Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

• US 6,420,392 B1
• Filed: 10/09/1996
• Issued: 07/16/2002
• Est. Priority Date: 01/06/1994
• Status: Expired due to Fees

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Biftu, Tesfaye, Grewal, Gurmit, Shen, T Y, Cai, Xiong, Hussoin, Sajjat
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US08/669,371
• Time in Patent Office: 2,106 Days
• Field of Search: 514/336, 514/438, 514/471, 514/473, 546/283, 546/284, 549/483, 549/484, 549/488, 549/491, 549/496, 549/497, 549/498, 549/499, 549/500, 549/501, 549/502
• US Class Current: 514/336
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 307/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/16 by oxygen atoms
• CPC Class Codes: C07D 333/18 by sulfur atoms
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

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.

Claims

1. A compound having the following structure:

wherein;

Ar¹ is either

Ar² is

and wherein;

W is methyl sulfonyl;

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 alkynyl, alkylaryl;

(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, —

AN(R³)C(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 alkyl-heteroaromatic-lower alkyl, lower alkenyl, lower alkynyl, 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 hydrogen, lower alkyl, C_3-8 cycloalkyl, halo lower alkyl, 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 carbon atoms, where one or more carbons are replaced by S, N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C_1-6alkoxy-C_1-10alkyl, C_1-6alkylthio-C_1-10alkyl, C_1-6hydroxy-C_1-6alkyl, C_1-6carbonyl-C_1-6alkyl, C_1-6amino-C_1-6alkyl;

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(R)C(O)N(OM)R⁴, —

AN(OM)C(O)R⁴, —

AC(O)N(OM)R⁴, —

AS(O)_nR³, —

AS(O)_nCH₂C(O)R³, —

AS(O)_nCH₂CH(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 and aralkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group.

7. A pharmaceutical composition comprising a pharmaceutically active carrier and a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5 or 6.

8. A method for the treatment of a disorder mediated by platelet activating factor or products of 5-lipoxygenase 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 claim 1, 2, 3, 4, 5 or 6.

9. The method of claim 8, wherein the animal is a mammal selected from the group consisting of human, equine, canine and bovine.

10. The method of claim 8, wherein the disorders mediated by platelet activating factor or products of 5-lipoxygenase are selected from the group consisting of arthritis, acute inflammation, asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, gastrointestinal ulceration, myocardial infarction, inflammatory bowel diseases, and acute respiratory distress syndrome.

11. A method for the treatment of a disorder that is arthritis, acute inflammation, asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, gastrointestinal ulceration, myocardial infarction, an inflammatory bowel disease, or acute respiratory distress syndrome, comprising administering to an animal suffering from or susceptible such disorder an effective amount of a compound of claim 1, 2, 3, 4, 5 or 6.

2. A compound having the following structure:

wherein;

Ar¹ is either

Ar² is

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, —

C(O)N(OM)R⁴, —

S(O)_nR³, —

S(O)₄CH₂C(O)A, —

S(O)₄CH₂CH(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 alkynyl, alkylaryl;

(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, —

AN(R³)C(O)N(OM)R⁴, —

C(O)N(OM)R⁴, and —

C(O)NHR³;

wherein A is -lower alkyl-furan-lower alkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group;

R¹ and R² are independently selected from hydrogen, lower alkyl, C_3-8cycloalkyl, halo lower alkyl, 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 carbon atoms, where one or more carbons are replaced by S, N, or O alkenyl, alkynyl, aryl, aralkyl, alkaryl, C_1-6alkoxy-C_1-10alkyl, C_1-6alkylthio-C_1-10alkyl, C_1-6hydroxy-C_1-6alkyl, C_1-6carbonyl-C_1-6alkyl, C_1-6amino-C_1-6alkyl;

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, —

AN(OM)C(O)R⁴, —

AC(O)N(OM)R⁴, —

AS(O)_nR³—

AS(O)_nCH₂C(O)R³, —

AS(O)_nCH₂CH(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 and aralkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group.

3. A compound having the following structure:

wherein;

Ar¹ is either

Ar² is

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, —

C(O)N(OM)R⁴, —

S(O)_nR³, —

S(O)₄CH₂C(O)A, —

S(O)₄CH₂CH(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 alkynyl, alkylaryl;

(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, —

AN(R³)C(O)N(OM)R⁴, —

C(O)N(OM)R⁴, and —

C(O)NHR³;

wherein A is -lower alkyl-pyridine-lower alkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group;

R¹ and R² are independently selected from hydrogen, lower alkyl, C_3-8 cycloalkyl, halo lower alkyl, 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 carbon atoms, where one or more carbons are replaced by S, N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C_1-6alkoxy-C_1-10alkyl, C_1-6alkylthio-C_1-10alkyl, C_1-6hydroxy-C_1-6alkyl, C_1-6carbonyl-C_1-6alkyl, C_1-6amino-C_1-6alkyl;

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, —

AN(OM)C(O)R⁴, —

AC(O)N(OM)R⁴, —

AS(O)_nR³, —

AS(O)_nCH₂C(O)R³, —

AS(O)_nCH₂CH(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 and aralkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group.

4. A compound having the following structure:

wherein;

Ar¹ is either

Ar² is

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, —

C(O)N(OM)R⁴, —

S(O)_nR³, —

S(O)₄CH₂C(O)A, —

S(O)₄CH₂CH(OH)A, and —

C(O)NHA,

Y¹ is independently selected from the group consisting of;

(a) hydrogen;

(b) lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, alkylaryl;

(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, —

AN(R³)C(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 alkyl-heteroaromatic-lower alkyl, lower alkenyl, lower alkynyl, alkaryl or aralkyl;

M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group;

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 carbon atoms, where one or more carbons are replaced by S, N, or O, alkenyl, alkynyl, aryl, aralkyl, alkaryl, C_1-6alkoxy-C_1-10alkyl, C_1-6alkylthio-C_1-10alkyl, C_1-6hydroxy-C_1-6alkyl, C_1-6carbonyl-C_1-6alkyl, C_1-6amino-C_1-6alkyl;

wherein each n is independently 0, 1 or 2.

5. The compound of claim 4 having the structure:

6. The compound of claim 4 having the structure: