Benzene compound and pharmaceutical use thereof

• US 6,372,800 B1
• Filed: 10/19/2000
• Issued: 04/16/2002
• Est. Priority Date: 08/22/1994
• Status: Expired due to Term

• Current Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Original Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Inventors: Kiuchi, Masatoshi, Kohara, Toshiyuki, Mishina, Tadashi, Adachi, Kunitomo, Teshima, Koji, Chiba, Kenji, Fujita, Tetsuro
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/691,099
• Time in Patent Office: 544 Days
• Field of Search: 564/355, 564/223, 514/546, 514/630, 560/163
• US Class Current: 514/653
• CPC Class Codes: C07C 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 215/30 containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 215/56 with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
• CPC Class Codes: C07C 217/64 with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 217/72 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 219/22 and containing six-membered aromatic rings
• CPC Class Codes: C07C 225/16 and containing six-membered aromatic rings
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/31 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/73 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms

Abstract

A benzene compound of the formula

wherein each symbol is as defined in the specification; an optically active isomer or salt thereof, a medicinal composition containing the same, and an immunosuppressant containing the same as the active ingredient.

The compound, optically active isomer or salt has an excellent immunosuppressive effect and is useful as an inhibitor for the rejection reaction occurring in organ or bone marrow transplantation, and as a preventive or remedy for articular rheumatism, atopic eczema (dermatitis), Behcet'"'"'s disease, uveal disease, systemic lupus erythematosus, Sjögren'"'"'s syndrome, multiple sclerosis, myasthenia gravis, type I diabetes, endocrine ophthalmopathy, primary biliary, cirrhosis, Crohn'"'"'s disease, glomerulonephritis, sarcoidosis, psoriasis, pemphigus, aplastic anemia, idiopathic thrombocytopenic purpura, allergy, polyarteritis nodosa, progressive systemic sclerosis, mixed connective-tissue disease, aortitis syndrome, polymyositis, dermatomyositis, Wegener'"'"'s granuloma, ulcerative colitis, active chronic hepatitis, autoimmune hemolytic anemia, Evans'"'"' syndrome, bronchial asthma and pollinosis. It is useful also as an antifingal agent and hair growth stimulant.

Claims

1. A benzene compound of the formula

wherein,

W is a phenyl which may be substituted by hydroxy;

X is a straight-chain alkyl having carbon atoms in the number of p or a straight-chain alkoxy having carbon atoms in the number of (p−

1), wherein the straight-chain alkyl having carbon atoms in the number of p and the straight-chain alkoxy having carbon atoms in the number of (p−

1) may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyloxy, amino, an alkylamino, an acylamino, oxo, a haloalkyl, a halogen and a phenyl which may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyl, an acyloxy, amino, an alkylamino, an acylamino, a haloalkyl and a halogen;

Y is hydrogen, an alkyl, hydroxy, an alkoxy, an acyl, an acyloxy, amino, an alkylamino, an acylamino, a haloalkyl or a halogen;

Z is a straight-chain alkylene having carbon atoms in the number of q;

p and q are the same or different and each is an integer of 1 to 20, with the proviso of 6≦

p+q≦

23;

m is 1, 2 or 3;

n is 2 or 3;

R¹ and R² are the same or different and each is hydrogen, an alkyl or an acyl;

R³ is hydrogen, an alkyl or an acyl; and

R⁴ is hydrogen, an alkyl or an acyl,

an optically active isomer thereof or a salt thereof.

2. A benzene compound according to claim 1 of the formula

wherein

X¹ is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;

Y¹ is hydrogen, an alkyl, hydroxy or an alkoxy;

Z¹ is a straight-chain alkylene having 2 to 4 carbon atoms;

R¹ and R² are the same or different and each is hydrogen, an alkyl or an acyl;

R³ is hydrogen, an alkyl or an acyl; and

R⁵ is hydrogen or hydroxy,

an optically active isomer thereof or a salt thereof.

3. The benzene compound of claim 2, having the formula

wherein X² is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;

Z¹ is a straight-chain alkylene having 2 to 4 carbon atoms;

R¹ and R² are the same or different and each is hydrogen, an alkyl or an acyl;

R³ is hydrogen, an alkyl or an acyl; and

R⁵ is hydrogen or hydroxy;

an optically active isomer thereof or a salt thereof.

4. The benzene compound of claim 3, having the formula

wherein X² is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;

Z¹ is a straight-chain alkylene having 2 to 4 carbon atoms; and

R⁵ is hydrogen or hydroxy,

an optically active isomer thereof or a salt thereof.

5. A pharmaceutical composition comprising the compound claimed in claim 1.

6. A method for immunosuppression of an immune system of a mammal comprising administering to a mammal a therapeutically effective amount of a benzene compound of claim 1.

7. The method according to claim 6, wherein the immunosuppression comprises suppressing rejection in an organ or bone marrow transplantation.

8. The method according to claim 7, wherein the suppressing of rejection in an organ or bone marrow transplantation comprises preventing treatment of graft-versus-host diseases.

9. A method for the prevention or treatment of an autoimmune disease comprising administering to a mammal a therapeutically effective amount of a benzene compound of claim 1.

10. The method according to claim 9, wherein the autoimmune disease is rheumatoid arthritis.

11. The method according to claim 9, wherein the autoimmune disease is psoriasis or atopic dermatitis.

12. The method according to claim 9, wherein the autoimmune disease is bronchial asthma or pollinosis.

13. The method according to claim 9, wherein the autoimmune disease is Behcet'"'"'s disease or uveitis.

14. The method according to claim 9, wherein the autoimmune disease is systemic lupus erythematosus.

15. The method according to claim 9, wherein the autoimmune disease is multiple sclerosis.

16. A method for the prevention or treatment of an allergy disease comprising administering to a mammal a therapeutically effective amount of a benzene compound of claim 1.