Phenylheteroalkylamine derivatives

Details Phenylheteroalkylamine derivatives Phenylheteroalkylamine derivatives

2002-08-22

2004-06-01

Solola, Taofiq (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C514S524000

Reexamination Certificate

active

06743939

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel phenylheteroalkylamine derivatives, processes for their preparation, compositions containing them and their use in therapy.
BACKGROUND OF THE INVENTION
Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes—constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald,
Ann. Rep. Med. Chem.,
1996, 31, 221-230).
Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a compound of formula (I)
wherein:
X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy, halogen, CF
3
, OCF
3
, CN, C≡CH, S(O)
m
CH
3
, S(O)
p
CF
3
, NO
2
or NHCHO;
m and p independently represent an integer 0, 1 or 2;
Z represents H or fluoro;
V represents O, S(O)
n
or NR
3
;
W represents C1 to 4 alkyl, C2 to 4 alkenyl, C2 to 4 alkynyl, C3 to 6 cycloalkyl or a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S and N; any of said groups being optionally further substituted by C1 to 4 alkyl, C1 to 4 alkoxy, C1 to 4 alkylthio, C3 to 6 cycloalkyl; halogen or phenyl; said phenyl group being optionally further substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF
3
, OCF
3
, CN or NO
2
;
or 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, NO
2
or NR
4
R
5
; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
R
1
and R
2
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, NR
6
R
7
, 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, CF
3
, OCF
3
, CN or NO
2
;
or the group NR
1
R
2
together represents a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or NR
8
; said ring being optionally substituted by C1 to 4 alkyl, C1 to 4 alkoxy or OH; said alkyl group being optionally substituted by C1 to 4 alkoxy, OH or NR
9
R
10
;
or the group NR
1
R
2
together represents part of a five membered aromatic azacyclic ring optionally incorporating one further N atom;
R
3
represents H or C1 to 4 alkyl;
R
4
, R
5
, R
6
, R
7
, R
9
and R
10
independently represent H or C1 to 4 alkyl;
R
8
represents H or C1 to 6 alkyl; said alkyl group being optionally substituted by C1 to 4 alkoxy, OH, NR
11
R
12
, 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, CF
3
, OCF
3
, CN or NO
2
;
R
11
and R
12
independently represent H or C1 to 4 alkyl;
n represents an integer 0, 1 or 2;
or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors of the enzyme nitric oxide synthase (NOS). In particular, the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase (iNOS).
The invention further provides a process for the preparation of compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
According to the invention there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof, for use as a medicament.
Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate 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.
A more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
The compounds of the present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2). Thus, in a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders. And there is also provided a method of treating, or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof in combination with a COX-2 inhibitor.
In one preferred embodiment, V represents O. In another preferred embodiment, V represents S.
In another preferred embodiment, X and Y independently represent Br, Cl, CH
3
, CF
3
or CN. It is particularly preferred that X represents Cl or CF
3
. It is also particularly preferred that Y represents Cl, CN or CF
3
.
Preferably, W represents an optionally substituted five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N. Particular examples are those wherein W represents thienyl, furyl, imidazolyl, pyridyl, thiazolyl or triazolyl.
Preferably, R
1
and R
2
independently represent H or C1 to 4 alkyl optionally substituted by C1 to 4 alkoxy or hydroxy. More preferably, R
1
and R
2
inde

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