US 6,887,871 B2Granted

Use of phenylheteroakylamine derivatives

AssigneeAstraZeneca AB

InventorsDavid Cheshire, Stephen Connolly, David Cox, Peter Hamley, Antonio Mete, Austen Pimm

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Abstract

There is disclosed the use of a compound of formula (I) wherein R1, R2, X, Y, V, W and Z are as defined in the specification, and pharmaceutically acceptable salts, enantiomers or racemates thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial. Certain novel compounds of formula (Ia) and pharmaceutically acceptable salts thereof, and enantiomers and racemates thereof are disclosed; together with processes for their preparation, compositions containing them and their use in therapy. The compounds of formulae (I) and (Ia) are inhibitors of the enzyme nitric oxide synthase and are thereby particularly useful in the treatment or prophylaxis of inflammatory disease.

Claims6

Dependent claims

A compound of formula (Ia)

wherein
X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy, halogen, CF3, OCF3, CN, C≡CH, S(O)mCH3, S(O)pCF3, NO2 or NHCHO;
m and p independently represent an integer 0, 1 or 2;
Z represents H or fluoro;
V represents O;
W represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said phenyl or aromatic heterocyclic ring being optionally substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO2 or NR4R5;
said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
R1 and R2 independently represent H, C1 to 4 alkyl or C3 to 6 cycloalkyl;
said alkyl group being optionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR6R7, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said phenyl or aromatic heterocyclic ring being optionally further substituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
or the group NR1R2 together represents a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or NR8;
said ring being substituted by OH or by C1 to 4 alkyl substituted by C1 to 4 alkoxy, OH or NR9R10;
or the group NR1R2 together represents part of a five membered aromatic azacyclic ring optionally incorporating one further N atom;
R4, R5R6, R7, R9 and R10 independently represent H or C1 to 4 alkyl;
R8 represents H or C1 to 6 alkyl;
said alkyl group being optionally substituted by C1 to 4 alkoxy, OH, NR11R12, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said phenyl or aromatic
heterocyclic ring being optionally further substituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
R11 and R12 independently represent H or C1 to 4 alkyl;
or a pharmaceutically acceptable salt, enantiomer or racemate thereof,
with the proviso that when W represents optionally substituted phenyl, thienyl, furanyl or pyrrolyl and R1 represents H, C1 to 4 alkyl or C3 to 6 cycloalkyl optionally substituted by C1 to 4 alkoxy, then R2 does not represent H, C1 to 4 alkyl or C3 to 6 cycloalkyl optionally substituted by C1 to 4 alkoxy;
and
with the proviso that when W represents thiazolyl or pyridyl, then either Z represents F;
or at least one of X and Y represents CN;
or R1 and R2 do not independently represent H or CH3.

23 more elements

A compound selected from the group consisting of:

2-[[(3R)-3-(2,5-dichlorophenoxy)-3-(2-thienyl)propyl]amino]ethanol;
4-chloro-2-{[(1R)-3-(4-hydroxy-1-piperidinyl)-1-phenylpropyl]oxy}-benzonitrile;
4-chloro-2-{[(1R)-3-[(2-hydroxyethyl)methylamino]-1-phenylpropyl]oxy}-benzonitrile;
4-chloro-2-{[(1R)-3-[(3R)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;
4-chloro-2-{[(1R)-3-[(3S)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;
4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl)propoxy]benzonitrile;
4-chloro-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-(3-hydroxypropyl)amino]propyl]oxy}benzonitrile;
4-chloro-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;
4-bromo-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;
4-bromo-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(3-hydroxypropyl)amino]propyl}oxy)benzonitrile;
4-bromo-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1phenylpropyl]oxy]benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[(1H-imidazol-2-ylmethyl)amino]-1-phenylpropyl]oxy]benzonitrile;
4-chloro-2-[[(1R)-3-[[2-(dimethylamino)ethyl]amino]-1-phenylpropyl]oxy]-5-fluoro benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[[2-(4-morpholinyl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-1-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-4-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-phenylpropyl]oxy]benzonitrile;
2-[[(1R)-3-[(2-aminoethyl)amino]-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile;
4-chloro-5-fluoro-2-[[(1R)-1-phenyl-3-[(3,3,3-trifluoropropyl)amino]propyl]oxy]benzonitrile;
2-{[(1R)-3-amino-1-(2-thiazolyl)propyl[oxy}-4-chlorobenzonitrile;
4-chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrile;
2-[3-amino-1-(2-oxazolyl)propoxyl]-4-chlorobenzonitrile;
γ-(2,5-dichlorophenoxy)-2-oxazolepropanamine;
2-[[-3-amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;
4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrile;
2-[3-amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;
2-[3-amino-1-(1,6-dihydro-6-oxo-2pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;
2-[3-amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrile;
2-[[3-amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrile;
4-chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrile;
(R)-γ-(2,5-dichlorophenoxy)-5-isoxazolepropanamine;
4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-thienyl)propyl]oxy]benzonitrile;
2-[[(1R)-3-[(2-aminoethyl)amino]-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;
4-chloro-2-[3-(methylamino)-1-(2-thiazolyl)propoxy]-benzonitrile;
2-[[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;
4-chloro-5-fluoro-2-{[(1R)-3-[(2-fluoroethyl)amino]-1-phenylpropyl]oxy}benzonitrile;
3-[[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]amino]-1-propanol;
1-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-4-piperidinemethanol;
N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-2-thiophenemethanamine;
N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-5-methyl-2-furanmethanamine;
5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrile;
2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile;
4-chloro-2-[[(1R)-3-[(1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrile;
2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrile;
2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;
(R)-γ-(2,5-dichlorophenoxy)-3-isoxazolepropanamine;
2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)-benzonitrile;
2-[[(1R)-3-amino-1-(5-methyl-3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;
or pharmaceutically acceptable salts thereof, enantiomers thereof and racemates thereof.

48 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/204,742Filed 20 Feb 2001
Priority: GB 000415323 Feb 2000
Published: US 2003/0158185 A121 Aug 2003
Granted: 3 May 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification45 codes

C07D 213/64
One oxygen atom: attached in position 2 or 6
A61K 31/137
Having aromatic rings , e.g. ketamine, nortriptyline: arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
A61K 31/277
Nitriles; Isonitriles: having a ring, e.g. verapamil
A61K 31/341
Having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide: not condensed with another ring, e.g. ranitidine,…