阅读说明：本技术 具有hsp调节活性的1,4-二氢吡啶衍生物 (1,4-dihydropyridine derivatives having HSP modulating activity ) 是由 F·富洛普 L·威驰 Z·土耳其 B·潘客 I·霍尔瓦斯 G·巴洛格 S·伯纳斯 á· 于 2012-11-22 设计创作，主要内容包括：本申请涉及具有HSP调节活性的1,4-二氢吡啶衍生物。本发明提供用于治疗或预防性治疗由热激蛋白介导的障碍的式(I)的1,4-二氢吡啶衍生物和立体异构体,包括对映异构体、非对映异构体、外消旋混合物、对映异构体的混合物和其组合,以及其多晶型物、药学上可接受的盐、溶剂合物、酯和前药,<Image he="483" wi="573" file="DDA0002208376630000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R<Sup>1</Sup>是任选取代的C<Sub>6-24</Sub>芳基或包含1-3个氮原子或其它杂原子(如氧和硫)的5-6元杂芳基,和其组合；R<Sup>2</Sup>和R<Sup>3</Sup>独立地是氢或C<Sub>1-6</Sub>烷基；R<Sup>4</Sup>和R<Sup>5</Sup>独立地是氢、任选地被氨基、单-或二-(C<Sub>1-6</Sub>烷基)氨基、或5-24元任选地稠合的杂环取代的C<Sub>1-6</Sub>烷基,所述杂环通过氮连接且任选地包含另外1-3个N、O、S杂原子且任选地被C<Sub>1-6</Sub>烷基或C<Sub>1-6</Sub>烷氧基取代；R<Sup>6</Sup>是C<Sub>1-6</Sub>烷基、C<Sub>3-7</Sub>环烷基、C<Sub>3-7</Sub>环烷基C<Sub>1-6</Sub>烷基或芳基C<Sub>1-6</Sub>烷基。(The present application relates to 1,4-dihydropyridine derivatives having HSP modulating activity. The present invention provides 1,4-dihydropyridine derivatives and stereoisomers of formula (I), including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, and combinations thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters, and prodrugs thereof, useful for the therapeutic or prophylactic treatment of disorders mediated by heat shock proteins, wherein R is 1 Is optionally substituted C 6‑24 Aryl or 5-6 membered heteroaryl containing 1-3 nitrogen atoms or other heteroatoms (such as oxygen and sulfur), and combinations thereof; r 2 And R 3 Independently is hydrogen or C 1‑6 An alkyl group; r 4 And R 5 Independently hydrogen, optionally substituted by amino, mono-or di- (C) 1‑6 Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused 1‑6 Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O, S heteroatoms and optionally being C 1‑6 Alkyl or C 1‑6 Alkoxy substitution; r 6 Is C 1‑6 Alkyl radical, C 3‑7 Cycloalkyl radical, C 3‑7 Cycloalkyl radical C 1‑6 Alkyl or aryl radicals C 1‑6 An alkyl group.)

1. A compound of the formula (I),

wherein

R¹Is optionally substituted by 1 or 2 halogens, straight or branched C_1-6Alkyl radical, C_1-6Alkyl or C_1-6Alkoxy-substituted phenyl;

R²and R³Independently is hydrogen or C_1-6An alkyl group;

R⁴is C_2-6Alkyl, by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; or

R⁴Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is C_2-6Alkyl, by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical C_1-6Alkyl or aryl radicals C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof, and polymorphs, pharmaceutically acceptable salts, or solvates thereof.

2. The compound of claim 1, wherein

R¹Is substituted by 1 or 2 halogen, or halogen C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴is by ammoniaRadical, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; or

R⁴Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

3. The compound of claim 1, wherein

R¹Is substituted by 1 or 2 halogen, or halogen C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently by ammoniaRadical, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

4. The compound of claim 1, wherein

R¹Is substituted by 1 or 2 halogen, or trifluoro C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently by amino, mono-or di (C)_1-6Alkyl) amino, or 5-12 membered heterocycle substituted optionally benzofused C_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

5. The compound of claim 1, wherein

R¹Is substituted by 1 or 2 halogen, or trifluoro C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently is optionally substitutedQuinoline ring substituted C_1-3Alkyl, said isoquinoline ring being linked through nitrogen and optionally being interrupted by 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

6. A compound of formula (I) selected from

6- (2-pyrrolidin-1-yl-ethyl) -1, 2-dimethyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2- (2-dimethylaminoethyl) -1, 6-dimethyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

1, 2-dimethyl-6- (2-morpholin-4-yl-ethyl) -4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

1-methyl-2, 6-bis- [2- (4-methyl-piperazin-1-yl) -ethyl ] -4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

1-methyl-2, 6-bis- (2-piperidin-1-yl-ethyl) -4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (2-chlorophenyl) -1-methyl-2, 6-bis- (2-pyrrolidin-1-yl-ethyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (2-chlorophenyl) -1, 2-dimethyl-6- (2-morpholine-4-ethyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

4- (2-chlorophenyl) -1-methyl-2, 6-bis- [2- (4-methyl-piperazin-1-yl) -ethyl ] -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester tetrahydrate salt;

4- (2-chlorophenyl) -2, 6-bis- (2-dimethylamino-ethyl) -1-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (4-trifluoromethylphenyl) -2, 6-bis- (2-dimethylaminoethyl) -1-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (3, 5-difluorophenyl) -2, 6-bis- (2-dimethylamino-ethyl) -1-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (3, 5-difluorophenyl) -2- (2-dimethylamino-ethyl) -1, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2, 6-diethyl-1-methyl-4- (trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester;

2- (2-dimethylamino-ethyl) -1-methyl-6- (2-piperidin-1-yl-ethyl) -4- (4-trifluoro-methyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

2- (2-dimethylamino-ethyl) -1-methyl-6- (2-morpholin-1-yl-ethyl) -4- (4-trifluoro-methyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

2- [2- (1,2,3, 4-tetrahydroisoquinolin-2-yl) -ethyl ] -1, 6-dimethyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester fumarate;

2- [2- (6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-2-yl) -ethyl ] -1, 6-dimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2- [2- (6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-2-yl) -ethyl ] -6- (2-dimethyl-amino-ethyl) -1-methyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

1, 2-dimethyl-6- [2- (1,2,4, 5-tetrahydrobenzo [ d ] azepin-3-yl) -ethyl ] -4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester fumarate;

1, 2-dimethyl-6-pyrrolidin-1-ylmethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2-cyano-1, 6-dimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester;

1, 2-dimethyl-6-piperidin-1-ylmethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2- (1,2,3, 4-tetrahydro-1H-isoquinolin-2-ylmethyl) -1, 6-dimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2-cyano-1-methyl-6-pyrrolidin-1-ylmethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

2-cyano-6- (2-dimethylaminoethyl) -1-methyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride; or a stereoisomer, polymorph, pharmaceutically acceptable salt or solvate thereof.

7. The compound according to claim 1, selected from

2- (2-dimethylaminoethyl) -1, 6-dimethyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

1-methyl-2, 6-bis- (2-piperidin-1-yl-ethyl) -4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

4- (4-trifluoromethylphenyl) -2, 6-bis- (2-dimethylaminoethyl) -1-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester dihydrochloride;

2, 6-diethyl-1-methyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester;

2- [2- (1,2,3, 4-tetrahydroisoquinolin-2-yl) -ethyl ] -1, 6-dimethyl-4- (4-trifluoromethyl-phenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester fumarate;

2-cyano-1, 6-dimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester; and

2- (1,2,3, 4-tetrahydro-1H-isoquinolin-2-ylmethyl) -1, 6-dimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester hydrochloride;

or a stereoisomer, polymorph, pharmaceutically acceptable salt or solvate thereof.

8. The compound or stereoisomer of claim 1, comprising an enantiomer, a diastereomer, a racemic mixture, a mixture of enantiomers, or a combination thereof, as well as polymorphs, pharmaceutically acceptable salts, or solvates thereof, in enantiomerically enriched form.

9. A pharmaceutical composition comprising a compound or stereoisomer of claim 1, including an enantiomer, a diastereomer, a racemic mixture, a mixture of enantiomers, or a combination thereof, and a polymorph, a pharmaceutically acceptable salt, or a solvate thereof; and one or more pharmaceutically acceptable carriers, excipients, or a combination thereof.

10. A pharmaceutical composition comprising a compound or stereoisomer of claim 1, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof, as well as polymorphs, pharmaceutically acceptable salts, or solvates thereof, in admixture with a therapeutic agent useful in the treatment of neurodegenerative diseases; and one or more pharmaceutically acceptable carriers, excipients, or a combination thereof.

11. A compound represented by the formula (I),

wherein

R¹Is optionally substituted by 1 or 2 halogens, straight or branched C_1-6Alkyl radical, C_1-6Alkyl or C_1-6Alkoxy-substituted phenyl;

R²and R³Independently is hydrogen or C_1-6An alkyl group;

R⁴is C_2-6Alkyl, by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy radicalSubstituted by radicals; and is

R⁵Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; or

R⁴Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is C_2-6Alkyl, by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical C_1-6Alkyl or aryl radicals C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof, as well as polymorphs, pharmaceutically acceptable salts, or solvates thereof, for use in the therapeutic or prophylactic treatment of disorders of heat shock protein modulation, wherein the treatment affects only cells under stress, while non-stressed healthy cells remain unaffected during the treatment.

12. The compound according to claim 11, for its use, wherein the disorder of heat shock protein modulation is selected from the group consisting of neurodegenerative diseases characterized by progressive neurological dysfunction, in particular alzheimer's disease, frontotemporal dementia, dementia with lewy bodies, corticobasal degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), parkinson's disease, huntington's disease, poly-Q related neurodegenerative diseases, multiple sclerosis, hereditary spastic paraparesis, spinocerebellar atrophy, brain cancer related diseases, degenerative neurological diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke related diseases, prion diseases, amyloidosis, friedrich's ataxia, metabolism (diabetes) related diseases, Toxin-related diseases, or charcot-marie-tussileypathy; or any combination thereof.

13. A compound according to claim 11, for use thereof, wherein

R¹Is substituted by 1 or 2 halogen, or halogen C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴is substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; or

R⁴Is hydrogen; -CN; or optionally substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁵Is substituted by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

14. A compound according to claim 11, for use thereof, wherein

R¹Is substituted by 1 or 2 halogen, or halogen C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently by amino, mono-or di (C)_1-6Alkyl) amino, or 5-to 24-membered heterocycle-substituted C optionally fused_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

15. A compound according to claim 11, for use thereof, wherein

R¹Is substituted by 1 or 2 halogen, or trifluoro C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently by ammoniaRadical, mono-or di (C)_1-6Alkyl) amino, or 5-12 membered heterocycle substituted optionally benzofused C_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O or S heteroatoms and optionally being C_1-6Alkyl or 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

16. A compound according to claim 11, for use thereof, wherein

R¹Is substituted by 1 or 2 halogen, or trifluoro C_1-6Alkyl-substituted phenyl;

R²and R³Independently is C_1-6An alkyl group;

R⁴and R⁵Independently is C optionally substituted with an isoquinoline ring_1-3Alkyl, said isoquinoline ring being linked through nitrogen and optionally being interrupted by 1-3C_1-6Alkoxy substitution; and is

R⁶Is C_1-6An alkyl group; or

Stereoisomers, including enantiomers, diastereomers, racemic mixtures, enantiomeric mixtures, or combinations thereof; and their polymorphs, pharmaceutically acceptable salts or solvates.

17. The compound of claim 11, for use thereof, wherein the heat shock protein is selected from HSP-70 and HSP-25.

18. The compound of claim 11, for its use, further comprising administering at least one therapeutic agent useful in the treatment of a neurodegenerative disease.

19. The compound of claim 11, for its use, further comprising a thermal treatment performed simultaneously, separately or sequentially with the administration of an effective amount of the compound.

Background

1. Field of the invention

The present invention relates, in part, to novel compounds useful as pharmaceuticals, to pharmaceutical and cosmetic compositions comprising the novel compounds, and to such compounds for the treatment and prevention of pathophysiological conditions and diseases mediated or affected by heat shock proteins (Hsp), also known as stress proteins. More specifically, the present invention relates to certain 1,4-dihydropyridines having selective Hsp modulating activity in vitro and in vivo, to the use of such compounds in the field of the treatment and prevention of pathophysiological conditions mediated by Hsp, including for example neurodegenerative diseases, cancer, metabolic syndrome, diabetes, obesity, inflammation and skin diseases, as well as diseases and/or disorders that would benefit from altered Hsp function under different metabolic or environmental stress conditions, and to pharmaceutical and cosmetic compositions comprising such compounds.

2. Description of the Prior Art

Heat shock proteins (Hsp) are functionally related proteins whose amount in cells varies when the cells are exposed to high temperature or other stresses ranging from hypoxia, inflammation or infection to environmental pollutants (Goldberg et al, Nature,426: 895-. Certain Hsps can also act as molecular chaperones under normal, unstressed conditions by regulating the proper folding and function of numerous important cellular proteins.

The major heat shock proteins are grouped according to their molecular weight (Hsp 100, Hsp90, Hsp70, Hsp60, and "small Hsp" (stsp)).

Some members of the Hsp family are expressed at low to moderate levels in all organisms because of their important role in protein maintenance. Because of their diverse and critical functions, Hsp plays an important role in the etiology of several human diseases (Solti et al, br.j. pharmacol.,146: 769-. For example abnormally high levels of all kinds of Hsp or certain classes of Hsp are characteristic in different cancer cells and this is usually applicable to type II diabetes, neurodegeneration, cardiovascular disease or aging (V i gh et al; prog. lipid Res.,44(5): 303-.

In order to highlight the mechanism of action of the different Hsp classes and to provide compounds that mitigate their activity and are suitable for drug development, a great deal of research has been carried out in the last decade.

Hsp 70

With the exception of some archaebacteria (Large et al, biochem. Soc. Trans.37:46-51,2009), the evolutionarily conserved family of Hsp70 chaperones and its helper chaperones are present in all ATP-containing compartments of living organisms (Macario et al, Genetics,152: 1277-. A functional Hsp70 chaperone protein network requires ATP-driven interactions between many different substrate-specific and less specific J-domain helper chaperone proteins (49 in humans) that target fewer Hsp70 isoforms on hundreds of protein substrates in a Cell (Kampinge et al, Cell Stress chaprons, 14:105-111,2009) and are regulated by different nucleotide exchange factors such as glucose regulated protein E (Harrison, Cell Stress chaprons 8:218-224,2003), BAG (Kabbage et al, Cell Life Sci.,65:1390-1402,2008), HspBP1(Kabani et al, Cell Lett., 339: 339-342,2002) and Hsp110 proteins (Sha et al, Cell Stress chaprons, 12: 351-8,2007). These networks are critical for: co-translational folding of nascent polypeptides, remodeling of native protein complexes, transduction of cellular signals, regulation of Cell cycle, proliferation and apoptosis (Jolly et al, J.Natl.cancer Inst.,92: 1564-.

In normal cells, quality control systems prevent the accumulation of toxic misfolded protein species. However, misfolding can often occur by escaping quality control in response to mutagenic, ageing or oxidative stress (Soskic et al, Exp. Gerontol.,43: 247-.

As a post-mitotic cell, neurons appear to be particularly sensitive to these effects, and many neurodegenerative disorders (such as alzheimer's disease, parkinson's disease, and huntington's disease) involve abnormal accumulation of misfolded or misprocessed proteins. Genetic studies have routinely linked Hsp70 and its helper chaperones to this process, and as a result, it has emerged as a potential drug target (Evans et al, J Med chem.,53: 4585-. Alzheimer's Disease (AD) is the most common neurodegenerative disease, and its patients are characterized by progressive memory loss and accumulation of Senile Plaques (SP) consisting of β -amyloid (a β) and neurofibrillary tangles (NFT) assembled from tau. Current models suggest that self-association of either a β or tau into β -sheet rich oligomers can lead to neuronal cell death. Hsp70 has been shown to play an important role in the cytotoxicity of A.beta.and tau (for a review, see (Evans et al, J Med chem.,53:4585-4602,2010) for example, sub-stoichiometric levels of Hsp72 block the early stages of A.beta.aggregation in vitro (Evans et al, J Biol chem.,281:33182-33191,2006), and Hsp70 has been shown to alter the processing of amyloid precursor protein (Kumar et al, Hum Mol Genet.,16:848-864,2007) and to protect against A.beta-induced cytotoxicity by inhibiting aspartate-specific cysteine protease-9 and accelerating the elimination of A.beta. (Veereshiwarayya et al, J Biol chem.,281:29468-29478,2006) in addition to these effects on A.beta., the binding protein of microtubule 70 also binds to the tau sequence (this region is repeated from tau binding sites in tau 2 (Saerr et al, j Neurosci Res.,86(12):2763-2773, 2008). This finding suggests that Hsc70 may compete for aggregation and toxicity, and in line with this model, overexpression of Hsp70 in a mouse model reduces aggregated tau (Petrucelli et al, Hum Mol gene., 13:703-714, 2004).

Pharmacological upregulation of Hsp70 expression

Many pharmacological agents have been shown to increase cellular expression of Hsp70 by different mechanisms (Sloan et al, Curr Opin Drug Discov devel.,12: 666-one 681, 2009). However, a distinction should be made between the following molecules: molecules that act through defined stimuli within the Hsp70 regulatory pathway, and those that affect Hsp70 levels by inducing cellular stress. The use of compounds of the latter stress-inducing mechanism may have a higher propensity to cause cell death or other undesirable effects (as a result of chronic stress) and thus may be less desirable as therapeutic agents.

Another distinction between Hsp70 inducers, which increase Hsp70 expression under a wide range of stress conditions, and Hsp70 co-inducers, the only effect of which is to enhance a preexisting stress response and have little or no effect in non-stressed or healthy systems, can be made between the modes of action of different Hsp70 up-regulators. The co-inducer mechanism can thus selectively exhibit a role in diseased tissue, thereby inherently reducing the risk of unwanted side effects in healthy tissue (Sloan et al, Curr Opin Drug Discov Devel, 12: 666-one 681, 2009).

Modulators of protein processing

Proteasome inhibitors such as bortezomib (Lauricella et al, Apoptosis,11:607-625,2006), MG-132 and lactacystin (Kim et al, Biochem Biophys Res Commun, 264:352-358,1999) exhibit significant Hsp70 induction mediated by inhibition of protein degradation, accumulation of unfolded protein and induction of cellular stress response (Sloan et al, Curr Opin Drug Discov devel, 12:666-681, 2009). Lactacystin selectively induces Heat Shock Responses (HSR) in preference to the developed protein responses and reduces nuclear inclusion bodies in a neuronal P127Q model of Huntington's disease (Kim et al, J neurochem.,91: 1044. 1056, 2004). In many cases, Hsp70 induces other, mechanism-based and undesirable cellular effects or apoptosis (Sloan et al, Curr Opin Drug discodevel, 12:666-681, 2009). Although proteasome inhibitors are approved clinically for oncology, their limited therapeutic window may preclude the significant applicability of these drugs in the treatment of protein folding diseases.

Inducers of chemical reactivity

The chemical induction of Hsp70 has been described with respect to: n-ethylmaleimide (Senisterra et al, Biochemistry,36:11002-11011,1997), electrophilic serine protease inhibitors such as 3, 4-Dichloroisocoumarin (DCIC) and N-a-tosyl-L-lysine chloromethyl ketone (TLCK) (Rossi et al, J Biol chem.,273:16446-16452,1998), curcumin (a major component of Curcuma rhizome) (Dunsmore et al, Crit cared., 29:2199-2204,2001), cyclopentenone PG, characterized by PGA1, Δ 7-PGA 1, PGA2 and Δ 12-PGJ2(Lee et al, Proc Natl Acad Sci U S A,92:7207-7211, 1995).

Cyclopentenone PG is capable of inducing Hsp70 and has been reported to induce HSF-1 activation (7-15 fold) (Hamel et al, Cell Stress Chaperones,5: 121-. Sodium salicylate enhanced Hsp70 induction in spinal cord cultures (1mM/40 ℃) compared to heat shock alone, and a 250 μ M dose of indomethacin reduced the temperature required to achieve HSF-1 activation in HeLa cells under heat shock conditions. This activity of indomethacin is associated with an increase in HSF-1 phosphorylation and cytoprotection in HeLa cells; pre-treatment with indomethacin (250. mu.M/40 ℃) increased the cell viability of the subsequent heat shock at 44.5 ℃ from 3% without pre-treatment to about 40% (Lee et al, Proc Natl Acad Sci U S A,92: 7207-.

Recent evidence has also suggested that PPAR γ agonists may have utility in Hsp-dependent processes in addition to their well-characterized insulin sensitizing effects: the reduction in Hsp70 induction observed in the heart of a rat model of insulin resistance was improved by treatment with the PPAR γ agonist pioglitazone (10 mg/kg/day). Other reperfusion experiments also demonstrated that pioglitazone could aid functional recovery in isolated rat hearts (Taniguchi et al, Diabetes,55: 2371-.

Celastrol, a quinone methide triterpene isolated from preparations used in Chinese herbal medicine, effectively co-induces Hsp70 (Westertide et al, J Biol chem.,279: 56053-one 56060,2004) in synergy with other stresses via an HSF-1 dependent mechanism. The drug has been shown to be neuroprotective in a model of multi-Q-aggregated Huntington's disease (Zhang et al, J Mol Med.,85:1421- & 1428,2007) and cytoprotective in a mouse transgenic model of amyotrophic lateral sclerosis (Kiaei et al, neurogene Dis.,2:246- & 254, 2005). Several other natural products, including triterpenoid enones glycyrrhizin (Yan et al, Cell Stress Chaperones,9:378-389,2004) and carbenoxolone (Nagayama et al, Life Sci.,69:2867-2873,2001), as well as masked acetal paeoniflorin (Yan et al, Cell Stress chaprones, 9:378-389,2004), can induce Hsp70 by a similar mechanism to celastrol.

Co-inducible hydroxylamine derivatives

A family of hydroxylamine derivatives, including the prototype clopidogrel, was identified as co-inducers of HSR and have utility in a variety of disease models (Vigh et al, Nat Med.,3:1150-1154, 1997). Treatment of myogenic rat H9c2 cells with clopidogrel (10. mu.M) 16H prior to heat shock resulted in a 4-fold increase in Hsp70 levels compared to heat shock alone (Vigh et al, NatMed.,3:1150-1154,1997), which induction provided cytoprotection (at 100. mu.M) in rat neonatal cardiomyocytes undergoing lethal heat shock (Polakowski et al, Eur J Pharmacol.,435:73-77,2002). The mechanism of action is thought to be through the modulation of HSF-1 binding and phosphorylation of HSF-1, resulting in an effect on HSF-1/DNA binding (Hargitai et al, Biochem Biophys Res Commun, 307: 689-.

It has been demonstrated that the clopidogrel analog BRX-220 significantly elevated Hsp70 levels in post-traumatic neurons compared to vehicle (kalman et al, Exp neurol.,176:87-97,2002). Free alkali, Acremochlorohydrin, of BRX-220, also delays the progression of the amyotrophic lateral sclerosis phenotype in a mouse model (Kalman et al, J neurohem., 107: 339-.

Another hydroxylamine derivative, NG-094, significantly improved multi-Q mediated paralysis in the emerging new caenorhabditis elegans (c. elegans) model, reduced the number of Q35-YFP aggregates, and delayed the acceleration of multi-Q dependent aging (hallimann et al, J Biol chem.,286:18784-18794, 2011).

Metabolites and nutrients

Several metabolites and nutrients at relatively high doses have also been shown to have an effect on Hsp levels with concomitant functional benefits: alpha-lipoic acid ameliorates Hsp70 deficiency in type I diabetic patients (Strokov et al, Bull Exp biolMed.,130: 986-; and studies in the brain of aged rats confirmed increased Hsp expression (Hsp70 and heme oxygenase) in response to administration of acetyl-l-carnitine, a compound found in the mitochondrial membrane (Calabrese et al, artificial Redox Signal,8:404-416, 2006).

Teprenone used in the treatment of gastric ulcers is a well-characterized inducer of Hsp70 that has shown cytoprotective benefits in several models including gastric necrosis (Tomisato et al, Biol Pharm Bull.,24: 887-. Other chaperones, including HspB8(Sanbe et al, PLoS ONE,4: e5351,2009) are also induced by teprenone, which may further contribute to the cytoprotective properties of the molecule. Carvacrol, a major compound in the oils of many origanum species, has the ability to co-induce cellular Hsp70 expression in vitro (Wieten et al, Arthritis rheum, 62:1026-1035, 2010). Carvacrol specifically promotes T cell recognition of endogenous Hsp70, as demonstrated by the in vitro activation of Hsp 70-specific T cell hybridomas and the in vivo amplified T cell response to Hsp70 (Wieten et al, Arthritis rheum, 62: 1026-.

Promiscuous Hsp70 inducer

The SirT-1 activator resveratrol induces Hsp70 and exhibits cytoprotection in human peripheral lymphocytes in response to heat shock and hydrogen peroxide treatment (Putics et al, Artificial Redox Signal,10:65-75,2008).

Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, showed co-induction of Hsp70 in a heat shock reporter gene assay. This effect, which is eliminated in HSF-1 knock-out cells, is thought to be caused by the stabilization of the cytosolic HSF-1 pool (Yang et al, PLoS ONE,3: e2864,2008).

Illimoex has shown efficacy in phase II clinical trials for the treatment of metastatic melanoma by increasing the amount of Reactive Oxygen Species (ROS) in the cells and selectively inducing apoptosis in hypoxic tumor cells. This effect is accompanied by an increase in tumor cell specificity of hypoxic tumor cells (Revill et al, Elesclomol. drugs Future (2008)33:310- > 315), but the development of this drug has recently been suspended because of safety concerns.

Other compounds that may act by mechanisms that are sometimes incompletely characterized to induce Hsp70 include tetrahydropyrimidine (ectoine), a natural product isolated from halophilic microorganisms (Buomino et al, Cell Stresscarbones, 10:197- -.

Many of the Hsp70 inducers described above may rely on covalent modification of proteins in their mode of action and may lead to the initiation of HSR, which may be problematic because of non-specific effects and immunogenicity. In some cases, the molecule may simply be a cellular stressor, activating the cellular defense mechanisms (including Hsp expression). This chronic stress of the cells can deliver short-term efficacy, but is less likely to predict long-term effects on cellular response and viability. A co-inducer compound that enhances the response to an existing stress without exhibiting an effect in a non-stressed environment can provide a higher degree of tissue selectivity than non-specific stressors by acting as: enhancing an existing, but insufficient stress response to ongoing disease-related stress.

Genetic upregulation of Hsp70

The increase in Hsp70 has been shown to be beneficial in several over-expression studies, and in many cases has been associated with cytoprotection or attenuation of stress-induced injury (Broome et al, FASEB J.,20: 1549-S1551, 2006; Choo-Kang et al, Am J Physiol Lung Cell Mol Physiol.,281: L58-68,2001; Chung et al, Proc Natl Acad Sci U S A,105(5): 1739-S1744, 2008; Marber et al, J Clin invest.,95: 1446-S1456, 1995; Muchowski et al, Proc Natl Acad Sci U S A,97: 7841-S7846, 2000; Zheng et al, J Cereb Blood blob., 28:53-63,2008).

Exposure of cells or whole organisms to temperatures in excess of 40 ℃ ("heat stress") can cause up-regulation of chaperones, including Hsp 70. Many different compensatory mechanisms are activated in heat stress and therefore it is difficult to assess which effects are caused only by Hsp 70. To overcome this challenge, mice that over-express only rat Hsp70 under β -actin promotion have been developed. In these transgenic mice, overexpression of the rat inducible 70-kD heat stress protein increased cardiac resistance to ischemic injury (Marber et al, J Clin invest.,95: 1446-. In another study, Hsp72 overexpressing mice showed a decrease in resistance to diet-induced hyperglycemia (Chung et al, Proc Natl Acad Sci U S A,105: 1739-shell 1744,2008) and age-related markers of oxidative stress (lipid peroxidation, glutathione content, superoxide dismutase, and catalase levels) (Broome et al, FASEB J.,20: 1549-shell 1551, 2006). Increased expression of a particular isoform of Hsp70 has also been demonstrated in Hsp70 overexpressing mice (about 10-fold) with reduced susceptibility to cerebral ischemia/reperfusion injury (Zheng et al, J Cereb Blood Flow metab.,28:53-63,2008). This protection from cerebral ischemia is accompanied by a decrease in activation of NF κ B throughout the brain, suggesting that Hsp70 may ameliorate ischemic injury by reducing inflammatory processes (Zheng et al, J Cereb Blood Flow couple, 28:53-63,2008). The effect of Hsp70 overexpression on the discontinuous protein folding process has been demonstrated in an in vitro model of huntington's disease, and aggregation of huntingtin proteins carrying extended polyglutamine repeats is significantly reduced in yeast overexpressing Hsp70 (or Hsp40), suggesting a direct role for these chaperones in preventing misfolding and/or aggregation of the pathogenic protein (muchwski et al, Proc Natl Acad Sci USA,97: 7841-.

Similarly, in a cellular model of cystic fibrosis, the trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) containing the misfolding-prone Δ F508 mutant can be normalized in IB-3 cells with plasmid-induced overexpression of Hsp70, suggesting that Hsp70 plays a role in chaperoning and proper folding of the mutant CFTR, enabling it to be trafficked to the Cell surface (Choo-Kang et al, Am J Physiol Lung Cell Mol Physiol.,281: L58-68,2001).

Small Hsp

Unlike the ATPase chaperone proteins Hsp100, Hsp90, Hsp70 and Hsp60, small Hsp (sHsp) with conserved alpha-crystallization domains passively bind misfolded intermediates independent of ATP hydrolysis (Jakob et al, J biol chem.,268: 1517-one 1520, 1993). In the absence of stress, sHsp predominantly assembles into large oligomer complexes (Garrido et al, Cell Cycle,5: 2592-loop 2601,2006) which under stress conditions can dissociate into amphipathic dimers which prevent aggregation of misfolded polypeptides (Jakob et al, J Biol chem.,268: 1517-loop 1520,1993) and protect against thermal cleavage (Haslebeck et al, Nat Struct Mol Biol.,12: 842-loop 846, 2005; Horvath et al, Biochimica et Biophysica Acta (BBA) -Biomembranes,1778: 3-loop 1664, 2008). sHsp cooperates with Hsp70/Hsp40 and Hsp100 or the GroEL/GroES chaperone network in refolding of misfolded proteins (for review, see (Nakamoto et al, Cell Mol Life Sci, 64:294-306, 2007.) human Hsp27 and Hsp70 are often, although not necessarily, co-expressed in response to a variety of physiological and environmental stimuli (Garrido et al, Cycle,5:2592-2601, 2006; Vigh et al, Trends Biochem Sci, 32:357-363, 2007). since sHsp has strong Cell protective properties (Garrido et al, Cell Cycle,5:2592-2601,2006), their inhibition is important in pharmacological treatment for cancer (Cudel et al, Med chem.,14:2839, 2007), while sHsp's incremental injury can be regulated by Foltra et al, Garr J-13, Sp et al, Garrr-13, Sp, S-S2, S-S2, S-, j Biol Chem 283: 784-; wu et al, Neurobiol Aging,31: 1055-. According to a recent study, Hsp27 can protect neurons from acute and chronic toxic effects of ethanol in transgenic mouse models (Toth et al, Cell Stress and Chaperones,15: 807-.

Although small compounds that modulate Hsp are known, and some of them are in clinical trials, to date none of them are marketed as pharmaceutically active agents. There is an increasing need for specific potent Hsp modulating compounds that meet demanding biological and pharmaceutical requirements for entry into human clinical trials. Ideal candidates for therapeutic use are compounds that do not induce/silence the classical heat shock protein response itself. Instead, they only modulate the expression of specific classes of Hsp that are altered by mild physical or pathophysiological stress. Such Hsp co-modulators are unique drug candidates because they can enhance/reduce Hsp expression in diseased cells without significantly affecting healthy cells, and thus are less likely to have significant side effects.

It is therefore a main object of the present invention to provide compounds having selective stress protein modulating activity, in particular co-modulating activity, which are therefore useful in the treatment of neurodegenerative disorders, cancer diseases, metabolic syndrome, lysosomal storage diseases, skin diseases, and additionally in combination therapy.

The present invention provides certain, in part, novel 1,4-dihydropyridines having selective Hsp-modulating activity. It has been surprisingly and unexpectedly found that said compounds show a selective Hsp co-modulating activity which has not been described so far in relation to 1,4-dihydropyridine derivatives.

A number of documents disclose 1,4-dihydropyridine derivatives and their use, but none of them disclose the use of specific compounds of the present invention as Hsp modulators.

1,4-dihydropyridines are particularly well known in pharmacology as L-type calcium channel blockers (Edraki et al, Drug Discovery Today,14: 1058-; and has been widely used in the treatment of cardiovascular disease (Hope and Lazzara, Adv Intern Med.,27:435-52, 1982). The calcium antagonist 1,4-dihydropyridine has been described for use in the treatment of neuropathy in diabetes (Taber, j. et al, US 5,438,144). Derivatives of 4- (3-chlorophenyl) -5-substituted-carbamoyl-1, 4-dihydropyridine-3-carboxylic acid exhibit selective inhibition of N-type calcium channels and are effective in treating: acute stage of ischemic cerebrovascular disorder; progressive neurodegenerative diseases such as alzheimer's disease, AIDS-related dementia, parkinson's disease, etc. (Nakajo, a. et al, US 6,610,717). Some ester derivatives of 4-nitrophenyl-1, 4-dihydropyridine-5-phosphonic acid are useful for the treatment of cancer or precancerous conditions (Krouse, a.j., WO 2008/137107). Compounds with a concentrated 1,4-dihydropyridine backbone have been reported to lower elevated blood glucose levels (Ono, m. et al, WO 2005/025507) or to prevent cancer cell division (Mauger, j., et al, WO 2007/012972). 2, 6-unsubstituted-1, 4-dihydropyridine derivatives have sirtuin deacetylase activity and are useful in the treatment of cancer, metabolic diseases, cardiovascular diseases and neurodegenerative diseases (Antonello et al, J.Med.chem.,52:5496-504,200, et al)9). N-substituted-1, 4-dihydropyridines have been reported to have coronary vasodilatory and antihypertensive activity (Meyer, h. et al, HU 164867). Some N-substituted-1, 4-dihydropyridine derivatives are useful for the treatment of acute and chronic ischemic disorders by improving blood viscosity (Behner, O.O., EP 0451654), while other N-substituted derivatives exhibit selective Ca²⁺Dependent K⁺Channel modulating activity and can be used for the treatment of central nervous system disorders (Heine, h., g., EP 0705819 and Heine, h., g., EP 0717036).

Disclosure of Invention

The present invention relates to partially novel 1,4-dihydropyridine derivatives which exhibit broad utility by exhibiting Hsp modulating activity and are therefore useful in the treatment and prevention of diseases and pathophysiological conditions mediated by Hsp.

The present invention is based on the following unexpected findings: the 1,4-dihydropyridine derivatives of formula (I), although having no or negligible effect on Ca-channels, are capable of selectively co-regulating Hsp activity, which means that they act only by enhancing or inhibiting the existing stress response and have little or no effect in non-stressed or healthy systems, they selectively show a role in diseased tissue and thus they may reduce the risk of unwanted side effects in healthy tissue. 1,4-dihydropyridine derivatives of formula (I) as co-modulators may provide suitable therapeutic drug candidates for a number of disease states. According to one non-limiting embodiment, depending on the particular Hsp class involved, the 1,4-dihydropyridine derivatives of formula (I) may be used for the treatment and prevention of neurodegenerative diseases, cancer diseases, metabolic syndrome, lysosomal storage disorders or skin disorders. As defined earlier, stress protein co-regulators are substances that: by itself does not affect Hsp production, but can modulate Hsp induction in conjunction with other mild stresses present in different disease states. Since the compounds of the present invention are capable of modulating stress responses in stressed cells without affecting unstressed cells, they are unlikely to produce significant side effects compared to many classes of existing drugs.

Drawings

FIG. 1 Hsp70 co-inducing activity of the compound of example 23 on SHSY5Y cells.

Figure 2 the selective co-induction activity of the compound of example 23 on Hsp70 compared to other Hsp.

Figure 3 Hsp25 co-inducing activity of the compound of example 11 on SHSY5Y cells.

FIG. 4 Hsp70 silencer activity of the compound of example 27 on B16F-10 melanoma cells.

Figure 5 fasting plasma glucose levels (a) and Hsp70 protein levels (B) (measured by western blot) of brown adipose tissue in Zucker obese rats treated with the compound of example 1.

FIG. 6 shows neuroprotection and memory protection of the compound of example 23 (PB: saline).

Figure 7 effect of systemically administered compound of example 23 on UVB-induced increase in skin thickness of SKH-1 hairless mice.

Figure 8 effect of the compound of example 17 on the mean survival time of experimental mouse metastatic melanoma model.

Figure 9 effect of the compound of example 23 on lysosomal stability of B16 melanoma cells.

Figure 10 effect of the compound of example 23 on longevity of ALS model mice.

The following abbreviations and definitions are used throughout this application.

Abbreviations

Amyloid beta-beta

AD Alzheimer's disease

APP amyloid precursor protein

ATPase

CFTR cystic fibrosis transmembrane conductance regulator

DCIC 3, 4-dichloro isocoumarin

DMEM-F12 Dulbecco's modified eagle's Medium nutrient mixture F-12

GFP Green fluorescent protein

HSF heat shock factor

Hsp heat shock proteins

HSR heat shock response

Maximum tolerated dose of MTD

NEF nucleotide exchange factor

Nuclear factor kappa-light chain-enhancer of NF kappa B activated B cells

NFT neurofibrillary tangles

PB physiological saline

PBS phosphate buffered saline

PGS prostaglandins

PPAR gamma peroxisome proliferator-activated receptor gamma

PVDF (polyvinylidene fluoride)

SDS-PAGE sodium dodecyl sulfate-Polyacrylamide gel electrophoresis

SP senile plaque

TLCK N-a-tosyl-L-lysine chloromethyl ketone

YFP yellow fluorescent protein

Definition of

The term "Hsp modulation" denotes the process of: it increases or decreases cellular expression, membrane binding and/or function of Hsp100, Hsp90, Hsp70, Hsp60 and "small Hsp" proteins by different mechanisms.

The term "HSP-co-modulating activity" means the action of "HSP-co-modulators" which do not modulate stress responses by themselves, but are capable of modulating stress responses in the presence of mild stress or pathophysiological conditions. Chaperonin co-regulators act like "smart drugs" by selectively interacting with only those cells under acute or chronic stress. These types of molecules may provide important novel therapies in a number of acute and chronic diseases, where cellular expression, membrane binding and/or function of Hsp100, Hsp90, Hsp70, Hsp60 and "small Hsp" proteins are increased or decreased by different mechanisms.

Furthermore, "modulating" also means changing the ratio of different Hsps.

The term "Hsp up-regulation" refers to the process of: it increases cellular expression and/or function of Hsp100, Hsp90, Hsp70, Hsp60, and "small Hsp" proteins by different mechanisms.

The term "Hsp inducer" denotes such compounds: it increases Hsp expression over a wide range of pathophysiological conditions, unlike Hsp co-inducers, which only act to enhance the existing stress response and have little or no effect in non-stressed or healthy systems.

The term Hsp "chaperone co-inducer" or Hsp "co-inducer" denotes such compounds: it does not induce a stress response on its own, but is able to alter the stress response in the presence of mild stress or pathophysiological conditions. Chaperonin co-inducers act like "smart drugs" by selectively interacting only with those cells under acute stress. These types of molecules can provide important novel therapies in a number of acute and chronic diseases.

The term "Hsp silencer" denotes a compound that: which reduces Hsp expression and/or function under a wide range of stresses, including pathophysiological conditions.

The term "Hsp inhibitor" denotes a compound that: which is capable of exhibiting detectable inhibition of one or more Hsp. The inhibition of Hsp can be determined using the methods described and incorporated herein by reference (Wyshocka et al, mol. Cel. biochem.215:153-156, 2000).

The skilled person will recognize that in vivo Hsp inhibitors need not be in vitro Hsp inhibitors, e.g. a compound in the form of a prodrug exhibits little or no activity in an in vitro assay. Such prodrug forms may be altered by metabolic processes or other biochemical processes in the patient to produce the active compound in vivo.

The term "prodrug" means any pharmaceutically acceptable salt, ester or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof. Different forms of prodrugs are well known in the art. See, e.g., Design of Prodrugs, Bundgaard, eds., Elseview,1985 and Method in Enzymology, Widder, K.et al, eds.; academy, 1985, Vol.42, pp.309-396; bundgaard, H. "Design and Application of precursors", see A Textbook of drug Design and Development, Krosgaard-Larsen and H.Bundgaard, eds, 1991, Chapter 5, pp 113 and 191; and Bundgaard, h., Advanced Drug Delivery Review,1992,8,1-38, each of which is incorporated herein by reference.

The term "pathophysiological condition" means any disease, disorder or action that produces a detrimental biological effect in a subject.

Pathophysiological conditions that are selectively modulated by heat shock protein activity of the compounds of the invention include, but are not limited to: for example

-neurodegenerative diseases characterized by progressive neurological dysfunction, in particular alzheimer's disease, frontotemporal dementia, dementia with lewy bodies, corticobasal degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), parkinson's disease, huntington's disease, poly-Q-related neurodegenerative diseases, multiple sclerosis, hereditary spastic paraplegia, spinocerebellar atrophy, brain cancer related diseases, degenerative neurological diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke related diseases, prion diseases, amyloidosis, friedrich's ataxia, metabolism (diabetes) related diseases, toxin related diseases, charcot-marie-charles neuropathy and others;

-cancer diseases, in particular breast cancer, small cell lung cancer, melanoma, squamous cell cancer, non-small cell lung cancer, bladder cancer, head and neck cancer, ovarian cancer, prostate cancer, kaposi's sarcoma, glioblastoma, glioma, colorectal cancer, genitourinary cancer, gastrointestinal cancer, kidney cancer, hematological cancer, cervical cancer, colon cancer, cutaneous T-cell lymphoma, esophageal cancer, liver cancer, neuroblastoma, oral dysplasia, pancreatic cancer, peripheral T-cell lymphoma, pheochromocytoma, sarcoma, testicular cancer, thyroid cancer and the like;

non-hodgkin's lymphoma, multiple myeloma, leukemia (including acute myelogenous leukemia, chronic lymphocytic leukemia), myelodysplastic syndrome, and mesothelioma;

-metabolic syndrome and related disorders due to or manifested by increased insulin resistance, impaired glucose tolerance, type II diabetes, central obesity, elevated triglyceride levels, reduced HDL cholesterol, thrombogenic and pro-inflammatory states, polycystic ovary syndrome (PCOS), etc.;

lysosomal storage diseases, in particular aspartylglucosaminuria, cystinosis, Fabry's disease, fucosidosis, galactosialidosis, gaucher's disease, GM1 gangliosidosis, Mokao syndrome type B, GM2 gangliosidosis (O, B, AB, B1 variants), Krabbe's disease, metachromatic leukodystrophy (arylsulfatase A and SAP1 deficient), mucolipidosis II and III (I cytopathy), mucolipidosis I (sialorrhoea storage disease), mucolipidosis IV, mucopolysaccharidosis I (Hurler and Scheie syndrome), mucopolysaccharidosis II (Hunter syndrome), mucopolysaccharidosis III (Morphe syndrome A, B, C, D), mucopolysaccharidosis IV (Mokao syndrome A, B), mucopolysaccharidosis (Marangler-Marangler syndrome), Mucopolysaccharidosis VII (beta glucuronidase deficiency), multiple sulfatase deficiency, neuronal ceroid lipofuscinosis, Niemann-Pick disease (A, B and C), pompe disease, compact osteogenesis imperfecta, schinder disease, sialyl storage disease, wolfman disease (cholesteryl ester storage disease), alpha-mannosidosis, beta-mannosidosis;

skin disorders, in particular non-infectious rashes (dermatitis, psoriasis and others), UV-induced inflammation, non-cancerous skin growth (seborrheic keratosis, keratoacanthoma, keloids and others) and skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma, kaposi's sarcoma, paget's papillomatosis).

The term "thermal therapy", also known as "hyperthermia", denotes such medical treatments: wherein body tissues are exposed to slightly higher temperatures or increased body temperature by inducing fever to treat diseases and conditions, particularly cancer, inflammation, metabolic syndrome, benign prostatic hypertrophy, to reduce hemorrhoids, to stimulate the immune system, to increase the level of white blood cells against the disease, to treat pain.

The term "metabolic syndrome" refers to a combination of medical conditions that when taken together increase the risk of developing cardiovascular disease and diabetes. Symptoms and features include fasting hyperglycemia (type II diabetes, impaired glucose tolerance or increased insulin resistance); hypertension; central obesity; overweight with fatty deposits; reduced HDL cholesterol; elevated triglycerides.

The term "subject" refers to an animal, or to one or more cells derived from an animal. Preferably, the animal is a mammal, most preferably a human. The cells may be in any form, including, but not limited to, cells retained in a tissue, cell clusters, immortalized cells, transfected or transformed cells, and cells derived from an animal that has been physically or phenotypically altered.

The term "patient" means any mammal, preferably a human.

A "pharmaceutically acceptable salt" can be prepared from any compound of the present invention having a functional group capable of forming a salt (e.g., a base or acid functional group). Pharmaceutically acceptable salts can be prepared with organic or inorganic acids or bases. The compounds of the invention containing one or more basic functional groups (e.g., amino, alkylamino) are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the purified compound of the invention in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmitate (palmoate), pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, bisulfate, bisulf, Tartrate, thiocyanate, tosylate and undecanoate salts. Other acids (such as oxalic acid), while not themselves pharmaceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The compounds of the invention containing one or more acidic functional groups are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compound, or separately by reacting the pure compound in its free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative pharmaceutically acceptable cations include alkali or alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Some illustrative examples of bases that may be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tetrabutylammonium hydroxide, and the like. Representative organic amines useful for the formation of base addition salts include: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. By such quaternization, water-or oil-soluble or dispersible products can be obtained. See, e.g., Berge et al, "Pharmaceutical Salts", J.pharm.Sci.1977,66: 1-19.

It is to be understood that reference to a salt includes solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during crystallization using pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs often have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and solubility. Various factors (such as recrystallization solvent, crystallization rate, and storage temperature) may cause a single crystal form to dominate.

The term "alkyl" as used herein denotes an optionally substituted straight chain, or optionally substituted branched chain saturated hydrocarbon group having 1-6 carbons. Examples of alkyl residues include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-pentyl, hexyl and the like.

The term "cycloalkyl" as used herein denotes a cyclic alkyl mono-residue wherein each cyclic moiety has from 3 to 7 carbon atoms. Examples of cycloalkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "alkoxy" as used herein denotes an alkyl-O-group, wherein the term alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term "aryl" as used herein denotes aryl groups having from 6 to 10 skeletal ring carbons, such as phenyl and naphthyl.

The term "arylalkyl" as used herein denotes an alkyl residue as defined above wherein at least one H atom is replaced by an aryl residue as defined above, e.g. benzyl, 2-phenylethyl and the like.

The term "heteroaryl" as used herein means: aromatic groups containing 5 to 6 backbone ring atoms, wherein 1 to 4 ring atoms are nitrogen atoms, or heteroaryl groups containing 1 to 3 nitrogen atoms or other heteroatoms (such as oxygen and sulfur), and combinations thereof. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, and the like.

The term "alk-X-alk" as used herein means alk-O-alk, alk-S-alk, alk-SO-alk₂-alk groups, wherein alk is an alkyl group containing 1 to 6 carbon atoms. Examples of alk-X-alk include, but are not limited to, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl, methylsulfinylmethyl, ethylsulfinylmethyl, methylsulfonylmethyl, ethylsulfonylmethyl, and the like.

The term "halogen" as used herein denotes fluorine, chlorine, bromine, iodine.

The term "heterocyclic" as used herein denotes an optionally substituted and fused, and in the heterocyclic moiety, partially saturated cyclic residue containing 5 to 24 ring atoms, wherein one of said ring atoms is nitrogen, and optionally other heteroatoms are, for example, oxygen, nitrogen, sulfur, such as, but not limited to, pyrrolidinyl (pirrolidinyl), piperidinyl, piperazinyl, pyrrolidinyl (pyrrolidinyl), morpholinyl, tetrahydroisoquinolinyl, tetrahydrobenzazepinyl (azepinyl), and the like. The heterocyclic ring may optionally be substituted at any position by an alkyl, alkoxy residue as defined above.

The term "mono-or di-alkylamino" as used herein denotes the group-NHR, -NRR ', wherein R and R' are alkyl as defined above.

An "optionally substituted" group may be substituted or unsubstituted.

Some compounds of the invention may contain one or more chiral centers and may therefore exist in enantiomeric as well as diastereomeric forms. The scope of the present invention is intended to encompass all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers, and racemic mixtures of enantiomers (optical isomers).

Furthermore, different forms may be separated using well-known techniques, and some embodiments of the invention may characterize a purified or enriched species of a given enantiomer or diastereomer.

By "pharmacological or dermatological or cosmetic composition" is meant a mixture of one or more compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically and/or dermatologically or cosmetically acceptable carriers and/or excipients. The purpose of the pharmacological composition is to facilitate the administration of the compound to the organism.

The phrase "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material: which is involved in carrying or transporting the subject agent from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline water; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible materials employed in pharmaceutical formulations.

By "excipient" is meant an inert substance added to the pharmacological composition to further facilitate administration of the compound. Examples of excipients include, but are not limited to: calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

By "pharmaceutically effective amount" is meant an amount that provides a therapeutic and/or prophylactic effect. The specific dose of the compound to be administered in accordance with the invention to obtain a therapeutic and/or prophylactic effect will of course depend on the particular circumstances of the case, including, for example, the specific compound to be administered, the route of administration, the pathophysiological condition to be treated and the individual to be treated. Typical daily doses (administered in single or divided doses) contain dosage levels of the active compounds of the invention from about 0.01mg/kg to about 50-100mg/kg body weight. The preferred daily dose is generally from about 0.05mg/kg to about 20mg/kg, and desirably from about 0.1mg/kg to about 10 mg/kg. Factors such as clearance, half-life, and Maximum Tolerated Dose (MTD) remain to be determined, but one of ordinary skill in the art can determine these using standard procedures.

The pharmaceutical composition comprising the compound of formula (I) as an active ingredient may additionally comprise an agent useful for treating neurodegenerative diseases, cancer diseases, metabolic syndrome, lysosomal storage diseases, or skin disorders, or the pharmaceutical composition comprising the compound of formula (I) may be co-administered with such an agent.

Additional agents useful in the treatment of neurodegenerative diseases, cancer diseases, metabolic syndrome, lysosomal storage diseases, or skin disorders refer to, but are not limited to, antineoplastic agents, agents for oral antidiabetic agents, agents for anti-dementia agents, agents for anti-parkinson agents, agents for anti-multiple sclerosis agents, agents for anti-ALS agents, agents for anti-friedreich ataxia agents, agents for anti-epileptic agents, and other treatments.

Antineoplastic agents include, but are not limited to: such as alkylating agents (cyclophosphamide, ifosfamide, carmustine, etc.), antimetabolites (methotrexate, raltitrexed, pemetrexed, cytarabine, fludarabine, cytarabine, fluorouracil, tegafur, gemcitabine, capecitabine, etc.), plant alkaloids and terpenoids (vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (etoposide, irinotecan, topotecan, amsacrine, etoposide phosphate, teniposide, etc.), cytotoxic antibiotics (actinomycin, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, mitomycin, etc.), and other antineoplastic agents (cisplatin, carboplatin, oxaliplatin, etc.).

Agents for oral antidiabetic drugs include, but are not limited to: for example, insulin and analogs, biguanides (metformin, buformin, etc.), thiazolidinediones (rosiglitazone, pioglitazone, etc.), sulfonylureas (tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, etc.), non-sulfonylurea secretagogues (repaglinide, nateglinide, etc.), alpha-glucosidase inhibitors (miglitol, acarbose, etc.), incretin mimetics (exenatide, liraglutide, taloprtide, etc.), dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, sitagliptin, saxagliptin, etc.), amylin analogs (pramlintide, etc.).

Agents for anti-dementia drugs include, but are not limited to: such as donepezil, galantamine, rivastigmine, memantine, and the like. Anti-parkinson agents include, but are not limited to: such as biperiden, methabenzthiat, propiconazole, L-DOPA, amantadine, ropinirole, pramipexole, selegiline, entacapone, etc. anti-ALS drugs (riluzole). Anti-multiple sclerosis drugs include, but are not limited to: such as fingolimod, interferon-beta-1 a and 1b, glatiramer acetate, mitoxantrone, natalizumab, and the like. Anti-friedreich ataxia drug (idebenone). Anti-epileptic drugs include, but are not limited to: such as carbamazepine, lorazepine, clonazepam, ethosuximide, felbamate, phenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, topiramate, hemi-sodium valproate, valproic acid, zonisamide, clobazam, vigabatrin, and the like.

Agents for treating lysosomal storage diseases include, but are not limited to: such as glycosyltransferase inhibitors, beta-glucocerebrosidase, imiglucerase; acarbose α, acarbose β, glucosidase α, laronidase, idosulfatase, golthioesterase, α -glucosidase, N-butyl-deoxynojirimycin, 1-deoxynojirimycin, galactose, galactosidastatin bisulfite, isofagomine, 2, 5-anhydro-2, 5-D-glucitol, N-octyl-4-epi-b-valienamine, pyrimethamine, and the like.

The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and solutions and propylene glycol are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Topical application of the pharmaceutical or dermatological compositions of the present invention is particularly useful when the desired treatment involves the application of an area or organ that is readily accessible by topical application. For topical application to the skin, the pharmaceutical or dermatological composition should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compounds of the present invention include, but are not limited to: mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or creams containing the active compound suspended or dissolved in a carrier. Suitable vectors include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetyl stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. The invention also includes a transdermal patch for topical application.

These compositions can be prepared by mixing the active substances with the corresponding carriers and/or excipients by methods known per se in the preparation of pharmaceutical compositions and cosmetics. The compositions generally contain from 0.5 to 99.5% by weight of active compound.

Compounds of the invention

The present invention provides partially novel 1,4-dihydropyridine derivatives and stereoisomers of formula (I), including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, and combinations thereof, as appropriate, and polymorphs, pharmaceutically acceptable salts, solvates, esters, and prodrugs thereof, which are useful in the therapeutic or prophylactic treatment of disorders mediated by heat shock proteins,

wherein

R¹Is C optionally substituted by one or more substituents_6-24Aryl, said substituents being independently selected from: halogen, -NO₂Straight or branched chain C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, 5-6 membered heteroaryl comprising 1-4 nitrogen atoms, -CN, -SO₂NH₂、C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl and alk-X-alk groups, wherein X is O, S, SO₂And alk is C_1-6An alkyl group; or 5-6 membered heteroaryl containing 1-3 nitrogen atoms or other heteroatoms (such as oxygen and sulfur), and combinations thereof;

R²and R³Independently is hydrogen or C_1-6An alkyl group;

R⁴and R⁵Independently hydrogen, -CN, optionally substituted by amino, mono-or di- (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with a 5-to 24-membered optionally fused heterocyclic ring_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O, S heteroatoms and optionally being C_1-6Alkyl or C_1-6Alkoxy substitution;

R⁶is C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical C_1-6Alkyl or aryl radicals C_1-6An alkyl group.

In certain embodiments, R¹Is independently optionally substituted by 1 or 2 halogen, halo C_1-6Alkyl-substituted phenyl; r²、R³Independently is C_1-6An alkyl group; r⁴、R⁵Independently is optionally substituted by amino, mono-or di- (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with a 5-to 24-membered optionally fused heterocyclic ring_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O, S heteroatoms and optionally being C_1-6Alkyl or C_1-6Alkoxy substitution; r⁶Is C_1-6An alkyl group.

In a preferred embodiment, R¹Is halogenated C_1-6Alkyl-substituted phenyl; r²、R³Independently is C_1-6An alkyl group; r⁴、R⁵Independently is optionally mono-or di- (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with a 5-to 24-membered optionally fused heterocyclic ring_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O, S heteroatoms and optionally being C_1-6Alkyl or C_1-6Alkoxy substitution; r⁶Is C_1-6An alkyl group.

In an alternative preferred embodiment, R¹Is halogenated-C_1-6Alkyl-substituted phenyl; r²、R³Independent of each otherGround is C_1-6An alkyl group; r⁴、R⁵Independently is optionally mono-or di- (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with 6-membered heterocycle_1-6Alkyl, said heterocycle being linked by nitrogen and optionally comprising a further N heteroatom and optionally being C_1-6Alkyl substitution; r⁶Is C_1-6An alkyl group.

In other selected preferred embodiments, R¹Is fluorinated with-C_1-6Alkyl-substituted phenyl; r²And R³Is C_1-6An alkyl group; r⁴And R⁵Independently is optionally di (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with a 5-12 membered optionally fused heterocyclic ring_1-6Alkyl, said heterocycle being linked by nitrogen and optionally comprising 1 additional N heteroatom and optionally being C_1-6Alkyl or C_1-6Alkoxy substitution; r⁶Is C_1-6An alkyl group.

TABLE 1 exemplary Compounds of formula (I)

TABLE 1

Hydrochloride salt

Fumarate salt

Selected compounds of the invention include, but are not limited to: examples 1,4, 5, 6,7, 8, 11, 12, 14, 15, 16, 17, 23, 24, 25, 26, 27, 33, 34, 35, 41, 42, 43, 44, 45, 47, 49.

Detailed Description

In one aspect, the present invention provides 1,4-dihydropyridine derivatives and stereoisomers of formula (I), including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, and combinations thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters, and prodrugs thereof, useful for the therapeutic or prophylactic treatment of disorders mediated by heat shock proteins

Wherein

R¹Is C optionally substituted by one or more substituents_6-24Aryl, said substituents being independently selected from: halogen, straight or branched C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, 5-6 membered heteroaryl comprising 1-4 nitrogen atoms, -CN, -SO₂NH₂、C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl and alk-X-alk groups, wherein X is O, S, SO₂And alk is C_1-6An alkyl group; or 5-6 membered heteroaryl containing 1-3 nitrogen atoms or other heteroatoms (such as oxygen and sulfur), and combinations thereof;

R²and R³Independently is hydrogen or C_1-6An alkyl group;

R⁴and R⁵Independently hydrogen, optionally substituted by amino, mono-or di- (C)_1-6Alkyl) amino-substituted C_1-6Alkyl, or C optionally substituted with a 5-to 24-membered optionally fused heterocyclic ring_1-6Alkyl, said heterocycle being linked through the nitrogen and optionally comprising a further 1-3N, O, S heteroatoms and optionally being C_1-6Alkyl or C_1-6Alkoxy substitution;

R⁶is C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical C_1-6Alkyl or aryl radicals C_1-6An alkyl group.

Other aspects of the invention provide compounds of formula (I) as described above for use in the therapeutic or prophylactic treatment of a disorder mediated by Hsp70 and Hsp25, and wherein the Hsp-mediated disorder is selected from: a neurodegenerative disease, a cancer disease, a metabolic syndrome, a lysosomal storage disease, and a skin disorder condition, and wherein the treatment further comprises administering at least one therapeutic agent selected from an agent useful for treating a neurodegenerative disease, a cancer disease, a metabolic syndrome, a lysosomal storage disease, or a skin disorder.

Another aspect of the present invention provides a pharmaceutical and optionally cosmetic composition for the therapeutic or prophylactic treatment of disorders mediated by Hsp, comprising a compound of formula (I) as described above and one or more pharmaceutically or cosmetically acceptable carriers and/or excipients.

A further aspect of the invention provides a pharmaceutical and optionally cosmetic composition for the therapeutic or prophylactic treatment of a disorder mediated by Hsp, comprising a compound of formula (I) as described above and one or more pharmaceutically or cosmetically acceptable carriers and/or excipients, wherein the disorder is selected from: a neurodegenerative disease, a cancer disease, a metabolic syndrome, a lysosomal storage disease, and a skin disorder condition, and wherein the treatment further comprises administering at least one therapeutic agent selected from an agent useful for treating a neurodegenerative disease, a cancer disease, a metabolic syndrome, a lysosomal storage disease, or a skin disorder.

Another aspect of the invention provides a compound of formula (I) as described above for use in a combination therapy, wherein the combination therapy comprises administering to a patient an effective amount of a compound of formula (I) as described above, simultaneously, separately or sequentially, together with heat treatment or together with other therapies for the treatment of a given pathophysiological state.

Another aspect of the present invention provides certain novel compounds and stereoisomers of formula (I), including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers and combinations thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters and prodrugs thereof, in enantiomerically enriched form, as described below, and further provides pharmacological and cosmetic compositions containing them.