Patent GB-1377258-A (GB)
Title: Derivatives of 9-oxo-13-trans-prostenoic acid esters
IPC: C07D221/20
Filed: 1972-06-07
Abstract: 1377258 Prostaglandins AMERICAN CYANIMID CO 7 July 1972 [14 July 1971 (2) 16 Dec 1971] 31996/72 Heading C2C [Also in Division C5] The invention comprises prostaglandins of the formula wherein n is 1 or 2; Y is R 1  is a straight chain C 3-10  alkyl, a straight chain C 2-6  alkyl having one branched CH 3  group, a straight chain C 3-6  alkenyl, a straight chain C 3-6 -#-haloalkyl, a straight chain C 3-6 -#-mercaptoalkyl, a straight chain C 4-7 -#-carboxyalkyl or a radical of the formulµ wherein p is 2 to 4, q is 3 to 6, R 3  is C 1-3  alkyl, R 4  and R 5  each are H or C 1-4  alkyl or R 4  and R 5 , together with the N atom to which they are attached, form a 1-pyrrolidinyl, piperidino or morpholino group; R 2  is OH, C 1-4  alkoxy, pyridyloxy, 2,2,2-trichloroethoxy, wherein R 6  is H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, cyclohexyl, phenyl-C 1-4  alkyl, or C 1-4 - #-hydroxyalkyl, and R 7  is H, C 1-4  alkyl, OH, C 2-4  alkenyl, C 2-4  alkynyl, cyclohexyl, phenyl, trifluoromethylphenyl, di - (C 1-4  alkyl) aminophenyl, chlorophenyl, C 1-4  alkylphenyl, pyridyl, phenyl-C 1-4  alkyl, pyridyl-C 1-4  alkyl, C 1-4  #- hydroxyalkyl, #-C 1-4  alkoxy-C 1-4  alkyl, #-di- (C 1-4  alkyl)amino-C 1-4  alkyl, #-piperidino-C 1-4 - alkyl, #-(1-pyrrohdinyl)-C 1-4  alkyl, #-morpholino-C 1-4  alkyl, NH 2 , di-(C 1-4  alkyl)amino, piperidino, hexamethyleneimino morpholino, anilino, or 4-(C 1-4  alkyl)-1-piperazinyl, or R 6  and R 7 , taken together with the N atom to which they are attached, form a 1-pyrrolidinyl, morpholino, hexamethyleneimino, 4 - phenylpiperidino, 4- (C 1-4  alkyl) - 1 - piperazinyl, 4 - phenyl - 1- piperazinyl, 3 - pyrrolin - 1 - yl, 1,2,5,6 - tetrahydro - 1 - pyridyl, 3 - azabicyclo[3,2,2]non- 3 - yl, N,N<SP>1</SP> - bis - di - (C 1-4  alkyl)aminophenylureido or 3 - azaspiro[5,5]undec - 3 - yl; and Z is a radical of the formula  cis wherein m is 1 to 8, with the provisos that (i) when R 2  is N(R 6 )R 7 , then R 1  is a straight chain C 3-10  alkyl, a straight chain C 2-6  alkyl having one branched CH 3 , a straight chain C 3-6  alkenyl straight chain #-halo-C 3-6  alkyl or a radical of the formulµ (ii) when R 1  is #-carboxyalkyl then R 2  is OH, and (iii) when R 1  is -(CH 2 ) p -CH-(COOR 3 ) 2  then R 2  is C 1-4  alkoxy, pharmaceutically acceptable acid addition salts of the compounds of the above formula which possess basic nitrogen atoms and salts of the compounds of the above formula when R 1  is #-carboxyalkyl and/ or R 2  is H with pharmaceutioally acceptable cations. The compounds are prepared by reacting cyclopentenones of the Formula II: wherein R<SP>1</SP> is alkyl and Z<SP>1</SP> is with reagents of the formula wherein R<SP>11</SP> is C 1-6  alkyl and R is C 3-10  alkyl, C 2-4  alkyl having one branched CH 3 , C 3-6  alkenyl or C 3-6 -#-chloroalkyl, in inert solvents and hydrolysing the resulting adducts, and, if desired, when Z<SP>1</SP> is -CH 2 - in the resulting product of the Formula IV: converting 2<SP>1</SP> to CH 2 CH = CH(CH 2 ) p  by reacting compound of Formula IV with ethylene glycol, reducing the resulting 9.9-ethylenedioxy compounds, treating the aldehydes thus obtained with reagents of the formula and hydrolysis the resulting compounds; and, if desired, converting the compounds of Formula IV above wherein 2<SP>1</SP> is replaced by 2 and wherein R is #-chloroalkyl into compound in which R is #-fluoro-, bromo- or iodo-alkyl, #- carboxyalkyl, (CH 2 ) p S-R 3 , -(CH 2 ) p S(O)R 3 , (CH 2 ) p OR 3 , -(CH 2 ) p -CH(CO 2 R 3 ) 2  or (CH 2 ) q - N(R 4 )R 5  by standard methods, and, if desired, hydrolysing the esters to the corresponding acids, and re-esterifying the resulting acids; converting them to amides of the invention via the formation of the corresponding acid chlorides and if desired reducing the 9-oxo group to the 9-hydroxy group. The following intermediates are also prepared: 4 - chloro - 1 - tetrahydropyran - 2<SP>1 </SP>- yloxybutane, diethyl - (1,1 - dimethyl - 5 - tetrahydropyran - 2<SP>1 </SP>- yloxypentyl) - malonate, diethyl (1,1 - dimethyl - 5 - hydroxypentyl)- malonate, 3,3 - dimethyl - 7 - hydroxyheptanoic acid, 3,3 - dimethyl - 7 - chloroheptanoic acid and its ethyl ester, ethyl 3,3-dimethyl-7-iodoheptanoate, diethyl - (5 - chloro - 1,1 - dimethyl) pentyl)malonate, methyl and ethyl 1-(#-ethoxycarbonylalkyl) - 2 - oxocyclopentanecarboxylate, methyl and ethyl 1-( #-ethoxycarbonylalkyl) - 2 - oxacyclohexanecarboxylate, 2 - (#- carboxyalkyl) cyclopentan-1-one, 2-(#-carboxyalkyl) cyclohexan - 2 - one, 2 - (# - ethoxycarbonylalkyl) cyclopentan - 2 - one, 2 - (#- ethoxycarbonylalkyl) cyclopentan - 2 - one, 1- acetoxy - 2 - (# - ethoxycarbonylalkyl) cyclopent - 1 - ene, 1 - acetoxy - 2 - (# - ethoxycarbonylalkyl) cyclohex - 1 - ene, 2 - bromo - 2- (# - ethoxycarbonylalkyl) cyclopentan - 1 - one, 2 - bromo - 2 - (# - ethoxycarbonylalkyl) cyclohexan - 1 - one, 1 - methoxyimino - 2 - (# - ethoxycarbonylalkyl) - 2 - cyclopentene, 1 - methoxyimino - 2 - (# - ethoxycarbonylalkyl)- 2- cyclohexene, 1 - methoxyimino - 2 - (# - hydroxyalkyl) - 2 - cyclopentene and 1 - methoxyimino - 2 - (# - hydroxyalkyl) - 2 - cyclohexene, and the p-toluenesulphonates thereof, 1-methoxyimino - 2 - (#,# - diethoxycarbonylalkyl)- 2-cyclopentene (or cyclohexene), 1-methoxyimino - 2 - (#,# - dicarboxyalkyl) - 2 - cyclopentene (or cyclohexene, 1-methoxyimino-2-(#- carboxyalkyl) - 2 - cyclopentene (or cyclohexene), compounds of the above Formula I in which Y is -OCH 2 CH 2 O-, R 1  is #-iodoalkyl, -(CH 2 ) p OR 3 , -(CH 2 ) q N(R 4 )R 5 , #-phthalimidoalkyl, R 2  is ethoxy and 2 is (CH 2 ) m , and compounds of the Formula II above. Pharmaceutical compositions contain the above prostaglandins and pharmaceutically acceptable carriers or diluents. The compounds possess hypotensive, antimicrobial, antifungal and anti-inflammatory, activities. They also inhibit the secretion of gastric acid, provide protection against the ulcerogenic properties of indomethacin, and possess activity as fertility controlling agents, central nervous system regulatory agents, salt-and water-retention regulatory agents, fat metabolic regulatory agents, serum chlolesterol-lowering agents and as abortifacients, anticonvulsants, and bronchodilators.