Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)

• US 7,482,372 B2
• Filed: 03/30/2005
• Issued: 01/27/2009
• Est. Priority Date: 05/25/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Duan, Jingwu, Sheppeck, James E., Wasserman, Zelda, Xue, Chu-Biao
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Ward; Paul V.
• Application Number:
  US11/093,670
• Publication Number:
  US 20050171096A1
• Time in Patent Office: 1,399 Days
• Field of Search: 514/183, 514/311, 514/385, 514/396, 514/399, 514/409, 514/412, 514/422, 514/425, 514/393, 548/300.1, 548/300.7, 548/407, 548/408, 548/409, 546/112, 546/134, 546/16
• US Class Current: 514/393
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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 233/76 : with substituted hydrocarbon radicals attached to the third ring carbon atom
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• 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 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present application describes novel hydantoin derivatives of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, and n are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), aggrecanase, or a combination thereof.

Claims

1. A compound is of the following formulae:

2. A compound according to claim 1, wherein;

Z is phenyl substituted with 0-1 R^b;

Z^a is selected from;

phenyl substituted with 0-3 R^c, naphthyl substituted with 0-3 R^c; and

a heterocycle substituted with 0-3 R^c and selected from the group;

pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, pyrazolyl, and pyrazolo[1,5-a]pyridinyl;

R^b, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a3, S(O)_pR^a3, and CF₃;

R^c, at each occurrence, is independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, OR^a, Cl, F, Br, ═

O, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR_aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, and (CR^aR^a1)_rNR^aSO₂R^a3;

alternatively, when two R^c groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered carbocyclic or heterocyclic ring consisting of;

carbon atoms and 0-1 heteroatoms selected from the group consisting of N, O, and S(O)_p; and

R^e, at each occurrence, is independently selected from H, C_1-6 alkyl, C_1-6 alkoxy, phenoxy, benzoxy, phenyl substituted with 0-1 R^c1, and a 5-6 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0-1 R^c1.

3. A compound according to claim 1, wherein the compound is selected from the group:

(cis,trans)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4-dioxo-1,3-diazaspiro[4.5]decane-6-carboxamide;

(cis,trans)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-carboxamide;

(cis,trans)-2-(2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamide;

(cis,trans)-N-(2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

(cis,trans)-N-(2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl)-2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamide;

(cis,trans)-N-(2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

(trans)-N-[(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide;

(trans)-N-[(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

(cis)-N-[(2,4-dioxo-1,3-diazaspiro[4.5 ]dec-6-yl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

(cis)-N-[(2,4-dioxo-1,3-diazaspiro[4.5 ]dec-6-yl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

6({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione;

6({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-1,3-diazaspiro[4.5]decanane-2,4-dione;

2-(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamide;

6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-1,3-diazaspiro[4.4]nonane-2,4-dione;

N-(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)benzamide; and

(cis,trans)-N-(2,4-dioxo-1,3-diazaspiro[4.5]dec-6-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

or a pharmaceutically acceptable salt form thereof.

4. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt form thereof.

5. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt form thereof.

6. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt form thereof.