(2s,5r)-5-(hydroxymethyl)morpholine-2-carboxamides as agonists of sstr4

Abstract

The present disclosure provides cis-5-(hydroxymethyl)morpholine-2-carboxamides that are agonists of somatostatin receptor 4 (SSTR4), and are therefore useful for the treatment of diseases or medical conditions associated with SSTR4. Also provided are pharmaceutical compositions containing the same, and processes for preparing said compounds.

Description

This disclosure provides cis-5-(hydroxymethyl)morpholine-2-carboxamide, an agonist of somatostatin receptor 4 (SSTR4), and therefore for the treatment of diseases or medical conditions related to SSTR4. Pharmaceutical compositions containing the compound and methods for preparing said compounds are also provided. Abstract

Claims

CLAIMS 1. A compound of formula (I) whereinR5 is methyl; R6 is -C1-4-Alkyl or -C3-6-Cycloalkyl; or R5 and R6 together with the carbon atom to which they are attached form a C3- 6-Cycloalkyl; A is a phenyl-ring, which may be substituted with 1 to 3 substituents, inde- pendently selected from among a group consisting of -halogen, -CF3, -C1-4-Al- kyl, -C3-6-Cycloalkyl, -C2-4-Alkynyl and -O-C1-4-Alkyl; or A is a 6-10 membered heteroaryl, which may be substituted with 1 to 3 substit- uents, independently selected from among a group consisting of -halogen, -CF3, -C1-4-Alkyl, and -O-C1-4-Alkyl; or a salt thereof.

2. A compound according to claim 1, wherein R5 and R6 are methyl; or a salt thereof.

3. A compound according to claim 1 or 2, wherein A is a phenyl-ring, which may be substituted with 1 to 3 substituents, independently selected from among a group consisting of -halogen, -CF3, -C1-4- Alkyl, -C3-6-Cycloalkyl, -C2-4-Alkynyl and -O-C1-4-Alkyl; wherein R5 is methyl; wherein R6 is methyl; or a salt thereof.

4. A compound according to any one of claims 1 to 3, wherein the compound is according to formula (Ia) whereinR1 is selected from among a group consisting of -H, -halogen, -CF3, -C1-4-Alkyl, -C3-6-Cycloalkyl and -O-C1-4-Alkyl; R2 is selected from among a group consisting of -H, -halogen and -C1-4-Alkyl; R3 is selected from among a group consisting of -H, -halogen, -C1-4-Alkyl, -C3- 6-Cycloalkyl and -C2-4-Alkynyl; R4 is selected from among a group consisting of -H, -halogen and -C1-4-Alkyl; R5 is methyl; R6 is methyl; or a salt thereof.

5. A compound according to claim 1 or 2 according to formula (I)wherein A is selected from among a group consisting ofandwhich may be substituted with 1 to 3 substituents, independently selected from among a group consisting of -halogen, -CF3, -C1-4-Alkyl, and -O-C1-4-Alkyl; wherein R5 is methyl;wherein R6 is methyl; or a salt thereof.

6. A compound according to any one of claims 1, 2, or 5 wherein A is selected from among a group consisting ofwherein R1 is selected from among a group consisting of -H, -halogen, -CF3, -C1-4-Alkyl, and -O-C1-4-Alkyl; R2, R3, R4, R7, R8 and R9 are independently selected from among a group consisting of -H, -halogen and -C1-4-Alkyl; R5 is methyl; R6 is methyl; R10 is -H or -C1-4-Alkyl; or a salt thereof.

7. A compound according to any one of claims 1 to 6, wherein the compound is selected from among the group consisting ofor a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 4 or 7, wherein the compound is selected from among the group consisting ofor a pharmaceutically acceptable salt thereof.

9. A compound according to any one of the claims 1 to 8 in its salt free form.

10. A compound according to any one of claims 1 to 9 or a pharmaceutically ac- ceptable salt thereof for use as a medicament.

11. A compound according to any one of claims 1 to 9 or a pharmaceutically ac- ceptable salt thereof for use in a treatment of a disease and / or condition associ- ated with or modulated by SSTR4 activity.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically ac- ceptable salt thereof for use in a treatment of a disease, disorder and / or condition selected from among the group consisting of pain or pain associated conditions, conditions associated with inflammation, neurological and psychiatric condi- tions such as psychosis spectrum disorders, schizophrenia (positive and nega- tive symptoms and cognitive impairment associated with schizophrenia), psy- chosis, dysfunction in learning and memory, and dementia like Alzheimer’s dis- ease.

13. A compound according to any one of claims 1 to 9 or a pharmaceutically ac- ceptable salt thereof for use in treatment of a disease and / or condition selected from among the group consisting of acute pain, visceral pain, neuropathic pain, inflammatory pain, receptor-mediated pain, inflammatory changes connected with diseases of the airways and lungs, mild cognitive impairments, cognitive impairments associated with psychosis spectrum disorders, cognitive impair- ments associated with neurodegenerative disorders, cognitive impairments as- sociated with seizure disorders and epilepsy and treatment of positive symptoms in psychiatric disorders.

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. A medicament combination which comprises, besides one or more compounds according to one or more of claims 1 to 9, or a pharmaceutically acceptable salt thereof as further active substances a substance selected from the group consist- ing of anti-inflammatory drugs, cholinergic therapies, beta-amyloid-targeted therapies, tau-related therapy, neuroprotective therapies, analgesic drugs, anti- migraine drugs, antidepressants, mood stabilizers, typical and atypical antipsy- chotics, anxiolytics, antiepileptic drugs, sleeping agents, cognitive enhancers, stimulants, additional psychoactive drugs, chemotherapeutic drugs, and treat- ment options used for metabolic disorders.

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