Hydroxylamine derivatives

• US 5,453,439 A
• Filed: 02/08/1993
• Issued: 09/26/1995
• Est. Priority Date: 02/07/1992
• Status: Expired due to Fees

• Current Assignee: Syngenta Limited (China National Chemical Corporation)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC), Zeneca Pharma S.A. (Astrazeneca PLC)
• Inventors: Ple, Patrick
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): SCALZO, CATHERINE KILBY
• Application Number:
  US08/014,520
• Time in Patent Office: 960 Days
• Field of Search: 549/419, 549/417, 549/423, 514/459
• US Class Current: 514/459
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 309/10 Oxygen atoms

Abstract

The invention concerns hydroxylamine derivatives of the formula I ##STR1## wherein R⁴ is hydrogen, carbamoyl, (1-4C)alkyl, (2-5C)alkanoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, benzoyl or phenylsulphonyl;

R⁵ includes hydrogen, (1-4C)alkyl and (2-5C)alkanoyl;

R⁶ is hydrogen, (1-4C)alkyl, phenyl or phenyl-(1-4C)alkyl;

R⁷ is hydrogen or (1-4C)alkyl;

Ar¹ is phenylene;

A¹ is a direct link to X¹, or A¹ is (1-4C)alkylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

Ar² is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl;

R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which together with the carbon atom to which A² and A³ are attached define a ring having 5 or 6 ring atoms, wherein each of A² and A³ is independently (1-3C)alkylene and X² is oxy, thio, sulphinyl, sulphonyl or imino;

or a pharmaceutically-acceptable salt thereof;

processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Claims

1. A hydroxylamine derivative of the formula I

wherein

R⁴ is hydrogen, carbamoyl, (1-4C)alkyl, (2-5C)alkanoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C) alkylcarbamoyl, benzoyl or phenylsulphonyl and wherein the benzoyl or phenylsulphonyl group may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

R⁵ is hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, and (2-5C) alkanoyl;

R⁶ is hydrogen, (1-4C)alkyl, phenyl or phenyl-(1-4C)alkyl and wherein each phenyl group may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C) alkoxy;

R⁷ is hydrogen or (1-4C) alkyl;

Ar¹ is phenylene which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

wherein

A¹ is a direct link to X¹ ;

X¹ is thio, sulphinyl or sulphonyl;

Ar² is phenylene, which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxy;

R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which together with the carbon atom to which A² and A³ are attached define a ring having 6 ring atoms, wherein each of A² and A³ is independently (1-3C)alkylene and X² is oxy, and which ring may optionally bear one or two substituents selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

or a pharmaceutically-acceptable salt thereof.

2. The hydroxylamine derivative of the formula I as claimed in claim 1 selected from:

N-[4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α

-methylbenzyl}-O-methylhydroxylamine,

O-acetyl-N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-.alpha.-methylbenzyl}acetohydroxamic acid or

N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α

-methylbenzyl}-N-hydroxyurea;

or a pharmaceutically-acceptable salt thereof.

3. A pharmaceutical composition which comprises a hydroxylamine derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 and 2 in association with a pharmaceutically-acceptable diluent or carrier.

4. A method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of a hydroxylamine derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 and 2.

5. A pharmaceutical composition which comprises a hydroxylamine derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-4 in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.

6. A hydroxylamine derivative of the formula I as claimed in claim 1 wherein

R⁴ is hydrogen, carbamoyl, acetyl, propionyl, benzoyl or phenylsulphonyl and wherein said benzoyl or phenylsulphonyl group may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy;

R⁵ is hydrogen, methyl, ethyl, propyl, acetyl and propenyl;

R⁶ is hydrogen, methyl, ethyl or phenyl and wherein said phenyl group may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy;

R⁷ is hydrogen;

Ar¹ is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy;

Ar¹ is a direct link to X¹ and X¹ is thio;

Ar² is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which together with the carbon atoms to which A² and A³ are attached define a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may optionally bear one or two substituents selected from methyl and ethyl;

or a pharmaceutically-acceptable salt thereof.

7. A hydroxylamine derivative of the formula I as claimed in claim 1 wherein

R⁴ is hydrogen, carbamoyl, acetyl, benzoyl or phenylsulphonyl;

R⁵ is hydrogen, methyl, ethyl or acetyl;

R⁶ is hydrogen, methyl or ethyl;

R⁷ is hydrogen;

Ar¹ is 1,4-phenylene;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar² is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro and chloro;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which together with the carbon atom to which A2 and A3 are attached define a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may optionally bear one or two methyl substituents;

or a pharmaceutically-acceptable salt thereof.

8. A hydroxylamine derivative of the formula I as claimed in claim 1 wherein

R⁴ is hydrogen, carbamoyl, acetyl or phenylsulphonyl;

R⁵ is hydrogen or methyl;

R⁶ is methyl;

R⁷ is hydrogen;

Ar¹ is 1,4-phenylene;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar² is 1,3-phenylene or 5-fluoro-1,3-phenylene

R¹ is methyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which together with the carbon atom to which A² and A³ are attached define a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may optionally bear a methyl substituent alpha to X² ;

or a pharmaceutically-acceptable salt thereof.

9. A method of treating an inflammatory or allergic condition mediated by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an anti-inflammatory or anti-allergic effective amount of a hydroxylamine derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-5.