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IE41470B1 - (3 -hydroxy-2 -(substituted 1-alkenyl)-5-oxo-1 -cyclopentyl)heptanoic acids - Google Patents

(3 -hydroxy-2 -(substituted 1-alkenyl)-5-oxo-1 -cyclopentyl)heptanoic acids

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Publication number
IE41470B1
IE41470B1 IE767/75A IE76775A IE41470B1 IE 41470 B1 IE41470 B1 IE 41470B1 IE 767/75 A IE767/75 A IE 767/75A IE 76775 A IE76775 A IE 76775A IE 41470 B1 IE41470 B1 IE 41470B1
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IE
Ireland
Prior art keywords
oxo
hydroxy
heptanoic acid
cyclopentyl
trans
Prior art date
Application number
IE767/75A
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IE41470L (en
Original Assignee
Searle & Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Searle & Co filed Critical Searle & Co
Publication of IE41470L publication Critical patent/IE41470L/en
Publication of IE41470B1 publication Critical patent/IE41470B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

Prostanoic acid derivatives of the following formula are prepared, in which R' denotes an alkyl radical having 1-7 C atoms and R'' denotes a straight-chain alkyl radical having 6-9 C atoms. These compounds are obtained by reacting an appropriate ketone, which is optionally protected on the hydroxy group, with an organometallic compound of the formula R'M or R''M in which M denotes lithium or magnesium halogen to introduce the substituent R' or R'' and optionally subsequently removing the protective group. The compound of the formula I, which is present as the free acid, can be converted into alkyl esters having 1-7 C atoms in the alkyl radical. On account of their antifertility properties, the prostanoic acid derivatives are utilisable pharmaceutical agents.

Description

The present invention relates to a group of novel chemical compounds having the following general formula wherein R is hydrogen or an alkyl radical containing 1 to 7 5 carbon atoms; R1 is an alkyl radical containing 1 to 7 carbon atoms; and R is a straight-chain alkyl radical containing 6 to 9 carbon atoms. Examples of the alkyl radicals referred to above are methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, or nonyl.
The compounds of the present invention are prepared - 2 41470 by the reaction of an organo-metallic reagent of the formula R'''M with a ketone of the formula wherein one of R''' and R'111 is an alkyl group containing 1 to 7 carbon atoms and the other is an alkyl group containing 6 to 9 carbon atoms; M is lithium or Mg-halogen; and Z is hydrogen or a hydroxy protecting group. Preferred halogens are bromine, iodine, or chlorine. Possible hydroxy protecting groups for Z are 2 - tetrahydropyranyl or tri(lower alkyl)silyl with 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 an ether such as tetrahydrofuran or diethyl ether. The reaction is further carried out at a low temperature such as in a Dry Ice Bath.
It is preferred to introduce a protecting group at Z, carry out the indicated reaction, and then remove the protecting group in a known manner. Thus, the use of the protecting group enhances the process of the present invention.
The free carboxylic acids obtained by the process described above can optionally be converted to the corresponding alkyl esters by the appropriate diazoalkane and known procedures. Methyl esters obtained by use of diazomethane are particularly preferred esters.
Where the process of the present invention produces a mixture of stereoisomers, the mixture of products thus obtained can be separated by standard known procedures which would include chromatography. The present invention encompasses any racemic mixture of isomers obtained in a reaction and also any individual pure compounds which can be Isolated from the mixtures.
The starting materials of the present invention are prepared from an appropriate 7-(2- formyl - 3ξ - hydroxy - oxo - 1 - cyclopentenyl)heptanoic acid of the following structural formula: The 3 - hydroxy group in the above compound is optionally protected by suitable blocking group and then the ethylenic linkage in the cyclopentane ring is reduced. The resulting aldehyde is then condensed with a triphenylacylmethylenephosphorane reagent of the formula II φ3Ρ=ΟΗ—C—R wherein R'''' is defined as above. This gives the necessary 20 desired starting material.
The compounds of this invention are useful pharmacological agents as a result of their anti-fertility properties. The present compounds are particularly useful for this purpose because they do not exhibit many of the other effects ordinarily associated with prostaglandin derivatives. The anti-fertility properties are shown by the following assay procedure: Sexually mature Syrian golden hamsters, 9-10 weeks old are caged with males in the late afternoon. Vaginal smears are taken daily in the morning by means of a pipette. The presence of sperm is considered positive evidence of insemination. The day of insemination is designated as day one of pregnancy. Pregnant females are then injected daily with test compound beginning on day one to day five. Route of administration is either subcutaneous or intragastric. The daily injection is usually in a volume of 0.2 cc. corn oil. All animals are killed with Dry Ice on the morning of day six. The entire reproductive tract is removed and the uterus and ovaries trimmed of extraneous tissue. The total number of implantation sites is counted and recorded. By observation, day six size sites are designated as normal and any sites which are smaller and/or pale or resorbing are designated as abnormal. The total number of corpora lutea are counted and recorded. Again, by observation, the red corpora are considered normal and the pale, pink or white, regressed corpora are considered abnormal. A single dose of compound is classified as active or inactive on the basis of the percent implantation, which is derived 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, - 5 41470 the test result is considered to be active. An ED5Q can then be determined. The compounds of this invention were found to be active by this procedure.
The present invention also provides a pharmaceutical 5 composition comprising a compound of the formula wherein R is hydrogen, or an alkyl radical containing 1 to 7 carbon atoms; R' is an alkyl radical containing 1 to 7 carbon atoms; and R'1 is a straight chain alkyl radical containing 6 to 9 carbon atoms together with a pharmaceutically acceptable carrier or divalent. The pharmaceutical composition is prepared by mixing a compound of the above formula with a pharmaceutically acceptable carrier or divalent.
The following Examples are 1 to 4 given to illustrate more fully the present invention. In these Examples, temperatures are given in degrees Centigrade (°C.) and quantities of materials in parts by weight unless otherwise noted.
EXAMPLE A To a solution of 2 parts of 7 - (2 - formyl - 3ξ hydroxy - 5 - oxo - 1 - cyclopentenyl)heptanoio acid and part by volume of dihydropyran in 6.7 parts of methylene chloride was added a solution containing 0.02 part of p - toluenesulfonic acid in 0.18 part of tetrahydrofuran.
A rapid exothermic reaction ensued. After that reaction subsided, the mixture was diluted with 400 parts of methylene chloride, then washed with aqueous sodium sulfate and dried over anhydrous sodium sulfate. Concentration of that dried mixture under reduced pressure afforded, as a pale yellow oil, 7 - - formyl - 3ξ - (tetrahydropyran - 2 yloxy) - 5 - oxo - 1 - cyclopentenyf]heptanoic acid.
To the latter crude product was added 32 parts by volume of chromous sulfate solution, prepared from chromic sulfate as described in Organic Synthesis, Volume 49, page 98. The resulting reaction mixture was stirred under nitrogen for about 30 minutes, at the end of which time 3 parts of ammonium sulfate and 25 parts of sucrose were added and the mixture was finally acidified by the addition of IM aqueous citric acid. That mixture was extracted with diethyl ether and the ethereal extract was separated, washed successively with saturated ammonium chloride and saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 7 - [28 - formyl -3ξ~ (tetrahydropyran - 2 - yloxy) - 5 - oxo - la - cyclopentyl]heptanoic acid.
A solution containing 2.2 parts of 7 - [2^- formyl 3? - (tetrahydropyran - 2 - yloxy) - 5 - oxo - la cyclopentylj heptanoic acid and 5 parts of triphenylheptanoylmethylenephosphorane in 101 parts of benzene was heated at the reflux temperature for about 4 hours, then was cooled, stored at room temperature for about 4 days, washed successively with aqueous citric acid and aqueous sodium chloride, then dried over anhydrous sodium sulfate and chromatographed on a silicic acid column. Elution of the column with 15% ethyl acetate in benzene afforded 7 -[3a 5 (tetrahydropyran - 2 - yloxy) - 2β - (3 - oxo - trans - 1 nonenyl) - 5 - oxo - la - cyolopentane]heptanoic acid, followed by 7 - [3β - tetrahydropyran - 2 - yloxy) - 2β (3 - oxo - trans - 1 - nonenyl) - 5 - oxo - la cyclopentyl]heptanoic acid.
When the last step of the above procedure was repeated using triphenyl octanoylmethylenephosphorane and triphenylnonanoylmethylenephosphorane in place of the triphenyl n heptanoylmethylenephosphorane, the desired products obtained were respectively, 7 - [38 ~ (tetrahydropyran - 2 - yloxy) - 2β - (3 - oxo - trans - 1 decenyl) - 5 - oxo - la-cyclopentyl]heptanoic acid and 7 c [3β - (tetrahydropyran - 2 - yloxy) - 2β - (3 - oxo - trans 1 - undecylenyl) - 5 - oxo - la-cyclopentyl]heptanoic acid.
EXAMPLE B A solution of 8.3 parts of 7 - (2 - formyl - 3ξ hydroxy - 5 - oxo - 1 - cyclopentenyl)heptanoic acid in 150 parts by volume of 50% aqueous acetic acid solution was stirred with 15 parts of zinc powder at 0-5° for about 2 hours. At the end of that 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 diethyl ether and the resulting organic solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and the - 8 41470 solvent was then evaporated under reduced pressure. The resulting residue was mixed with triphenylheptanoylmethylenephosphorane obtained from 30 parts of triphenyl(2 oxononyl)phosphonium chloride, and dissolved in 530 parts of benzene. The resulting mixture was allowed to stand at 25° for 5 days, and then concentrated under reduced pressure. The resulting residue was extracted with diethyl ether and the ethereal extract was washed with cold hydrochloric acid, and then with cold water before it was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue Was chromatographed on silicic acid, with the solvents prepared by shaking together 330 parts of hexane, 880 parts of benezene, 400 parts of methanol and 200 parts of water. The resulting lower layer was used as the stationary phase and the upper layer was used as the eluant. Elution of the column afforded 7 - [38 - hydroxy - 28 - (3 - oxo trans - 1 - nonenyl) - 5 - oxo - la - cyclopentyljheptanoic acid first, followed by 7 - [3a - hydroxy - 28 - (3 - oxo trans 1 - nonenyl) - 5 - oxo - la - cyclopentyl]heptanoic acid.
EXAMPLE 1 To a solution containing 2.2 parts of 7 - [38 (tetrahydropyran - 2 - yloxy) - 2β - (3 - oxo - trans - 1 nonenyl) - 5 - oxo - la - cyclopentyl]heptanoic acid dissolved in 89 parts of tetrahydrofuran was added 5 parts by volume of a 3M methylmagnesium bromide ethereal solution. The addition was carried out in an atmosphere of nitrogen at about -78° and after completion of the addition, stirring was continued at that temperature for about 0.5 hour. At the end of that reaction period, the reaction mixture was poured into cold aqueous citric acid and that acidic mixture was extracted with diethyl ether. The ethereal extract was washed with dilute aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated to dryness and the residue chromatographed on a silicic acid column.
Benezene - methanol was used as the upper phase and aqueous methanol as the lower phase. The product obtained was 7 - [3β - (tetrahydropyran - 2 - yloxy) - 2β - (3ξ - hydroxy · 3ξ - methyl - trans - 1 - nonenyl) - 5 - oxo - la cyclopentyl]heptanoic acid. This material was dissolved in 70 parts by volume of a 20:10:3 solution containing acetic acid: water:tetrahydrofuran and that solution was allowed to stand at room temperature for about 24 hours. At the end of that time, the solvent was removed by distillation under reduced pressure and the residue was adsorbed on a silicic acid column, then eluted with ethyl acetate and benzene mixture.
In this way, there was obtained 7 - [3β - hydroxy - 2β 20 (3ξ - hydroxy - 3ξ - methyl - trans - 1 - nonenyl) - 5 - oxo la - cyclopentyljheptanoic acid, melting at 85-87° and exhibiting nuclear magnetic resonance maxima, in deuteromethanol, at 61.33, 64.33 and 65.77.
EXAMPLE 2 A solution of 15 parts of 7 - [3β - hydroxy - 2β (3 - oxo - trans - 1 - nonenyl) - 5 - oxo - la cyclopentyl]heptanoic acid and 22 parts by volume of bis(trimethylsilyl)acetamide in 27 parts of tetrahydrofuran was allowed to stand at 25° for 24 hours to give a solution of - β38 - trimethylsilyloxy - 2β - (3 - oxo - trans - 1 nonenyl) - 5 - oxo - la - cyclopentyljheptanoic acid. The mixture was then diluted with 1335 parts of tetrahydrofuran, cooled to -78° and treated with 500 parts by volume of 3M ethereal methyImagnesium bromide for 20 minutes at -70°. The cold reaction mixture was then poured into cold aqueous 3% citric acid solution and the resulting mixture was extracted with diethyl ather. The ethereal extract was washed with 10% ammonium chloride solution, dried over sodium sulphate and concentrated. The final product was purified by partition chromatography on silicic acid. The solvent system was prepared by shaking 13 parts of benzene, 4 parts of methanol and 2 parts of water.
The lower layer was used as the stationary phase and the upper layer was used as the moving phase. The crystalline product obtained after chromatography was saturated with heptane containing a small amount of ethyl acetate and then filtered to give 7 - [38 - hydroxy - 28 - (3ξ - hydroxy - 3ξ methyl - trans - 1 - nonenyl) - 5 - oxo - la - cyclopentyl]heptanoic acid melting at 85-87°.
EXAMPLE 3 If 7 - [38 " (tetrahydropyran - 2 - yloxy) - 2β (3 - oxo - trans - 1 - decenyl) - 5 - oxo - la cyclopentyfj heptanoic acid is reacted with methyImagnesium bromide according to the procedures described in Example 1, the final product obtained is 7 - [38 - hydroxy - 28 - (3ξ hydroxy - 3ξ - methyl - trans - 1 - decenyl) - 5 - oxo la - cyclopentyl]heptanoic acid.
Similarly, when 7 - [36 - (tetrahydropyran - 2 11 yloxy) - 2β - (3 - oxo - trans - 1 - undecylenyl) - 5 oxo - 1« - cyclopentyl]heptanoic acid was reacted with methylmagnesium bromide by the procedure referred to above, the final product obtained was 7 - [3(3 - hydroxy - 2(3 (3ξ - hydroxy - 3ξ ~ methyl - trans - 1 - undecylenyl) - 5 oxo - la - cyclopentyl]heptanoic acid.
EXAMPLE 4 To a mixture consisting of 7 parts of potassium hydroxide dissolved in 13 parts of water and 100 parts by volume of diethyl ether, there was added 6 parts of N nitrosomethylurea. The resulting mixture was stirred until most of the solid was dissolved and the yellow ethereal solution was decanted into a solution consisting of one part of 7 - [_3β - hydroxy - 2β - (3ξ - hydroxy - 3ξ - methyl trans - 1 - nonenyl) - 5 - oxo - la - cyclopentyl heptanoic acid and 35 parts of diethyl ether. After standing for several minutes, the mixture was treated by the dropwise, addition of glacial acetic acid in order to destroy the excess reagent. The colorless ethereal solution was washed successively with cold water, cold dilute aqueous sodium bicarbonate and cold water, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residual crude product was adsorbed on a silicic acid chromatographic column, then eluted with ethyl acetate in benzene to afford methyl 7 - [3β - hydroxy - 2β - (3ξ hydroxy - 3£ - methyl - trans - 1 - nonenyl) - 5 oxo - la cyclopentyl]heptanoate.

Claims (10)

1. CLAIMS: 1. A compound of the formula wherein R is hydrogen or an alkyl radical containing 1 to 5 7 carbon atoms; R' is an alkyl radical containing 1 to 7 carbon atoms; and R'' is a straight chain alkyl radical containing 6 to 9 carbon atoms.
2. A compound of the formula 10 wherein R' 1 is a straight chain alkyl radical containing 6 to 9 carbon atoms.
3. 7 - [3β - hydroxy - 2β - (3ξ - hydroxy - 3 ξ methyl - trans - 1 - nonenyl) - 5 - oxo - la cyclopentyl]heptanoic acid. 15
4. A process for the preparation of a compound of the formula “ 13 41470 wherein R, R' and R'' are as defined in claim 1; which comprises reacting an organo- metallic reagent of the formula R' ' 'M with a ketone of the formula wherein one of R''' and R''' 1 is an alkyl group containing 1 to 7 carbon atoms and the other is a straight chain alkyl group containing 6 to 9 carbon atoms? M is lithium or Mg halogen; and Z is hydrogen or a hydroxy protecting group; 10 with the removal of any protecting group by hydrolysis and optionally followed by esterification of the carboxylic acid.
5. A process as claimed in Claim 4 for the preparation of 7 - [3β - hydroxy - 2β - (3ζ - hydroxy - 3ξ 15 methyl - trans - 1 - nonenyl) - 5 - oxo - 11a cyclopentyl]heptanoic acid which comprises reacting 7 [3β - (tetrahydropyran - 2 - yloxy) - 2β - (3 - oxo - trans 1 - nonenyl) - 5 - oxo - la - cyclopentyl]heptanoic acid with methylmagnesium bromide with the removal of the tetrahydropyranyl group by hydrolysis.
6. A process as claimed in Claim 4 for the preparation of 7 - |J3B - hydroxy - 2β - (3ξ - hydroxy - 3ξ 5 methyl - trans - 1 - nonenyl) - 5 - oxo - la cyalopentyljheptanoic acid which comprises reacting 7 |_3β - trimethylsilyloxy - 2β - (3 - oxo - trans - 1 - nonenyl) - 5 - oxo - la - cyclopentyl]heptanoic acid with methylmagnesium bromide with the removal of the trimethylsilyl 10 group by hydrolysis.
7. A process as claimed in Claim 4, substantially as herein described with reference to any of Examples 1 to 4.
8. A heptanoic acid whenever prepared by a process as claimed in any of claims 4 to 7. 15
9. A pharmaceutical composition comprising a heptanoic acid as claimed in any of claims 1 to 3 and 8 together with a pharmaceutically acceptable carrier or diluent.
10. A process for preparing a pharmaceutical 20 composition which comprises mixing a heptanoic acid as claimed in any of claims 1 to 3 and 8 with a pharmaceutically acceptable carrier or diluent.
IE767/75A 1974-04-08 1975-04-07 (3 -hydroxy-2 -(substituted 1-alkenyl)-5-oxo-1 -cyclopentyl)heptanoic acids IE41470B1 (en)

Applications Claiming Priority (1)

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US45879974A 1974-04-08 1974-04-08

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IE41470B1 true IE41470B1 (en) 1980-01-16

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JP (1) JPS5835183B2 (en)
AT (1) AT348154B (en)
BE (1) BE827694A (en)
CA (1) CA1071625A (en)
CH (1) CH609971A5 (en)
DE (1) DE2515115A1 (en)
DK (1) DK147075A (en)
ES (1) ES436362A1 (en)
FR (1) FR2266500B1 (en)
GB (1) GB1496716A (en)
IE (1) IE41470B1 (en)
NL (1) NL7504104A (en)
SE (1) SE420998B (en)
ZA (1) ZA752183B (en)

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JPS60140266U (en) * 1984-02-25 1985-09-17 ソニー株式会社 magnetic disk device
JPS6121075U (en) * 1984-07-07 1986-02-06 ティーディーケイ株式会社 disk cartridge

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CH609971A5 (en) 1979-03-30
NL7504104A (en) 1975-10-10
JPS50137960A (en) 1975-11-01
JPS5835183B2 (en) 1983-08-01
ZA752183B (en) 1976-06-30
DK147075A (en) 1975-10-09
GB1496716A (en) 1977-12-30
BE827694A (en) 1975-10-08
ATA261475A (en) 1978-06-15
SE7503928L (en) 1975-10-09
FR2266500B1 (en) 1978-07-28
DE2515115A1 (en) 1975-10-16
AU7990675A (en) 1976-10-14
CA1071625A (en) 1980-02-12
SE420998B (en) 1981-11-16
IE41470L (en) 1975-10-08
ES436362A1 (en) 1977-01-01
AT348154B (en) 1979-02-12
FR2266500A1 (en) 1975-10-31

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