Patent EA-001600-B1 (EA)
Title: Naphthyl compounds, intermediate compounds for production thereof, use of naphthyl compounds, method of lowering serum cholesterol
Inventor: BRYANT HENRY U
IPC: C07C41/26
Filed: 1997-08-22
Abstract: 1. A compound of formula I   wherein R<1> is -H, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R<2> is H, -F, -Cl , -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R<3> and R<4> are, independently, -H, -F, -Cl, -CH3, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that both R<3> and R<4> cannot be hydrogen; n is 2 or 3; and R<5> is 1-piperidinyl, 1-pyrrolidinyl, methy-l-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to Claim 1 wherein R<1> and R<3> each are -OH. 3. A compound according to Claim 1 wherein R<1> is hydroxy and R<3> is methoxy. 4. A compound according to Claim 1 wherein R<1> is methoxy and R<3> is hydroxy. 5. A compound according to Claim 1 wherein n is two and R<5> is 1-piperidinyl. 6. A compound according to Claim 1 wherein said salt thereof is the hydrochloride salt. 7. A compound according to Claim 1 wherein R<1> and R<3> each are -OH, R<5> is piperidinyl, n is two, and said salt thereof is the hydrochloride salt. 8. A compound according to Claim 1 wherein R<1> is hydroxy, R<3> is methoxy, R<5> is piperidinyl, n is two, and said salt thereof is the hydrochloride salt. 9. A compound according to Claim 1 wherein R<1> is methoxy, R<3> is hydroxy, R<5> is piperidinyl, n is two, and said salt thereof is the hydrochloride salt. 10. A compound according to Claim 1 selected from the group consisting of  1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthalene hydrochloride, 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)naphthalene hydrochloride, 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-hydroxyphenyl)-6-hydroxynaphthalene hydrochloride, 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-hydroxyphenyl)naphthalene hydrochloride, 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-hydroxyphenyl)-6-methoxynaphthalene hydrochloride, and 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-hydroxynaphthalene hydrochloride. 11. A use of the compound according to any preceding Claim comprising administering to a patient in need thereof an effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof for inhibiting bone loss or bone resorption. 12. The use of the compound according to Claim 11 wherein said bone loss or bone resorption is due to menopause or ovariectomy. 13. The use to Claim 11 or 12 wherein said patient is a postmenopausal female. 14. The use of the compound according to Claims 1 to 10 or a pharmaceutically acceptable salt or solvate thereof for lowering serum cholesterol. 15. A method of lowering serum cholesterol comprising administering to a patient in need thereof an effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof. 16. A compound of formula II   wherein: R<1a> is -H or -OR<6> in which R<6> is a hydroxy protecting group; R<2a> is -H, -F, -Cl, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R<3a> is -H, -F, -Cl, or -OR<7> in which R<7> is a hydroxy protecting group; R<4a> is -H, -F, -Cl, -CH3, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that neither of R<3a> and R<4a> can be hydrogen; R<5a> is -OH, -COW, or -O(CO)W; and W is -H or C1-C6 alkyl; or a pharmaceutically acceptable salt or solvate thereof. 17. A compound according to Claim 16 wherein R<1a> is -OR<6> and R<2a> is -OR<7>. 18. A compound of formula III   wherein: R<1a> is -H or -OR<5> in which R<5> is a hydroxy protecting group; R<2a> is -H, -F, -Cl, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R<3a> and R<4a> are, independently, -H, -F, -Cl, -CH3, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that neither of R<3a> and R<4a> can be hydrogen. 19. A compound of formula IV   wherein: R<1a>s -H or -OR<6>in which R<6>is a hydroxy protecting group; R<2a>s -H, -F, -Cl, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2C4-C6 lkyl); R<3a>s -H, -F, -Cl, or -OR<7>in which R<7>s a hydroxy protecting group; R<4a>s -H, -F, -Cl, -CH3 -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that neither of R<3a> and R<4a> can be hydrogen; R<8> is -OH or -OCO(C1-C6 alkyl); wherein a dotted line is an optional non-saturation; or a pharmaceutically acceptable salt or solvate thereof. 20. A compound of formula VI   wherein: R<1a> is -H or -OR<6> in which R<6> is a hydroxy protecting group; R<2a> is -H, -F, -Cl, -OH, -O(C1-C4C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R<3a> is -H, -F, -Cl, or -OR<7> in which R<7> is a hydroxy protecting group; R<4a> is -H, -F, -Cl, -CH3, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that neither of R<3a> and R<4a> can be hydrogen; n is 2 or 3 and Q is a leaving group; or a pharmaceutically acceptable salt or solvate thereof.