Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders
First Claim
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1. A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenanse in an animal, comprising administering to an animal in need of such treatment, an amount effective to reduce formation of oxygen radicals in vivo, of a compound of the formula:
- ##STR19## or pharmaceutically acceptable salts, wherein;
Ar1 is either ##STR20## and wherein;
W is independently selected from the group consisting of;
--S(O)n R3,--S(O)n CH2 CH(OH)A,and--C(O)NHA,X is O, S, S(O), CR5 ;
Y1, Y2 are independently selected from the group consisting of;
(a) hydrogen(b) lower alkyl, lower alkoxy, lower alkenyl, lower alkynl, alkylarlyl;
(c) --AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AN(OM)C(O)R4, --AC(O)N(OM)R4, and --C(O)N(OM)R4, and(d) --C(O)NHR3 ;
wherein at least one of Y1 and Y2 is (c); and
wherein each n is independently 0, 1 or 2;
A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkynl, alkaryl or aralkyl;
M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group;
R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, C3-8 -cycloalkyl, haloloweralkyl, halo-COOH;
R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl where one or more carbon atoms are replaced by S,N, or O, substituted or unsubstituted cycloalkyl of from 3 to 8 atoms, where one or more carbons are replaced by S,N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C1-6 alkoxy C1-10 alkyl, C1-6 alkylthio-C1-10 alkyl, C1-6 hydroxy-C1-6 alkyl, C1-6 carbonyl-C 1-6 alkyl, C1-6 -amino-C1-6 alkyl;
R5 is selected from the group consisting of;
(a) hydrogen;
(b) lower alkyl, lower alkenyl, lower alkynyl, alkaryl;
(c) --AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AC(O)N(OM)R4, --AS(O)n R3, --AS(O)n CH2 C(O)R3, --AS(O)n CH2 CH(OH)R3, --AC(O)NHR3 ;
wherein each n is independently 0, 1 or 2;
A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkynyl, alkaryl or aralkyl;
M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group in a pharmaceutically acceptable carrier.
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Abstract
2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. Also disclosed is a method to treat disorders mediated by PAF and/or leukotrienes that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to a patient in need of such therapy.
93 Citations
7 Claims
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1. A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenanse in an animal, comprising administering to an animal in need of such treatment, an amount effective to reduce formation of oxygen radicals in vivo, of a compound of the formula:
- ##STR19## or pharmaceutically acceptable salts, wherein;
Ar1 is either ##STR20## and wherein;
W is independently selected from the group consisting of;--S(O)n R3, --S(O)n CH2 CH(OH)A, and --C(O)NHA, X is O, S, S(O), CR5 ; Y1, Y2 are independently selected from the group consisting of; (a) hydrogen (b) lower alkyl, lower alkoxy, lower alkenyl, lower alkynl, alkylarlyl; (c) --AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AN(OM)C(O)R4, --AC(O)N(OM)R4, and --C(O)N(OM)R4, and (d) --C(O)NHR3 ; wherein at least one of Y1 and Y2 is (c); and wherein each n is independently 0, 1 or 2; A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkynl, alkaryl or aralkyl; M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group; R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, C3-8 -cycloalkyl, haloloweralkyl, halo-COOH; R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl where one or more carbon atoms are replaced by S,N, or O, substituted or unsubstituted cycloalkyl of from 3 to 8 atoms, where one or more carbons are replaced by S,N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C1-6 alkoxy C1-10 alkyl, C1-6 alkylthio-C1-10 alkyl, C1-6 hydroxy-C1-6 alkyl, C1-6 carbonyl-C 1-6 alkyl, C1-6 -amino-C1-6 alkyl; R5 is selected from the group consisting of; (a) hydrogen; (b) lower alkyl, lower alkenyl, lower alkynyl, alkaryl; (c) --AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AC(O)N(OM)R4, --AS(O)n R3, --AS(O)n CH2 C(O)R3, --AS(O)n CH2 CH(OH)R3, --AC(O)NHR3 ; wherein each n is independently 0, 1 or 2;
A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkynyl, alkaryl or aralkyl;
M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group in a pharmaceutically acceptable carrier. - View Dependent Claims (3, 4, 5)
- ##STR19## or pharmaceutically acceptable salts, wherein;
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2. A method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenanse in an animal, comprising administering to an animal in need of such treatment, an amount effective to reduce formation of oxygen radicals in vivo, of a compound of the formula:
- ##STR21## or pharmaceutically acceptable salts, wherein;
##STR22## and wherein;
W is independently selected from the group consisting of;--AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AN(OM)C(O)R4, --AC(O)N(OM)R4, --N(OM)C(O)N(R3) R4, --N(R3)C(O)N(OM)R4, --N(OM)C(O)R4, X is O, S, S(O),CR5 ; Y1, Y2 are independently selected from the group consisting of; (a) hydrogen (b) lower alkyl, lower alkoxy, lower alkenyl, lower alkynl, alkylarlyl; (c) --AN(OM)C(O)N(3)R4, --AN(R3)C(O)N(OM)R4, --AN(OM)C(O)R4, --AC(O)N(OM)R4, --C(O)N(OM) R4, and --C(O)NHR3 ; wherein A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkenyl, lower alkynl, alkaryl or aralkyl; M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group; R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, C3-8 cycloalkyl, haloloweralkyl, halo-COOH; R3 and R4 are independently sselected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted allyl where one or more carbon atoms are replaced by S,N, or O, substituted or unsubstituted cycloalkyl of from 3 to 8 atoms, where one or more carbons are replaced by S,N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C1-6 alkoxy C1-10 alkyl, C1-6 alkylthio-C1-10 alkyl, C1-6 hydroxy-C1-6 alkyl, C1-6 carbonyl-C1-6 alkyl, C1-6 -amino-C1-6 alkyl; R5 is selected from the group consisting of; (a) hydrogen; (b) lower alkyl, lower alkenyl, lower alkyny, alkaryl; (c) --AN(OM)C(O)N(R3)R4, --AN(R3)C(O)N(OM)R4, --AC(O)N(OM)R4, --AS(O)n R3, --AS(O)n CH2 C(O)R3, --AS(O)n CH2 CH(OH)R3, --AC(O)NHR3; wherein each n is independently 0, 1 or 2;
A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, lower alkenyl, lower alkynyl, alkaryl or aralkyl;
M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group in a pharmaceutically acceptable carrier. - View Dependent Claims (6, 7)
- ##STR21## or pharmaceutically acceptable salts, wherein;
Specification
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Current AssigneeMillennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
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Original AssigneeCytoMed, Inc. (Takeda Pharmaceutical Company Limited)
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InventorsBiftu, Tesfaye, Cai, Xiong, Grewal, Gurmit, Hussoin, Sajjat, Shen, T. Y.
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Primary Examiner(s)Weddington, Kevin E.
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Application NumberUS08/466,332Time in Patent Office1,050 DaysField of Search514/438, 514/461, 514/825, 514/826, 514/863, 514/912, 514/914, 514/921, 514/925US Class Current514/438CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 11/00 Drugs for disorders of the ...A61P 17/00 Drugs for dermatological di...A61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...A61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/08 Vasodilators for multiple i...A61P 9/10 for treating ischaemic or a...C07D 207/09 Radicals substituted by nit...C07D 307/12 Radicals substituted by oxy...C07D 307/14 Radicals substituted by nit...C07D 333/16 by oxygen atomsC07D 333/18 by sulfur atomsC07D 333/20 by nitrogen atoms nitro, ni...C07D 405/04 directly linked by a ring-m...C07D 405/12 linked by a chain containin...C07D 407/12 linked by a chain containin...View All
