Nitric oxide synthase inhibitors

Details Nitric oxide synthase inhibitors Nitric oxide synthase inhibitors

2000-11-29

2002-03-12

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C562S505000, C562S506000, C562S557000

Reexamination Certificate

active

06355689

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 inducible NO synthase (iNOS) over endothelial NO synthase (eNOS) and/or neuronal NO synthase (nNOS).
Thus W093/13055 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
cycloalkyl C
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, 0 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.
The co-pending International application WO 98/30537 also describes certain amidino compounds which are selective inhibitors of inducible nitric oxide synthase.
We have now found a novel class of compounds which as well as being selective iNOS inhibitors, display advantages including that they have a relatively long half-life, are orally bioavailable when administered in vivo, and may be prepared from relatively cheap starting materials.
Therefore, according to the present invention there is provided a compound of formula (I)
or a salt, solvate, or physiologically functional derivative thereof;
wherein R
1
is selected from C
1-4
alkyl, C
3-4
cycloalkyl, C
1-4
hydroxyalkyl, and C
1-4
haloalkyl.
In formula (I), R
1
is preferably C
1-4
alkyl, most preferably, methyl.
The compounds of formula (I) include two chiral centres i.e. the carbon which bears the R
1
substituent and the asymmetric centre in the amino acid group. It is intended that formula (I) includes all optical isomers either in substantially pure form or admixed in any proportions. In a preferred aspect, the amino acid group is in the natural L configuration. In a further preferred aspect the carbon bearing the group R
1
is in the R configuration. In the most preferred aspect, the amino acid is in the natural L configuration and the carbon bearing the group R
1
is in the R configuration. Throughout this specification, where the stereochemistry of two chiral centres within a molecule are given, the first configuration refers to the amino acid &agr; carbon and the second refers to the carbon bearing the R
1
substituent, for example, stereochemistry designated (R,S) means (R)-stereochemistry at the amino acid &agr; carbon, and (S)-stereochemistry at the carbon bearing the R
1
substituent.
Thus, in a further aspect, the present invention provides a compound selected from:
S-[(R)-2-(1-iminoethylamino)propyl]-L-cysteine;
S-[(S)-2-(1-iminoethylamino)propyl]-L-cysteine;
S-[(R/S)-2-(1-iminoethylamino)propyl]-L-cysteine;
S-[(R)-2-(1-iminoethylamino)propyl]-D-cysteine;
S-[(S)-2-(1-iminoethylamino)propyl]-D-cysteine;
S-[(R/S)-2-(1-iminoethylamino)propyl]-D-cysteine;
S-[(R/S)-2-(1-iminoethylamino)butyl]-L-cysteine;
S-[(R/S)-2-(1-iminoethylamino,2-cyclopropyl)ethyl]-L-cysteine; and
S-[(R/S)-2-(1-iminoethylamino,3-hydroxy)propyl]-L-cysteine.
and salts, solvates, and physiologically functional derivatives thereof.
In a preferred aspect, the present invention provides S-[(R)-2-(1-iminoethylamino)propyl]-L-cysteine or a salt, solvate, or physiologically functional derivative thereof. In a particularly preferred aspect, the present invention provides S-[(R)-2-(1-iminoethylamino)propyl]-L-cysteine or a salt thereof.
It is to be understood that the present invention covers all combinations of particular and preferred groups described herein.
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 include 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 acceptable 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 fai

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