Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-26
2001-10-02
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C558S008000
Reexamination Certificate
active
06297276
ABSTRACT:
The present invention relates to N-substituted urea derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as inhibitors of nitric oxide synthase, and in particular neuronal nitric oxide synthase.
It has been known since the early 1980's that the vascular relaxation brought about by acetycholine is dependent on the presence of the endothelium and this activity was ascibed 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 amyl nitrite, 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 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 toxic shock and therapy with certain cytkines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue N
G
-monomethyl-L-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of 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. Other potent NO synthase inhibitors are described in Narayanan et al., J. Med. Chem. 37, 885-887 (1994).
It has recently become apparent that there are at least three types of NO synthase enzymes as follows:
(i) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or receptor physical stimulation.
(ii) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca
++
independent enzyme 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 the constitutive enzyme acts as a transduction mechanism underlying several physiological responses. The function of the NO produced by the inducible enzyme is as a cytotoxic molecule for tumour cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesised by the inducible NO synthase.
It is believed that NO synthesis plays an important part in the pathology of a range of diseases of the nervous system, eg. ischemia. However, non-selective inhibitors of NO synthases cause profound changes in blood pressure and blood flow, including cerebral blood flow. Unfortunately, ischemic injury inherently reduces the blood supply to the brain and any further decrease in blood flow caused by a non-selective NO synthase inhibitor would have a deleterious effect, potentially opposing any beneficial effect of decreased NO production within the brain. Nevertheless, studies of middle cerebral artery occlusion in both rats and mice have demonstrated a substantial protection effect of low doses of NO synthase inhibitors (see for example Nowicki et al, Eur. J Pharmacol., 1991, 204, 339-340). At high doses, or in models of global ischemia, these inhibitors fail to provide protection. Thus, there is a need for a potent inhibitor of neuronal NO synthase with preferably little or no activity against the vascular endothelial NO synthase.
The NO synthase inhibitors proposed for therapeutic use so far, such as L-NMMA and L-NAME (L-nitroarginine methyl ester), are non-selective in that they inhibit all NO synthase enzymes identified to date. Use of such a non-selective NO synthase inhibitor would require great care to be taken in order to avoid the potentially serious consequences of over-inhibition of the other enzymes. 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 one NO synthase enzyme to a considerably greater extent compared to one or more of the other enzymes would be of even greater therapeutic benefit and much easier to use.
Unpublished PCT patent application PCT/GB93/02437 discloses a class of S-subsituted isothiourea derivatives which inhibit the NO synthase enzmyes, showing a slight selectivity of the inducible enzyme over the constitutive enzymes.
It has been found that a class of N-substituted urea derivatives or salts, esters or amides thereof are NO synthase inhibitors, showing selectivity of the neuronal NO synthase enzyme over the endothelial and inducible NO synthase enzymes. The term “urea derivatives” when used herein means “isothiourea derivatives” and “isourea derivatives”.
In one aspect the present invention provides the use of an N-substituted urea derivative or a salt, ester or amide thereof, other than N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine, for the manufacture of a medicament for the treatment of a condition where there is an advantage in inhibiting the neumonal NO synthase enzyme with less inhibition of the endothelial or inducible NO synthase enzymes.
In another aspect, the present invention provides a method of treatment of a condition where there is an advantage in inhibiting the neuronal NO synthase enzyme with less inhibition of the endothelial or inducible NO synthase enzyme comprising administering to a mammal in need thereof a therapeutically effective amount of an N-substituted urea derivative or a salt, ester or amide thereof, other than N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine.
More specifically, the present invention provides the use of a N-substituted urea derivative or salt, ester or amide thereof, other than N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine for the manufacture of a medicament for the treatment of a disease of the nervous system due to over production of the neuronal nitric oxide synthase enzyme. Such diseases include cerebral ischemia, CNS trauma, epilepsy, AIDS dementia, chronic neurodegenerative disease and chronic pain, and conditions in which non-adrenergic non-cholinergic nerve may be implicated such as priapism, obesity and hyperphagia, particularly cerebral ischemia.
In one embodiment of the present invention the N-substituted urea derivative is an N-substituted isothiourea derivative, other than N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine, preferably an N,S-disubstituted isothiourea derivative. In a second embodiment of the present invention the N-substituted urea derivative is an N-substituted isouraea, preferably an N,O-disubstituted isourea derivative.
Preferred urea derivatives include those of the formula (I)
wherein
Q is oxygen or sulphur
R
1
is hydrogen or C
1-8
hydrocarbyl;
R
2
is a mono- or bicyclic heterocyclic ring system, a C
1-10
hydrocarbyl group which may optionally contain an oxygen atom, a group S(O)
n
wherein n is 0, 1 or 2, or a group NR
3
wherein R
3
is hydrogen or a C
1-6
aliphatic group, each group R
2
optionally being substituted by one to five groups independently selected from
(i) C
1-6
alkyl or C
3-6
cycloalkyl each optionally substituted by one to three halo atoms;
(ii) a group OR
4
wherein R
4
is hydrogen, C
1-6
alkyl, ph
Bigham Eric Cleveland
Furfine Eric Steven
Garvey Edward Patrick
Oplinger Jeffrey Alan
Shearer Barry George
Badio Barbara P.
GlaxoSmithKline
Morgan Lorie Ann
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