Substituted urea and isothiourea derivatives as no synthase inhibitors
AssigneeGlaxoSmithKline LLC
InventorsJeffrey Alan Oplinger, Barry George Shearer, Eric Cleveland Bigham, Eric Steven Furfine, Edward Patrick Garvey
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Abstract
The use of an N-substituted urea derivative for the manufacture of a medicament for the treatment of a condition where there is an advantage in inhibiting the NO synthase enzyme, in particular cerebral ischemia, and pharmaceutical formulations therefor are disclosed. Novel N-substituted urea derivatives and processes for the preparation thereof are also described.
Claims6
A method of treatment of a condition requiring selective inhibition of the neuronal NO synthase enzyme, said condition being selected from the group consisting of cerebral ischemia, CNS trauma, epilepsy, AIDS dementia, chronic neurodegenerative disease, chronic pain, priapism, obesity, hyperphagia and combinations thereof;
- comprising administering to a mammal in need thereof a therapeutically effective amount of an N,O-disubstituted isourea derivative of formula (I), or a salt, ester or amide thereof
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- wherein:
- Q is oxygen;
- R1 is C1-8 hydrocarbyl;
- R2 is a mono-or bi-cyclic heterocyclic ring system, C1-4 hydrocarbyl group which may optionally contain an oxygen atom, a group S(O)n wherein n is 0, 1 or 2, or a group NR3 wherein R3 is a C1-6 aliphatic group, each group R2 optionally being substituted by one to five groups independently selected from:
- (i) C1-6 alkyl or C3-6 cycloalkyl each optionally substituted by one to three halo atoms;
- (ii) a group OR4 wherein R4 is hydrogen, C1-6 alkyl, phenyl or benzyl;
- (iii) a halo atom;
- (iv) a group CO2R5 wherein R4 is hydrogen or C1-4 alkyl;
- (v) a group NR6R7 wherein R6 and R7 are independently selected from hydrogen, C1-4 alkyl or a group
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- wherein Q and R1 are as defined above;
- (vi) nitro;
- or
- (vii) cyano.
A method of treatment of a condition requiring selective inhibition of the neuronal NO synthase enzyme comprising administering to a mammal in need thereof a therapeutically effective amount of an N,O-disubstituted isourea derivative, or a salt, ester or amide thereof, wherein the N,O-disubstituted isourea derivative is:
- O-Methyl-N-(4-(trifluoromethyl)phenyl)isourea,
- O-Ethyl-N-(4-trifluoromethyl)phenyl)isourea,
- N5-(iminomethoxymethyl)-L-ornithine,
- N5-(ethoxyiminomethyl)-L-ornithine,
- N5-(iminoisopropoxymethyl)-L-ornithine,
- N6-iminomethoxymethyl)-L-lysine,
- N6-(ethoxyiminomethyl)-L-lysine,
- 1-(3-(Aminomethyl)benzyl)-O-ethylisourea.
A pharmaceutical formulation suitable for oral or injection administration, said pharmaceutical formulation comprising a therapeutically effective amount of an N,O-disubstituted isourea derivative of formula (I), or a salt, ester or amide thereof which is:
- O-Methyl-N-(4-(trifluoromethyl)phenyl)isourea,
- O-Ethyl-N-(4trifluoromethyl)phenyl)isourea,
- N5-(iminomethoxymethyl)-L-ornithine,
- N5-(ethoxyiminomethyl)-L-ornithine,
- N5-(iminoisopropoxymethyl)-L-ornithine,
- N6-iminomethoxymethyl)-L-lysine,
- N6-(ethoxyiminomethyl)-L-lysine,
- 1-(3-(Aminomethyl)benzyl)-O-ethylisourea;
- together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients.
An N,O-disubstituted isourea derivative, or a salt, ester or amide thereof, wherein the N,O-disubstituted isourea derivative is:
- O-Methyl-N-(4-(trifluoromethyl)phenyl)isourea,
- O-Ethyl- N-(4-trifluoromethyl)phenyl)isourea,
- N5-(iminomethoxymethyl)-L-ornithine,
- N5-(ethoxyiminomethyl)-L-ornithine,
- N5-(iminoisopropoxymethyl)-L-ornithine,
- N6-iminomethoxymethyl)-L-lysine,
- N6-(ethoxyiminomethyl)-L-lysine,
- 1-(3-(Aminomethyl)benzyl)-O-ethylisourea.
Dependencies are inferred from the claim text.