-pentyn7aluminum converts, the product thus obtained is hydrolyzed to remove the triethylsilyl protective group and
hereinafter racemic methyl-7 ~ '[3ß-hydroxy-2ß- / 3 (S) -hydroxy.3-methyl-5- (ni-chlorophenyl Jl-pentin-l-yjT-i-oxocyclopent-lOL-yl ^ heptanoate and Racemic methyl 7- ^ 3ß-hydroxy-2ß-A5 (R) -hydroxy-3-methyl-5- (m-chlorophenyl) -l-pentyn-1-yl7-5-oxocyclopent-1A-yljheptanoate separates chromatographically. IN THE. Process according to claim 10, characterized in that one Methyl 7- (3-hydroxy-5-0x0-1-cyclopenten-l-yl) heptanoate with Dimethyl- / 5- (p-methoxyphenyl) -3-methyl-3-triethylsilyloxy-1-pentyne) aluminum reacted, the product thus obtained is hydrolyzed to remove the triethylsilyl protective group and subsequently racemic methyl 7- {3β-hydroxy-2β- / 3 (S) -hydroxy-3-methy1-5- (p-methoxyphenyl) -l-pentyn-1-yl) -5-oxocyclopentla-yl-heptanoate separates chromatographically. 15. The method according to claim 10, characterized in that methyl 7- (3-hydroxy-5-oxo-l-cyclopenten-l-yl) heptanoate with dimethyl (3-ethyl-6-phenyl-3-triethylsilyloxy -l-hexyne> aluminivun converts the product obtained in this way to remove the 809827/090 Triethylsilyl protective group hydrolyzed and subsequently the racemic methyl-7- / 3ß-hydroxy-2S- (3 (S) -hydroxy-3-ir: ethyl-6-pheny 1-1 -hexin-1-yl) -5-oxocyclopent-1 ~ \ -yl7heptar.oate by chromatography separates. 16. The method according to claim 10, characterized in that methyl -? - (3-hydroxy-5-oxo-l-cyclopenten-l-yl) -hept-5-cis-enoate with Di.Viethyi- (3-niethyl-5-phenyl-3-triethylsilyloxy-1-pentyne) aluminum reacted, the product thus obtained is hydrolyzed to remove the triethylsilyl protective group and subsequently racemic methyl-7- / Jß-hydroxy-2ß- (3 (RS) -hydroxy-3-ir.ethyl- enoate separates chromatographically. 17. Process according to claim 10, characterized in that methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) heptanoate is mixed with dimethyl- / ^I T- (m-chlorophenyl) -3-diethyl -3-triethylsilyloxy-lbutyn7-aluminum is converted, the product thus obtained is hydrolyzed to remove the triethylsilyl protective group and, according to the following, racemic methyl-7-j3ß-hydroxy-2ß- / 5 (S) -hydroxy-3-methyl- ⁱ * - Separates (m-chlorophenyl) -l-butyn-1-yl7-5-oxocyclopent-loc-yl-heptanoate by chromatography. 18. A pharmaceutical preparation, characterized by a content of one or more of the compounds according to claims 1-9 as an active ingredient. 19. Veterinary pharmaceuticals, characterized by a content of one or more of the compounds according to claims 1-9 as an active ingredient. 809827/090