Patent GB-1494588-A (GB)
Title: Prostaglandins
IPC: C07C401/00
Filed: 1976-02-02
Abstract: 1494588 2,2-Difluoroprostaglandins UPJOHN CO 2 Feb 1976 [24 Feb 1975] 03952/76 Headings C2C and C2P [Also in Division C3] The invention comprises 2,2-difluoroprostaglandins of the Formula I or mixtures comprises that compound and the enantiomer thereof, wherein g is 2, 3 or 4; M 1  is in which R 7  and R 8  are H or methyl, provided that they are not both methyl; R 1  is H, C 1-12  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, phenyl optionally substituted one to three times by chlorine atoms or C 1-4  alkyl radicals, p-(pacetamidobenzamido)phenyl, p - benzamidophenyl, p - acetamidophenyl, p - ureidophenyl, p - semicarbazonomethylphenyl or 2 - naphthyl; Q 1  is (CH 2 ) m CH 3 , in which m is 2, 3 or 4, cis- CH2CHCH2CH3, phenoxy or phenoxy substituted one to three times by fluorine or chlorine atoms, CF 3 , C 1-3  alkyl or C 1-3  alkoxy radicals with the proviso that not more than two substituents are other than alkyl ; R 5  is H, methyl or fluorine with the provisos (i) that R 5  is F only if Q is cis-CH = CH-CH 2 CH 3  or (CH 2 ) m CH 3 - and R 7  and R 8  are both H; (ii) that R 5  is methyl only if R 7  and R 8  are both H and (iii) that R 7  is H only if one of R 7  and R 8  methyl or Q 1  is cis-CH = CHCH 2 CH 3  or optionally substituted phenoxy; X is trans CH=CH nd Y is cis- CH = CH or -CH 2 CH- or X and Y are both -CH 2 CH 2 -, with the proviso that Q 1  is cis- -CH = CH- only if Y is cis-CH=CH and D is  and pharmaceutically acceptable salts thereof when R 1  is H. The compounds are prepared by known methods. The following intermediates are also described methyl 2 - oxo - 3,4 - bis(2 - tetrahydropyranyloxy)butyrate; methyl 2 - oxo - 3,4 - dihydroxybutyrate; methyl 2,2-difluoro-3,4 - bis(2-tetrahydropyranyloxy)butyrate; methyl tetrahydro - 2 - furoate; methyl 2 - (o - methoxy phenoxy) - 2 - methylpropionate; cis - 3 - hexenoic acid, its potassium salt and its methyl ester; 2,2 - dimethyl - cis - 3 - hexanoic acid, its potassium salt and methyl ester; 2,2-difluoro - cis - 3 - hexenoic acid, its potassium salt and methyl ester; 2,2-difluoro-5-bromopentanoic acid and its methyl ester; methyl 2 - acetoxy - 5 - bromoacetate, methyl 2- hydroxy - 5 - bromopentanoate; 2,2 - difluoro- 3,4 - bis(2 - tetrahydropyranyloxy) - butyraldehyde; methyl 2 - oxo - 3,4 - dihydroxybutyrate and its bis(2 - tetrahydropyronyl)ether; methyl 2 - oxo - 5 - bromopentanoate; 2- (2 - chloro - 2 - methylpropoxy)tetrahydropyran; 2 - (2,2 - dimethyl - 3 - hexynyloxy). tetrahydropyran; 2 - (2,2 - dimethyl - cis- 3 - hexenyloxyl - tetrahydropyran; 2,2 - difluoro - 3, 4-bis(tetrahydropyranyloxy)-butanal; 3, 3 difluoro - cis - 4 - heptene - 1,2 - diol and its bis(2 - tetrahydropyranyl)ether; cis - 3 - hexenol; 2,2 - dimethyl - cis - 3 - hexenol; 2,2 - difluoro - cis - 3 - hexenol; 2,2 - difluoro- 9α - hydroxy - 16 - phenoxy - 11α,15α - bis(2- tetrahydropyranyloxy) - 17,18,19,20 - tetranorprosta - cis - 5, trans - 13 - dienoic acid and its methyl ester; 2,2-difluoro-9α-hydroxy- 16 - phenoxy - 15 - methyl - 11α,15α - bis(2- tetrahydropyranyloxy) - 17,18,19,20 - tetranorprosta - cis - 5, trans - 13 - dienoic acid and its methyl ester; 2,2-difluoro-9-oxo-16-phenoxy- 11α,15 - bis(2 - tetrahydropyranyloxy) - 17,18,- 19,20 - tetranorprosta - cis - 5, trans - 13 - dienoic acid; 2,2 - difluoro - 9 - oxo - 16 - phenoxy - 11α,15 - bis(2 - tetrahydropyranyloxy) - 17,18,19,20 - tetranorprosten - trans- 13 - enoic acid; cyclopenta[b]furan - 2 - ols of the formula wherein M 7  is in which R 11  is H or methyl and THP is 2- tetrahydropyronyl or M 2  is and Z 3  is -C(R 5 ) 2 -Q 1 ; and the corresponding cyclopenta[b]furan - 2 - ones; cyclopenta[b]- furan-2-ones of the formula wherein Z 2  is -C(R 5 ) 2 -Q 1  and M 1  is oxo, 5α - hydroxy - 4# - (3 - hydroxy - 3 - methyl- 4 - phenoxy - trans - 1 - butenyl) - 3,3α#,4,5,- 6,6α# - hexahydro - 2H - cyclopenta[b]furan- 2 - one; and 5α - hydroxy - 4# - (3 - methoxy- 4 - phenoxy - trans - 1 - butenyl) - 3,3α#,4,5,- 6,6α#-hexahydro-2H-cyclopenta[b]-furan-2-one. Phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with compounds of the formula wherein X is Cl or methyl in the presence of butyllithium. (4,4 - Difluoro - 4 - carboxybutyl)triphenylphosphonium bromide is obtained by reacting 2,2 - difluoro - 5 - bromopentanoic acid with triphenylphosphine. Pharmaceutical compositions, suitable for oral, parenteral, rectal, vaginal and topical administration, contain the above prostaglandins or salts thereof together with pharmaceutically acceptable carriers. The compounds possess similar pharmacological properties to those of the naturally occurring prostaglandins.