CCR9 inhibitors and methods of use thereof

• US 20040038976A1
• Filed: 05/21/2003
• Published: 02/26/2004
• Est. Priority Date: 05/24/2002
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Shi, Zhan, Harriman, Geraldine C.B., Chen, Shaowu, Fleming, Paul
• Granted Patent: US 7,238,717 B2
• Time in Patent Office: Days
• US Class Current: 514/247
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 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 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07C 311/21 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/44 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/34 : having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
• CPC Class Codes: C07C 323/49 : to sulfur atoms
• CPC Class Codes: C07D 213/46 : Oxygen atoms
• CPC Class Codes: C07D 213/50 : Ketonic radicals
• CPC Class Codes: C07D 213/65 : attached in position 3 or 5
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 213/71 : to which a second hetero atom is attached
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 237/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/62 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The invention relates to compounds represented by Structural Formula I, which can bind to CCR9 receptors and block the binding of a ligand (e.g., TECK) to the receptors. The invention also relates to a method of inhibiting a function of CCR9, and to the use compounds represented by Structural Formula I in research, therapeutic, prophylactic and diagnostic methods.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1, wherein Ar₂ is phenyl, naphthyl, thienyl, or thianaphthenyl, each group being substituted or unsubstituted.

3. The compound of claim 1, wherein Ar₁ is phenyl, pyridyl, pyrimidinyl, or pyrazinyl, each group being substituted or unsubstituted.

4. The compound of claim 1, which is represented by the following structural formula:

5. The compound of claim 1, which is represented by the following structural formula:

6. The compound of claim 1 which is represented by the following structural formula:

7. The compound of claim 1 wherein the compound is represented by the following structural formula:

9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the compound of claim 1.

8. A compound selected from the group consisting of:

10. A method of inhibiting a CCR9 receptor function in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound represented by the following structural formula:

11. The method of claim 10, wherein the compound is represented by a structural formula selected from the group consisting of A, B, C, and D:

12. The method of claim 10 wherein the subject is being treated for an inflammatory disease or condition.

13. A method of treating or preventing an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

14. The method of claim 13, wherein the compound is represented by a structural formula selected from the group consisting of A, B, C, and D:

15. The method of claim 13, wherein the compound is selected from the group consisting of:

16. The method of claim 13, wherein the inflammatory disease or condition is Crohn'"'"'s disease or colitis.

17. The method of claim 13, wherein the inflammatory disease or condition is Celiac'"'"'s disease.

18. The method of claim 13, wherein the compound inhibits the binding of a ligand to CCR9.

19. The method of claim 18, wherein the ligand is TECK.

20. A method of inhibiting CCR9-mediated homing of leukocytes in a subject in need of such treatment comprising administering to the subject an effective amount of at least one compound represented by the following structural formula:

21. The method of claim 20, wherein the compound is represented by a structural formula selected from the group consisting of A, B, C, and D:

22. A method of inhibiting homing of leukocytes to mucosal tissue in a subject in need of such treatment, comprising adiministering to the subject an effective amount of at least one compound represented by the following structural formula: