N-4-piperidinyl compounds as ccr5 modulators

• US 20060167048A1
• Filed: 08/19/2003
• Published: 07/27/2006
• Est. Priority Date: 08/21/2002
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Winter, Jon, Cumming, John
• Application Number:
  US10/525,121
• Publication Number:
  US 20060167048A1
• Time in Patent Office: Days
• US Class Current: 514/316
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/12 Antidiarrhoeals
• 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 11/08 Bronchodilators
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 25/28 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 27/02 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 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/18 : for HIV
• 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 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• 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 211/58 : attached in position 4
• CPC Class Codes: C07D 211/62 : attached in position 4

Abstract

The invention provides a compound of formula (I): [Chemical formula should be inserted here. Please see paper copy.] wherein R₁, R₂, R₃, R_3a, R₄, R_4a, R₅, and R₆ are as defined; or a pharmaceutically acceptable salt thereof or a solvate thereof; compositions containing these compounds, processes for preparing them and their use as modulators of chemokine activity (especially CCR5 activity).

Claims

1. A compound of formula (I):

wherein;

R¹ is C_1-6 alkoxy;

optionally substituted by C_1-4 alkoxy or phenyl;

C_3-6 alkenyloxy, phenoxy or piperidin-4-yl;

1-substituted by C(O)R⁷ or S(O)₂R⁸;

R² is optionally substituted phenyl, optionally substituted heteroaryl or cycloalkyl;

R^2a, R⁴ and R^4a are, independently, hydrogen or C_1-4 alkyl;

R³ and R^3a are, independently, hydrogen or C_1-4 alkyl or C_1-4 alkoxy;

R⁵ is hydrogen, C_1-4 alkyl optionally substituted by halogen, hydroxy, C_1-4 alkoxy, C_3-7 cycloalkyl, SH, C_1-4 alkylthio, cyano or S(O)_q(C_1-4 alkyl);

C_3-4 alkenyl, C_3-4 alkynyl or C_3-7 cycloalkyl;

R⁶ is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C_1-2)alkyl, heteroaryl(C_1-2)alkyl, phenyl(C_1-2 alkyl)NH or heteroaryl(C_1-2 alkyl)NH;

R⁷ is C_1-6 alkyl;

optionally substituted by phenyl, heteroaryl, C_1-4 alkoxy, or C_1-4 alkoxy(C_1-4 alkoxy);

C_1-6 alkoxy, phenyl, heteroaryl or C_3-6 cycloalkyl;

R⁸ is C_1-6 alkyl;

optionally substituted by phenyl;

or phenyl;

wherein the phenyl and heteroaryl rings of any of the foregoing are independently optionally substituted by halo, cyano, nitro, hydroxy, C_1-4 alkyl, C_1-4 alkoxy, S(O)_mC_1-4 alkyl, S(O)₂NR⁹R¹⁰, NHS(O)₂(C_1-4 alkyl), NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, NHC(O)NH₂, C(O)NH₂, C(O)NH(C_1-4 alkyl), NHC(O)(C_1-4 alkyl), CO₂H, CO₂(C_1-4 alkyl), C(O)(C_1-4 alkyl), CF₃, CHF₂, CH₂F, CH₂CF₃ or OCF₃;

R⁹ and R¹⁰ are, independently, hydrogen or C_1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C_1-4 alkyl, C(O)H or C(O)(C_1-4 alkyl);

m, p and q are, independently, 0, 1 or 2;

or a pharmaceutically acceptable salt thereof or a solvate thereof.

2. A compound as claimed in claim 1 wherein R¹ is piperidin-4-yl 1-substituted by C(O)R⁷;

wherein R⁷ is C_1-6 alkyl;

optionally mono-substituted by phenyl;

C_1-6 alkoxy, phenyl or C_3-6 cycloalkyl, wherein the phenyl rings are optionally substituted by halogen;

or S(O)₂R⁸;

wherein R⁸ is phenyl or C_1-6 alkyl;

optionally mono-substituted by phenyl;

wherein the phenyl rings are optionally substituted by halogen, S(O)₂(C_1-4 alkyl) or NHC(O)(C_1-4 alkyl);

or R¹ is C_1-6 alkoxy;

optionally substituted by C_1-4 alkoxy or phenyl;

C_3-6 alkenyloxy or phenoxy;

optionally substituted by halogen.

3. A compound as claimed in claim 1 wherein R² is phenyl optionally substituted by halo, C_1-4 alkyl, C_1-4 alkoxy, S(O)_n(C_1-4 alkyl);

wherein n is 0, 1 or 2;

nitro, cyano or CF₃.

4. A compound as claimed in claim 1 wherein R^2a, R³, R^3a, R⁴ and R^4a are all hydrogen.

5. A compound as claimed in claim 1 wherein R⁵ is ethyl.

6. A compound as claimed in claim 1 wherein R⁶ is benzyl singly substituted by S(O)₂(C_1-4)alkyl or S(O)₂NR⁹R¹⁰;

wherein R⁹ and R¹⁰ are, independently, hydrogen or C_1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C_1-4 alkyl, C(O)H or C(O)(C_1-4 alkyl).

7. A process for preparing a compound of claim 1, formula (I) comprising:

a) treating a compound of formula (II);

 

with;

i. an acid chloride or chloroformate of formula R¹C(O)Cl, in the presence of a base and in a suitable solvent;

or

ii. when R¹ is a 1-substituted piperidin-4-yl, an acid of formula R¹CO₂H in the presence of a suitable coupling agent in a suitable solvent;

OR

b) reacting a compound of formula (VII);

i. with an acid chloride R⁷C(O)Cl or sulfonyl chloride R⁸S(O)₂Cl in the presence of a base and in a suitable solvent;

or

ii. with an acid of formula R⁷CO₂H in the presence of a suitable coupling agent in the presence of a suitable base in a suitable solvent.

8. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof as claimed in claim 1, and a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A method of treating a chemokine mediated disease state, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof as claimed in claim 1.

9-10. -10. (canceled)