Patent EA-003026-B1 (EA)
Title: Nitric oxide synthase inhibitors
Inventor: BESWICK PAUL JOHN
IPC: A61K/
Filed: 1999-05-27
Abstract: 1. A compound of formula (I);   or a salt, solvate, or physiologically functional derivative thereof; wherein R<1> is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl. 2. A compound of selected from the group consisting of: 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, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. 3. A compound of formula (I) which is S-[(R)-2-(1-iminoethylamino)propyl]-L-cysteine or a salt, solvate, or physiologically functional derivative thereof. 4. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an inhibitor of nitric oxide synthase is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I) as defined in any of Claim 1-3, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. 5. A method according to Claim 4 wherein the clinical condition is selected from the group consisting of arthritis, asthma, ileus, and migraine. 6. A use of compound of formula (I) as defined in any of Claim 1-3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in therapeutic treatment. 7. A pharmaceutical formulation comprising a compound of formula (I) as defined in any of Claim 1-3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredient. 8. A use of compound of formula (I) as defined in any of Claim 1-3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in preparation of a medicament for prophylaxis and treatment of clinical state for which an inhibitor of nitric oxide synthase is indicated. 9. A method according to Claim 8 wherein the clinical condition is selected from the group consisting of arthritis, asthma, ileus, and migraine. 10. A process for preparing a compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof wherein (i) reacting the compound of formula (II)   or an optical isomer, a salt, or a protected derivative thereof wherein R<1> is as determined above with a compound of formula (III)   or a salt thereof, wherein L is a leaving group; followed by the following steps in any order: (ii) optional removing any protecting groups; (iii) optional separating an optical isomer from a mixture of optical isomers; and (iv) optional converting the product to a corresponding salt, solvate, or physiologically functional derivative thereof. 11. A compound of formula (II)   or an optical isomer, a salt, or a protected derivative thereof, wherein R<1> is as determined above. 12. A protected derivative of a compound of formula (I) according to Claim 1, which is selected from: (R,R)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-methyl-4-thiohexanoate; (R,S)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-methyl-4-thiohexanoate; (S,S)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-methyl-4-thiohexanoate; (S,R)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-methyl-4-thiohexanoate; (R,R/S)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-ethyl-4-thiohexanoate; (R,R/S)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-butoxymethyl-4-thiohexanoate; and (R,R/S)-tert-butyl-2N-tert-butoxycarbonyl-6N-(1-iminoethyl)-2,6-diamino-5-cyclopropyl-4-thiohexanoate and salts and solvates thereof.