Treatment of osteoporosis with prostaglandins

Claim 1

A method for the treatment or prevention of non-growth related osteoporosis in an animal suffering from or susceptible to osteoporosis which comprises systemically administering to said animal an amount of a compound of the Formula I wherein N 1 is (1) --COOR 1 , wherein R 1 is (a) hydrogen, (b) (C 1 -C 12 )alkyl (c) (C 1 -C 10 )cycloalkyl, (d) (C 6 -C 12 )aralkyl, (e) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, (f) phenyl substituted in the para position by (i) --NH--CO--R 25 , (ii) --CO--R 26 , (iii) --O--CO--R 54 , or (iv) --CH═N--NH--CO--NH 2 wherein R 25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH 2 ; R 26 is methyl, phenyl, --NH 2 , or methoxy; and R 54 is phenyl or acetamidophenyl; inclusive, or (g) a pharmacologically acceptable cation; (2) --CH 2 OH, (3) --COL 4 , wherein L 4 is (a) amino of the formula --NR 51 R 52 , wherein R 51 and R 52 are (i) hydrogen (ii) (C 1 -C 12 )alkyl, (iii) (C 3 -C 10 )cycloalkyl, (iv) (C 7 -C 12 )aralkyl, (v) phenyl, optionally substituted with one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (vi) (C 2 -C 5 )carboxyalkyl, (vii) (C 2 -C 5 )carbamoylalkyl, (viii) (C 2 -C 5 )cyanoalkyl, (ix) (C 3 -C 6 )acetylalkyl, (x) (C 7 -C 11 )benzoalkyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, (xii) (C 6 -C 9 )pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, (xiii) (C 1 -C 4 )hydroxyalkyl, (xiv) (C 1 -C 4 )dihydroxyalkyl, (xv) (C 1 -C 4 )trihydroxyalkyl, with the further proviso that not more than one of R 51 and R 52 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C 1 -C 12 )alkyl of one to 12 carbon atoms, inclusive, (c) carbonylamino of the formula --NR 53 COR 51 , wherein R 53 is hydrogen or (C 1 -C 4 )alkyl and R 51 is other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula --NR 53 SO 2 R 51 , wherein R 51 and R 53 are as defined in (c), (e) --CH 2 NL 2 L 3 , wherein L 2 and L 3 are hydrogen or (C 1 -C 4 )alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when N 1 is --CH 2 NL 2 L 3 , (f) --CO 2 R 1 , (g) --CH 2 OH, (h) --CONR 5 R 6 , (i) --CH 2 --NR 5 R 6 , or (j) --CONHSO 2 CH 3 ; wherein M 1 is cis or trans--CH═CH--(CH 2 ) m --, --(CH 2 ) n --, --(CH 2 ) n-1 --CF 2 --, --CO--(CH 2 ) 3 --CH 2 --, trans--(CH 2 ) m --CH═CH--; --CH═CH--(CH 2 ) m-1 -- CF 2 --, or --CO--(CH 2 ) 3 --CF 2 --; wherein L 1 is α--OH:β--H, ═CH 2 , or oxo; wherein R 8 is hydrogen, hydroxy, or methyl; wherein E 1 is trans--CH═CH, --CH 2 --CH 2 --, or --C.tbd.C--; wherein Q 1 is α--OH:β--R 2 , α-R 2 :β--OH, or oxo; wherein A 1 is α--H:β--CH 3 , α--CH 3 :β--H; α--H:β--H, α--F:β--F or α--CH 3 :β--CH 3 ; wherein R 7 is: (1) --(CH 2 ) p --CH 3 , (2) cis--CH═CH--CH 2 --CH 3 , (3) --(CH 2 ) 2 --C.tbd.CH, (4) --(CH 2 ) 3 --CH═C(CH 3 ) 2 , or (5) --C(R 3 R 4 )--(CH 2 ) g --CH 2 R 14 ; wherein R 2 is hydrogen or methyl; wherein R 3 and R 4 are the same or different and are hydrogen or methyl; wherein R 5 and R 6 are the same or different and are hydrogen, methyl, or ethyl; wherein R 14 is hydrogen or (C 1 -C 4 )alkyl; wherein g is an integer of from one to 4, inclusive; wherein m is an integer of from 3 to 5, inclusive; wherein n is an integer of from 5 to 7, inclusive; 5 or 7; and wherein p is an integer from one to 6, inclusive or the pharmacologically acceptable salts thereof when N 1 is --CONR 53 SO 2 R 51 ; in an amount effective to treat or prevent said osteoporosis.

Claim 2

A method for the treatment or prevention of non-growth related osteoporosis in an animal suffering from or susceptible to osteoporosis which comprises systemically administering to said animal an amount of a compound of the Formula I wherein N 1 is (1) --COOR 1 , wherein R 1 is (a) hydrogen, (b) (C 1 -C 12 )alkyl (c) (C 1 -C 10 )cycloalkyl, (d) (C 6 -C 12 )aralkyl, (e) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, (f) phenyl substituted in the para position by (i) --NH--CO--R 25 , (ii) --CO--R 26 , (iii) --O--CO--R 54 , or (iv) --CH═N--NH--CO--NH 2 wherein R 25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH 2 ; R 26 is methyl, phenyl, --NH 2 , or methoxy; and R 54 is phenyl or acetamidophenyl; inclusive, or (g) a pharmacologically acceptable cation; (2) --CH 2 OH, (3) --COL 4 , wherein L 4 is (a) amino of the formula --NR 51 R 52 , wherein R 51 and R 52 are (i) hydrogen (ii) (C 1 -C 12 )alkyl, (iii) (C 3 -C 10 )cycloalkyl, (iv) (C 7 -C 12 )aralkyl, (v) phenyl, optionally substituted with one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (vi) (C 2 -C 5 )carboxyalkyl, (vii) (C 2 -C 5 )carbamoylalkyl, (viii) (C 2 -C 5 )cyanoalkyl, (ix) (C 3 -C 6 )acetylalkyl, (x) (C 7 -C 11 )benzoalkyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, (xii) (C 6 -C 9 )pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, (xiii) (C 1 -C 4 )hydroxyalkyl, (xiv) (C 1 -C 4 )dihydroxyalkyl, (xv) (C 1 -C 4 )trihydroxyalkyl, with the further proviso that not more than one of R 51 and R 52 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C 1 -C 12 )alkyl of one to 12 carbon atoms, inclusive, (c) carbonylamino of the formula --NR 53 COR 51 , wherein R 53 is hydrogen or (C 1 -C 4 )alkyl and R 51 is other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula --NR 53 SO 2 R 51 , wherein R 51 and R 53 are as defined in (c), (e) --CH 2 NL 2 L 3 , wherein L 2 and L 3 are hydrogen or (C 1 -C 4 )alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when N 1 is --CH 2 NL 2 L 3 , (f) --CO 2 R 1 , (g) --CH 2 OH, (h) --CONR 5 R 6 , (i) --CH 2 --NR 5 R 6 , or (j) --CONHSO 2 CH 3 ; wherein M 1 is cis or trans--CH═CH--(CH 2 ) m --, --(CH 2 ) n --, --(CH 2 ) n-1 --CF 2 --, --CO--(CH 2 ) 3 --CH 2 --, trans--(CH 2 ) m --CH═CH--; --CH═CH--(CH 2 ) m-1 -- CF 2 --, or --CO--(CH 2 ) 3 --CF 2 --; wherein L 1 is α--OH:β--H, ═CH 2 , or oxo; wherein R 8 is hydrogen, hydroxy, or methyl; wherein E 1 is trans--CH═CH, --CH 2 --CH 2 --, or --C.tbd.C--; wherein Q 1 is α--OH:β--R 2 , α-R 2 :β--OH, or oxo; wherein A 1 is α--H:β--CH 3 , α--CH 3 :β--H; α--H:β--H, α--F:β--F or α--CH 3 :β--CH 3 ; wherein R 7 is: (1) --(CH 2 ) p --CH 3 , (2) cis--CH═CH--CH 2 --CH 3 , (3) --(CH 2 ) 2 --C.tbd.CH, (4) --(CH 2 ) 3 --CH═C(CH 3 ) 2 , or (5) --C(R 3 R 4 )--(CH 2 ) g --CH 2 R 14 ; wherein R 2 is hydrogen or methyl; wherein R 3 and R 4 are the same or different and are hydrogen or methyl; wherein R 5 and R 6 are the same or different and are hydrogen, methyl, or ethyl; wherein R 14 is hydrogen or (C 1 -C 4 )alkyl; wherein g is an integer of from one to 4, inclusive; wherein m is an integer of from 3 to 5, inclusive; wherein n is an integer of from 5 to 7, inclusive; 5 or 7; and wherein p is an integer from one to 6, inclusive or the pharmacologically acceptable salts thereof when N 1 is --CONR 53 SO 2 R 51 ; in an amount effective to treat or prevent said osteoporosis.