Patent EA-001649-B1 (EA)
Title: 4-cyclic condenced compounds with iteroatoms substituted by aryl, intermediates, processes for preparing, compositions and methods for treating
Inventor: GREESE TIMOTHY A
IPC: C07D311/78
Filed: 1996-08-26
Abstract: 1. A compound of formula I or II:     wherein Y is -O-, -S-, -CH2-, -CH2CH2-, -CH=CH-, or -NR<4>-; B is -CH2 - or -CO-; R<1> and R<2> are each independently -H, -OH, -O(C1-C4-alkyl), -OCOC6H5, -OCO(C1-C6-alkyl), -OSO2(C4-C6-alkyl), OSO2CF3, Cl, or F; n is 1 or 2; W is -CH2- or >C=O; R<3> is 1-piperidinyl, 2-oxo-1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; and R<4> is C1-C3-alkyl, -COC6H5, -CO(C1-C6-alkyl), -C(O)OC6H5, -C(O)O(C1-C6-alkyl), SO2(C1-C6-alkyl), -SO2C6H5, or -SO2CF3; representing separate optical isomer or a mixture of optical isomers; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1 of Formula I, wherein Y is -S-. 3. A compound according to Claim 1 of Formula II wherein Y is -CH=CH-. 4. A compound according to any of Claims 1 to 3 wherein -O-(CH2)n-W-R<3> is 2-(1-piperidinyl)ethoxy. 5. A compound according to Claim 1 which is selected from the group consisting of: 3,9-dihydroxy-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-dimethoxy-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-bis(benzoyloxy)-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-bis(pivaloyloxy)-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-bis(1-butylsulfonyloxy)-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-bis(trifluoromethanesulfonyloxy)-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-dihydroxy-6-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-dihydroxy-6-[4-(2-dimethylaminoethoxy)phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-dihydroxy-6-[4-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl]-6-H-[1]benzothieno[3,2-c][1]benzopyran; 3,9-dihydroxy-6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6-H-benzofuro[3,2-c][1]benzopyran; 2,8-dimethoxy-5-[4-[2-(1-piperidinyl)ethoxy]phenyl]-11,12-dihydro-6H-benzo[c]phenanthrid-6-one; 2,8-dimethoxy-5-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6H-benzo[c]phenanthridine; 2,8-dihydroxy-5-[4-[2-(1-piperidinyl)ethoxy]phenyl]-6H-benzo[c]phenanthridine; and 2,8-dihydroxy-5-[4-[2-(1-piperidinyl)ethoxy]phenyl]-5H-benzo[b]naphtho[2,1-d)pyran. 6. A process for preparing a compound of the formula     wherein Y is -O-, -S-, -CH2-, -CH2CH2-, -CH=CH-, or -NR<4>-; B is -CH2 - or -CO-; R<1> and R<2> are each independently -H, -OH, -O(C1-C4-alkyl), -OCOC6H5, -OCO(C1-C6-alkyl), -OSO2(C4-C6-alkyl), OSO2CF3, Cl, or F; n is 1 or 2; W is -CH2- or >C=O; R<3> is 1-piperidinyl, 2-oxo-1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; R<4> is C1-C3-alkyl, -COC6H5, -CO(C1-C6-alkyl), -C(O)OC6H5, -C(O)O(C1-C6-alkyl), -OSO2(C1-C6-alkyl), -SO2C6H5, or -SO2CF3; representing separate optical isomer or a mixture of optical isomers; or a pharmaceutically acceptable salt thereof, which comprises: (1) reacting a compound of the formula   wherein R<1a> and R<2a> are each independently -H, -O(C1-C4-alkyl), -Cl, -F, or a protected -OH; Y is as defined above; and Z<a> is -OH, -OC6H5, or -O(C1-C4-alkyl), with a Grignard reagent of the formula   wherein G<a> is -OSi(CH3)3, a protected OH capable of being selectively deprotected in the presence of R<1a> and R<2a>, or -O-(CH2)n-W-R<3>; to obtain a compound of the formula   (2) in the instance when G<a> is -OSi(CH3)3 or a protected OH as defined, (a) treating the product of step (1) to selectively deprotect to obtain a compound of the formula   and thereafter (b) alkylating this compound to a compound of the formula   (3) deprotecting any protected -OH groups in R<1a> or R<2a> in the compound from step 1 or step 2, to obtain the compound of the formula:   and (4) optionally reacting the product of step 3 with pharmaceutically acceptable acid. 7. A compound of the formula   wherein Y is -O-, -S-, -CH2-, -CH2CH2-, -CH=CH-, or -NR<4>-; R<1a> and R<2a> are each independently -H, -O(C1-C4-alkyl), -Cl, -F or protected -OH; and Z is -OH, -OC6H5, -O(C1-C4-alkyl), or 4-hydroxyphenyl. representing separate optical isomer or a mixture of optical isomers. 8. A compound of the formula   wherein Y is -O-, -S-, -CH2-, -CH2CH2-, -CH=CH- or -NR<4>-; each of R<1a> and R<2a> is independently -H, -O(C1-C4-alkyl), -Cl, -F, or a protected -OH. 9. A pharmaceutical composition comprising a compound according to Claim 1 together with a pharmaceutically acceptable carrier, diluent or excipient. 10. A method for inhibiting bone loss or bone resorption comprising administering to a patient in need thereof an effective amount of a compound of Claim 1. 11. A method according to Claim 10 wherein said bone loss or bone resorption is due to menopause or ovariectomy. 12. A method of lowering serum cholesterol levels comprising administering to a patient in need thereof an effective amount of a compound of Claim 1. 13. A compound as claimed in Claim 1 having the formula   representing separate optical isomer or a mixture of optical isomers; or a pharmaceutically acceptable salt thereof. 14. A compound as claimed in Claim 1 which is hydrochloride. 15. A pharmaceutical composition comprising a compound according to Claim 14 together with a pharmaceutically acceptable carrier, diluent or excipient. 16. A method for inhibiting bone loss or bone resorption comprising administering to a patient in need thereof an effective amount of a compound of Claim 14. 17. A method according to Claim 16 wherein said bone loss or bone resorption is due to menopause or ovariectomy. 18. A method of lowering serum cholesterol levels comprising administering to a patient in need thereof an effective amount of a compound of Claim 14. 19. A method for inhibiting oestrogen-dependent cancer comprising administering to a patient in need thereof an effective amount of a compound of Claim 1. 20. A method according to Claim 19 wherein said cancer is breast cancer. 21. A method for inhibiting oestrogen-dependent cancer comprising administering to a patient in need thereof an effective amount of a compound of Claim 14. 22. A method according to Claim 21 wherein said cancer is breast cancer.