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Compounds and compositions for the treatment of pain

文档序号：1173439 发布日期：2020-09-18 浏览：23次 中文

阅读说明：本技术 用于治疗疼痛的化合物和组合物 (Compounds and compositions for the treatment of pain ) 是由 M·施密特 J·布利卡 F·西莫宁 J-J·布吉尼翁 F·比黑尔 K·伊尔哈巴齐 于 2019-02-05 设计创作，主要内容包括：本发明涉及用于治疗疼痛的化合物、吡啶衍生物和含有它们的药物组合物。本发明还涉及具体的化合物、包含它们的组合物及其用途,特别是在治疗疼痛中的用途。(The present invention relates to compounds, pyridine derivatives and pharmaceutical compositions containing them for the treatment of pain. The invention also relates to specific compounds, compositions containing them and their use, in particular in the treatment of pain.)

1.A compound for use in the treatment of pain, wherein the compound is a compound of formula (I):

ar is a carbocyclyl, heterocyclyl, aryl or heteroaryl ring, which ring may be optionally substituted with one or more groups selected from: halogen atom, (C)1-C10) Alkyl, cyano, carbocyclic, aryl, heterocyclic, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ', R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocyclic ring, (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkoxy substitution; the substituents may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution;

n is 0,1, 2 or 3;

R3represents a hydrogen atom, a halogen atom, NRR' or (C)1-C10) Alkyl or (C)1-C10) An alkoxy group;

R4represents a hydrogen atom, a halogen, NRR' or (C)1-C10) Alkyl or (C)1-C10) An alkoxy group;

R5represents a hydrogen atom, a halogen, NRR' or (C)1-C10) Alkyl or (C)1-C10) Alkane (I) and its preparation methodAn oxy group;

wherein R and R' are the same or different, as defined above;

or any salt thereof.

2. The compound for use according to claim 1, wherein the pain is chronic pain.

3. The compound for use according to claim 1 or 2, for reducing or blocking hyperalgesia and/or tolerance effects associated with the use of analgesic compounds, in particular opioid analgesic compounds.

4. The compound for use according to claim 3, wherein the analgesic compound is selected from the group consisting of morphine, fentanyl, sufentanil, alfentanil, heroin, oxycodone, hydromorphone, levorphanol, methadone, buprenorphine, butorphanol, meperidine and mixtures thereof.

5. A compound for use according to any one of claims 1 to 4, for use in the treatment of hyperalgesia associated with or associated with acute or chronic pain occurring in response to surgery, trauma or condition in a mammal.

6. The compound for use according to any one of claims 1 to 5, wherein the compound is a compound of formula (I), Ar is a carbocyclyl or heteroaryl group, preferably furyl, benzofuryl, pyrazolyl or pyridyl, which Ar groups may be optionally substituted by one or more groups selected from: halogen atom, (C)1-C10) Alkyl, aryl, OR-OR, wherein R is as defined above, preferably R is H, (C)1-C10) Alkyl, or-NRR ' groups, wherein R and R ' are as defined above, preferably R and R ' are independently H, (C)1-C10) Alkyl or heterocyclic.

7. The compound for use according to any one of claims 1 to 5, wherein the compoundIs a compound of formula (I), Ar is phenyl, preferably substituted with one or more groups selected from: halogen atom, (C)1-C10) Alkyl, cyano, aryl OR-OR, wherein R is as defined above, preferably R is H OR (C)1-C10) An alkyl group.

8. The compound for use according to any one of claims 1 to 5, wherein the compound is of formula (I) and Ar is 1-naphthyl.

9. The compound for use according to any one of claims 1 to 8, wherein the compound is of formula (I) and R4 and R5 both represent a hydrogen atom.

10. The compound for use according to any one of claims 1 to 9, wherein the compound is a compound of formula (I), R3Is NH2Halogen atoms such as Cl or F, (C)1-C4) Alkyl (e.g. methyl or ethyl), CF3, (C)1-C4) Alkoxy (e.g. methoxy, ethoxy, OCH)2CF3,O(CH2)2NH2) Ether group (e.g. methoxymethyl), NRR ' wherein R and R ' are as defined above, preferably R is H and R ' is (C)1-C10) Alkyl (more particularly methyl, n-butyl, ethyl, isopropyl), optionally substituted with aryl (e.g., phenyl), with alkoxy (e.g., methoxy), or with a heterocycle (e.g., piperidine), R 'may also be a heterocycle (e.g., piperidine), or alternatively, R and R' may form a heterocycle with the nitrogen to which they are attached, e.g., piperidine.

11. The compound for use according to any one of claims 1 to 10, wherein n is 0 and preferably Ar is phenyl substituted at least in the 2-position.

12. The compound for use according to any one of claims 1 to 11, wherein the compound is of formula (II):

Figure FDA0002618570210000031

wherein:

n is 0,1 or 2, preferably n is 0;

r3, R4 and R5 are as defined in any one of claims 1, 9 and 10 above, and

r1 and R2 are independently a hydrogen atom or a substituent of Ar is as defined in claim 1.

13. The compound for use according to claim 12, wherein R1Represents a halogen atom, (C)1-C10) Alkyl, cyano (-CN), aryl (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ', R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, aralkyl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is1The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution; and/or

R2Represents a hydrogen atom, a halogen atom, or (C)1-C10) Alkyl, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is2The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl and (C)1-C10) Alkoxy groups.

14. The compound for use according to claim 13, wherein the compound is a compound of the following formula (III):

Figure FDA0002618570210000041

wherein R is3、R4And R5As defined in any one of the preceding claims, and

R1represents a halogen atom, (C)1-C10) Alkyl, cyano (-CN), aryl (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, aralkyl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is1The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution;

R2represents a hydrogen atom, a halogen atom, or (C)1-C10) Alkyl, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkane (I) and its preparation methodRadical or (C)1-C10) Alkyl oxygen substituted; the R is2The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy groups.

15. The compound for use according to claim 14, wherein the compound is a compound of formula (III) having one or more of the following characteristics:

-R2is H, a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl) OR-OR, R is as defined above, more preferably R is H OR (C)1-C10) An alkyl group; and/or

-R1Represents a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl), carbocyclic (e.g. cyclopropyl, cyclopentyl), aryl (e.g. phenyl) OR-OR, wherein R is as defined above, more preferably R is H, (C)1-C10) Alkyl (e.g. methyl, ethyl, i-propyl or-CH)3(C3H5))、(C1-C10) An alkyl heterocyclic (e.g., 1-piperidinylethyl) or carbocyclic (e.g., cyclopropyl, cyclopentyl); and/or

-R3Is (C)1-C4) Alkyl (e.g. methyl or ethyl), NRR 'wherein R is H and R' is H, (C)1-C10) Alkyl (more particularly methyl, n-butyl, ethyl, isopropyl), optionally substituted with aryl (e.g., phenyl), with alkoxy (e.g., methoxy), or with a heterocycle (e.g., piperidine), R 'may also be a heterocycle (e.g., piperidine), or alternatively, R and R' may form a heterocycle with the nitrogen to which they are attached, e.g., piperidine; and/or

-R4And R5Independently a hydrogen atom, a halogen atom or (C)1-C10) Alkyl, preferably R4And R5Are all hydrogen atoms.

16. The compound for use according to any one of claims 1 to 15, wherein the compound is selected from:

3-phenylpyridine-2, 6-diamine, 1a,

3- (2-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1b,

3- (o-tolyl) pyridine-2, 6-diamine (trifluoroacetate), 1c,

3- (2-ethylphenyl) pyridine-2, 6-diamine (hydrochloride), 1d,

3- (2-isopropylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine (hydrochloride salt), 1g,

3- (3-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1h,

3- (4-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1i,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

3- (2, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1k,

3- (2, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1l,

3- (2, 6-dichlorophenyl) pyridine-2, 6-diamine, 1m,

3- (3, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1n,

3- (3, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1o,

3- (2-chloro-3- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1p,

3- (3-chloro-2-methylphenyl) pyridine-2, 6-diamine (trifluoroacetate), 1q,

3- ([1,1' -biphenyl ] -2-yl) pyridine-2, 6-diamine (hydrochloride), 1r,

2- (2, 6-diaminopyridin-3-yl) phenol, 2a,

3- (2-methoxyphenyl) pyridine-2, 6-diamine (trifluoroacetate), 2b,

3- (2- (trifluoromethoxy) phenyl) pyridine-2, 6-diamine (hydrochloride), 2c,

3- (2-ethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2d,

3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e,

3- (2-isopropoxyphenyl) pyridine-2, 6-diamine 2f,

3- (2-isobutoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2g,

3- (2-methoxyethoxyphenyl) pyridine-2, 6-diamine, 2h,

3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine 2i,

3- (2- (piperidin-1-yl) ethoxy) pyridine-2, 6-diamine 2j,

3- (4-fluoro-2-methoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2k,

3- (2, 3-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2l,

3- (2, 4-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 2m,

3- (furan-2-yl) pyridine-2, 6-diamine (trifluoroacetate), 3a,

3- (furan-3-yl) pyridine-2, 6-diamine (trifluoroacetate), 3b,

3- (benzofuran-2-yl) pyridine-2, 6-diamine (hydrochloride), 3c,

[3,4' -bipyridine ] -2, 6-diamine, 3d,

[3,3' -bipyridine ] -2, 6-diamine, 3e,

3 '-methyl- [3,4' -bipyridine ] -2, 6-diamine, 3f,

n- (6-amino-5- (2, 3-dichlorophenyl) pyridin-2-yl) acetamide, 4a,

3- (2, 3-dichlorophenyl) -N2-methylpyridine-2, 6-diamine, 5a,

3- (2, 3-dichlorophenyl) -N2-ethylpyridine-2, 6-diamine, 5b,

n2-butyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5c,

n2-benzyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5d,

3- (2, 3-dichlorophenyl) -N2-isopropylpyridine-2, 6-diamine, 5e,

3- (2, 3-dichlorophenyl) -N2-phenethylpyridine-2, 6-diamine, 5f,

3- (2, 3-dichlorophenyl) -N2- (2-methoxyethyl) pyridine-2, 6-diamine, 5g,

3- (2, 3-dichlorophenyl) -N2- (2- (piperidin-1-yl) ethyl) pyridine-2, 6-diamine, 5h,

5- (2, 3-dichlorophenyl) -6- (piperidin-1-yl) pyridin-2-amine, 5i,

5- (2, 3-dichlorophenyl) pyridin-2-amine, 6a,

5- (2, 3-dichlorophenyl) -6-methylpyridin-2-amine, 6b,

5- (2, 3-dichlorophenyl) -6-ethylpyridin-2-amine, 6c,

6-ethyl-5- (2-methoxyphenyl) pyridin-2-amine, 6d,

6- (methoxymethyl) -5- (2-methoxyphenyl) pyridin-2-amine, 6e,

5- (2-methoxyphenyl) -6- (trifluoromethoxy) pyridin-2-amine, 6f,

5- (2-methoxyphenyl) -6-propylpyridin-2-amine, 6g,

6-isopropyl-5- (2-methoxyphenyl) pyridine-2-amine, 6h,

6-cyclopropyl-5- (2-methoxyphenyl) pyridin-2-amine, 6i,

5- (2, 3-dichlorophenyl) -6-methoxypyridin-2-amine, 7a,

3- (2, 3-dichlorophenyl) -4-methoxypyridine-2, 6-diamine, 8a,

4-methyl-3- (o-tolyl) pyridine-2, 6-diamine, 8b,

3- (2, 3-dichlorophenyl) -5-fluoropyridine-2, 6-diamine 9a,

3- (2, 3-dichlorophenyl) -5-ethylpyridine-2, 6-diamine, 9b,

3-benzylpyridine-2, 6-diamine hydrochloride, 10a,

3- (4-fluorobenzyl) pyridine-2, 6-diamine, 10b,

3- (4-chlorobenzyl) pyridine-2, 6-diamine, 10c,

3- (3-chlorobenzyl) pyridine-2, 6-diamine, 10d,

3- (2-chlorobenzyl) pyridine-2, 6-diamine, 10e,

3- (2, 4-dichlorobenzyl) pyridine-2, 6-diamine (hydrochloride salt), 10f,

3-phenethylpyridine-2, 6-diamine, 11a,

5- (2-methoxy-phenyl) -3-methyl-pyridin-2-ylamine, 13

5- (2-methoxy-phenyl) -3-trifluoromethyl-pyridin-2-ylamine, 14

3-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 15

5- (2, 3-dichloro-phenyl) -3-fluoro-pyridin-2-ylamine, 16

5- (2, 3-dichloro-phenyl) -4-fluoro-pyridin-2-ylamine, 17

4-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 18

5- (2, 3-dichloro-phenyl) -4-methoxy-pyridin-2-ylamine (hydrochloride salt), 19

4-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 20

5- (2-methoxy-phenyl) -4-methyl-pyridin-2-ylamine, 21

5- (2, 3-dichloro-phenyl) -4-methyl-pyridin-2-ylamine, 22

5- (2-methoxy-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 23

5- (2, 3-dichloro-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 24

4- (2-Aminoethoxy) -5- (2-methoxyphenyl) pyridin-2-amine (dihydrochloride), 25

5- (2-methoxy-phenyl) -6-methyl-pyridin-2-ylamine, 26

5- (2-methoxy-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 27

5- (2, 3-dichloro-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 28

5- (3-chloro-2-methyl-phenyl) -6-ethyl-pyridin-2-ylamine (hydrochloride salt), 29

5- (2-Cyclopropylphenyl) -6-ethyl-pyridin-2-amine (hydrochloride salt), 30

5- [2- (Cyclopropoxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 31

6-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 32

5- (2, 3-dichloro-phenyl) -6-fluoro-pyridin-2-ylamine, 33

5- (2, 3-dichloro-phenyl) -6-trifluoromethyl-pyridin-2-ylamine, 34

6-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 35

5- (2-methoxy-phenyl) -6- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine, 36

6- (2-amino-ethoxy) -5- (2-methoxy-phenyl) -pyridin-2-ylamine, 37

6- (2-amino-ethoxy) -5- (2, 3-dichloro-phenyl) -pyridin-2-ylamine (dihydrochloride), 38

3- (2-Isopropoxy-6-methoxy-phenyl) -pyridine-2, 6-diamine, 39

3- (4-methoxy-2-methyl-phenyl) -pyridine-2, 6-diamine, 40

3- (4-chloro-2-fluoro-phenyl) -pyridine-2, 6-diamine, 41

3- (2-cyclopropyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 42

3- (2-phenoxy-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 43

3- (2-benzyl-phenyl) -pyridine-2, 6-diamine, 44

3- (2-chloro-4-fluoro-phenyl) -pyridine-2, 6-diamine, 45

3- (2-isopropoxy-4-methyl-phenyl) -pyridine-2, 6-diamine, 46

3- (4-chloro-2-cyclopentyloxy-phenyl) -pyridine-2, 6-diamine, 47

3- (2-Cyclopropoxy-phenyl) -pyridine-2, 6-diamine, 48

3- (2-Isopropoxy-5-methyl-phenyl) -pyridine-2, 6-diamine, 49

3- (5-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 50

3- (2, 6-dimethyl-phenyl) -pyridine-2, 6-diamine, 51

3- (2-Isopropoxy-5-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 52

3- (4-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 53

3- (4-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 54

3- (5-chloro-2-cyclopropyl-phenyl) -pyridine-2, 6-diamine, 55

3- (5-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 56

3- (2-methyl-4-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 57

3- (2-chloro-3-methyl-phenyl) -pyridine-2, 6-diamine, 58

3- (2-methylsulfanyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 59

2- (2, 6-diamino-pyridin-3-yl) -N, N-diethyl-benzamide (hydrochloride salt), 60

3- (2-dimethylamino-phenyl) -pyridine-2, 6-diamine (hydrochloride), 61

N- [2- (2, 6-diamino-pyridin-3-yl) -phenyl ] -acetamide, 62

3- (2-Methylsulfonylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 63

3- (2-Benzyloxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 64

3- [2- (cyclopropylmethoxy) phenyl ] pyridine-2, 6-diamine (hydrochloride salt), 65

3- (3-chloro-2-methyl-phenyl) -5-fluoro-pyridine-2, 6-diamine, 66

6-Ethyl-5- (1-naphthyl) pyridin-2-amine (hydrochloride salt), 67

3- (1-naphthyl) pyridine-2, 6-diamine, 68

3- (2-methoxy-1-naphthyl) pyridine-2, 6-diamine, 69

3- (2-Isopropoxy-1-naphthyl) pyridine-2, 6-diamine, 70

3- (4-methyl-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 71

3- (4-fluoro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 72

3- (4-chloro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 73

4- (2, 6-diamino-3-pyridinyl) naphthalen-1-ol (hydrochloride salt), 74

3- [4- (dimethylamino) -1-naphthyl ] pyridine-2, 6-diamine (hydrochloride), 75

5- [2- (cyclopentyloxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 76

3- (4-bromophenyl) pyridine-2, 6-diamine, 77

3- (6-Morpholino-3-pyridinyl) pyridine-2, 6-diamine, 78

3- [6- (1-piperidinyl) -3-pyridinyl ] pyridine-2, 6-diamine, 79

3- [6- (methylamino) -3-pyridinyl ] pyridine-2, 6-diamine, 80

3- (6-pyrrolidin-1-yl-3-pyridyl) pyridine-2, 6-diamine, 81

3- (6-amino-3-pyridyl) pyridine-2, 6-diamine, 82

3- [ 6-amino-5- (trifluoromethyl) -3-pyridinyl ] pyridine-2, 6-diamine, 83

3- (2-methyl-3-pyridyl) pyridine-2, 6-diamine, 84

3- (6-fluoro-2-methyl-3-pyridyl) pyridine-2, 6-diamine, 85

3- (6-fluoro-3-pyridyl) pyridine-2, 6-diamine, 86

3- (2-fluoro-3-pyridyl) pyridine-2, 6-diamine, 87

3- (4-methoxy-3-pyridyl) pyridine-2, 6-diamine, 88

3- (2-methoxy-3-pyridyl) pyridine-2, 6-diamine, 89

3- (3, 5-dimethyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 90

3- (5-methyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 91

2- (2, 6-diamino-3-pyridinyl) benzonitrile hydrochloride, 96

And one of its salts.

17. A compound of formula (III):

wherein R is3、R4And R5As defined in any one of claims 1, 9 and 10, and

R1represents a halogen atom, (C)1-C10) Alkyl, cyano (-CN), aryl (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, aralkyl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is1The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution;

R2represents a hydrogen atom, a halogen atom, or (C)1-C10) Alkyl, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is2The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy groups.

18. The compound of claim 17, wherein the compound exhibits one or more of the following characteristics:

-R2is H, a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl) OR-OR, R is as defined above, more preferably R is H OR (C)1-C10) An alkyl group; and/or

-R1Represents a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl), carbocyclic (e.g. cyclopropyl, cyclopentyl), aryl (e.g. phenyl) OR-OR, wherein R is as defined above, more preferably R is H, (C)1-C10) Alkyl (e.g. methyl, ethyl, i-propyl or-CH)3(C3H5))、(C1-C10) An alkyl heterocyclic group (e.g., 1-piperidinylethyl) or a carbocyclic group as defined above (e.g., cyclopropyl, cyclopentyl); and/or

-R3Is (C)1-C4) Alkyl (e.g. methyl or ethyl), NRR 'wherein R is H and R' is H, (C)1-C10) Alkyl (more particularly methyl, n-butyl, ethyl, isopropyl), optionally substituted with aryl (e.g., phenyl), with alkoxy (e.g., methoxy), or with a heterocycle (e.g., piperidine), R 'may also be a heterocycle (e.g., piperidine), or alternatively, R and R' may form a heterocycle with the nitrogen to which they are attached, e.g., piperidine; and/or

-R4And R5Independently a hydrogen atom, a halogen atom, a (C)1-C10) Alkyl or (C)1-C10) Alkoxy, preferably R4And R5Are all hydrogen atoms.

19. The compound of claim 17 or 18, wherein the compound is selected from the group consisting of:

3- (2-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1b,

3- (2-isopropylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine (hydrochloride salt), 1g,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

3- (2, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1k,

3- (2, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1l,

3- (2, 6-dichlorophenyl) pyridine-2, 6-diamine, 1m,

3- (2-chloro-3- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1p,

3- (3-chloro-2-methylphenyl) pyridine-2, 6-diamine (trifluoroacetate), 1q,

3- ([1,1' -biphenyl ] -2-yl) pyridine-2, 6-diamine (hydrochloride), 1r,

3- (2-methoxyphenyl) pyridine-2, 6-diamine (trifluoroacetate), 2b,

3- (2- (trifluoromethoxy) phenyl) pyridine-2, 6-diamine (hydrochloride), 2c,

3- (2-ethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2d,

3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e,

3- (2-isopropoxyphenyl) pyridine-2, 6-diamine 2f,

3- (2-isobutoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2g,

3- (2-methoxyethoxyphenyl) pyridine-2, 6-diamine, 2h,

3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine 2i,

3- (4-fluoro-2-methoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2k,

3- (2, 3-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2l,

3- (2, 4-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 2m,

3- (2, 3-dichlorophenyl) -N2-methylpyridine-2, 6-diamine, 5a,

3- (2, 3-dichlorophenyl) -N2-ethylpyridine-2, 6-diamine, 5b,

n2-butyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5c,

n2-benzyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5d,

3- (2, 3-dichlorophenyl) -N2-isopropylpyridine-2, 6-diamine, 5e,

3- (2, 3-dichlorophenyl) -N2-phenethylpyridine-2, 6-diamine, 5f,

3- (2, 3-dichlorophenyl) -N2- (2-methoxyethyl) pyridine-2, 6-diamine, 5g,

3- (2, 3-dichlorophenyl) -N2- (2- (piperidin-1-yl) ethyl) pyridine-2, 6-diamine, 5h,

5- (2, 3-dichlorophenyl) -6- (piperidin-1-yl) pyridin-2-amine, 5i,

5- (2, 3-dichlorophenyl) pyridin-2-amine, 6a,

5- (2, 3-dichlorophenyl) -6-methylpyridin-2-amine, 6b,

5- (2, 3-dichlorophenyl) -6-ethylpyridin-2-amine, 6c,

6-ethyl-5- (2-methoxyphenyl) pyridin-2-amine, 6d,

6- (methoxymethyl) -5- (2-methoxyphenyl) pyridin-2-amine, 6e,

5- (2-methoxyphenyl) -6- (trifluoromethoxy) pyridin-2-amine, 6f,

5- (2-methoxyphenyl) -6-propylpyridin-2-amine, 6g,

6-isopropyl-5- (2-methoxyphenyl) pyridine-2-amine, 6h,

6-cyclopropyl-5- (2-methoxyphenyl) pyridin-2-amine, 6i,

5- (2, 3-dichlorophenyl) -6-methoxypyridin-2-amine, 7a,

3- (2, 3-dichlorophenyl) -4-methoxypyridine-2, 6-diamine, 8a,

3- (2, 3-dichlorophenyl) -5-fluoropyridine-2, 6-diamine 9a,

3- (2, 3-dichlorophenyl) -5-ethylpyridine-2, 6-diamine, 9b,

and one of its salts (e.g., hydrochloride or trifluoroacetate).

More particularly, the compound of formula (III) is selected from:

3- (2-chlorophenyl) pyridine-2, 6-diamine, 1b,

3- (2-isopropylphenyl) pyridine-2, 6-diamine, 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine, 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine, 1g,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

5- (2-methoxy-phenyl) -3-methyl-pyridin-2-ylamine, 13

5- (2-methoxy-phenyl) -3-trifluoromethyl-pyridin-2-ylamine, 14

3-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 15

5- (2, 3-dichloro-phenyl) -3-fluoro-pyridin-2-ylamine, 16

5- (2, 3-dichloro-phenyl) -4-fluoro-pyridin-2-ylamine, 17

4-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 18

5- (2, 3-dichloro-phenyl) -4-methoxy-pyridin-2-ylamine (hydrochloride salt), 19

4-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 20

5- (2-methoxy-phenyl) -4-methyl-pyridin-2-ylamine, 21

5- (2, 3-dichloro-phenyl) -4-methyl-pyridin-2-ylamine, 22

5- (2-methoxy-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 23

5- (2, 3-dichloro-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 24

4- (2-Aminoethoxy) -5- (2-methoxyphenyl) pyridin-2-amine (dihydrochloride), 25

5- (2-methoxy-phenyl) -6-methyl-pyridin-2-ylamine, 26

5- (2-methoxy-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 27

5- (2, 3-dichloro-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 28

5- (3-chloro-2-methyl-phenyl) -6-ethyl-pyridin-2-ylamine (hydrochloride salt), 29

5- (2-Cyclopropylphenyl) -6-ethyl-pyridin-2-amine (hydrochloride salt), 30

5- [2- (Cyclopropoxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 31

6-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 32

5- (2, 3-dichloro-phenyl) -6-fluoro-pyridin-2-ylamine, 33

5- (2, 3-dichloro-phenyl) -6-trifluoromethyl-pyridin-2-ylamine, 34

6-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 35

5- (2-methoxy-phenyl) -6- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine, 36

6- (2-amino-ethoxy) -5- (2-methoxy-phenyl) -pyridin-2-ylamine, 37

6- (2-amino-ethoxy) -5- (2, 3-dichloro-phenyl) -pyridin-2-ylamine (dihydrochloride), 38

3- (2-Isopropoxy-6-methoxy-phenyl) -pyridine-2, 6-diamine, 39

3- (4-methoxy-2-methyl-phenyl) -pyridine-2, 6-diamine, 40

3- (4-chloro-2-fluoro-phenyl) -pyridine-2, 6-diamine, 41

3- (2-cyclopropyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 42

3- (2-phenoxy-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 43

3- (2-benzyl-phenyl) -pyridine-2, 6-diamine, 44

3- (2-chloro-4-fluoro-phenyl) -pyridine-2, 6-diamine, 45

3- (2-isopropoxy-4-methyl-phenyl) -pyridine-2, 6-diamine, 46

3- (4-chloro-2-cyclopentyloxy-phenyl) -pyridine-2, 6-diamine, 47

3- (2-Cyclopropoxy-phenyl) -pyridine-2, 6-diamine, 48

3- (2-Isopropoxy-5-methyl-phenyl) -pyridine-2, 6-diamine, 49

3- (5-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 50

3- (2, 6-dimethyl-phenyl) -pyridine-2, 6-diamine, 51

3- (2-Isopropoxy-5-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 52

3- (4-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 53

3- (4-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 54

3- (5-chloro-2-cyclopropyl-phenyl) -pyridine-2, 6-diamine, 55

3- (5-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 56

3- (2-methyl-4-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 57

3- (2-chloro-3-methyl-phenyl) -pyridine-2, 6-diamine, 58

3- (2-methylsulfanyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 59

2- (2, 6-diamino-pyridin-3-yl) -N, N-diethyl-benzamide (hydrochloride salt), 60

3- (2-dimethylamino-phenyl) -pyridine-2, 6-diamine (hydrochloride), 61

N- [2- (2, 6-diamino-pyridin-3-yl) -phenyl ] -acetamide, 62

3- (2-Methylsulfonylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 63

3- (2-Benzyloxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 64

3- [2- (cyclopropylmethoxy) phenyl ] pyridine-2, 6-diamine (hydrochloride salt), 65

3- (3-chloro-2-methyl-phenyl) -5-fluoro-pyridine-2, 6-diamine, 66

5- [2- (cyclopentyloxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 76

And one of its salts (e.g., hydrochloride or trifluoroacetate).

20. A compound of formula (I):

Figure FDA0002618570210000151

wherein:

n, R3, R4 and R5 are as defined in any one of claims 1 to 19, and

ar is 1-naphthyl, which naphthyl is optionally substituted as defined in claim 1.

21. The compound of claim 20, wherein the compound satisfies at least one or more, more particularly all, of the following characteristics:

n is a number of 0, and n is,

R3is (C)1-C10) Alkyl, such as ethyl, or NRR', such as NH2,

the 1-naphthyl group is unsubstituted or substituted with at least one group selected from: halogen atom, cyano group, (C)1-C10) Alkyl, -OR OR-NRR ', wherein R and R' are as defined above,

R4represents a hydrogen atom, and

R5represents a hydrogen atom.

22. The compound of claim 20 or 21, wherein the compound is selected from the group consisting of:

6-Ethyl-5- (1-naphthyl) pyridin-2-amine (hydrochloride salt), 67

3- (1-naphthyl) pyridine-2, 6-diamine, 68

3- (2-methoxy-1-naphthyl) pyridine-2, 6-diamine, 69

3- (2-Isopropoxy-1-naphthyl) pyridine-2, 6-diamine, 70

3- (4-methyl-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 71

3- (4-fluoro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 72

3- (4-chloro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 73

4- (2, 6-diamino-3-pyridinyl) naphthalen-1-ol (hydrochloride salt), 74

3- [4- (dimethylamino) -1-naphthyl ] pyridine-2, 6-diamine (hydrochloride), 75

23. A compound of formula (I):

wherein:

n, R3, R4 and R5 are as defined in any one of claims 1 to 19, and

ar is carbocyclyl or heteroaryl, preferably furyl, benzofuryl, pyrazolyl (preferably 4-pyrazolyl) or pyridyl (preferably 3-pyridyl or 4-pyridyl), which Ar groups may optionally be substituted as described above, more particularly by one or more groups selected from: halogen atom, (C)1-C10) Alkyl, aryl, -OR, wherein R is as defined above, preferably R is H, (C)1-C10) Alkyl, or-NRR ' groups, wherein R and R ' are as defined above, preferably R and R ' are independently H, (C)1-C10) Alkyl or heterocyclic.

24. The compound according to claim 23, wherein the compound fulfils at least one of the following characteristics or more particularly all of the following characteristics:

n is a number of 0, and n is,

R3is (C)1-C10) Alkyl, such as ethyl, or NRR', such as NH2,

R4represents a hydrogen atom, and

R5represents a hydrogen atom.

25. The compound of claim 23 or 24, wherein the compound is selected from the group consisting of:

3- (benzofuran-2-yl) pyridine-2, 6-diamine (hydrochloride), 3c

[3,4' -bipyridine ] -2, 6-diamine, 3d

[3,3' -bipyridine ] -2, 6-diamine, 3e,

3- (6-Morpholino-3-pyridinyl) pyridine-2, 6-diamine, 78

3- [6- (1-piperidinyl) -3-pyridinyl ] pyridine-2, 6-diamine, 79

3- [6- (methylamino) -3-pyridinyl ] pyridine-2, 6-diamine, 80

3- (6-pyrrolidin-1-yl-3-pyridyl) pyridine-2, 6-diamine, 81

3- (6-amino-3-pyridyl) pyridine-2, 6-diamine, 82

3- [ 6-amino-5- (trifluoromethyl) -3-pyridinyl ] pyridine-2, 6-diamine, 83

3- (2-methyl-3-pyridyl) pyridine-2, 6-diamine, 84

3- (6-fluoro-2-methyl-3-pyridyl) pyridine-2, 6-diamine, 85

3- (6-fluoro-3-pyridyl) pyridine-2, 6-diamine, 86

3- (2-fluoro-3-pyridyl) pyridine-2, 6-diamine, 87

3- (4-methoxy-3-pyridyl) pyridine-2, 6-diamine, 88

3- (2-methoxy-3-pyridyl) pyridine-2, 6-diamine, 89

3- (3, 5-dimethyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 90

3- (5-methyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 91

26. A pharmaceutical composition comprising at least one compound as defined in any one of claims 17-25 in a pharmaceutically acceptable vehicle or support.

27. A compound or composition according to any one of claims 17 to 26 for use in the treatment of pain, preferably chronic pain.

28. The compound or composition for use according to claim 27, for reducing or blocking hyperalgesia and/or tolerance effects associated with the use of analgesic compounds, in particular opioid analgesic compounds.

29. A compound or composition for use according to claim 27 or 28, for use in the treatment of hyperalgesia associated with or associated with acute or chronic pain occurring in response to surgery, trauma or condition in a mammal.

Background

The treatment of pain, particularly chronic pain, is a major public health concern. The use of opioid analgesics (e.g., morphine or fentanyl) constitutes an effective method for treating acute pain. However, their repeated and prolonged use results in a loss of effectiveness (tolerance), which in turn leads to hypersensitivity reactions to pain (hyperalgesia), making such treatments complex and vulnerable to the treatment of chronic pain.

The present invention describes a series of novel compounds, namely pyridine derivatives, with high affinity to neuropeptide ff (NPFF) receptors, in particular NPFF1 and NPFF2 receptors, which are involved in nociceptive signaling. In 2006, in PNAS (Simonin et al PNAS (2006)103,2,466-7), dipeptide RF9 (N acetate in WO 02/24192)α-adamantan-1-yl-L-Arg-L-Phe-NH2) Described as the first nanomolar NPFF receptor antagonist. RF9 administered in vivo in rats exhibited anti-hyperalgesic activity, reversing hyperalgesia caused by repeated administration of opioid analgesics. Similar results were later observed in mice (Elhabazi, K. et al British Journal of Pharmacology,2012,165, 2: 424-35).

Opioid analgesics are currently the treatment of choice for moderate or severe pain. For many patients, especially those with advanced cancer, the treatment of pain requires potent, repeated doses of opiates such as morphine or fentanyl. However, the clinical effectiveness and tolerability of this treatment is limited by two phenomena caused by the use of opiates. The first is a tolerance effect characterized by a shortened duration of action and a reduced analgesic intensity. The clinical outcome is that there is a continuing need to increase the dose of opioid drug to maintain the same analgesic effect regardless of the progression of the disease. The second problem is associated with repeated administration of large doses of opioid drugs, known as opioid drug (opioid) -induced hyperalgesia (OIH). Indeed, chronic administration of opiates results in an abnormal increase in pain, independent of the initial nociceptive stimulus.

It has been proposed that this hyperalgesia is the cause of tolerance. Tolerability was practically obvious, as the analgesic effect profile of each daily dose remained constant; thus, the development of hypersensitivity to pain will give the impression of reduced opioid effect. Thus, rather than the opioid losing its efficacy, the individual becomes hypersensitive to pain.

Both phenomena have been widely documented in animal and human studies. Overall, these phenomena have been observed after administration of all types of opiates, regardless of the route of administration or the dose used.

In addition, the administration of high doses of opiate drugs causes a number of side effects such as nausea, constipation, sedation, and respiratory deficits (e.g., delayed respiratory depression).

Currently, several strategies are being investigated to mitigate the effects of these tolerance and hyperalgesia induced by opiates:

1) one of the most common clinical strategies consists of combining opiates with adjuvants (adjuvants) such as anticonvulsants or antidepressants, particularly in the treatment of neuropathic pain. Despite some effectiveness, these additives still present a number of side effects, especially cardiac risks.

2) Rotation of opioids has also been used as an alternative selection strategy, supported by the fact that different opioids have different affinities for each receptor and that tolerance develops independently for each receptor. However, there is little description of the results, and this strategy is also the subject of much discussion.

3) NMDA receptor antagonists are known to block calcium channels, which leads to a reduction in hyperalgesia caused by opiates and a delay in tolerance in humans or animals. However, the clinical use of ketamine as an NMDA receptor antagonist involves a wide range of side effects in humans, especially hallucinations.

Although some degree of success has been reported, there is currently no strategy to effectively block the effects of hyperalgesia and tolerance associated with the repeated use of opioids. Therefore, it is essential to find alternative strategies, especially in the field of neuropathic or cancer pain. Indeed, in the case of these pathologies, the treatments currently used are relatively ineffective and involve the use of high doses of opiates, leading to a number of particularly disabling side effects. Thus, a major therapeutic problem involves the development of new drugs that act on new therapeutic targets involved in pain modulation.

Therapies are currently being investigated to improve the use of opioid analgesics in mammals, particularly human mammals, particularly during extended use or a single high dose administration, such as during surgical procedures.

The NPFF receptor is apparently a relevant target in the anti-opioid drug system leading to the loss of potency of opioid analgesics and the appearance of hyperalgesia. The design of drugs that inhibit the action of these receptors would likely restore the long-term effectiveness of opioid analgesics while preventing the appearance of hyperalgesia induced by the opioid drug.

In this case, the first patent application, publication number WO02/24192, describes Arg-Phe dipeptide derivatives, which provide evidence of this concept in vivo. In particular, a single administration of the Arg-Phe dipeptide derivative in rats blocks hyperalgesia caused by the administration of fentanyl, an opioid analgesic that acts as a mu receptor agonist and is typically used in a hospital setting.

The use of gable pirtine and its derivatives has been described in US4,851,420. They are described as analgesics and antipyretics. WO94/14780 describes pyridine derivatives as NO synthase inhibitors, which are more particularly suitable as analgesics for chronic neurodegenerative diseases and chronic pain.

Summary of The Invention

The present invention describes a family of compounds, the therapeutic use of which enables better treatment of postoperative or chronic pain associated with certain pathologies (pathologies) such as diabetes, cancer, inflammatory diseases (e.g. rheumatoid arthritis) or neuropathy. These types of pain are considered severe and especially disabling.

The compounds of the invention are pyridine derivatives which are strong NPFF1 and/or NPFF2 receptor ligands. Certain compounds exhibit selectivity for NPFF1 or NPFF 2.

More specifically, in mice, the compounds of the invention prevent fentanyl-induced long-lasting hyperalgesia and prevent the development of hyperalgesia associated with long-term morphine administration and the development of analgesic tolerance by NPFF1 receptor blockade.

The selectivity of this compound for NPFF1 receptors located in the supraspinal (supraspinal) region suggests that these receptors are involved in the control of OIH. As representative of this new family of NPFF receptor ligands, the advantages of said derivatives lie in the fact that: in contrast to the dipeptide represented by RF9, this compound showed very satisfactory in vivo activity after oral administration at a low dose of 1 mg/kg. Furthermore, its effectiveness by the oral route was demonstrated in a dose-dependent manner.

Furthermore, studies of the compounds indicated that NPFF receptor ligands have an intrinsic effect on hyperalgesia induced by postoperative pain, inflammatory pain or neuropathic pain, and that morphine analgesia is improved in these pain models.

Thus, the present invention describes a novel class of NPFF receptor ligand compounds which are administered in mammals, for example by the oral or subcutaneous route, in contrast to the hyperalgesic effects and analgesic tolerance induced by administration of opioid analgesics. In addition, the compounds of the present invention improve the analgesic effect of opiate drugs in different pain models. The envisaged therapeutic prospects are primarily due to the co-administration of these compounds with opioid analgesics in the case of post-operative pain therapy, and also for the treatment of severe chronic pain induced by inflammation, neuropathy, cancer, diabetes or drugs. Furthermore, the effect of the compounds of the invention on hypersensitivity reactions to pain makes it possible to envisage the administration of said compounds alone in the context of prophylactic treatment of pain.

Therefore, the object of the present invention relates to compounds and pharmaceutical compositions comprising said compounds for the treatment of pain, more particularly chronic pain. In particular, the compounds and compositions of the present invention prevent the development of hyperalgesia and the development of analgesic tolerance associated with chronic opioid (e.g., morphine) administration. In addition, the compounds and compositions of the present invention reduce hyperalgesia and analgesic tolerance induced by administration of opioid analgesics. In addition, the compounds and compositions of the present invention improve the analgesic effect of opiate drugs in the treatment of pain.

Therefore, the compounds and pharmaceutical compositions of the present invention can be used for the treatment of postoperative pain or severe chronic pain caused by inflammation, neuropathy, cancer, diabetes or drugs.

The invention also describes a method for treating pain in a subject, said method comprising administering to said subject an effective amount of a compound of the invention.

The invention also relates to specific compounds, in particular as medicaments, and to processes for their preparation. The invention also relates to pharmaceutical compositions comprising said specific compounds in a pharmaceutically acceptable carrier.

Drawings

FIG. 1 Effect of Compound 1j (designated cpd 1j) on fentanyl-induced hyperalgesia in mice. On day 0, a single dose of compound 1j (5mg/kg, p.o.) dissolved in 0.5% Tween80 (A, B) or 10% Kolliphor EL (C, D) was administered to the mice 35min prior to fentanyl injection (4X 60. mu.g/kg; 15min interval; s.c.). Nociceptive responses were measured every 1h after the last fentanyl injection using the tail infusion test (48 ℃) until returning to baseline, once daily from day 1 to day 4. E, F: mice were administered increasing doses of compound 1j or vehicle (0.2, 1 and 5mg/kg, sc.) on day 0, and after 20 minutes, animals received four consecutive injections of fentanyl (60 μ g/kg; 15min intervals; s.c.). As detailed in the methods, Hyperalgesia Index (HI) was calculated from day 1 to day 4(B, D and group F). Data are expressed as mean ± s.e.m, n ═ 6 to 10. Fisher assay showed p <0.001 compared to vehicle + saline group. + + + + by Fisher test showed p <0.01 compared to the fentanyl pretreated vehicle group.

Figure 2 effect of compound 1j on morphine-induced hyperalgesia and tolerance. A. From day 0 to day 7, mice received oral R1359(5mg/kg) or vehicle treatment daily 35min prior to morphine (10 mg/kg; s.c.) or saline administration. Basal nociceptive latency was measured once daily using the tail dip test (48 ℃) and then treated (day 1 to day 7). Morphine (5 mg/kg; s.c.) with or without compound 1j was monitored for analgesia during 4h at 48 ℃ using a tail dip test on days 0 and 8. B: comparison of hyperalgesia index values calculated from day 1 to day 7 between test groups. C: comparison of analgesic peaks achieved on days 0 and 8 for the morphine + vehicle and morphine + compound 1j groups. Data are expressed as mean ± s.e.m, n ═ 8 to 10. Fisher assay showed p <0.001 compared to vehicle + saline group. + + + + by Fisher test showed p <0.001 compared to morphine pre-treated vehicle group. Angle by Paired t-test (Paired t-test) showed p <0.01 compared to peak analgesia value in the same group on day 0, angle by Paired t-test showed p <0.001 compared to peak analgesia value in the same group on day 0.μ μ showed p <0.01 compared to morphine-pretreated vehicle group by Unpaired t-test (Unpaired t-test).

Figure 3 effect of compound 1j alone or in combination with morphine on stomachache. A: mice that were plantar-notched on day 0 were treated with compound 1j (5mg/kg, po) or vehicle 35min daily from day 1 to day 6 prior to morphine injection (2.5mg/kg, sc.) or saline injection. The mechanical nociception threshold was measured with Von Frey cellosilk (Von freyfilames) 30min after morphine sc. injection every day. Animals were also measured for mechanical nociception threshold on day 15 to check if they returned to normal mechanical sensitivity. B: comparison of allodynia index values calculated from day 1 to day 6 between test groups. Data are expressed as mean ± s.e.m, n ═ 7 to 9. + p <0.01 compared to morphine pre-treated vehicle group as shown by Fisher test.

Figure 4 effect of compound 1j, alone or in combination with morphine on neuropathic pain. A: mice receiving CCI on day 0 were treated with compound 1j (5mg/kg, p.o.) or vehicle 35min daily between day 11 and day 21 prior to morphine or saline injection. The mechanical nociceptive threshold was measured with Von Frey cellosilk 30min after sc. morphine injections daily. On day 11 post-CCI, mice were pretested with Von Frey fiber to verify neuropathic pain development prior to any treatment. B: comparison of allodynia index values calculated from day 11 to day 21 between test groups. Data are expressed as mean ± s.e.m, n ═ 8-11. Fisher assay showed p <0.05 compared to vehicle + saline group. + p <0.01 compared to morphine pre-treated vehicle group as shown by Fisher test.

FIG. 5 Effect of Compound 1j on a morphine-induced model of hyperalgesia and analgesic tolerance in NPFF1R knockout mice. A: comparison of the basal nociception values of NPFF1R KO mice with WT from their littermates. B: from day 0 to day 7, KO and WT mice received daily oral treatment with R1359(5mg/kg) or vehicle 35min prior to morphine (10 mg/kg; s.c.) or saline injection. Basal nociceptive latency was measured once daily using the tail dip test (48 ℃) and then treated (day 1 to day 7). Morphine (5 mg/kg; s.c.) with or without compound 1j was monitored for analgesia during 4h at 48 ℃ using a tail dip test on days 0 and 8. C: comparison of the hyperalgesia index values calculated from day 1 to day 7 between KO mice treated with morphine in combination with compound 1j or without compound 1j and WT mice. C: comparison of the analgesia peaks achieved by KO treated with morphine + vehicle or morphine + compound 1j with WT animal groups on days 0 and 8. Data are expressed as mean ± s.e.m, n ═ 8-11. And & by unpaired t-test showed p <0.01 compared to WT group. Fisher assay showed p <0.05 compared to vehicle + morphine WT group. + showed p <0.05 by Fisher assay compared to morphine-pretreated vehicle WT group. Degree ° ° p <0.001 compared to the peak analgesic value of the same group on day 0 as shown by paired t-test. μ showed p <0.05 by unpaired t-test compared to the morphine-pretreated vehicle WT group on day d.

FIG. 6 dose-responsive effect of Compound 1c (designated cpd 1c) on fentanyl-induced hyperalgesia. A. Mice were administered an increasing dose of compound 1c or vehicle (0.2, 1 and 5mg/kg, sc.) on day 0, and after 20min, animals received four consecutive fentanyl injections (60 μ g/kg; 15min intervals; s.c.). Nociceptive responses were measured every 1h after the last fentanyl injection using the tail dip test (48 ℃) until baseline was returned and once daily from day 1 to day 4. B: comparison of hyperalgesia index values calculated from day 1 to day 4 between test groups. Data are expressed as mean ± s.e.m, n ═ 6 to 12. + by Fisher test, p <0.01 compared to the fentanyl pre-treated vehicle group.

FIG. 7 Effect of different doses of Compound 1j (A) and Compound 1c (B) on NPVF (alternative name RFRP-3) inhibiting forskolin stimulated cAMP production in hNPFF1R expressing HEK-293 cells.

Detailed Description

The compounds of the invention for use in the treatment of pain have the following general formula (I):

wherein:

ar is a carbocyclyl, heterocyclyl, aryl or heteroaryl ring, which ring may be optionally substituted with one or more groups selected from: halogen atom, (C)1-C10) Alkyl, cyano (-CN), carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ', R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocyclic ring, (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkoxy substitution; the substituents may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution;

n is 0,1, 2 or 3;

R3represents a hydrogen atom, a halogen atom, NRR' or (C)1-C10) Alkyl or (C)1-C10) An alkoxy group;

R4represents a hydrogen atom, a halogen, NRR' or (C)1-C10) Alkyl or (C)1-C10) An alkoxy group;

R5represents a hydrogen atom, a halogen, NRR' or (C)1-C10) Alkyl or (C)1-C10) An alkoxy group;

wherein R and R' are the same or different, as defined above;

or any salt thereof.

According to a particular embodiment, the compounds described in US4,851,420 and WO94/14780 are excluded from the invention.

According to a particular embodiment, the compounds excluded by the invention are compounds selected from: 2, 6-diamino-3- (2,4, 5-trichlorophenyl) pyridine, 2, 6-diamino-3- (phenyl) pyridine, 2, 6-diamino-3- (4-methoxyphenyl) pyridine, 2, 6-diamino-3- (3, 4-dimethoxyphenylphenyl) pyridine, 2, 6-diamino-3- (naphthalen-2-yl) pyridine and 2, 6-diamino-3- (3, 5-dichlorophenyl) pyridine.

Definition of

As used herein, the term "about" will be understood by those of ordinary skill in the art, and will vary to some extent in the context in which it is used. "about" means up to ± 10% of the particular term if the use of that term in the context in which it is used is unclear to a person of ordinary skill in the art.

In accordance with the present invention, the terms "comprises" or "comprising" (and other similar terms, such as "comprises" and "comprising") are open-ended and generally can be construed to include all of the specifically noted features and any optional, additional, or unspecified features. According to a specific embodiment, it can also be interpreted as: the phrase "consisting essentially of", including any optional, additional, and unspecified features that do not materially affect the basic novel characteristics of the claimed invention, or the phrase "consisting of", including only the specified features unless otherwise specified.

Terms referred to herein in the prefix, e.g. C1-C3、C1-C6Or C2-C6Or with a lower number of carbon atoms, e.g. C1-C2、C1-C5Or C2-C5Are used together. If, for example, the term C is used1-C3It means that the corresponding hydrocarbon chain may contain 1-3 carbon atomsEspecially 1,2 or 3 carbon atoms. If, for example, the term C is used1-C6It means that the corresponding hydrocarbon chain may comprise 1 to 6 carbon atoms, in particular 1,2, 3,4, 5 or 6 carbon atoms. If, for example, the term C is used2-C6It means that the corresponding hydrocarbon chain may comprise 2 to 6 carbon atoms, in particular 2,3, 4,5 or 6 carbon atoms.

According to the invention, the term "(C)1-C10) Alkyl "denotes a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having 1 to 10, preferably 1 to 8,1 to 6 or 1 to 4, carbon atoms. Among the saturated alkyl groups, mention may be made of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, neopentyl, n-hexyl. The term alkyl may also denote alkyl having both linear and cyclic hydrocarbon groups, e.g. -CH3(C3H5). The unsaturated alkyl group may be an alkenyl or alkynyl group. The term "alkenyl" refers to an unsaturated, straight, branched, or cyclic aliphatic group containing at least one carbon-carbon double bond. Term "(C)2-C6) Alkenyl "more specifically means ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl or hexenyl.

The term "alkynyl" refers to an unsaturated, straight, branched, or cyclic aliphatic group containing at least one carbon-carbon triple bond. Term "(C)2-C6) Alkynyl "more particularly means ethynyl, propynyl, butynyl, pentynyl, isopentynyl or hexynyl.

The alkyl group may be substituted by at least one halogen atom or NRR 'group (R and R' are as defined above, more particularly and independently a hydrogen atom or (C) as defined above1-C10) Alkyl) substituted. In this context, when halogenated, alkyl may more specifically be CF3Or CH2CF3。

The alkyl group may be interrupted by at least one heteroatom or group such as oxygen, sulfur atom, NR group, - - -C (O) NR- -or- -N (R) C (O) - -wherein R is as defined above and which more particularly comprises a hydrogen atom or as defined aboveYi (C)1-C10) Alkyl, leading to the formation of ether, thioether, amine, carboxamide (carboxamine) or amide bond formation within the alkyl chain or within the ring, respectively, which results in the formation of a heterocyclic ring within the ring. When the alkyl group is an ether group, it may be-O (CH)2)mOCH3Wherein m is an integer from 1 to 6, such as 1,2 or 3.

As used herein, "carbocyclyl" means a non-aromatic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl group is a ring system, two or more rings may be joined together in a fused, bridged or spiro-linked manner. Carbocycles may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Thus, carbocycles include cycloalkyl, cycloalkenyl, and cycloalkynyl. Carbocyclyl groups may have 3 to 20 carbon atoms, however, the present definition also covers occurrences of the term "carbocyclyl" where no numerical range is given. The carbocyclyl group may also be a medium size carbocyclyl group having 3 to 10 carbon atoms. The carbocyclyl group may also be a carbocyclyl group having 3 to 6 carbon atoms. Carbocyclyl may be named "C3-6 carbocyclyl" or a similar name. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 3-dihydro-indene, bicyclo [2.2.2] octyl, adamantyl, and spiro [4.4] nonanyl. In a preferred embodiment, a "carbocycle" is cyclopentyl or cyclohexyl.

As used herein, "heterocycle" or "heterocyclyl" means a non-aromatic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclic rings may be joined together in a fused, bridged or spiro-linked manner. The heterocyclic ring may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. One or more heteroatoms may be present in a non-aromatic or aromatic ring of the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e. the number of atoms making up the ring backbone, including carbon and heteroatoms), however, the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is given. The heterocyclyl group may also be a medium sized heterocyclyl group having 3-10 ring members. The heterocyclic group may also be a heterocyclic group having 3 to 6 ring members. The heterocyclic group may be named "3-6 membered heterocyclyl "or similar names. In a preferred 6 membered monocyclic heterocyclyl said one or more heteroatoms are selected from 1 to 3O, N or S, in a preferred 5 membered monocyclic heterocyclyl said one or more heteroatoms are selected from 1 or 2 heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azaA group, a dioxolanyl group, an imidazolinyl group, an imidazolidinyl group, a morpholinyl group, an oxirane group, an oxepanyl group, a thiepanyl group, a piperidinyl group, a piperazinyl group, a dioxopiperazinyl group, a pyrrolidinyl group, a pyrrolidinonyl group, a pyrrolidinedionyl group, a 4-piperidinonyl group, a pyrazolinyl group, a pyrazolidinyl group, a 1, 3-dioxin group, a 1, 3-dioxane group, a 1, 4-dioxin group, a 1, 4-dioxane group, a 1, 3-oxathianyl group, a 1, 4-oxathianyl group, a 2H-l, a 2-oxazinyl group, a trioxanyl group, a hexahydro-l, a 3, 5-triazinyl group, a 1, 3-dioxolyl group, a 1, 3-dioxolanyl group, a 1, 3-dithiacyclopentadienyl group, 1, 3-dithiolyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl (1,3-oxathiolanyl), tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-l, 4-thiazinyl, and thiomorpholinyl (thiomorpholinyl). "(heterocyclyl) alkyl" is a heterocyclyl group attached as a substituent through an alkylene group. Examples include, but are not limited to, piperidinylethyl or imidazolinylmethyl.

The term alkoxy refers to an alkyl chain attached to the rest of the compound through an oxygen atom (ether linkage). The alkyl chain corresponds to the definition given above, including interrupted or substituted alkyl groups as defined above. Examples which may be mentioned are methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy and hexyloxy. Alkoxy may be amino (C)1-C10) An alkoxy group. Amino (C)1-C10) Alkoxy means a substituted amino group (-NH)2) Terminating and attached via an oxygen atom toAlkoxy chains of the rest of the molecule.

The term "aromatic" refers to a ring or ring system having a conjugated pi electron system, including carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

The term "aryl" corresponds to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 12 carbon atoms. For example, the term "aryl" includes phenyl or naphthyl. In a preferred embodiment, aryl is phenyl.

As used herein, the term "heteroaryl" corresponds to an aromatic monocyclic or polycyclic group containing 5 to 14 atoms and containing at least one heteroatom, such as a nitrogen, oxygen or sulfur atom. Examples of such monocyclic or polycyclic heteroaryls may be: pyridyl, thiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuryl, triazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, furazanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, dihydropyridinyl, pyrimidinyl, s-triazinyl, oxazolyl or thiofuryl (thiofuryl).

In a preferred embodiment, heteroaryl is thienyl, furyl, benzofuryl, pyridyl, pyrazolyl, pyrazinyl or thiazolyl.

The 5-to 10-membered ring of the terms R and R ' or R ' and R ' includes heterocyclyl or heteroaryl as defined above having 5-10 ring members, preferably 5-7 ring members.

Term (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkoxy heterocycle), (C)1-C10) Alkyl heteroaryl and (C)1-C10) Alkoxyheteroaryl refers to a carbocycle, aryl, heterocycle or heteroaryl, respectively, substituted with alkyl or alkoxy.

Aryl and heteroaryl groups may be linked to the rest of the compound through an alkyl group as defined above, and thus they are referred to as aralkyl (or aryl (C), respectively1-C10) Alkyl) or heteroaralkyl.

As used herein, the term "halogen" or "halo" means any one of the radioactive stable atoms of group 7 of the periodic table of elements, such as fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

The specific or preferred embodiments described herein may be combined with each other when chemically feasible. For example, the specifically described embodiments defined with respect to Ar may be combined with the specifically described embodiments with respect to n, R3, R4, and/or R5.

Compound and use thereof

According to a particular embodiment, the compounds of the invention are compounds of formula (I) wherein Ar is an aryl group, preferably a phenyl group, optionally substituted as defined above, more particularly by one or more groups chosen from halogen atoms, cyano groups, (C)1-C10) Alkyl, aryl OR-OR, wherein R is as defined above, preferably R is H OR (C)1-C10) An alkyl group.

According to a particular embodiment a, the compounds of the invention are compounds of formula (I) wherein Ar is 1-naphthyl, said naphthyl being optionally substituted as defined above. According to this particular embodiment, at least one of the following features, or more particularly all of the following features, are satisfied:

n is a number of 0, and n is,

R3is (C)1-C10) Alkyl, such as ethyl, or NRR', such as NH2,

1-naphthyl is unsubstituted or substituted by at least one atom selected from halogen atoms, cyano, (C)1-C10) Alkyl, -OR OR-NRR ', wherein R and R' are as defined above,

R4represents a hydrogen atom, and

R5represents a hydrogen atom.

According to another embodiment B, the compounds of the invention are compounds of formula (I) wherein Ar is carbocyclyl or heteroaryl, preferably furyl, benzofuryl, pyrazolyl (preferably 4-pyrazolyl) or pyridyl (preferably 3-pyridyl or 4-pyridyl), which Ar groups may optionally be substituted as specified above, more particularly by one or more groups selected from: halogen atom, (C)1-C10) Alkyl, aryl, -OR, wherein R is as defined above, preferably R is H, (C)1-C10) Alkyl, or-NRR ' groups, wherein R and R ' are as defined above, preferably R and R ' are independently H, (C)1-C10) Alkyl or heterocyclic. According to this particular embodiment, at least one or more particularly all of the following features are satisfied:

n is a number of 0, and n is,

R3is (C)1-C10) Alkyl, such as ethyl, or NRR', such as NH2,

R4represents a hydrogen atom, and

R5represents a hydrogen atom.

According to another embodiment C, the compounds of the invention are compounds of formula (I) wherein Ar is a heterocycle, which is optionally substituted as defined above, and R is3Represents a halogen atom, NRR' or (C)1-C10) Alkyl, (C)1-C10) An alkoxy group. According to this particular embodiment, n is preferably 1.

According to a particular embodiment, the compounds of the invention are of formula (I), wherein R4Represents H, a halogen atom, an alkyl group (e.g. CH)3Or CF3) Alkoxy (e.g. OCH)3、OCH2CF3、O(CH2)2CF3)、O(CH2)2NH2). According to a preferred embodiment, R4Represents H.

According to another particular embodiment, the compounds of the invention are of formula (I), wherein R5Represents H, a halogen atom or an alkyl group (e.g. CH)3Or CF3). According to a preferred embodiment, R5Represents H.

According to a more specific embodiment, the compounds of the invention are of formula (I), wherein R4And R5All represent hydrogen atoms.

According to a particular embodiment, the compounds of the invention are of formula (I), wherein R3Is NH2Halogen atoms such as Cl or F, (C)1-C4) Alkyl (e.g. methyl or ethyl), CF3、(C1-C4) Alkoxy (e.g. methoxy, ethoxy, OCH)2CF3、O(CH2)2NH2) Ether group (e.g. methoxymethyl), NRR ' wherein R and R ' are as defined above, preferably R is H and R ' is (C)1-C10) Alkyl (more particularly methyl, n-butyl, ethyl, isopropyl), optionally substituted with aryl (e.g., phenyl), with alkoxy (e.g., methoxy), or with a heterocycle (e.g., piperidine), R 'may also be a heterocycle (e.g., piperidine), or alternatively, R and R' may form a heterocycle with the nitrogen to which they are attached, e.g., piperidine.

According to a particular embodiment, the compounds of the invention are of formula (I), wherein R3Is NH2。

According to a particular embodiment, the compounds of the invention are of formula (I) wherein n is 1. When n is 1, R3Is NH2And R is4And R5When it is a hydrogen atom, Ar is preferably an aryl group, more preferably a phenyl group, more particularly substituted with only one or two chlorine atoms (i.e. the phenyl group is substituted with only one or two chlorine atoms), wherein preferably at least one of the chlorine atoms is in the 2 or 3 or 4 position, more preferably only one chlorine is in the 2 position or two chlorine atoms are in the 2 and 4 positions.

According to another particular embodiment, the compounds of the invention are of formula (I) wherein n is 0. In a more specific embodiment, n is 0 and Ar is substituted at least in the 2-position (substituents are as defined above).

According to a particular embodiment, the compounds of the invention are of formula (II):

wherein:

n is 0,1 or 2, preferably n is 0;

R3、R4and R5As defined above, and

R1and R2The substituents independently being a hydrogen atom or Ar are as defined above.

In a preferred embodiment, the compound of formula (II) is a compound of formula (II) wherein the following is defined:

R1represents a halogen atom, (C)1-C10) Alkyl, cyano (-CN), aryl (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, aralkyl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is1The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution; and/or

R2Represents a hydrogen atom, a halogen atom, or (C)1-C10) Alkyl, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is2The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl and (C)1-C10) Alkoxy groups.

More preferably, R2Is H and R1Represents a halogen atom, (C)1-C10) Alkyl OR-OR, most preferably n is 0. Even more preferably, R1In the 2-position of the phenyl radical of the formula (II).

According to another particular embodiment, the compound of the invention is a compound of formula (III):

wherein R is3、R4And R5As defined above, including preferred embodiments as defined above, and

R1represents a halogen atom, (C)1-C10) Alkyl, cyano (-CN), aryl (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, aralkyl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is1The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy and aryl group substitution;

R2represents a hydrogen atom, a halogen atom, or (C)1-C10) Alkyl, -C (O) R, -C (O)2R、-C(O)NRR’、-CONHOR、-CONHSO2R、-NRR’、-N(R)C(O)R’、-N(R)NR’R”、-N(R)C(O)2R’、-N(R)C(O)NR’R”、-N(R)S(O)2R’、-OR、-SR、-S(O)R、-S(O2) R, -S (O) NRR' or-S (O)2NRR ' wherein R, R ' and R ' are independently H, (C)1-C10) Alkyl, carbocycle, aryl, heterocycle, heteroaryl, (C)1-C10) Alkyl carbocycle, (C)1-C10) Alkylaryl, (C)1-C10) Alkyl heterocycle), (C)1-C10) Alkyl heteroaryl, (C)1-C10) Alkoxy carbocycle, (C)1-C10) Alkoxyaryl group, (C)1-C10) Alkoxy heterocycle) or (C)1-C10) The alkoxyheteroaryl, or R and R ' or R ' and R ' may form a 5-10 membered ring, said 5-10 membered ring being optionally substituted with at least one-OH, halogen, (C)1-C10) Alkyl or (C)1-C10) Alkyl oxygen substituted; the R is2The radical may be further substituted by at least one member selected from the group consisting of halogen atoms, hydroxyl groups, (C)1-C10) Alkyl, (C)1-C10) Alkoxy groups.

The compound of formula (III) preferably has one or more of the following characteristics:

-R2is H, a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl) OR-OR, R is as defined above, more preferably R is H OR (C)1-C10) An alkyl group; and/or

-R1Represents a halogen atom, (C)1-C10) Alkyl (preferably (C)1-C4) Alkyl), carbocyclic (e.g. cyclopropyl, cyclopentyl), aryl (e.g. phenyl) OR-OR, wherein R is as defined above, more preferably R is H, (C)1-C10) Alkyl (e.g. methyl, ethyl, i-propyl or-CH)3(C3H5))、(C1-C10) An alkyl heterocyclic ring (e.g. 1-piperidinylethyl) or a carbocyclic group as defined above (e.g. cyclopropyl, cyclopentyl); and/or

-R3Is (C)1-C4) Alkyl (e.g. methyl or ethyl), NRR 'wherein R is H and R' is H, (C)1-C10) Alkyl (more particularly methyl, n-butyl, ethyl, isopropyl), optionally substituted with aryl (e.g., phenyl), with alkoxy (e.g., methoxy), or with a heterocycle (e.g., piperidine), R 'may also be a heterocycle (e.g., piperidine), or alternatively, R and R' may form a heterocycle with the nitrogen to which they are attached, e.g., piperidine; and/or

-R4And R5Independently a hydrogen atom, a halogen atom, a (C)1-C10) Alkyl or (C)1-C10) Alkoxy, preferably R4And R5Are all hydrogen atoms.

According to a further particular aspect of the invention, the invention also relates to the compounds of formula (III), as defined above, the compounds of embodiments a or B and their use, in particular in the field of therapy, more particularly in the treatment of pain.

The invention also relates to pharmaceutical compositions comprising at least one compound of formula (III), embodiment a or embodiment B in a pharmaceutically acceptable vehicle or support.

Compounds of formula (I), (II) or (III) as defined above are exemplified in the examples below.

3- (2-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1b,

3- (o-tolyl) pyridine-2, 6-diamine (trifluoroacetate), 1c,

3- (2-ethylphenyl) pyridine-2, 6-diamine (hydrochloride), 1d,

3- (2-isopropylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine (hydrochloride salt), 1g,

3- (3-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1h,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

3- (2, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1k,

3- (2-chloro-3- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1p,

3- ([1,1' -biphenyl ] -2-yl) pyridine-2, 6-diamine (hydrochloride), 1r,

2- (2, 6-diaminopyridin-3-yl) phenol, 2a,

3- (2-methoxyphenyl) pyridine-2, 6-diamine (trifluoroacetate), 2b,

3- (2- (trifluoromethoxy) phenyl) pyridine-2, 6-diamine (hydrochloride), 2c,

3- (2-ethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2d,

3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e,

3- (2-isopropoxyphenyl) pyridine-2, 6-diamine 2f,

3- (2-isobutoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2g,

3- (2-methoxyethoxyphenyl) pyridine-2, 6-diamine, 2h,

3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine 2i,

3- (2- (piperidin-1-yl) ethoxy) pyridine-2, 6-diamine 2j,

3- (4-fluoro-2-methoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2k,

3- (2, 3-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2l,

3- (2, 4-dimethoxyphenylpyridine-2, 6-diamine (hydrochloride), 2m,

n- (6-amino-5- (2, 3-dichlorophenyl) pyridin-2-yl) acetamide, 4a,

3- (2, 3-dichlorophenyl) -N2-methylpyridine-2, 6-diamine, 5a,

3- (2, 3-dichlorophenyl) -N2-ethylpyridine-2, 6-diamine, 5b,

n2-benzyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5d,

5- (2, 3-dichlorophenyl) -6-methylpyridin-2-amine, 6b,

5- (2, 3-dichlorophenyl) -6-ethylpyridin-2-amine, 6c,

6-ethyl-5- (2-methoxyphenyl) pyridin-2-amine, 6d,

5- (2-methoxyphenyl) -6-propylpyridin-2-amine, 6g,

6-isopropyl-5- (2-methoxyphenyl) pyridine-2-amine, 6h,

6-cyclopropyl-5- (2-methoxyphenyl) pyridin-2-amine, 6i,

3- (2-chlorobenzyl) pyridine-2, 6-diamine, 10e,

3- (2, 4-dichlorobenzyl) pyridine-2, 6-diamine (hydrochloride salt), 10f,

3- (4-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1i

3- (2, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1l,

3- (2, 6-dichlorophenyl) pyridine-2, 6-diamine, 1m,

3- (3, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1n,

3- (3, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1o,

3- (3-chloro-2-methylphenyl) pyridine-2, 6-diamine (trifluoroacetate), 1q,

3- (Furan-2-yl) pyridine-2, 6-diamine (trifluoroacetate), 3a

3- (furan-2-yl) pyridine-2, 6-diamine (trifluoroacetate), 3b

3- (benzofuran-2-yl) pyridine-2, 6-diamine (hydrochloride), 3c

[3,4' -bipyridine ] -2, 6-diamine, 3d

[3,3' -bipyridine ] -2, 6-diamine, 3e,

n2-butyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5c

3- (2, 3-dichlorophenyl) -N2-isopropylpyridine-2, 6-diamine, 5e,

3- (2, 3-dichlorophenyl) -N2-phenethylpyridine-2, 6-diamine, 5f,

3- (2, 3-dichlorophenyl) -N2- (2-methoxyethyl) pyridine-2, 6-diamine, 5g,

3- (2, 3-dichlorophenyl) -N2- (2- (piperidin-1-yl) ethyl) pyridine-2, 6-diamine, 5h,

5- (2, 3-dichlorophenyl) -6- (piperidin-1-yl) pyridin-2-amine, 5i,

5- (2, 3-dichlorophenyl) pyridin-2-amine, 6a,

6- (methoxymethyl) -5- (2-methoxyphenyl) pyridin-2-amine, 6e

5- (2-methoxyphenyl) -6- (trifluoromethoxy) pyridin-2-amine, 6f,

5- (2, 3-dichlorophenyl) -6-methoxypyridin-2-amine, 7a

4-methyl-3- (o-tolyl) pyridine-2, 6-diamine, 8b

3- (2, 3-dichlorophenyl) -4-methoxypyridine-2, 6-diamine, 8a

3- (2, 3-dichlorophenyl) -5-fluoropyridine-2, 6-diamine, 9a

3- (2, 3-dichlorophenyl) -5-ethylpyridine-2, 6-diamine, 9b

3-benzylpyridine-2, 6-diamine hydrochloride, 10a,

3- (4-fluorobenzyl) pyridine-2, 6-diamine, 10b,

3- (4-chlorobenzyl) pyridine-2, 6-diamine, 10c,

3- (3-chlorobenzyl) pyridine-2, 6-diamine, 10d,

3-phenethylpyridine-2, 6-diamine, 11a, or

3-phenylpyridine-2, 6-diamine, 1a.

5- (2-methoxy-phenyl) -3-methyl-pyridin-2-ylamine, 13

5- (2-methoxy-phenyl) -3-trifluoromethyl-pyridin-2-ylamine, 14

3-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 15

5- (2, 3-dichloro-phenyl) -3-fluoro-pyridin-2-ylamine, 16

5- (2, 3-dichloro-phenyl) -4-fluoro-pyridin-2-ylamine, 17

4-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 18

5- (2, 3-dichloro-phenyl) -4-methoxy-pyridin-2-ylamine (hydrochloride salt), 19

4-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 20

5- (2-methoxy-phenyl) -4-methyl-pyridin-2-ylamine, 21

5- (2, 3-dichloro-phenyl) -4-methyl-pyridin-2-ylamine, 22

5- (2-methoxy-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 23

5- (2, 3-dichloro-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 24

4- (2-Aminoethoxy) -5- (2-methoxyphenyl) pyridin-2-amine (dihydrochloride), 25

5- (2-methoxy-phenyl) -6-methyl-pyridin-2-ylamine, 26

5- (2-methoxy-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 27

5- (2, 3-dichloro-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 28

5- (3-chloro-2-methyl-phenyl) -6-ethyl-pyridin-2-ylamine (hydrochloride salt), 29

5- (2-Cyclopropylphenyl) -6-ethyl-pyridin-2-amine (hydrochloride salt), 30

5- [2- (Cyclopropoxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 31

6-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 32

5- (2, 3-dichloro-phenyl) -6-fluoro-pyridin-2-ylamine, 33

5- (2, 3-dichloro-phenyl) -6-trifluoromethyl-pyridin-2-ylamine, 34

6-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 35

5- (2-methoxy-phenyl) -6- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine, 36

6- (2-amino-ethoxy) -5- (2-methoxy-phenyl) -pyridin-2-ylamine, 37

6- (2-amino-ethoxy) -5- (2, 3-dichloro-phenyl) -pyridin-2-ylamine (dihydrochloride), 38

3- (2-Isopropoxy-6-methoxy-phenyl) -pyridine-2, 6-diamine, 39

3- (4-methoxy-2-methyl-phenyl) -pyridine-2, 6-diamine, 40

3- (4-chloro-2-fluoro-phenyl) -pyridine-2, 6-diamine, 41

3- (2-cyclopropyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 42

3- (2-phenoxy-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 43

3- (2-benzyl-phenyl) -pyridine-2, 6-diamine, 44

3- (2-chloro-4-fluoro-phenyl) -pyridine-2, 6-diamine, 45

3- (2-isopropoxy-4-methyl-phenyl) -pyridine-2, 6-diamine, 46

3- (4-chloro-2-cyclopentyloxy-phenyl) -pyridine-2, 6-diamine, 47

3- (2-Cyclopropoxy-phenyl) -pyridine-2, 6-diamine, 48

3- (2-Isopropoxy-5-methyl-phenyl) -pyridine-2, 6-diamine, 49

3- (5-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 50

3- (2, 6-dimethyl-phenyl) -pyridine-2, 6-diamine, 51

3- (2-Isopropoxy-5-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 52

3- (4-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 53

3- (4-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 54

3- (5-chloro-2-cyclopropyl-phenyl) -pyridine-2, 6-diamine, 55

3- (5-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 56

3- (2-methyl-4-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 57

3- (2-chloro-3-methyl-phenyl) -pyridine-2, 6-diamine, 58

3- (2-Methylalkyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 59

2- (2, 6-diamino-pyridin-3-yl) -N, N-diethyl-benzamide (hydrochloride salt), 60

3- (2-dimethylamino-phenyl) -pyridine-2, 6-diamine (hydrochloride), 61

N- [2- (2, 6-diamino-pyridin-3-yl) -phenyl ] -acetamide, 62

3- (2-Methylsulfonylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 63

3- (2-Benzyloxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 64

3- [2- (cyclopropylmethoxy) phenyl ] pyridine-2, 6-diamine (hydrochloride salt), 65

3- (3-chloro-2-methyl-phenyl) -5-fluoro-pyridine-2, 6-diamine, 66

6-Ethyl-5- (1-naphthyl) pyridin-2-amine (hydrochloride salt), 67

3- (1-naphthyl) pyridine-2, 6-diamine, 68

3- (2-methoxy-1-naphthyl) pyridine-2, 6-diamine, 69

3- (2-Isopropoxy-1-naphthyl) pyridine-2, 6-diamine, 70

3- (4-methyl-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 71

3- (4-fluoro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 72

3- (4-chloro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 73

4- (2, 6-diamino-3-pyridinyl) naphthalen-1-ol (hydrochloride salt), 74

3- [4- (dimethylamino) -1-naphthyl ] pyridine-2, 6-diamine (hydrochloride), 75

5- [2- (cyclopentyloxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 76

3- (4-bromophenyl) pyridine-2, 6-diamine, 77

3- (6-Morpholino-3-pyridinyl) pyridine-2, 6-diamine, 78

3- [6- (1-piperidinyl) -3-pyridinyl ] pyridine-2, 6-diamine, 79

3- [6- (methylamino) -3-pyridinyl ] pyridine-2, 6-diamine, 80

3- (6-pyrrolidin-1-yl-3-pyridyl) pyridine-2, 6-diamine, 81

3- (6-amino-3-pyridyl) pyridine-2, 6-diamine, 82

3- [ 6-amino-5- (trifluoromethyl) -3-pyridinyl ] pyridine-2, 6-diamine, 83

3- (2-methyl-3-pyridyl) pyridine-2, 6-diamine, 84

3- (6-fluoro-2-methyl-3-pyridyl) pyridine-2, 6-diamine, 85

3- (6-fluoro-3-pyridyl) pyridine-2, 6-diamine, 86

3- (2-fluoro-3-pyridyl) pyridine-2, 6-diamine, 87

3- (4-methoxy-3-pyridyl) pyridine-2, 6-diamine, 88

3- (2-methoxy-3-pyridyl) pyridine-2, 6-diamine, 89

3- (3, 5-dimethyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 90

3- (5-methyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 91

2- (2, 6-diamino-3-pyridinyl) benzonitrile hydrochloride, 96

According to a preferred embodiment, the compound of formula (I), (II) or (III) is selected from:

3- (2-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1b,

3- (o-tolyl) pyridine-2, 6-diamine (trifluoroacetate), 1c,

3- (2-ethylphenyl) pyridine-2, 6-diamine (hydrochloride), 1d,

3- (2-isopropylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine (hydrochloride salt), 1g,

3- (3-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1h,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

3- (2, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1k,

3- (2-chloro-3- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1p,

3- ([1,1' -biphenyl ] -2-yl) pyridine-2, 6-diamine (hydrochloride), 1r,

2- (2, 6-diaminopyridin-3-yl) phenol, 2a,

3- (2-methoxyphenyl) pyridine-2, 6-diamine (trifluoroacetate), 2b,

3- (2- (trifluoromethoxy) phenyl) pyridine-2, 6-diamine (hydrochloride), 2c,

3- (2-ethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2d,

3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e,

3- (2-isopropoxyphenyl) pyridine-2, 6-diamine 2f,

3- (2-isobutoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2g,

3- (2-methoxyethoxyphenyl) pyridine-2, 6-diamine, 2h,

3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine 2i,

3- (2- (piperidin-1-yl) ethoxy) pyridine-2, 6-diamine 2j,

3- (4-fluoro-2-methoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2k,

3- (2, 3-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2l,

3- (2, 4-dimethoxyphenylpyridine-2, 6-diamine (hydrochloride), 2m,

n- (6-amino-5- (2, 3-dichlorophenyl) pyridin-2-yl) acetamide, 4a,

3- (2, 3-dichlorophenyl) -N2-methylpyridine-2, 6-diamine, 5a,

3- (2, 3-dichlorophenyl) -N2-ethylpyridine-2, 6-diamine,5b,

N2-benzyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5d,

5- (2, 3-dichlorophenyl) -6-methylpyridin-2-amine, 6b,

5- (2, 3-dichlorophenyl) -6-ethylpyridin-2-amine, 6c,

6-ethyl-5- (2-methoxyphenyl) pyridin-2-amine, 6d,

5- (2-methoxyphenyl) -6-propylpyridin-2-amine, 6g,

6-isopropyl-5- (2-methoxyphenyl) pyridin-2-amine,6h,

6-cyclopropyl-5- (2-methoxyphenyl) pyridin-2-amine, 6i,

3- (2-chlorobenzyl) pyridine-2, 6-diamine, 10e,

3- (2, 4-dichlorobenzyl) pyridine-2, 6-diamine (hydrochloride salt), 10f,

including their salts (e.g., hydrochloride or trifluoroacetate salts).

According to a preferred embodiment, the compound of formula (III) is selected from:

3- (2-chlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1b,

3- (2-isopropylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine (hydrochloride salt), 1g,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

3- (2, 4-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1k,

3- (2, 5-dichlorophenyl) pyridine-2, 6-diamine (trifluoroacetate), 1l,

3- (2, 6-dichlorophenyl) pyridine-2, 6-diamine, 1m,

3- (2-chloro-3- (trifluoromethyl) phenyl) pyridine-2, 6-diamine (trifluoroacetate), 1p,

3- (3-chloro-2-methylphenyl) pyridine-2, 6-diamine (trifluoroacetate), 1q,

3- ([1,1' -biphenyl ] -2-yl) pyridine-2, 6-diamine (hydrochloride), 1r,

3- (2-methoxyphenyl) pyridine-2, 6-diamine (trifluoroacetate), 2b,

3- (2- (trifluoromethoxy) phenyl) pyridine-2, 6-diamine (hydrochloride), 2c,

3- (2-ethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2d,

3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e,

3- (2-isopropoxyphenyl) pyridine-2, 6-diamine 2f,

3- (2-isobutoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2g,

3- (2-methoxyethoxyphenyl) pyridine-2, 6-diamine, 2h,

3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine 2i,

3- (4-fluoro-2-methoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2k,

3- (2, 3-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride), 2l,

3- (2, 4-dimethoxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 2m,

3- (2, 3-dichlorophenyl) -N2-methylpyridine-2, 6-diamine, 5a,

3- (2, 3-dichlorophenyl) -N2-ethylpyridine-2, 6-diamine, 5b,

n2-butyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5c,

n2-benzyl-3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 5d,

3- (2, 3-dichlorophenyl) -N2-isopropylpyridine-2, 6-diamine, 5e,

3- (2, 3-dichlorophenyl) -N2-phenethylpyridine-2, 6-diamine, 5f,

3- (2, 3-dichlorophenyl) -N2- (2-methoxyethyl) pyridine-2, 6-diamine, 5g,

3- (2, 3-dichlorophenyl) -N2- (2- (piperidin-1-yl) ethyl) pyridine-2, 6-diamine, 5h,

5- (2, 3-dichlorophenyl) -6- (piperidin-1-yl) pyridin-2-amine, 5i,

5- (2, 3-dichlorophenyl) pyridin-2-amine, 6a,

5- (2, 3-dichlorophenyl) -6-methylpyridin-2-amine, 6b,

5- (2, 3-dichlorophenyl) -6-ethylpyridin-2-amine, 6c,

6-ethyl-5- (2-methoxyphenyl) pyridin-2-amine, 6d,

6- (methoxymethyl) -5- (2-methoxyphenyl) pyridin-2-amine, 6e,

5- (2-methoxyphenyl) -6- (trifluoromethoxy) pyridin-2-amine, 6f,

5- (2-methoxyphenyl) -6-propylpyridin-2-amine, 6g,

6-isopropyl-5- (2-methoxyphenyl) pyridin-2-amine,6h,

6-cyclopropyl-5- (2-methoxyphenyl) pyridin-2-amine, 6i,

5- (2, 3-dichlorophenyl) -6-methoxypyridin-2-amine, 7a,

3- (2, 3-dichlorophenyl) -4-methoxypyridine-2, 6-diamine, 8a,

3- (2, 3-dichlorophenyl) -5-fluoropyridine-2, 6-diamine 9a,

3- (2, 3-dichlorophenyl) -5-ethylpyridine-2, 6-diamine, 9b,

and one of its salts (e.g., hydrochloride or trifluoroacetate).

More particularly, the compound of formula (III) is selected from:

3- (2-chlorophenyl) pyridine-2, 6-diamine, 1b,

3- (2-isopropylphenyl) pyridine-2, 6-diamine, 1e,

3- (2- (trifluoromethyl) phenyl) pyridine-2, 6-diamine, 1f,

3- (2- (methoxymethyl) phenyl) pyridine-2, 6-diamine, 1g,

3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j,

5- (2-methoxy-phenyl) -3-methyl-pyridin-2-ylamine, 13

5- (2-methoxy-phenyl) -3-trifluoromethyl-pyridin-2-ylamine, 14

3-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 15

5- (2, 3-dichloro-phenyl) -3-fluoro-pyridin-2-ylamine, 16

5- (2, 3-dichloro-phenyl) -4-fluoro-pyridin-2-ylamine, 17

4-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 18

5- (2, 3-dichloro-phenyl) -4-methoxy-pyridin-2-ylamine (hydrochloride salt), 19

4-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 20

5- (2-methoxy-phenyl) -4-methyl-pyridin-2-ylamine, 21

5- (2, 3-dichloro-phenyl) -4-methyl-pyridin-2-ylamine, 22

5- (2-methoxy-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 23

5- (2, 3-dichloro-phenyl) -4- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine (hydrochloride), 24

4- (2-Aminoethoxy) -5- (2-methoxyphenyl) pyridin-2-amine (dihydrochloride), 25

5- (2-methoxy-phenyl) -6-methyl-pyridin-2-ylamine, 26

5- (2-methoxy-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 27

5- (2, 3-dichloro-phenyl) -4, 6-dimethyl-pyridin-2-ylamine, 28

5- (3-chloro-2-methyl-phenyl) -6-ethyl-pyridin-2-ylamine (hydrochloride salt), 29

5- (2-Cyclopropylphenyl) -6-ethyl-pyridin-2-amine (hydrochloride salt), 30

5- [2- (Cyclopropoxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 31

6-fluoro-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 32

5- (2, 3-dichloro-phenyl) -6-fluoro-pyridin-2-ylamine, 33

5- (2, 3-dichloro-phenyl) -6-trifluoromethyl-pyridin-2-ylamine, 34

6-methoxy-5- (2-methoxy-phenyl) -pyridin-2-ylamine, 35

5- (2-methoxy-phenyl) -6- (2,2, 2-trifluoro-ethoxy) -pyridin-2-ylamine, 36

6- (2-amino-ethoxy) -5- (2-methoxy-phenyl) -pyridin-2-ylamine, 37

6- (2-amino-ethoxy) -5- (2, 3-dichloro-phenyl) -pyridin-2-ylamine (dihydrochloride), 38

3- (2-Isopropoxy-6-methoxy-phenyl) -pyridine-2, 6-diamine, 39

3- (4-methoxy-2-methyl-phenyl) -pyridine-2, 6-diamine, 40

3- (4-chloro-2-fluoro-phenyl) -pyridine-2, 6-diamine, 41

3- (2-cyclopropyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 42

3- (2-phenoxy-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 43

3- (2-benzyl-phenyl) -pyridine-2, 6-diamine, 44

3- (2-chloro-4-fluoro-phenyl) -pyridine-2, 6-diamine, 45

3- (2-isopropoxy-4-methyl-phenyl) -pyridine-2, 6-diamine, 46

3- (4-chloro-2-cyclopentyloxy-phenyl) -pyridine-2, 6-diamine, 47

3- (2-Cyclopropoxy-phenyl) -pyridine-2, 6-diamine, 48

3- (2-Isopropoxy-5-methyl-phenyl) -pyridine-2, 6-diamine, 49

3- (5-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 50

3- (2, 6-dimethyl-phenyl) -pyridine-2, 6-diamine, 51

3- (2-Isopropoxy-5-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 52

3- (4-fluoro-2-isopropoxy-phenyl) -pyridine-2, 6-diamine, 53

3- (4-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 54

3- (5-chloro-2-cyclopropyl-phenyl) -pyridine-2, 6-diamine, 55

3- (5-chloro-2-methyl-phenyl) -pyridine-2, 6-diamine, 56

3- (2-methyl-4-trifluoromethyl-phenyl) -pyridine-2, 6-diamine, 57

3- (2-chloro-3-methyl-phenyl) -pyridine-2, 6-diamine, 58

3- (2-Methylalkyl-phenyl) -pyridine-2, 6-diamine (hydrochloride salt), 59

2- (2, 6-diamino-pyridin-3-yl) -N, N-diethyl-benzamide (hydrochloride salt), 60

3- (2-dimethylamino-phenyl) -pyridine-2, 6-diamine (hydrochloride), 61

N- [2- (2, 6-diamino-pyridin-3-yl) -phenyl ] -acetamide, 62

3- (2-Methylsulfonylphenyl) pyridine-2, 6-diamine (hydrochloride salt), 63

3- (2-Benzyloxyphenyl) pyridine-2, 6-diamine (hydrochloride salt), 64

3- [2- (cyclopropylmethoxy) phenyl ] pyridine-2, 6-diamine (hydrochloride salt), 65

3- (3-chloro-2-methyl-phenyl) -5-fluoro-pyridine-2, 6-diamine, 66

5- [2- (cyclopentyloxy) phenyl ] -6-ethyl-pyridin-2-amine (hydrochloride salt), 76

And one of its salts (e.g., hydrochloride or trifluoroacetate).

According to a particular embodiment, the compound of embodiment a is selected from:

6-Ethyl-5- (1-naphthyl) pyridin-2-amine (hydrochloride salt), 67

3- (1-naphthyl) pyridine-2, 6-diamine, 68

3- (2-methoxy-1-naphthyl) pyridine-2, 6-diamine, 69

3- (2-Isopropoxy-1-naphthyl) pyridine-2, 6-diamine, 70

3- (4-methyl-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 71

3- (4-fluoro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 72

3- (4-chloro-1-naphthyl) pyridine-2, 6-diamine (hydrochloride salt), 73

4- (2, 6-diamino-3-pyridinyl) naphthalen-1-ol (hydrochloride salt), 74

3- [4- (dimethylamino) -1-naphthyl ] pyridine-2, 6-diamine (hydrochloride), 75

According to a particular embodiment, the compound of embodiment B is selected from:

3- (benzofuran-2-yl) pyridine-2, 6-diamine (hydrochloride), 3c

[3,4' -bipyridine ] -2, 6-diamine, 3d,

[3,3' -bipyridine ] -2, 6-diamine, 3e,

3- (6-Morpholino-3-pyridinyl) pyridine-2, 6-diamine, 78

3- [6- (1-piperidinyl) -3-pyridinyl ] pyridine-2, 6-diamine, 79

3- [6- (methylamino) -3-pyridinyl ] pyridine-2, 6-diamine, 80

3- (6-pyrrolidin-1-yl-3-pyridyl) pyridine-2, 6-diamine, 81

3- (6-amino-3-pyridyl) pyridine-2, 6-diamine, 82

3- [ 6-amino-5- (trifluoromethyl) -3-pyridinyl ] pyridine-2, 6-diamine, 83

3- (2-methyl-3-pyridyl) pyridine-2, 6-diamine, 84

3- (6-fluoro-2-methyl-3-pyridyl) pyridine-2, 6-diamine, 85

3- (6-fluoro-3-pyridyl) pyridine-2, 6-diamine, 86

3- (2-fluoro-3-pyridyl) pyridine-2, 6-diamine, 87

3- (4-methoxy-3-pyridyl) pyridine-2, 6-diamine, 88

3- (2-methoxy-3-pyridyl) pyridine-2, 6-diamine, 89

3- (3, 5-dimethyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 90

3- (5-methyl-1H-pyrazol-4-yl) pyridine-2, 6-diamine, 91

The compounds of the invention, including the compounds of formula (I), (II) or (III) or the compounds of embodiment a or B as defined above are useful for the treatment of pain, preferably chronic pain.

According to another particular embodiment, the compounds of the invention are used to reduce or block hyperalgesia and/or tolerance effects associated with the use of analgesic compounds, in particular opioid analgesic compounds.

The compounds of the invention also include the enantiomers (pure enantiomers or mixtures, in particular racemic mixtures), geometric isomers, salts, hydrates and solvates thereof, solid forms thereof, and mixtures of said forms.

When the compounds of the present invention are in the form of salts, they are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, hydroxynaphthoate, glycerophosphate, ketoglutarate, and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977,66, 2.

Compounds of formula (I) (including any of the embodiments described in detail above), (II) or (III) may be prepared according to techniques known to those skilled in the art. In this regard, the present invention describes a variety of synthetic routes, which are exemplified in the examples below and can be carried out by those skilled in the art. The starting compounds are commercially available or can be synthesized according to standard methods. It will be appreciated that the invention is not limited to a particular synthetic route but extends to other processes which can produce the indicated compounds. The compounds of the invention may be produced by any chemical or genetic technique known in the art. More specifically, the compounds of the present invention may be prepared by one of the methods described in the following schemes.

The compounds of the invention are strong NPFF1 and/or NPFF2 receptor ligands (table 1). Ligands are compounds that bind to one or more binding sites of the NPFF1 and/or NPFF2 receptor. They may be partial or full antagonists or agonists of the NPFF1 or NPFF2 receptor or both.

Certain compounds K of the inventioni<100 nM. Certain compounds exhibit some selectivity for NPFF1 or NPFF 2. In addition to these pharmacological properties, the compounds of the invention may also possess highly satisfactory in vivo activity; they can reduce, even block, the incidence of hyperalgesia and analgesic tolerance induced by the administration of opioid analgesics.

An object of the present invention therefore relates to a compound of formula (III), a compound of embodiment a or a compound of embodiment B of the present invention, including the variants, combinations of variants and specific compounds given above, as a medicament, and also to a process for preparing these compounds.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (III), a compound of embodiment a or a compound of embodiment B of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier, support or vehicle" is meant any carrier that is physiologically acceptable to a subject, particularly a human or animal subject, wherein the carrier depends on the type of administration.

The compounds and pharmaceutical compositions of the invention are particularly useful in methods of treatment, particularly for the treatment of pain. In particular, the compounds and compositions of the present invention reduce or block the hyperalgesic and/or tolerogenic effects associated with the use of analgesic compounds, particularly opioid analgesic compounds. Therefore, the compounds and pharmaceutical compositions of the present invention can be used for the treatment of postoperative pain or severe chronic pain caused by inflammation, neuropathy, cancer, diabetes or drugs.

The present invention also relates to a method for treating pain in a subject, said method comprising administering to said subject an effective amount of a compound or a pharmaceutical composition of the present invention.

The invention also relates to the use of at least one compound according to the invention for the preparation of a pharmaceutical composition intended to treat pain or to reduce or block the hyperalgesic and/or tolerogenic effects associated with the use of analgesic compounds, in particular opioid analgesic compounds.

In case the compound or pharmaceutical composition of the invention is intended to reduce or block the hyperalgesic and/or tolerogenic effects caused by the use of analgesic compounds, in particular opioid analgesic compounds, said compound or pharmaceutical composition containing said compound may be administered simultaneously, separately or sequentially with the analgesic compound.

According to a particular variant, one object of the present invention relates to a pharmaceutical composition comprising at least one compound of the invention, at least one analgesic compound, in particular an opioid drug, and a pharmaceutically acceptable carrier.

Analgesic compounds

Analgesic compounds for use in the context of the present invention are typically opioid compounds, i.e. compounds which act on opioid receptors. They are commonly used to treat severe and persistent pain. Preferably, they are morphine compounds, in particular morphine or morphine-like compounds, i.e. compounds derived from morphine and/or which act on morphine receptors and/or recruit one or more metabolic pathways common to morphine. As specific examples, compounds which may be mentioned are in particular: morphine, fentanyl, sufentanil (sufenntanil), alfentanil, heroin, oxycodone, hydromorphone, levorphanol (levophanol), methadone, buprenorphine, butorphanol (butophanol), meperidine, and the like.

The invention is very particularly suitable for inhibiting hyperalgesia induced by morphine, fentanyl or heroin.

The term "treatment" includes both curative (curative treatment) and prophylactic treatment of pain. Therapeutic treatment is defined as treatment that alleviates, ameliorates and/or eliminates, alleviates and/or stabilizes pain or soreness. Prophylactic treatment includes treatment to prevent pain as well as treatment to reduce and/or delay pain or the risk of developing pain.

By reducing or blocking the hyperalgesic and/or tolerogenic effects associated with the use of opiates, the compounds of the present invention prolong the duration of action and/or increase the intensity of their analgesic effect without causing hypersensitivity to pain. Thus, there is a growing need to reduce, or even eliminate, the increase in opioid dosage to maintain the same analgesic effect.

In general, administration of an opioid analgesic to a mammalian subject appears to be always accompanied by hyperalgesia, and thus the compounds of the present invention may be used each time an opioid analgesic is administered to a subject.

Furthermore, as noted above, administration of high doses of opiates results in a number of side effects, such as nausea, constipation, sedation, and respiratory defects (e.g., delayed respiratory depression). The compounds of the present invention allow the use of lower doses of opioid drugs, thus limiting the adverse side effects of the opioid drugs, such as nausea, constipation, sedation, or respiratory defects, including delayed respiratory depression.

Furthermore, the effect of the compounds of the invention on opioid drug-induced hypersensitivity to pain makes it possible to administer the compounds alone also in the case of prophylactic treatment.

Hyperalgesia induced by stress (stress) or opioids can be prolonged or transient, significant or moderate. The presence of hyperalgesia can be detected, measured and characterized by standard clinical tests (observation, etc.).

In the context of the present invention, the term "inhibition" means a reduction or a blocking (or a reduction or an inhibition) in a partial or complete, temporary or prolonged manner. Accordingly, these terms may be used interchangeably in this specification. The ability to inhibit hyperalgesia and the extent of such inhibition can be determined according to various tests known to those skilled in the art. Furthermore, the term "inhibit" refers to both inhibiting the occurrence of hyperalgesia (e.g., for prophylactic treatment) and inhibiting the occurrence or duration of hyperalgesia (for therapeutic treatment).

The compounds or compositions of the present invention may be administered in a variety of ways and in a variety of forms. Thus, they may be administered orally or, more usually, by systemic routes, such as intravenous, intramuscular, subcutaneous, transdermal, intraarterial routes, and the like. Preferably, the compounds or compositions of the present invention are administered by the oral route. For injection, the compounds are typically packaged in the form of a liquid suspension, which may be injected, for example, by syringe or infusion (perfusion). In this regard, the compounds are typically dissolved in saline, physiological solution, isotonic or buffered solutions, and the like, known to those of skill in the art that are pharmaceutically compatible. Thus, the composition may contain one or more substances or excipients selected from dispersants, solubilizers, stabilizers, preservatives, and the like. Substances or excipients which can be used in liquid and/or injectable preparations are, in particular, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, gum arabic and the like.

According to a particular variant, the compounds of the invention are administered by the same route as the analgesic compounds, for example by the oral route.

The compounds may also be administered in the form of gels, oils, tablets, suppositories, powders, gelatin capsules, capsules and the like, optionally by means of dosage forms or devices ensuring prolonged and/or delayed release. For this type of formulation, substances such as cellulose, carbonates or starches are advantageously used.

It is understood that the flow rate and/or dosage of administration can be adjusted by one skilled in the art depending on the patient, pain observed, the analgesic involved, the mode of administration, and the like. Typically, the compound is administered at a dose of 0.1 μ g to 10mg/kg body weight, more usually 1 μ g to 1000 μ g/kg body weight. Furthermore, administration by the oral route or by injection may comprise several times daily (2,3 or 4) administration, if desired.

In addition, a delayed or extended system may be advantageous for long-term treatment to ensure effective and long-term pain treatment of the subject.

The invention is useful in the prophylactic or therapeutic treatment of hyperalgesia in a variety of conditions, such as hyperalgesia associated with or associated with acute or chronic pain occurring in response to surgery, trauma or condition in a mammal.

The invention can be used for any mammal, in particular a human being, but also for animals, in particular domestic or breeding animals, in particular horses, dogs, etc.

The invention is particularly suitable for use in the prevention or treatment of sensitization processes induced by limited administration of opioid analgesics, such as strong morphine-like drugs (e.g., morphine or fentanyl or derivatives thereof), during surgical or traumatic procedures.

The invention may also be used for the prevention or treatment of chronic pain in mammals, particularly patients, suffering from conditions such as cancer, burns, where analgesics (e.g. morphine) may typically be administered chronically, optionally in delayed form.

The compounds of the invention can also be used to prevent or reduce the tolerability process in a very significant way, thus making it possible to reduce the daily dose of morphine and thus improve the clinical condition of the patient (side effects of morphine-like drugs, such as intestinal disorders).

The reversal of opioid-induced hyperalgesia makes it possible to maintain the effectiveness of the opioid over time, thus making it possible to use lower doses of analgesics, which in turn cause little or no side effects.

The compounds of formula (I), (II) or (III) of the present invention, including any of the embodiments described in detail above, may also be used in the prophylactic or therapeutic treatment of pain.

The compounds of formula (I), (II) or (III) of the present invention, including any of the embodiments described in detail above, may also be useful in the treatment of opioid drug dependence (drug addiction).

According to a particular embodiment, the invention also relates to a kit suitable for use in a treatment by the above-mentioned method. These kits comprise: compositions containing a compound of formula (I) of the invention (including any of the embodiments), (II) or (III) detailed above, in the dosages given above, and a second composition containing an analgesic compound, preferably an opioid compound, in the dosages given above, for simultaneous, separate or sequential administration in an effective amount according to the invention.

Other aspects and advantages of the present invention will become apparent from consideration of the following examples, which must be considered as illustrative and not restrictive.

Examples-brief description of the examples

1-general synthetic method for preparing 3-aryl (heteroaryl) -2,6 diaminopyridine derivatives from 2, 6-diaminopyridine

EXAMPLE 1 preparation of 3- (2, 3-dichlorophenyl) pyridine-2, 6-diamine, 1j (method 1)

Example 2 preparation of 3- (furan-2-yl) pyridine-2, 6-diamine, 3b (method 2)

2-preparation of 3-heteroaryl-2, 6-diaminopyridine derivatives starting from 3-iodo-2, 6-dichloropyridine (method 3)

EXAMPLE 3 preparation of [3,4' -bipyridine ] -2, 6-diamine 3d

3-preparation of 3 (2-alkoxyphenyl) -2, 6-diaminopyridine derivatives starting from 2b methods 4 and 5

EXAMPLE 4 preparation of 3- (2-butoxyphenyl) pyridine-2, 6-diamine, 2e

EXAMPLE 5 preparation of 3- (2-Isopropoxyphenyl) pyridine-2, 6-diamine, 2f

4-preparation of 3 (2-alkoxy phenyl) -2,6 diamino pyridine derivative by using 3-iodine-2, 6-dichloropyridine as raw material

EXAMPLE 6 preparation of 3- (2- (cyclopentyloxy) phenyl) pyridine-2, 6-diamine, 2i

5-preparation of 3-aryl-N2-alkylpyridine-2, 6 diamine starting from 1j by reductive amination of 4a (method 7)

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