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1. IL209214 - AMINO ACID DERIVATIVES, METHOD FOR PREPARING SAME AND THERAPEUTIC USE THEREOF

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

[ EN ]

CLAIMS

1. A compound having the following formula (I):

RXNH-CH (R2 ) -CH2 -S -S-CH2-C { 3 ) (RJ -CONH-C- (R5) (Rfi) -COOR, wherein:

Ri represents an (acyloxy) alkyl carbamate group

- (CO) -0-C (Re) (R9) -OC (0) -R10, wherein

Re and R9 independently of each other represent a hydrogen atom, an alkyl, aryl , arylakyl, cycloalkyl, cycloheteroalkyl , heteroalkyl, heteroaryl or heteroarylalkyl grou ; or

taken together, Ra and R9 may form a cycloalkyl with 5 or 6 members

Rio represents an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;

R2 represents:

a linear or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms, optionally substituted with:

❖ an OH, OR , SH, SRn or S(0)Rn radical, in each of these radicals, Rn represents a linear or branched hydrocarbon chain with 1 to 4 carbon atoms, a phenyl radical or a benzyl radical,

❖ a phenyl or benzyl radical, optionally substituted with:

• 1 to 5 halogen atoms, notably fluorine ,

• an OH, ORn, SH, SRn or S(0)Rn radical, Rn having the same meaning as earlier,

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a methylene radical substituted with a 5 or 6 members, aromatic or saturated, heterocycle, the heteroatom being, a nitrogen or sulfur atom, optionally oxidized as an N-oxide or S - oxide,

when R4 represents a hydrogen atom, R3 represents:

a phenyl or benzyl radical optionally substituted with:

❖ 1 to 5 halogen atoms;

❖ an SRii , S(0) Rn or O n radical, Rn having the same meaning as earlier;

·♦· an amino group optionally mono- or di- substituted with a cyclic or linear aliphatic group having 1 to 6 carbon atoms;

a heteroaryl with 5 or 6 members, the heteroatom being an oxygen, a sulfur or nitrogen atom;

a methylene group substituted a 5 or 6 members, aromatic or saturated, heterocycle, the heteroatom being an oxygen, nitrogen or sulfur atom, the nitrogen and sulfur atoms may be oxidized as an N-oxide or S-oxide;

when R4 is different from H , R3 and R4 taken together form a saturated cycle with 5 or 6 members ;

R5 and R6 independently of each other represent: a hydrogen atom,

a linear or branched saturated hydrocarbon chain, having from 1 to 6 carbon atoms, optionally substituted with an OH , ORn , SH or SRn , COOH or COORn radical, in each of these radicals, n has the same meaning as earlier,

a phenyl or benzyl radical, optionally substituted with:

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❖ a linear or branched alkyl chain with 1 to 4 carbon atoms;

J* 1 to 5 halogens, notably fluorine or bromine ;

❖ an OH, ORii, SH or SRn radical, Ru having the definition as earlier;

or taken together R5 and R6 from a saturated cycle with 5 or 6 members;

R7 represents

a hydrogen atom;

a phenyl or benzyl radical optionally substituted with 1 to 5 halogens, notably fluorine ;

a group of formula CRX2 (Ri3) C (0) 0R14 ; a group OCR12 (R13) OC (0) R14 ;

a group OCR12 (Ri3) OC (0) 0R14 ;

Ri2 and Ri3 independently of each other represent a hydrogen atom, an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl , heteroalkyl, heteroaryl or heteroarylalkyl group;

taken together Ri2 and Rl3 may form a cycloalkyl with 5 or 6 members;

Ri4 represents an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;

as well as the addition salts of said compound {I) with pharmaceutically acceptable mineral or organic bases and each of their isomers, in particular their optical enantiomers.

2. The compound according to claim 1, characterized in that the radical Ri advantageously represents an (acyloxy) alkyl carbamate group

- (CO) -0-C (R8) (R9) -OC (0) -R10, wherein RB and R9 independently of each other represent a hydrogen atom 46

or an alkyl group; and Ri0 represents an alkyl group, in particular an isopropyl.

3. The compound according to any of the preceding claims, characterized in that the radical R2 represents an alkyl radical having from 1 to 4 carbon atoms, substituted with an SRn or S(0)Rn radical Rn having the same meaning as in claim 1, in particular Rn represents a linear or branched saturated hydrocarbon chain with 1 to 4 carbon atoms and more particularly a methyl group.

. The compound according to any of the preceding claims, characterized in that the radical R4 represents a hydrogen atom.

5. The compound according to claim 1, characterized in that the radical R3 represents:

a benzyl or phenyl radical,

- a methylene radical substituted with an either aromatic or saturated heterocycle with 5 or 6 atoms, having as a heteroatom, a nitrogen of sulfur atom, optionally oxidized as an N-oxide or S-oxide.

6. The compound according to any of claims 1 to 3 , characterized in that the radicals R4 and R3 form together with the carbon which bears them, a cycloalkyl with 5 or 6 members, in particular a cyclopentane or a cyclohexane.

7. The compound according to any of the preceding claims, characterized in that the radical R5 represents a hydrogen atom.

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8. The compound according to any of the preceding claims, characterized in that the radical R6 represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, substituted with an OH, SH, COOH or COORn radical, in each of these radicals, Rn has the same meaning as earlier.

9. The compound according to any of the preceding claims, characterized in that the radical R7 represents a hydrogen atom, a phenyl or benzyl radical or an alkyl radical having from 1 to 4 carbon atoms.

10. The compound according to any of the preceding claims, characterized in that it is selected from the following compounds:

1- (l-{2- [ (1 -ethoxycarbonyloxy-ethoxy carbonylmethyl ) -carbamoyl] -3 -phenyl- propyldisulfanylmethyl } -3 -methylsulfanyl-propylcarbamoyloxy) -ethyl isobutyric acid ester,

1-{1- [2- (benzyloxycarbonylmethyl -carbamoyl) -3 -phenyl -propyl -disulfanylmethyl] -3 -methylsulfanyl -propylcarbamoyloxy} -ethyl isobutyric acid ester, l-{l- [2- (carboxymethyl -carbamoyl ) -3 -phenyl -propyldisulfanylmethyl] -3 -methylsulfanyl-propylcarbamoyloxy} -ethyl isobutyric acid ester,

1- (l-{2- [ (1 -ethoxycarbonyloxy-ethoxycarbonylmethyl) -carbamoyl] -3 -phenyl -propyldisulfanylmethyl } -3 -methane-sulfinyl-propylcarbamoloxy) -ethyl isobutyric acid ester,

1-{1- [2 -benzyloxycarbonylmethyl -carbamoyl) - 3 -phenyl -propyl -disulfanylmethyl] -3 -methanesulfinyl -propylcarbamoyloxy} -ethyl isobutyric acid ester, l-{l-2 [2- (carboxymethyl -carbamoyl) -3 -phenyl -propyldisulfanylmethyl] -3 -methanesulfinyl -propylcarbamoyl-oxy} -ethyl isobutyric acid ester,

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2- ({l- [2- (1-isobutyryloxy-ethoxycarbonylamino) -4-methane-sulfinyl -butyldisulfanyImethyl] -cyclopentanecarbonyl } -amino) -succinic acid,

2- ({1- [2- (1-isobutyryloxy-ethoxycarbonylamino) -4-methyl-sulfanyl -butyldisulfanylmethyl] -cyclopentanecarbonyl} -amino) -succinic acid,

Benzyl 2-{{l-[2-(l- isobutyryloxy-ethoxycarbonylamino) - 4-methanesulfinyl -butyldisulfanylmethyl] -cyclopentanecarbonyl } -amino) -succinic acid ester

Benzyl 2- ({l- [2- (1-isobutyryloxy-ethoxycarbonylamino) -4-methylsulfanyl -butyldisulfanylmethyl] -cyclopentanecarbonyl } -amino) -succinic acid.

11. As a drug, the compound formula (I) according to any of the preceding claims.

12. A pharmaceutical composition, characterized in that it comprises at least one compound of formula (I), according to any of claims 1 to 10, and a pharmaceutically appropriate excipient, in particular an appropriate excipient for administration via an oral, nasal or intravenous route.

13. The pharmaceutical composition according to claim 12, characterized in that it further comprises at least one derivative of cannabinoids, in particular Δ9-tetrahydrocannabinol , and/or morphine, or one of its derivatives, or more advantageously one derivative of Gaba, in particular gabapentin or pregabalin.

14. The pharmaceutical composition according to claims 12 or 13, characterized in that it is intended for the treatment of depression, multiple sclerosis, 49

and different types of pain, such as acute pain, inflammatory pain, nociceptive pain, neurogenic pain, neuropathic pain, psychogenic pain, allodynia.

15. A pharmaceutical composition comprising i) at least one compound of formula (I) , according to any of claims 1 to 10

ii) at least one derivative of cannabinoids and/or iii) morphine or one of its derivatives, and/or iv) at least one derivative of Gaba, such as gabapentin or pregabalin, as combination products for simultaneous, separate use or spread out in time.

16. The composition according to claim 15, intended for treating depression, addictions and pain, in particular inflammatory pain, nociceptive pain, neurogenic pain, neuropathic pain, psychogenic pain, and their characteristics such a hyperalgia and allodynia .

17. The compound according to any one of claims 1-10 as described in

the specification and in the drawings.

18. The drug according to claim 11 as described in the specification and

in the drawings.

19. The composition according to any one of claims 12-16 as described

in the specification and in the drawings.


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