Patent GB-1471070-A (GB)
Title: Prostenoic acid derivatives and method for preparing same
IPC: C07C31/133
Filed: 1974-04-29
Abstract: 1471070 Prostaglandins AMERICAN CYANAMID CO 29 April 1974 [11 May 1973] 18749/74 Heading C2C [Also in Division C3] The invention comprises prostaglandins of the Formula A wherein R 1  is C 1-4  alkoxy, #-hydroxy-C 1-4  alkoxy or #-tetrahydropyran-2<SP>1</SP>-yloxy-C 1-4  alkoxy ; R 2  is H, C 1-4  alkyl or triphenylmethyl; R 3  is straight chain C 2-10  alkyl optionally substituted with 1 or 2 C 1-4  alkyl radicals, straight chain C 3-10  alkenylmethyl, optionally substituted by 1 or 2 C 1-4  alkyl radicals, C 4-9  cycloalkyl, C 5-10  alkylcycloalkyl, C 6-12  cycloalkyl-alkyl, in which the cycloalkyl is optionally substituted by a C 1-4  alkyl radical, C 5-9  cycloalkenyl, C 6-10  alkyl-cycloalkenyl, C 6-12  cycloalkenyl-alkyl in which the cycloalkenyl is optionally substituted by a C 1-4  alkyl radical, adamantyl or adamantyl-C 1-4  alkyl; R 4  is OH, C 1-12  alkoxy, C 1-12  alkoxy or 2-tetrahydropyranyloxy; R 3  is H or C 1-3  alkyl; V is >C=O, and Z is -(CH 2 ) n -, -(CH 2 ) n -C(R 5 ) 2 .CH 2 -, -(CH 2 ) n .CH(R 6 )-, -(CH 2 ) n -O-CH 2  or cis- CH 2 -CH=CH-(CH 2 ) p , wherein n is 3 to 8, p is 2 to 6, R 5  is C 1-3  alkyl and R 6  is C 1-3  alkyl, F or phenyl; and the radical -C 13 -C 14  is ethylene or trans-vinylene, and non-toxic salts thereof when R 4  is OH; subject to the following provisos: (i) when R 1  is #-hydroxy-C 1-4  alkoxy, then R 4  is not 2-tetrahydropyranyloxy; (ii) when R 1  is #-tetrahydropyran-2<SP>1</SP>-yloxy-C 1-4  alkoxy, then R 4  is not OH or R 2  is not alkyl; (iii) when R 2  is H, then R 1  is not #-tetrahydropyran-2<SP>1</SP>- yloxy-C 1-4  alkoxy or R 4  is not 2-tetrahydropyranyloxy; (iv) when R 2  is triphenylmethyl, then R 4  is not OH or R 1  is not #-hydroxy-C 1-4  alkoxy; (v) when R 7  is C 1-3  alkyl, then R 2  must be hydrogen; and (vi) when C 13 -C 14  is ethylene, then Z is not cis-CH 2 CH = CH(CH 2 ) p . The compounds are prepared by reacting cyclopentenones of the Formula B wherein R<SP>1</SP> 1  is C 1-4  alkoxy or #-tetrahydropyran- 2<SP>1</SP>-yloxy-C 1-4  alkoxy; and R<SP>1</SP> 4  is 2-tetrahydrohydropyranyloxy or C 1-12  alkoxy with compounds of the formula wherein R is C 1-7  alkyl and R<SP>1</SP> 2  is C 1-4  alkyl or triphenylmethyl to give cyclopentanones of the formula followed by hydrolysis with weak acids to give compounds of the formula A above in which Y is >C=O, R 1  is C 1-4  alkoxy or #-hydroxy- C 1-4  alkoxy; R 4  is OH or C 1-12  alkoxy, R<SP>9</SP> is H or C 1-4  alkyl and -C 13 -C 14 - is trams-vinylene ; and if desired, reducing said compounds to give corresponding compounds in which Y is >CH(OH), and, when desired oxidizing alkyl or 2-tetrahydropyranyl 9,15-dihydroxy-13-transprostenoates with magnese dioxide or 2,3-dichloro-5,6-dioyano-1,4-benzoquinone to the corresponding alkyl or 2-tetrahydropyranyl 9-hydroxy- 15 - oxo - 13 - trans - prostenoates, protecting all free hydroxy groups and treating the resulting protected compounds with C 1-3  alkylmagnesium halides, and removing the protecting groups; if desired, oxidizing 9-hydroxy groups to 9-oxo groups, and if desired hydrogenating C 12 -C 16  trans-vinylene to ethylene, and if desired hydrolysing any resulting ester, and converting the resulting acids to salts. The following intermediates and starting materials are also prepared: cyclopentenones of Formula B above in which R<SP>1</SP> 1  is R<SP>1</SP> is C 1-4  alkoxy, #-tetrahydropyran-2<SP>1</SP>-yloxy-C 1-4   alkoxy  or #-hydroxy-C 1-4  alkoxy, Br and H, and R<SP>1</SP> 4  is H, 2-tetrahydropyronyloxy or C 1-12  alkoxy; cis - 1 - ethyl - 2 - (2,2 - dimethoxyethyl)- cyclopropane, cis-1-ethyl-2-(2-hydroxyethyl)- cyclopropane, cyclopentylacetyl chloride, compounds of the formula HC#C-CH(OR<SP>10</SP>)R 3  and IHC = CHCH(OR<SP>10</SP>)R 3 , wherein R<SP>10</SP> is H, triphenylmethyl, methyl or 2-tetrahydpyronyl; 1 - chloro - 4 - cyclopentyl - 1 - trans - buten -3 - one; 4 - cyclopentyl - 1 - iodo - 1 - trans - buten- 3 - one; 4 - cyclopentyl - triodo - 3 - (p - methoxy phenyl diphenyl-methoxy)-1-traps-butene; 1- chloro - trans - 1 - octen - 3 - one, 1 - iodo - trans- 1 - octen - 3 - one; and 1 - iodo - 3-(p - -methoxy phenyldiphenylmethoxy) - trans-1-octene. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above prostaglandins or salts thereof, together with pharmaceutically acceptable carriers or diluents. The compounds possess prostaglandin-like pharmacological properties.