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1. AU2009248056 - Novel 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): RiNH-CH (R2) -CH2-S-S-CH 2-C (R3) (R4 ) -CONH-C- (R5 ) (R6) -COOR 7 wherein:
Ri represents an (acyloxy)alkyl carbamate group - (CO) -O-C (R8 ) (R9) -OC (0) -R10 , wherein
- R8 and R9 independently of each other represent a hydrogen atom, an alkyl, aryl, arylakyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group; or
- taken together, R8 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, ORii, SH, SRii or S (0) R11 radical, in each of these radicals, R11 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,
e an OH, ORii, SH, SRIi or S(O)R 11 radical, R11 having the same meaning as earlier,
- 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:
4 1 to 5 halogen atoms;
an SR 11 , S (0) R11 or OR,- radical, R11 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, ORii, SH or SR11, COOH or COOR11 radical, in each of these radicals, R11 has the same meaning as earlier,
- a phenyl or benzyl radical, optionally substituted with:
a linear or branched alkyl chain with 1 to 4 carbon atoms;
* 1 to 5 halogens, notably fluorine or bromine;
an OH, ORii, SH or SR 11 radical, R11 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 CR12(R 13)C(O)OR14;
- a group OCR 12 (R13 )OC(O)R 14 ;
- a group OCR 12 (R13 )OC(O)OR 14 ;
R12 and R13 independently of each other represent a hydrogen atom, an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;
taken together R12 and R13 may form a cycloalkyl with 5 or 6 members;
R14 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 R, advantageously represents an (acyloxy)alkyl carbamate group
-  (CO) -O-C (Re) (R9) -OC (0) -R10, wherein R8 and R9 independently of each other represent a hydrogen atom or an alkyl group; and R10 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 SR1 or S(O)R11 radical R11 having the same meaning as in claim 1, in particular R11 represents a linear or branched saturated hydrocarbon chain with 1 to 4 carbon atoms and more particularly a methyl group.
4. 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.
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 COOR1 1 radical, in each of these radicals, R11 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-(1-{2-[(1    -ethoxycarbonyloxy-ethoxy carbonylmethyl) carbamoyl] -3 -phenyl- propyldisulfanylmethyl}-3 methylsulfanyl-propylcarbamoyloxy)-ethyl isobutyric acid ester,
1-{l-[2-(benzyloxycarbonylmethyl-carbamoyl)-3-phenyl propyl-disulfanylmethyl)-3-methylsulfanyl propylcarbamoyloxyl-ethyl isobutyric acid ester,
1-{1-[2-(carboxymethyl-carbamoyl)-3-phenyl-propyl disulfanylmethyl]-3-methylsulfanyl-propylcarbamoyloxy} ethyl isobutyric acid ester,
1-(1-{2-[(1      -ethoxycarbonyloxy-ethoxycarbonylmethyl) carbamoyl]-3-phenyl-propyldisulfanylmethyl}-3-methane sulfinyl-propylcarbamoloxy)-ethyl isobutyric acid ester,
1-{l-[2-benzyloxycarbonylmethyl-carbamoyl)-3-phenyl propyl-disulfanylmethyl]-3-methanesulfinyl propylcarbamoyloxy}-ethyl isobutyric acid ester,
1-{1-2       [2-(carboxymethyl-carbamoyl)-3-phenyl-propyl disulfanylmethyl]-3-methanesulfinyl-propylcarbamoyl oxy}-ethyl isobutyric acid ester,
2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4 methane-sulfinyl-butyldisulfanylmethyl) cyclopentanecarbonyl}-amino)-succinic acid,
2-({l-[2-(l-isobutyryloxy-ethoxycarbonylamino)-4 methyl-sulfanyl-butyldisulfanylmethyl] cyclopentanecarbonyl}-amino)-succinic acid,
Benzyl 2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino) 4
methanesulfinyl-butyldisulfanylmethyl] cyclopentanecarbonyl}-amino)-succinic acid ester Benzyl 2-({1-[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 A9-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, 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.