Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reissue Patent
1999-05-04
2001-11-06
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S520000, C514S538000, C514S631000, C558S418000, C560S027000, C560S035000, C564S225000, C564S243000, C564S244000, C564S245000, C564S246000
Reissue Patent
active
RE037438
ABSTRACT:
This application is filed pursuant to 35 USC section 371 as a United States National Phase Application of International Application No. PCT/GB95/02978 filed Dec. 20, 1995 which claims priority from GB9425701.1 filed Dec. 20, 1994.
The present invention relates to acetamidine derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as selective inhibitors of nitric oxide synthase.
It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amylnitrite, glyceryltrinitrite and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesised from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase enzyme and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews, 43, 109-142 (1991)). It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve systemic hypotension such as septic (toxic) shock and therapy with certain cytokines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, NG-monomethyl-L-arginine (L-NMMA), and the therapeutic use of L-NMMA for the treatment of septic (toxic) shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three isoenzymes of NO synthase (reviewed in Knowles and Moncada, Biochem. J. (1994) 298, 249-258) as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme (eNOS) which is present in vascular endothelial cells, and that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme (nNOS), located in the brain and some peripheral nervous systems, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme (INOS) which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed, this inducible NO synthase synthesises NO for long periods.
The NO released by eNOS and nNOS acts as a transduction mechanism underlying several physiological responses. The NO produced by iNOS acts as a cytotoxic molecule for tumour cells and invading micro-organisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilatation and tissue damage, may result largely from the effects of NO synthesised by iNOS.
The NO synthase inhibitors proposed for therapeutic use so far, such as L-NMMA and nitroarginine, are non-selective in that they inhibit all the NO synthase isoenzymes. Use of such a non-selective NO synthase inhibitor requires that great care is taken in order to avoid the potentially serious consequences of over-inhibition of the eNOS including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of septic and/or toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, whilst non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit iNOS or nNOS to a considerably greater extent than eNOS would be of even greater therapeutic benefit and much easier to use.
We have found that a class of acetamidine derivatives are inhibitors of NO synthase, and are useful in the treatment of systemic hypotension, and in particular the treatment of septic shock. In addition these compounds show a marked selectivity of one of the isoenzyme with little or no inhibition of the other isoenzymes.
Accordingly, the present invention provides an acetamidine derivative of formula (I)
or a salt thereof, wherein
R
1
is hydrogen, a C
1-6
hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR
3
wherein X is oxygen C(O)
m
wherein m is 1 or 2, S(O)
n
wherein n is 0, 1 or 2, or a group NR
4
wherein R
4
is hydrogen or C
1-6
alkyl; and R
3
is hydrogen, C
1-6
alkyl, or a group NR
5
R
6
wherein R
5
and R
6
are independently hydrogen or C
1-6
alkyl, provided that R
3
is not NR
5
R
6
when X is oxygen or S(O)
n
;
R
1a
and R
1b
are independently selected from hydrogen or halo;
R
2
is a C
1-14
hydrocarbyl group which may optionally contain one or two heteroatoms, the group R
2
being optionally substituted by one or more groups independently selected from halo; N
3
; nitro; CF
3
; ZR
7
wherein Z is oxygen, C(O)
m′
wherein m′ is 1 or 2, S(O)
n′
wherein n′ is 0, 1 or 2, or a group NR
8
wherein R
8
is hydrogen or C
1-6
alkyl and R
7
is hydrogen, C
1-6
alkyl or a group NR
9
R
8
wherein R
9
and R
10
are independently hydrogen or C
1-6
alkyl; or R
2
is substituted by a group
wherein R
11
has a definition the same as for R
1
;
with the proviso that when R
1
is a C
1-6
alkyl group and R
2
is a C
1-14
hydrocarbyl substituted by two groups ZR
7
wherein one group ZR
7
is CO
2
H, the other groups ZR
7
is not NH
2
.
In preferred embodiments, R
1
is hydrogen, a C
1-6
hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR
3
wherein X is oxygen, C(O)
m
wherein m is 1 or 2, S(O)
n
wherein n is 0, 1 or 2, or a group NR
3
wherein R
4
is hydrogen or C
1-6
alkyl; and R
3
is hydrogen, C
1-6
alkyl, or a group NR
5
R
6
wherein R
5
and R
6
are independently hydrogen or C
1-6
alkyl, provided that R
3
is not NR
5
R
6
when X is oxygen or S(O)
n
; and/or
R
1a
and R
1b
are independently selected from hydrogen or halo; and/or
R
2
is a C
1-14
hydrocarbyl group which may optionally contain one or two heteroatoms, the group R
2
being optionally substituted by one or two groups which may be the same or different, and are selected from halo; ZR
7
wherein Z is oxygen, C(O)
m′
wherein m′ is 1 or 2, S(O)
n′
wherein n′ is 0, 1 or 2, or a group NR
8
wherein R
8
is hydrogen or C
1-6
alkyl and R
7
is hydrogen, C
1-6
alkyl or a group NR
9
R
10
wherein R
9
and R
10
are independently hydrogen or C
1-6
alkyl; or R
2
is substituted by a group
wherein R
11
has a definition the same as for R
1
;
with the proviso that when R
1
is a C
1-6
alkyl group and R
2
is a C
1-14
hydrocarbyl substituted by two groups ZR
7
wherein one group ZR
7
is CO
2
H, the other group ZR
7
is not NH
2
.
Suitably, R
1
is hydrogen, C
1-4
alkyl, halo, nitro, NR
4
R
3
or SR
3
wherein R
3
and R
4
is as hereinbefore defined.
Suitably, R
2
is a C
1-8
hydrocarbyl group optionally containing one or two heteroatoms, each group R
2
being optionally substituted by one group ZR
7
wherein Z and R
7
are as hereinbefore defined, or a group
wherein R
12
is fluoro, hydrogen or NH
2
.
Preferably R
1
is hydrogen, halo (for example fluoro) or NH
2
.
Preferably R
1a
and R
1b
are independently hydrogen or fluoro.
Preferably R
2
is a group
wherein p, q and r are independently 0, 1 or 2 and R
12
is as hereinbefore defined.
One embodiment of the present invention provides a compound of formula (IA)
wherei
Collins Jon Loren
Furfine Eric Steven
Garvey Edward Patrick
Oplinger Jeffrey Alan
Shearer Barry George
Glaxo Wellcome Inc.
Kumar Shailendra
Morgan Lorie Ann
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