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US 5,308,852 AGranted
Heteroarylnaphthalenes as inhibitors of leukotriene biosynthesis
AssigneeMerck Frosst Canada, Inc.
InventorsYves Girard, Daniel Delorme, Rejean Fortin, Daniel Dube, Pierre Hamel, Carol Lepine, Yves Ducharme
Life of this patent
Estimating the term…
Abstract
Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.
Claims11
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.
31 more elements
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.
3 more elements
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
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 ______________________________________
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 ______________________________________
The compound [1S, 5R]-1-(3-Furyl)-3-cyano-6-{6-[3-(3.alpha.-hydroxy-6,8-dioxabicyclo[3.2.1]o ctanyl)]pyridin-2-ylmethoxy}naphthalene.
Dependencies are inferred from the claim text.