Nitric oxide synthase inhibitors

Details Nitric oxide synthase inhibitors Nitric oxide synthase inhibitors

1999-08-24

2002-04-09

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acids and salts thereof

C560S148000, C514S562000

Reexamination Certificate

active

06369272

ABSTRACT:

The present invention relates to novel amidino compounds, to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use as selective inhibitors of inducible nitric oxide synthase.
Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase enzyme and is involved in a number of biological actions. Excess nitric oxide production is also thought to be involved in a number of conditions, including septic shock and many inflammatory diseases. The biochemical synthesis of nitric oxide from L-arginine is catalysed by the enzyme NO synthase. Many inhibitors of NO synthase have been described and proposed for therapeutic use.
More recently, it has been an object in this field to provide NO synthase inhibitors displaying selectivity for either inducible NO synthase (iNOS) or neuronal NO synthase (nNOS) over endothelial NO synthase (eNOS).
Thus WO93/13055 describes selective NO synthase inhibitors of formula
and salts, and pharmaceutically acceptable esters and amides thereof, in which:
R
1
is a C
1-6
straight or branched chain alkyl group, a C
2-6
alkenyl group, a C
2-6
alkynyl group, a C
3-6
cycloalkyl group or a C
3-6
cycloalkylC
1-6
alkyl group;
Q is an alkylene, alkenylene or alkynylene group having 3 to 6 carbon atoms and which may optionally be substituted by one or more C
1-3
alkyl groups;
a group of formula —(CH
2
)
p
X(CH
2
)
q
— where p is 2 or 3, q is 1 or 2 and X is S(O)
x
where x is 0, 1 or 2, O or NR
2
where R
2
is H or C
1-6
alkyl; or
a group of formula —(CH
2
)
r
A(CH
2
)
s
— where r is 0, 1 or 2, s is 0, 1 or 2 and A is a 3 to 6 membered carbocylic or heterocyclic ring which may optionally be substituted by one or more suitable substituents such as C
1-6
alkyl, C
1-6
alkoxy, hydroxy, halo, nitro, cyano, trifluoroC
1-6
alkyl, amino, C
1-6
alkylamino or diC
1-6
alkylamino.
We have now found compounds falling within the scope of WO 93/13055 which as well as being selective iNOS inhibitors, display advantages including that they have a long half-life and are orally bioavailable when administered in vivo.
Therefore, according to the present invention there is provided a compound of formula (I)
or a salt, solvate, or physiologically functional derivative thereof.
Formula (I) includes an asymmetric centre in the amino acid group, and although the natural L or (S) configuration of arginine is preferred, it is intended that formula (I) includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.
Thus, in the alternative, the present invention provides a compound selected from:
(R/S)-[2-(1-iminoethylamino)ethyl]-DL-homocysteine
(S)-[2-(1-iminoethylamino)ethyl]-L-homocysteine; and
(R)-[2-(1-iminoethylamino)ethyl]-D-homocysteine
and salts, solvates, and physiologically functional derivatives thereof.
In a preferred aspect, the present invention provides (S)-[2-(1-iminoethylamino)ethyl]-L-homocysteine or a salt, solvate, or physiologically functional derivative thereof. In a particularly preferred aspect, the present invention provides (S)-2-(1-iminoethylamino)ethyl]-L-homocysteine or a salt thereof.
Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
By the term “physiologically functional derivative” is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives indude esters, amides, and carbamates; preferably esters and amides.
Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic, and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.
Pharmaceutically acceptable esters and amides of the compounds of formula (I) may have the acid group converted to a C
1-6
alkyl, aryl, aryl C
1-6
alkyl, or amino acid ester or amide. Pharmaceutically accceptable amides and carbamates of the compounds of formula (I) may have an amino group converted to a C
1-6
alkyl, aryl, aryl C
1-6
alkyl, or amino acid amide or carbamate.
As mentioned above, the compounds of formula (I) are inhibitors of NO synthase as demonstrated in the NOS inhibition assays below.
Therefore, compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which an inhibitor of NO synthase is indicated, in particular, an inhibitor of iNOS. Such conditions include inflammatory conditions, shock states, immune disorders, and disorders of gastrointestinal motility. The compounds of formula (I) and pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof may also be of use in the prophylaxis and treatment of diseases of the central nervous system including migraine.
By shock states is meant those resulting from overproduction of NO, such as septic shock, haemorrhagic shock, traumatic shock, or shock caused by fulminant hepatic failure or by therapy with cytokines such as TNF, IL-1 and IL-2 or therapy with cytokine-inducing agents, for example 5,6-dimethylxanthenone acetic acid.
Examples of inflammatory conditions and immune disorders include those of the joint, particularly arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel diseases, gastritis and mucosalI inflammation resulting from infection, the enteropathy provoked by non-steroidal antiinflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas (e.g. diabetes melitus and complications thereof), of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g. systemic lupus erythematosis) and inflammatory sequelae of viral or bacterial infections.
Furthermore, there is evidence for overproduction of NO by iNOS in atherosclerosis and following hypoxic or ischaemic insults (with or without reperfusion), for example in the brain or in ischaemic heart disease.
Disorders of gastrointestinal motility include ifeus, for example post-operative ileus and ileus during sepsis.
By diseases of the central nervous system is meant those for which overproduction of NO is implicated, for example migraine, psychosis, anxiety, schizophrenia, sleep disorders, cerebral ischaemia, CNS trauma, epilepsy, multiple sclerosis, AIDS dementia, chronic neurodegenerative disease (e.g. Lewy Body Dementia, Huntington's disease, Parkinson's disease, or Alzheimer's disease) and acute and chronic pain, and conditions in which non-adrenergic non-choliner

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