Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient

• US 20060178399A1
• Filed: 03/12/2004
• Published: 08/10/2006
• Est. Priority Date: 03/14/2003
• Status: Active Grant

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Shibayama, Shiro, Takaoka, Yoshikazu, Nishizawa, Rena
• Granted Patent: US 7,910,741 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 211/22 : by oxygen atoms
• CPC Class Codes: C07D 211/32 : by oxygen atoms
• CPC Class Codes: C07D 211/34 : with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/48 : having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 211/66 : having a hetero atom as the second substituent in position 4
• CPC Class Codes: C07D 211/72 : with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/74 : Oxygen atoms
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/108 : to an acyclic saturated chain
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/08 : linked by a carbon chain containing alicyclic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : 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
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

A compound represented by the following general formula (I), its salt, solvates thereof or prodrugs thereof: (wherein each symbol is as defined in the description.) The compounds represented by the general formula (I) are useful in preventing and/or treating various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis, etc.), immunological diseases (autoimmune diseases, rejection in organ transplantation, immunosuppression, psoriasis, multiple sclerosis, etc.), infection with human immunodeficiency virus (acquired immunodeficiency syndrome, etc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchoplumonary aspergillosis, allergic eosinophilic gastroenteritis, etc.), ischemic reperfusion injury, acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes, cancer metastasis and so on.

Claims

1. A compound represented by formula (I):

2. The compound according to claim 1, wherein R¹ is an acidic group which may be protected.

3. The compound according to claim 2, wherein the acidic group is carboxy or sulfonamide.

4. The compound according to claim 1, wherein X and Y are each independently a bond or a divalent group selected from (1)—

CR⁷R⁸—

, (2)—

NR⁹—

, (3)—

CO—

, (4)—

O—

, (5)—

S—

, (6)—

SO—

, (7)—

SO₂— and

(8)—

C(═

N—

OR¹⁰)—

, wherein R⁷ and R⁸ each independently represents a hydrogen atom, C1-4 alkyl, —

OR¹¹ or phenyl;

R⁹ represents a hydrogen atom C1-4 alkyl, or phenyl;

R¹⁰ and R¹¹ each independently represents a hydrogen atom or C1-4 alkyl.

5. The compound according to claim 4, wherein X is a bond, —

O—

or —

CH₂—

.

6. The compound according to claim 1, wherein Y is C1-3 alkylene.

7. The compound according to claim 1, wherein ring D is a 5- to 10-membered nitrogen-containing heterocyclic group which may have a substituent(s).

8. The compound according to claim 1, wherein ring A and ring B, which are the same or different, are each a 5- to 10-membered homocyclic group or heterocyclic group which may have a substituent(s).

9. The compound according to claim 1, wherein ring A and ring B, which are the same or different, are each a 5- or 6-membered aromatic ring which may have a substituent(s).

10. The compound according to claim 1, wherein R² is

11. The compound according to claim 1, which is represented by formula (Ia):

12. The compound according to claim 1, which is selected from the group consisting of

(1) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,

(2) N-[4-(4-{[4-(butyl{[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,

(3) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1-yl]methyl}-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]methanesulfonamide,

(4) N-[4-(4-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]methanesulfonamide,

(5) 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yl]amino}carbonyl)amino]benzamide,

(6) N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}methanesulfonamide,

(7) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yl]amino}carbonyl)amino]-2-fluorobenzamide,

(8) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yl]amino}carbonyl)amino]-2,4-difluorobenzamide,

(9) N-[4-(4-{[4-(butyl{[(3-cyano-4-fluorophenyl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]methanesulfonamide,

(10) N-[4-(4-{[4-(butyl{[(3-hydroxycyclohexyl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]methanesulfonamide, and

(11) N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(1,3-thiazol-4-ylmethyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}methanesulfonamide.

13. The compound according to claim 1, which is useful as a CCR5 regulator.

14. The compound according to claim 13, wherein the CCR5 regulator is a CCR5 antagonist.

15. The compound according to claim 13, which is useful as an agent for treatment and/or prevention for a disease through the intervention of CCR5.

16. The compound according to claim 15, wherein the disease through the intervention of CCR5 is infection with human immunodeficiency virus.

17. The compound according to claim 16, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome.

18. The compound according to claim 15, wherein the disease through the intervention of CCR5 is immunological diseases.

19. The compound according to claim 18, wherein the immunological disease is rejection in organ transplantation.

20. The compound according to claim 15, wherein the disease through the intervention of CCR5 is inflammatory diseases.

21. The compound according to claim 20, wherein the inflammatory disease is asthma.

23. A pharmaceutical composition, which comprises the compound represented by formula (I) according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.

24. A medicament which comprises the compound represented by formula (I) according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof, in combination with one or at least two of a reverse transferase inhibitor, a protease inhibitor, a CCR2 antagonist, a CCR3 antagonist, a CCR4 antagonist, a CCR5 antagonist, a CXCR4 antagonist, a fusion inhibitor, an antibody against a surface antigen of HIV-1, and a vaccine of HIV-1.

22. (canceled)

25. A method for treating or preventing a disease through the intervention of CCR5 in a mammal, which comprises administering to a mammal an effective amount of a compound represented by formula (I):

27. The method according to claim 25, wherein the disease through the intervention of CCR5 is infection with human immunodeficiency virus, immunological diseases or inflammatory diseases.

28. The method according to claim 27, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome.

29. The method according to claim 27, wherein the immunological disease is rejection in organ transplantation.

30. The method according to claim 27, wherein the inflammatory disease is asthma.

26. (canceled)