Patent GB-1439511-A (GB)
Title: N-substituted prostaglandin carboxamides
IPC: C07D333/34
Filed: 1973-05-29
Abstract: 1439511 Prostaglandins; phosphonate intermediate PFIZER Inc 29 May 1973 [7 June 1972] 25613/73 Headings C2C and C2P The invention comprises prostaglandins of the Formula I wherein R is C 2 -C 8  alkanoyl, C 4-8  cycloalkanoyl, C 7-11  arylcarbonyl optionally substituted by CH 3 , OCH 3  or halogen, O 1-7  alkylsulphonyl, heteroarylsulphonyl or arylsulphonyl optionally substituted by CH 3 , OCH 3  or halogen; R 1  is H or C 1-3  alkyl; R 2  is C 5-11  alkyl; R 4  is H; W is a single bond or cis double bond; Z is a single bond or trans double bond; m is oxo or X is alpha-hydroxy and Y is H, or X and Y when taken together form a single bond, wherein M, X and Y are so selected as to complete the structure of a prostaglandin of the A, E or F series ; and the formates, alkanoates or benzoates of any free 9, 11 and 15 hydroxy groups; and prostaglandins of the Formulae V and IIc wherein THP is 2-tetrahydropyranyl and the C 9  and C 15  formates, alkanoates and benzoates of the compounds of Formula IIc. The prostaglandins of the F series of Formula I above are prepared by hydrolysing the corresponding compounds of Formula V above in which M is or compounds of Formula He with aqueous acetic acid, reducing the corresponding prostaglandins of the E series of Formula I in which M is oxo with sodium borohydride, or by the basic hydrolysis of compounds of Formula I in which W is a single bond, Z is a trans double bond, Y is H, X is alpha-hydroxy and M is The prostaglandins of the E series are obtained by hydrolysing with aqueous acetic acid the corresponding compounds of Formula V above in which M is oxo, resulting from the oxidation of the appropriate compounds of Formula V above in which M is The prostaglandins of the A series of Formula I above are made by dehydrating the corresponding prostaglandins of the E series of Formula I. Compounds of Formula V above in which M is are prepared by reacting compounds of the Formula L with compounds of the formula (C 6 H 5 ) 3 P = CH-CH 2 -CH 2 -CH 2 -CO-NHR and, if desired, hydrogenating the resulting compounds. Compounds of Formula V in which M is are obtained by reducing the corresponding compounds of Formula V in which M is oxo, or by the basic hydrolysis of compounds of Formula V above in which M is The compounds of Formula IIc above are obtained by the basic hydrolysis of the corresponding compounds of Formula I in which W is a single bond. R 4  and Y are both H, X is alpha- (2-tetrahydropyranyloxy) and M is The compounds resulting from the above processes may be acylated to give the corresponding formates, alkanoates, or benzoates, or may be hydrogenated to give the corresponding compounds in which W is a single bond and Z is a trans double bond or a single bond. The following intermediates are also prepared: compounds of Formula L above and the corresponding compounds in which both tetrahydropyranyl radicals are replaced by hydrogen atoms; 4# -benzyloxymethyl-5x-(2-tetrahydropyranyloxy) - 3,3a#,4,5,6,6a# - hexahydro- 2H - cyclopenta[b]furan - 2 - ol; 3,3a#,4,5,6,6a#- hexahydro - 2H - cyclopenta[b]furan - 2 - ones which are substituted in the 4#-position by alkyl or trans- 1 -alkenyl radicals substituted in the 3-position by oxo, hydroxy or 2-tetrahydropyranyloxy radicals and in the 5α- position by hydroxy, 2-tetrahydropyranyloxy or p - phenylbenzoyloxy radicals; N-acetyl (or methansulphonyl) - 7 - [2# - benzoloxymethyl - 3α - (2 - tetrahydropyranyloxy) - 5α- hydroxy (or acetoxy)cyclopent - 1α - yl] i cis- 5 - heptenamide, N - acetyl (or methanesulphonyl) - 7 - [2# - hydroxymethyl (or formyl) - 3x - (2 - tetrahydropyranylxoy) - 5α- acetoxycyclopent - 1α - yl] - heptanamide, N - acetyl (or methanesulphonyl) - 9α - acetoxy- 11 α - (2 - tetrahydropyranyloxy) - 15 - oxo - 13- trans - prostenamide and N - acetyl (or methanesulphonyl) - 9α - acetoxy - 11α - (2- tetrahydropyronyloxy) - 15 - oxo - 16,16- dimethyl-13-trans-prostenamide Dimethyl 2 - oxo - 3,3 - dimethylphosphonate is prepared by reacting dimethyl methylphosphonate and methyl 2,2-dimethylhexanoate in the presence of butyl lithium. Pharmaceutical compositions, suitable for oral, parenteral, topical, intranasal or intravaginal administration, contain the prostaglands of Formula I above or formates, alkanoates or benzoates thereof together with pharmaceutically acceptable carriers. The compounds possess similar pharmacological properties to those of the naturally occurring prostaglandins.