NOVEL DIZOCILPINE DERIVATIVES AS PERIPHERAL NMDA RECEPTOR ANTAGONISTS

• US 20190307738A1
• Filed: 06/13/2017
• Published: 10/10/2019
• Est. Priority Date: 06/13/2016
• Status: Active Grant

• Current Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Assistance Publique - Hopitaux De Paris, Centre National De La Recherche Scientifique, Hôpital Marie Lannelongue, Universite Paris - Sud
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Inventors: COHEN-KAMINSKY, Sylvia, HUMBERT, Marc, DUMAS, Sebastien, BRU-MERCIER, Gilles, MESSAOUDI, Samir, BRION, Jean-Daniel, ALAMI, Mouad, GALVANI, Gilles
• Granted Patent: US 11,376,245 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 451/00 : Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof

Abstract

The present invention relates to compounds of formula (I) for use as peripheral NMDA receptor antagonists.

Claims

1. Compound of formula (I):

2. Compound according to claim 1, of formula (I):

3. Compound according to claim 1, wherein R₁ represents —

OH, a (C₁-C₆)alkyl group, or a (C₃-C₇)cycloalkyl group.

4. Compound according to claim 1, wherein R₂ represents a methyl group or an ethyl group.

5. Compound according to claim 1, wherein n is 1 or 2.

6. Compound according to claim 1, wherein R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are a hydrogen atom.

7. Compound according to claim 1, wherein the anionic counterion X⁻

is chosen from I⁻

and Cl⁻

.

8. Compound according to claim 1, chosen from:

9. Medicament comprising as pharmaceutical active agent at least one compound as defined in claim 1.

10. A pharmaceutical composition comprising at least one compound as defined in claim 1, and at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition as claimed in claim 10, wherein said compound is in combination with at least one other therapeutic agent.

17. A pharmaceutical composition as claimed in claim 11, wherein said compound is in combination with at least one other therapeutic agent chosen from vasodilator agents and/or other ionotropic and/or metabotropic glutamate receptor antagonists.

18. A pharmaceutical composition as claimed in claim 11, wherein said compound is in combination with at least one other therapeutic agent chosen from other NMDAR antagonists.

12. Compound of formula (I):

13. Compound according to claim 12, of formula (I):

14. A method for preventing and/or inhibiting a disease or condition in a subject comprising administering to the subject a compound according to claim 12, wherein the disease or a condition involves peripheral NMDA receptors.

15. A method for preventing and/or inhibiting a disease or condition in a subject comprising administering to the subject a compound according to the claim 14, wherein the disease or the condition is selected from the group consisting of pulmonary hypertension, pulmonary diseases involving inflammation, fibrosis and remodeling, non-neuronal cancers diabetes, atherosclerosis, sickle cell disease, diseases involving thrombosis, acute infections, chronic infectious diseases, inflammatory/autoimmune diseases, heart failure, arrhythmias, renal disorders, pain, psoriasis, atopic dermatitis and osteoporosis.

16. A method for preventing and/or inhibiting a disease in a subject comprising administering to the subject a compound according to claim 14, wherein the disease is pulmonary arterial hypertension.