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1. WO2020157026 - DÉRIVÉS HYDROXYLÉS DE COMPOSÉS DE 1-OXA-4,9-DIAZASPIRO-UNDÉCANE AYANT UNE ACTIVITÉ MULTIMODALE CONTRE LA DOULEUR

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS:

1. Compound of Formula I

wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R3’ is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;

R3’ is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

3. Compound according to claims 1 or 2 wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 cycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is substituted or unsubstituted C1-6 alkyl;

R3’ is selected from hydrogen and unsubstituted C1-6 alkyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

4. Compound according to any one of claims 1 to 3, wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 cycloalkyl; preferably is selected from a substituted or unsubstituted group selected from methyl, ethyl, isopropyl and cyclopropyl;

R2 is substituted or unsubstituted monocyclic aryl; preferably is substituted or unsubstituted phenyl;

R3 is substituted or unsubstituted C1-6 alkyl; preferably is selected from a substituted or unsubstituted group selected from methyl and ethyl;

R3’ is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; preferably is selected from hydrogen and substituted or unsubstituted methyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

5. Compound according to any one of claims 1 to 4 wherein the compound of formula (I) is a compound of formula (I’)


wherein R1, R2, R3 and R3’ are as defined in the previous claims for the compound of formula (I);

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

6. Compound according to any one of claims 1 to 4 wherein the compound of formula (I) is a compound of formula (I’’)


wherein R1, R2, R3 and R3’ are as defined in the previous claims for the compound of formula (I);

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

7. Compound according to any one of claims 1 to 6 wherein the compound is selected from


optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.

8. Process for the preparation of a compound of general formula (I) according to claim 1


wherein

R1, R2, R3 and R3’ are as defined in the preceeding claims;

which comprises

b) wherein R3’ is H and R1, R2 and R3 are as already defined in the description, by reacting a compound of formula (VII)


with a Grignard reagent of formula (IX),

wherein T represents chloro, bromo or iodo, in an aprotic solvent such as tetrahydrofuran, and R1, R2 and R3 are as already defined in the description, at a suitable temperature, preferably at room temperature;

or

b) wherein R1, R2, R3 and R3’ are as already defined in the description, by reaction of a compound of formula (X)

with a compound of formula (VIIIa) or (VIIIb),

,

wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, and wherein R2 is as already defined in the description;

or

c) wherein R3’ is different from H and R1, R2 and R3 are as already defined in the description, by reaction of a compound of general formula I, wherein R3’ is H and R1, R2 and R3 are as already defined in the description, with a compound of formula (XIa) or (XIb) wherein R3’ is different from H,


and wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, under alkylation or etherification conditions; or

d) wherein R3’ is H, R3 is methyl, and R1 and R2 and are as already defined in the description, by hydration of an olefine compound of formula (XVI)

wherein R1 and R2 and are as already defined in the description, under acidic media, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane.

9. Use of compounds of Formula (Ia), (Ib), (Ic), (II), (IIP), (III), (IIIP), (IV), (V), (VP), (VI), (VII), (VIIP), (VIIH), (VIIIa), (VIIIb), (IX), (X), (XP), (XH), (XIa), (XIb), (XIIH), (XIIP), (XIII), (XIV), (XIVP), (XV), (XVP), (XVI), (XVIP) or (XbH)

wherein R1, R2, R3 and R3’ are as already defined in the preceeding claims, P represents a suitable protecting group, preferably Boc, Z represents alkoxy or a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, W represents a leaving group such as chloro or bromo, and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

10. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

11. A compound as defined in any one of claims 1 to 7 for use as a medicament.

12. A compound as defined in any one of claims 1 to 7 for use as a medicament for the treatment of pain, especially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.