Chemical compounds

• US 7,709,500 B2
• Filed: 02/17/2003
• Issued: 05/04/2010
• Est. Priority Date: 02/18/2002
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Purdie, Mark, Springthorpe, Brian, Furber, Mark, Alcaraz, Lilian
• Primary Examiner(s): Chang; Celia
• Application Number:
  US10/504,936
• Publication Number:
  US 20050107428A1
• Time in Patent Office: 2,633 Days
• Field of Search: 514/249, 514/269, 514/307, 514/318, 514/323, 514/326, 544/315, 544/353, 546/141, 546/193, 546/201, 546/210
• US Class Current: 514/318
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/00 Drugs for disorders of the respiratory system
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 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 31/08 for leprosy
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/46 : having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/52 : having an aryl radical as the second substituent in position 4
• 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 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 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The invention provides compounds of formula (I):

wherein: X is CH₂, O, S(O)₂ or NR¹⁰; Y is a bond, CH₂, NR³⁵, CH₂NH, CH₂NHC(O), CH(OH), CH(NHCOR³³), CH(NHSO₂R³⁴), CH₂O or CH₂S; Z is C(O), or when Y is a bond Z can also be S(O)₂; R¹ is optionally substituted aryl, optionally substituted heterocyclyl or C_4-6 cycloalkyl fused to a benzene ring; and R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸, R⁹, R¹⁰, R³², R³³, R³⁴ and R³⁵ are as defined herein; are modulators of chemokine (especially CCR3) activity (for use in, for example, treating asthma). The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.

Claims

1. A compound of formula (I):

2. A compound as claimed in claim 1, wherein R³² is hydrogen.

3. A compound as claimed in claim 1 wherein R², R³, R⁴, R⁵, and R⁶ are all hydrogen.

4. A compound as claimed in claim 1 wherein R⁹ is optionally substituted heterocyclyl;

wherein the heterocyclyl group is;

thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl, 1,6-dihydropyridinyl, pyrimidinyl, indolyl, indazolyl, 2,3-dihydro-1H-indazolyl, an imidazopyridinyl, 2,1,3-benzothiadiazolyl, quinoxalinyl, quinolinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinoline, isoquinolinyl, 1,2-dihydroisoquinolinyl, cinnolinyl, 3,4-dihydrophthalazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 1,3-dihydro-2H-isoindolyl, pyrazolotriazinyl, pyrazolopyrimidinyl, imidazobenzothiazolyl, imidazopyrimidinyl, or 2,1,3-benzoxadiazolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, 4,5,6,7-tetrahydroindazole or 2,3-dihydro-1H-benzimidazole;

wherein the heterocyclyl is unsubstituted or substituted by one or more of;

oxo (where possible), halogen, C_1-4 alkyl, CF₃, C_1-4 alkoxy, S(O)₂(C_1-4 alkyl), S(O)₂NH₂, S(O)₂NH(C_1-4 alkyl), S(O)₂N(C_1-4 alkyl)₂ or OCF₃.

5. A process for preparing a compound as claimed in claim 1, the process comprising reacting a compound of formula (II):

6. A composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, and a pharmaceutically acceptable adjuvant, diluent or carrier thereof.

7. A method of treating obstructive disease of airways a in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, salt thereof, as claimed in claim 1.

8. A method according to claim 7, wherein the obstructive disease of airways is selected from the group consisting of chronic obstructive pulmonary disease (COPD);

asthma;

bronchitis;

acute, allergic, atrophic, or chronic rhinitis;

membranous rhinitis;

seasonal rhinitis;

sarcoidosis;

farmer'"'"'s lung and related diseases;

nasal polyposis;

fibroid lung;

idiopathic interstitial pneumonia;

antitussive activity;

chronic cough associated with inflammatory conditions of the airways; and

iatrogrenic induced cough.

9. A method according to claim 8, wherein the acute, allergic, atrophic, or chronic rhinitis is rhinitis caseoa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa.

10. A method according to claim 8, wherein the membranous rhinitis is croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis.

11. A method according to claim 8, wherein the seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis.

12. A method according to claim 7, wherein the obstructive disease of airways is asthma.

13. A method according to claim 7, wherein the obstructive disease of airways is rhinitis.

14. A method of treating a disease or condition selected from psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia greata, and vernal conjunctivitis a in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1.