Claims
- 1. A compound of the Formula: ##STR54## wherein: R.sup.1 and R.sup.5 is each independently H, OH, lower alkyl, or lower alkoxy;
- R.sup.2 is H, lower alkyl, or together with R.sup.1 forms a double bonded oxygen (.dbd.O);
- R.sup.3 is H, lower alkyl, hydroxy lower alkyl, or lower alkoxy lower alkyl, or R.sup.1 and R.sup.3 may join to form a mono-oxa, mono-carbon bridge;
- R.sup.4 is H or lower alkyl;
- R.sup.6 is H or lower alkyl;
- R.sup.7 is H, OH, lower alkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyloxy, or O--R.sup.15 ;
- R.sup.8 is H, halogen, lower alkyl, hydroxy, lower alkoxy, CF.sub.3, CN, or COR.sup.13 ;
- R.sup.9 is H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, (R.sup.8).sub.2 -phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO.sub.2, CF.sub.3, N.sub.3, N(R.sup.12).sub.2, NR.sup.12 COR.sup.13, NR.sup.12 CON(R.sup.12).sub.2, SR.sup.14, S(O)R.sup.14, S(O).sub.2 R.sup.14, S(O).sub.2 N(R.sup.12).sub.2, COR.sup.13, CON(R.sup.12).sub.2, CO.sub.2 R.sup.13, C(R.sup.13).sub.2 OC(CR.sup.13).sub.2 --CO.sub.2 R.sup.13, C(R.sup.13).sub.2 CN, or halogen;
- R.sup.10 and R.sup.11 is each independently H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkylthio lower alkyl, (R.sup.8).sub.2 -phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO.sub.2, CF.sub.3, N.sub.3, N(R.sup.16).sub.2, NR.sup.16 COR.sup.13, NR.sup.16 CON(R.sup.16).sub.2, SR.sup.14, S(O)R.sup.14, S(O).sub.2 R.sup.14, S(O).sub.2 N(R.sup.16).sub.2, COR.sup.13, CON(R.sup.16).sub.2, CO.sub.2 R.sup.13, C(R.sup.13).sub.2 OC(CR.sup.13).sub.2 --CO.sub.2 R.sup.13, C(R.sup.13).sub.2 CN, halogen, C(R.sup.13).sub.2 NR.sup.16 COR.sup.13, or C(R.sup.13).sub.2 NR.sup.16 CON(R.sup.13).sub.2 ;
- R.sup.12 is H or lower alkyl, or two R.sup.12 groups attached to the same nitrogen may form a saturated ring of 5 or 6 members, optionally containing a second heteroatom chosen from O, S or NR.sup.4 ;
- R.sup.13 is H or lower alkyl;
- R.sup.14 is lower alkyl, CF.sub.3, or phenyl-(R.sup.8).sub.2 ;
- R.sup.15 is carboxy lower alkylcarbonyl, pyridylcarbonyl, hydroxy lower alkylcarbonyl, polyoxa lower alkylcarbonyl, a functionalized or unfunctionalized derivative of a standard amino acid, or a benzoyl group substituted by CH.sub.2 N(R.sup.12).sub.2 ;
- R.sup.16 is H, lower alkyl, or OR.sup.13 ;
- X.sup.1 is O, or C(R.sup.6).sub.2 ;
- X.sup.2 is O, or (CR.sup. 6).sub.2 ;
- one but not of X.sup.1 or X.sup.2 is O;
- X.sup.3 is C(R.sup.6).sub.2 O or OC(R.sup.6).sub.2 ;
- Ar.sup.1 is arylene-(R.sup.8).sub.2, wherein arylene is phenylene, pyridylene or thiazylene
- Ar.sup.2 is aryl-(R.sup.9).sub.2 wherein aryl is a 5-membered aromatic ring wherein one carbon atom is replaced by O or S and 0-3 carbon atoms are replaced by N; a 5-membered aromatic ring wherein 1-4 carbon atoms are replaced by N; a 6-membered aromatic ring wherein 0-3 carbon atoms are replaced by N; 2- or 4-pyranone; 2- or 4-pyridinone; or a bicyclic 8-, 9-, or 10-membered aromatic ring wherein 0-2 carbon atoms are replaced by either O or S or a combination thereof and 0-3 carbon atoms are replaced by N; with the proviso that Ar.sup.2 is not phenyl when X.sup.3 is OC(R.sup.6).sub.2, Ar.sup.1 is thiazylene, and R.sup.7 is lower alkoxy; with the further proviso that Ar.sup.2 is not phenyl when X.sup.3 is OC(R.sup.6).sub.2, and Ar.sup.1 is phenylene or pyridylene;
- Ar.sup.2 is attached to either ring of the naphthalene ring system;
- m is 1;
- p is 0 to 6; and
- q is 1 or 2;
- or a pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1 of the Formula: ##STR55## wherein R.sup.10 is H, lower alkyl, or halogen.
- 3. A compound of the Formula: ##STR56## wherein: R.sup.1 and R.sup.3 is each independently H or CH.sub.3 or together are --CH.sub.2 O-- or --OCH.sub.2 ;
- R.sup.7 is OH or OCH.sub.3 ;
- Ar.sup.1 is Phe, 5,3-Pye, 2,4-Tze, 6,2-Pye, 4,2-Pye, or 2,4-Pye;
- Ar.sup.2 is Ph, 3-Fu, 2-Th, 3-Th, 2-Tz, 5-Tz, 5-Pym, or 5-Tet;
- R.sup.11 is CO.sub.2 CH.sub.3, C(OH)(CH.sub.3).sub.2, CH(OH)CH.sub.3, CH(OCH.sub.3)CH.sub.3, CH.sub.2 CH.sub.3, CO(CH.sub.2).sub.3 CH.sub.3, CON(CH.sub.3).sub.2, CH.sub.2 SC.sub.6 H.sub.5, CH.sub.2 SCH.sub.3, CH.sub.2 CN, COCH.sub.2 SCH.sub.3, CH.sub.2 OCH.sub.2 CO.sub.2 CH.sub.3, CN, CHO, H, COCH.sub.3, or CH.sub.2 N(OH)COCH.sub.3.
- 4. A compound of the Formula: ##STR57## wherein the substituents are as follows:
- ______________________________________[EX.] R.sup.1 R.sup.3 R.sup.7 Ar.sup.1 Ar.sup.2 R.sup.11______________________________________ [1] H H OH Phe Ph CN [2] H H OH Phe Ph CO.sub.2 H [3] H H OH Phe Ph COMe [4] H H OH Phe Ph C(OH)Me.sub.2 [5] H H OH Phe Ph CH.sub.2 OH [6] H H OH Phe Ph CH.sub.2 OMe [7] H H OH Phe Ph CH(OH)Me [8] H H OH Phe Ph CH(OMe)Me [9] H H OH Phe Ph Et[10] H H OH Phe Ph COBu[11] H H OH Phe Ph CONMe.sub.2[12] H H OH Phe Ph CH.sub.2 SPh[13] H H OH Phe Ph CH.sub.2 SMe[14] H H OH Phe Ph CH.sub.2 CN[15] H H OH Phe Ph COCH.sub.2 SMe[16] H H OH Phe Ph CH.sub.2 OCH.sub.2 CO.sub.2 Me[17] H H OH Phe Ph CN[18] H H OH Phe 3-Fu CN[19] H H OH Phe 3-Fu CO.sub.2 Me[20] H H OH Phe 3-Fu CHO[21] H H OH 5,3-Pye 3-Fu CN[22] --CH.sub.2 O-- OH 5,3-Pye 3-Fu CN[23] --CH.sub.2 O-- OH Phe 3-Fu CN[24] H H OH 2,4-Tze 3-Fu CN[25]* Me H OH Phe 3-Fu CN[26]** Me H OH Phe 3-Fu CN[27]** Me H OMe Phe 3-Fu CN[28] --CH.sub.2 O-- OMe Phe 3-Fu CN[29] H H OH 6,2-Pye 3-Fu CN[30]* Me Me OH Phe 3-Fu CN[31] --CH.sub.2 O-- OH Phe 2-Th CN[32] --CH.sub.2 O-- OH Phe 3-Th CN[33] --CH.sub.2 O-- OMe Phe 3-Th CN[34] H H OH 5,3-Pye 3-Th CN[35] H H OH Phe 3-Th CN[36] --CH.sub.2 O-- OH 5,3-Pye 3-Th CN[37] H H OH Phe 2-Tz CO.sub.2 Me[38] H H OH Phe 5-Tz CO.sub.2 Me[39] H H OH Phe Ph H[40] H H OH 4,2-Pye 3-Fu CN[41] H H OMe 6,2-Pye 3-Fu CN[42] --CH.sub.2 O-- OH 6,2-Pye 3-Fu CN[43] --CH.sub.2 O-- OMe 6,2-Pye 3-Fu CN[44] --CH.sub.2 O-- OH 4,2-Pye 3-Fu CN[45] --CH.sub.2 O-- OMe 4,2-Pye 3-Fu CN[46] --CH.sub.2 O-- OH 2,4-Pye 3-Fu CN[47] --CH.sub.2 O-- OMe 2,4-Pye 3-Fu CN[48] H H OH 2,4-Pye 3-Fu CN[49] H H OMe 2,4-Pye 3-Fu CN[50] H H OH 6,2-Pye 3-Th CN[51] H H OH 2,4-Pye 3-Th CN[55] CH.sub.2 OH OH OH 6,2-Pye 3-Fu CN[56] --CH.sub.2 O-- OH 6,2-Pye 3-Th CN[57] H H OH PHe 5-Pym CO.sub.2 Me[58] --CH.sub.2 O-- OH 6,2-Pye 3-Fu COMe[59] H H OH Ph 3-Fu CH.sub.2 N(OH) COMe[60] H H OH Ph Tet CO.sub.2 Me[61] H H OH Ph 2-MeTet CO.sub.2 Me[72] --CH.sub.2 O-- OH 6,2-Pye 3-Fu CN______________________________________ *.alpha. isomer **.beta. iosmer
- 5. A compound of the Formula: ##STR58## wherein the substituents are as follows:
- ______________________________________[EX.] R.sup.1 R.sup.3 R.sup.7 R.sup.8 Ar.sup.2 R.sup.11______________________________________[63] --CH.sub.2 O-- OH F 3-Fu CO.sub.2 Me[64] --CH.sub.2 O-- OH F 3-Fu CN[65] --CH.sub.2 O-- OMe F 3-Fu CN[66] --CH.sub.2 O-- OMe H 3-Fu CN[67] --CH.sub.2 O-- OMe F 3-Th CN[68] H H OMe F 3-Fu CN[69] H H OMe F 3-Th CN______________________________________
- 6. A compound of the Formula: ##STR59## wherein the substituents are as follows:
- ______________________________________R.sup.15 Ar.sup.2 R.sup.11______________________________________--CO(CH.sub.2).sub.2 CO.sub.2 H Ph COCH.sub.3--CO(CH.sub.2).sub.2 CO.sub.2 H Ph CN--CO(CH.sub.2).sub.2 CO.sub.2 H Ph CN--CO-3-Py Ph CN--CO(CH.sub.2).sub.2 CO.sub.2 Me Ph CN--COCH.sub.2 NH.sub.2 Ph CN--COCH.sub.2 OH 3-Fu CN--COCH.sub.2 NH.sub.2 3-Fu CN--COCH.sub.2 NMe.sub.2 3-Fu CN--COCH.sub.2 NMe.sub.2 Ph CN--COCH.sub.2 NHMe 3-Fu CN--COCH(NH.sub.2)CH.sub.2 CO.sub.2 Me 3-Fu CN--COCH(NHt-BOC)CH.sub.2 CO.sub.2 H 3-Fu CN______________________________________
- 7. The compound [1S, 5R]-1-(3-Furyl)-3-cyano-6-{6-[3-(3.alpha.-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethoxy}naphthalene.
- 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
- 9. The pharmaceutical composition of claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H.sub.1 - or H.sub.2 -receptor antagonists; antihistaminic agents; prostaglandin antagonists; and ACE antagonists.
- 10. A pharmaceutical composition according to claim 7, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.
- 11. A pharmaceutical composition of claim 10, wherein the weight ratio of said compound of claim 1 to said second active ingredient ranges from about 1000:1 to 1:1000.
CROSS-REFERENCE
This is a continuation-in-part of Ser. No. 07/906,067, Jun. 29, 1992, now abandoned.
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Continuation in Parts (1)
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Number |
Date |
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Parent |
906067 |
Jun 1992 |
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