Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
First Claim
Patent Images
1. A method for the treatment of inflammatory bowel disease, comprising administering to a host suffering from or susceptible to inflammatory bowel disease a compound of the following formula:
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wherein Ar is aryl or heteroaryl group this is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R3;
m is 0 or 1;
n is 1-6;
W is independently —
AN(OM)C(O)N(R3)R4, —
N(OM)C(O)N(R3)R4, —
AN(R3)C(O)N(OM)R4, —
C(O)N(OM)R4, —
C(O)NHA;
A is lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkynylene, alkylaryl, arylalkyl, alkylarylene, or arylalkylene wherein one or more carbons optionally can be replaced by O, N or S (with valence completed with hydrogen or oxygen as necessary), provided that —
Y—
A—
, —
A—
, or —
AW—
do not include two adjacent heteroatoms;
M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
X is O, S, S(O), S(O)2, NR3, or CHR5;
Y is O, S, S(O), S(O)2, NR3, or CHR5;
Z is O, S, S(O), S(O)2, or NR3;
R1 and R2 are independently hydrogen, lower alkyl, C3-8 cycloalkyl, halo lower alkyl, halo or —
COOH;
R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C1-6alkoxy-C1-10alkyl, C1-6alkylthio-C1-10alkyl, heteroaryl, or heteroarylalkyl; and
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, —
AN(OM)C(O)N(R3)R4, —
AN(R3)C(O)N(OM)R4, —
AN(OM)C(O)R4, —
AC(O)N(OM)R4, —
AS(O)xR3, —
AS(O)xCH2C(O)R3, —
AS(O)xCH2CH(OH)R3, or —
AC(O)NHR3, wherein x is 0-2.
2 Assignments
0 Petitions
Accused Products
Abstract
Tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and 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. It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.
52 Citations
21 Claims
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1. A method for the treatment of inflammatory bowel disease, comprising administering to a host suffering from or susceptible to inflammatory bowel disease a compound of the following formula:
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wherein Ar is aryl or heteroaryl group this is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R3; m is 0 or 1;
n is 1-6;
W is independently —
AN(OM)C(O)N(R3)R4, —
N(OM)C(O)N(R3)R4, —
AN(R3)C(O)N(OM)R4, —
C(O)N(OM)R4, —
C(O)NHA;
A is lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkynylene, alkylaryl, arylalkyl, alkylarylene, or arylalkylene wherein one or more carbons optionally can be replaced by O, N or S (with valence completed with hydrogen or oxygen as necessary), provided that —
Y—
A—
, —
A—
, or —
AW—
do not include two adjacent heteroatoms;
M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
X is O, S, S(O), S(O)2, NR3, or CHR5;
Y is O, S, S(O), S(O)2, NR3, or CHR5;
Z is O, S, S(O), S(O)2, or NR3;
R1 and R2 are independently hydrogen, lower alkyl, C3-8 cycloalkyl, halo lower alkyl, halo or —
COOH;
R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C1-6alkoxy-C1-10alkyl, C1-6alkylthio-C1-10alkyl, heteroaryl, or heteroarylalkyl; and
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, —
AN(OM)C(O)N(R3)R4, —
AN(R3)C(O)N(OM)R4, —
AN(OM)C(O)R4, —
AC(O)N(OM)R4, —
AS(O)xR3, —
AS(O)xCH2C(O)R3, —
AS(O)xCH2CH(OH)R3, or —
AC(O)NHR3, wherein x is 0-2.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butyl)tetrahydrofuran;
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrofuran;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butyl)tetrahydrofuran;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrofuran;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-butyl-N′
-hydroxyureidyl-1-butyl)tetrahydrofuran;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-butyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrofuran;
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butyl)tetrahydrothiophene;
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrothiophene;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butyl)tetrahydrothiophene;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-methyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrothiophene;
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-butyl-N′
-hydroxyureidyl-1-butyl)tetrahydrothiophene; and
trans-2-(4-fluorophenoxymethyl)-5-(4-N′
-butyl-N′
-hydroxyureidyl-1-butynyl)tetrahydrothiophene; and
pharmaceutically acceptable salts thereof.
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15. The method of claim 1 wherein the host is suffering from or susceptible to Crohn'"'"'s disease.
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16. The method of claim 13 wherein the host is suffering from or susceptible to Crohn'"'"'s disease.
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17. The method of claim 1 wherein the host is a mammal, an equine, a canine or a bovine.
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18. The method of claim 1 wherein the host is a human.
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19. The method of claim 13 wherein the host is a mammal, an equine, a canine or a bovine.
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20. The method of claim 13 wherein the host is a mammal, an equine, a canine, a bovine or a human.
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21. A method for the treatment of inflammatory bowel disease, comprising administering to a host suffering from or susceptible to inflammatory bowel disease a compound of the following formula:
-
wherein Ar is aryl or heteroaryl group this is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R3; m is 0 or 1;
n is 1-6;
W is independently —
N(R3)C(O)N(OM)R4, —
AN(OM)C(O)R4, —
N(OM)C(O)R4, —
AC(O)N(OM)R4;
A is lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkynylene, alkylaryl, arylalkyl, alkylarylene, or arylalkylene wherein one or more carbons optionally can be replaced by O, N or S (with valence completed with hydrogen or oxygen as necessary), provided that —
Y—
A—
, —
A—
, or —
AW—
do not include two adjacent heteroatoms,M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
X is O, S, S(O), S(O)2, NR3, or CHR5;
Y is O, S, S(O), S(O)2, NR3, or CHR5;
Z is O, S, S(O), S(O)2, or NR3;
R1 and R2 are independently hydrogen, lower alkyl, C3-8 cycloalkyl, halo lower alkyl, halo or —
COOH;
R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C1-6alkoxy-C1-10alkyl, C1-6alkylthio-C1-10alkyl, heteroaryl, or heteroarylalkyl; and
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, —
AN(OM)C(O)N(R3)R4, —
AN(R3)C(O)N(OM)R4, —
AN(OM)C(O)R4, —
AC(O)N(OM)R4, —
AS(O)xR3, —
AS(O)xCH2C(O)R3, —
AS(O)xCH2CH(OH)R3, or —
AC(O)NHR3, wherein x is 0-2.
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Specification
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Current AssigneeLeukoSite, Inc. (Takeda Pharmaceutical Company Limited)
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Original AssigneeMillennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
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InventorsCai, Xiong, Qian, Changgeng, Fura, Aberra
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Primary Examiner(s)Criares, Theodore J.
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Application NumberUS09/392,054Time in Patent Office1,357 DaysField of Search514/473, 514/598, 514/472, 514/447, 514/445, 514/446, 514/448, 514/617, 514/645, 514/525US Class Current514/473CPC Class CodesC07D 307/14 Radicals substituted by nit...C07D 471/04 Ortho-condensed systems
