Patent GB-1428137-A (GB)
Title: Prostanoic acid derivatives
IPC: C07D277/20
Filed: 1972-09-27
Abstract: 1428137 Prostaglandins IMPERIAL CHEMICAL INDUSTRIES Ltd 7 Sept 1973 [27 Sept 1972] 44652/72 Headings C2C and C2P [Also in Division C3] The invention comprises prostaglandins of the Formula I wherein R<SP>1</SP> is hydroxymethyl, carboxy C 2 -C 11  alkoxycarbonyl or C 2 -C 11  alkoxymethyl; either R<SP>2</SP> is OH or C 1 -C 4  alkanoyloxy and R<SP>3</SP> is H, or, except when R<SP>1</SP> is hydroxymethyl or alkoxymethyl, R<SP>2</SP> and R<SP>3</SP> together form an oxo radical; A<SP>1</SP> is -CH 2 CH 2 - or -CH=CH-; A<SP>2</SP> is -CH 2 CH 2 - or trans-CH = CH-; either X is straight chain C 1 -C 3  alkylene optionally substituted by 1 or 2 C 1 -C 3  alkyl radicals; Y is O, S, SO, SO 2  NH, C 1 -C 4  alkylamino, or a direct bond; or X and Y are each a direct bond; R<SP>4</SP> is a radical derived from an aromatic 5- membered ring containing 1 or 2 nonadjacent nitrogen heteroatoms, or 1 nitrogen atom and 1 nonadjacent sulphur heteroatom, or an aromatic fused benzo-homologue thereof, or an aromatic 6-membered ring containing 1 or 2 nonadjacent nitrogen heteroatoms or a fused benzo-homologue thereof, or from indoline, pyridazine, benzo(b)furan or benzo(b)thiophene which radical is optionally substituted with 1 to 4 substituents selected from halogen, C 1 -C 5  alkyl or C 1 -C 5  alkoxy, R<SP>5</SP> is H or C 1 -C 5  alkyl, and which prostaglandin is optionally substituted by a C 1 -C 4  alkyl radical on carbon atoms 2, 3 or 4 thereof; and for those compounds wherein R<SP>1</SP> is carboxy the pharmaceutically or veterinarily acceptable salts thereof, and for those compounds wherein R<SP>1</SP> is carboxy and R<SP>2</SP> is OH the 1,9-α-lactones thereof. The compounds are prepared by one of the following methods: (a) for those compounds wherein R<SP>1</SP> is COOH and R<SP>5</SP> is H, the hydrolysis of compounds of the Formula II or of mixed anhydrides thereof, wherein either R<SP>8</SP> is OH or C 1 -C 4  alkanoyloxy and R<SP>3</SP> is H or R<SP>8</SP> and R<SP>3</SP> together form an oxo radical, and R<SP>6</SP> and R<SP>7</SP> are each 2-tetrahydropyranyloxy or C 1 -C 6  acyloxy, or R<SP>3</SP> is H, R<SP>8</SP> is C 1 -C 15  acyloxy, R<SP>7</SP> is OH or C 1 -C 15  aeyloxy and R<SP>6</SP> is OH; or (b) for those compounds wherein R<SP>1</SP> is COOH, R<SP>2</SP> is OH, R<SP>3</SP> is H and A<SP>1</SP> is the reaction of lactols of the formula III with (4 - carboxybutyl)triphenylphosphonium salts in the presence of strong bases; or (c) for those compounds wherein R<SP>3</SP> is OH and R<SP>5</SP> is H, the reduction of enones of the Formula IV (d) for those compounds wherein R<SP>1</SP> is alkoxycarbonyl, esterification of the corresponding acids; or (e) for those compounds wherein R<SP>1</SP> is CH 2 OH, reduction of the corresponding compounds of Formula I in which R<SP>1</SP> is alkoxycarbonyl; or (f) for those compounds which are 1,9α-lactones, heating the corresponding compounds of Formula I wherein R<SP>1</SP> is COOH or alkoxycarbonyl and R<SP>2</SP> is OH; (g) for those compounds in which A<SP>1</SP> is trans-CH = CH-, the separation of mixtures of compounds of Formula I wherein A<SP>1</SP> is cis-CH=CH- and those in which A<SP>1</SP> is trans-CH = CH-; (h) for those compounds in which R<SP>5</SP> is alkyl, the reaction of compounds of Formula I wherein R<SP>5</SP> is H with alkyl halides in the presence of strong bases; or (i) for those compounds wherein Y is SO or SO 2 , the oxidation of compounds of Formula I wherein X is S; or (j) for those compounds wherein R<SP>2</SP> is OH and R<SP>3</SP> is H, the reduction of those compounds of Formula I wherein R<SP>2</SP> and R<SP>3</SP> together form an oxo radical. The following intermediates are also prepared: compounds of the Formulµ II, III and IV above; lactones and lactols of the Formulµ VII, VIII, IX, XXI and XXII wherein Ac is acyl and THP is tetrahydropyran-2-yl; compounds of Formula II above wherein R<SP>3</SP> is H, R<SP>8</SP> is OH and R<SP>7</SP> and R<SP>6</SP> are each 2-tetrahydropyranyloxy; the methyl esters of acids of Formula II above wherein R<SP>3</SP> is H, R<SP>6</SP> is OH and R<SP>7</SP> and R<SP>8</SP> are each p-phenylbenzoyloxy; ethyl (5-indoyloxy)acetate; methyl 7 - [2# - formyl - 3α,5α - di - (4 - phenylbenzoyloxy) - cyclopent - 1α - yl]hept - 5 - cis - enoate; 4# - dimethoxy - 3,3a#,4,5,6,6a# - hexahydro- 5α-hydroxy - 2H - cyclopenta[b]furan - 2 - one, and the 2-tetrahydropyranyl ether thereof; 4# - dimethoxy - 3,3a#,4,5,6,61a# - hexahydro- 5α - (2 - tetrahydropyranyloxy) - 2H - cyclopenta[b]furan - 2 - ol; 7 - [2# - dimethoxymethyl - 5α - hydroxy - 3α - (2 - tetrahydropyronyloxy)cyclopent- 1α - yl]hept - 5 - cisenoic acid and H and the methyl ester thereof; methyl 7 - [2# - dimethoxymethyl - 3α,5α- dihydroxycyclo - pent - 1α - yl]hept - 5 - cisenoate and the 3α,5α - di - (4 - phenylbenzoate) thereof; enones of the Formula XXIX wherein PB is 4-phenylbenzoyl; 2,5-di-chloro- 3-hydroxypyridine; compounds of Formula II above wherein R<SP>3</SP> is H, R<SP>6</SP> and R<SP>7</SP> are OH and R<SP>8</SP> is 4-phenylbenzoyloxy; methyl 7-[2#-dimethoxymethyl - 5α - (4 - phenyl - benzoyloxy)- 3α - (2 - tetrahydropyranyloxy)cyclopent- 1α - yl]hept - 5 - cis - enoate; methyl 7-[2#- dimethoxymethyl - 3α - hydroxy - 5α - (4- phenylbenzoyloxy)cyclopent - 1α - yl]hept- 5 - cis - enoate; methyl 7 - [2# - dimethoxymethyl - 3α - hydroxy - 5α - (4 - phenylbenzoyoxy)cyclopent - 1α - yl]heptanoate; methy 7 - [2# - formyl - 3α - hydroxy - 5α - (4 - phenylbenzoyloxy)cyclopent - 1α - yl]heptanoate; 7 - [2# - dimethoxymethyl - 5α - hydroxy - 3α- (tetrahydropyran - 2 - yloxy)cyclopent - 1α- yl] - 2 - methyl - 5 - cis - heptenoic acid and the methyl ester thereof; methyl 7-[2#-dimethoxymethyl - 5α - (4 - phenylbenzoyloxy)- 3α - hydroxycyclopent - 1α - yl] - 2 - methyl- 5 - cis - heptenoate and the 2-tetrahydropyranyl ether thereof; ethyl (5-chloro-3-pyridyloxy)- acetate methy 7 - [2# - formyl - 3α - hydroxy- 5α - (4 - phenylbenzoyloxy) - cyclopent - 1α- yl] - 2 - methyl - 5 - cis - heptenoate; methyl 11α - hydroxy - 16 - (indol - 5 - yloxy) - 15- oxo - 9α - (4 - phenylbenzoyloxy) - 17,18,19,20- tetranor - 13 - trans - prostenoate, methyl 11α - hydroxy - 16 - (indol - 5 - yloxy) - 2 - methyl - 15 - oxo - 9α - (4 - phenylbenzoyloxy)- 17,18,19,20 - tetranor - 5 - cis, 13 - transprostadienoate, compounds of Formula II above in which R<SP>6</SP> and R<SP>7</SP> are 2-tetrahydropyranyloxy and R<SP>3</SP> and R<SP>8</SP> together form an oxo group; phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with alkyl esters of acids of the formula R<SP>4</SP>XYCOOH in the presence of strong bases. Dimethyl [2 - oxo - 3 - (1 - methylindolin- 5 - yl - oxy)propyl]phosphonate is obtained by hydrogenating dimethyl [2-oxo-3-(1-methylindol-5-yloxy)propyl]phosphonate. Pharmaceutical compositions, in a form suitable for oral administration, inhalation or infusion or in the form of suppositories, contain the above prostaglandins or pharmaceutically acceptable salts thereof together with diluents or carriers.