Claims
- 1. A method of treating osteoarthritis, the method comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula (I):
- 2. The method of claim 1 wherein the estrogen agonist/antagonist is a compound of formula (IA)
- 3. The method of claim 1 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
- 4. The method of claim 3 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt.
- 5. A method of treating osteoarthritis, the method comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
- 6. A method of treating osteoarthritis, the method comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula V or VI:
- 7. The method of claim 6 wherein the estrogen agonist/antagonist is the compound TSE-424 of formula Va below:
- 9. A method of treating osteoarthritis, the method comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula III (EM-652) below or formula IV (EM-800) below:
- 10. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula (I): 48wherein: A is selected from CH2 and NR; B, D and E are independently selected from CH and N; Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4; (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4; (c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4; (d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4; (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4; (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4; or (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4; Z1 is
(a) —(CH2)p W(CH2)q—; (b) —O(CH2)p CR5R6—; (c) —O(CH2)pW(CH2)q—; (d) —OCHR2CHR3—; or (e) —SCHR2CHR3—; G is
(a) —NR7R8; (b) 49wherein n is 0, 1 or 2; m is 1, 2 or 3; Z2 is —NH—, —O—, —S—, or —CH2—; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4; or (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4; or Z1 and G in combination may be 50W is
(a) —CH2—; (b) —CH═CH—; (c) —O—; (d) —NR2—; (e) —S(O)n—; (f) 51(g) —CR2(OH)—; (h) —CONR2—; (i) —NR2CO—; (j) 52(k) —C≡C—; R is hydrogen or C1-C6 alkyl; R2 and R3 are independently
(a) hydrogen; or (b) C1-C4 alkyl; R4 is
(a) hydrogen; (b) halogen; (c) C1-C6 alkyl; (d) C1-C4 alkoxy; (e) C1-C4 acyloxy; (f) C1-C4 alkylthio; (g) C1-C4 alkylsulfinyl; (h) C1-C4 alkylsulfonyl; (i) hydroxy (C1-C4)alkyl; (j) aryl (C1-C4)alkyl; (k) —CO2H; (l) —CN; (m) —CONHOR; (n) —SO2NHR; (o) —NH2; (p) C1-C4 alkylamino; (q) C1-C4 dialkylamino; (r) —NHSO2R; (s) —NO2; (t) -aryl; or (u) —OH; R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring; R7 and R8 are independently
(a) phenyl; (b) a C3-C10 carbocyclic ring, saturated or unsaturated; (c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—; (d) H; (e) C1-C6 alkyl; or (f) form a 3 to 8 membered nitrogen containing ring with R5 or R6; R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy; a ring formed by R7 and R8 may be optionally fused to a phenyl ring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
- 11. The kit of claim 10 wherein the estrogen agonist/antagonist is a compound of formula (IA):
- 12. The kit of claim 10 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
- 13. The kit of claim 12 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt.
- 14. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist that is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604 and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
- 15. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula V or VI: 55wherein: R1B is selected from H, OH, —O—C(O)—C1-C12 alkyl (straight chain or branched), —O—C1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers; R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, —O—C(O)—C1-C12 (straight chain or branched), —O—C1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl; XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen; s is 2 or 3; YA is the moiety: 56wherein: a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, —OH, —CF3, or —OCF3; or b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, —CO2H, —CN, —CONHR1B, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NHSO2R1B, —NHCOR1B, —NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, —CO2H, —CN, —CONHR1B, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NHSO2R1B, —NHCOR1B, —NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, —CO2H, —CN, —CONHR1B, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NHSO2R1B, —NHCOR1B, —NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, —CO2H, —CN, —CONHR1B, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NHSO2R1B, —NHCOR1B, —NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, —CO2H, —CN, —CONHR1B, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NHSO2R1B, —NHCOR1B, —NO2, or phenyl optionally substituted with 1-3 (C1-C4) alkyl; or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and
(b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
- 16. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula Va (TSE-424) below: 57or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
- 17. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist of formula III (EM-652) below or formula IV (EM-800) below: 58or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof, and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) instructions describing a method of using the pharmaceutical composition to treat osteoarthritis.
- 18. The kit of claim 10 wherein the kit further comprises an additional compound that is useful to treat osteoarthritis arthritis.
- 19. The kit of claim 18 wherein the additional compound is a nonsteroidal anti-inflammatory drug.
- 20. The kit of claim 18 wherein the additional compound is a COX-2 inhibitor.
- 21. The kit of claim 20 wherein the COX-2 inhibitor is Celebrex® or Vioxx®.
- 22. A kit for use by a consumer to treat osteoarthritis, the kit comprising:
(a) an estrogen agonist/antagonist; (b) a COX-2 inhibitor; (c) instructions describing a method of using the estrogen agonist/antagonist and COX-2 inhibitors to treat osteoarthritis; and (d) a container for the estrogen agonist/antagonist, COX-2 inhibitor, and instructions.
- 23. The kit of claim 22 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof, and the COX-2 inhibitor is Celebrex® or Vioxx®.
- 24. A method of treating osteoarthritis, the method comprising the step of administering to a patient having or at risk of having osteoarthritis, an estrogen agonist/antagonist and a COX-2 inhibitor.
- 25. The method of claim 24 wherein the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof, and the COX-2 inhibitor is Celebrex® or Vioxx®.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional patent application No. 60/234,398, filed Sep. 21, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60234398 |
Sep 2000 |
US |