NOVEL COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS

• US 20100099721A1
• Filed: 12/23/2009
• Published: 04/22/2010
• Est. Priority Date: 11/03/2003
• Status: Abandoned Application

• Current Assignee: Probiodrug AG
• Original Assignee: Probiodrug AG
• Inventors: Niestroj, André J., Baer, Joachim, Demuth, Hans-Ulrich, Heiser, Ulrich, Rahfeld, Jens-Ulrich, Schulz, Ingo
• Application Number:
  US12/646,111
• Publication Number:
  US 20100099721A1
• Time in Patent Office: Days
• US Class Current: 514/367
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Inhibitors of prolyl endopeptidase of formula 1

W—KCONH—X—CON—Y—CO—Z  (1)

wherein K, W, X, Y and Z are specified in the description. The compounds are useful for the treatment of diseases such as mild cognitive impairment (MCI), Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease and Chorea Huntington.

Claims

1. A method of treating a subject, comprising:

administering to a mammalian subject in need thereof an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, including all stereoisomers thereof;

W—

KCONH—

X—

CON—

Y—

CO—

Z 

 

Formula (1)

wherein,

the mammalian subject is diagnosed with, or at risk for, a disease selected from the group consisting of;

Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, amnesia, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff'"'"'s syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and blood coagulation disorders;

W represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carbocyclyl, aryl, -alkylaryl or -alkylheteroaryl;

K represents O, NH or CH₂;

or K is absent and W—

CO represents the moiety of an amino acid or aza-amino acid;

NH—

X—

CO represents the moiety of non-cyclic amino acid or non-cyclic aza-amino acid, wherein when NH—

X—

CO represents the moiety of Asp or Glu the acid side chain of said Asp or Glu may optionally be joined via a peptide bond to another amino acid or aza-amino acid;

N—

Y—

CO—

is selected from a moiety of formula 2a, 2b, 2c, 2d, 2e, 2f, or 2g;

2. A method according to claim 1, wherein R¹-R¹⁵ and R¹⁷-R¹⁹ independently represent H, halogen, CN or alkyl.

3. A method according to claim 1, wherein R¹-R¹⁵ and R¹⁷-R¹⁹ are H.

4. A method according to claim 1, wherein X¹, X² and X³ independently represent CH₂ or CHMe.

5. A method according to claim 1, wherein X⁴ and X⁵ independently represent CH or CMe.

6. A method according to claim 1, wherein R²⁰, R²¹, R²³, R²⁴, R²⁶, R²⁷, R²⁸, R⁵² and R⁵³ are H.

7. A method according to claim 1, wherein m and n independently represent 0 or 1.

8. A method according to claim 7, wherein m and n are 0.

9. A method according to claim 1, wherein W represents -alkylaryl, -alkylheteroaryl, alkyl, alkenyl, alkynyl or cycloalkyl.

10. A method according to claim 9, wherein W represents alkenyl-, alkyl- or arylalkyl-.

11. A method according to claim 10, wherein W is arylalkyl-.

12. A method according to claim 9, wherein W is selected from the group consisting of -methylaryl, methylheteroaryl, C_2-6 alkenyl and C_2-6 alkyl.

13. A method according to claim 9, wherein aryl represents phenyl optionally substituted by alkyl and/or halo.

14. A method according to claim 9, wherein heteroaryl represents pyridyl optionally substituted by alkyl and/or halo.

15. A method according to claim 1, wherein W—

K—

CO represents allyloxycarbonyl (Aloc), t-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).

16. A method according to claim 15, wherein W—

K—

CO is benzyloxycarbonyl.

17. A method according to claim 1, wherein K represents O or CH₂, especially O.

18. A method according to claim 1, wherein NH—

X—

CO represents the moiety of a non-cyclic amino acid.

19. A method according to claim 1, wherein NH—

X—

CO represents a proteinogenic amino acid.

20. A method according to claim 19, wherein NH—

X—

CO is selected from the group consisting of L-Ala, L-Arg, L-Asp and L-Phe.

21. A method according to claim 1, wherein N—

Y—

CO represents a moiety of formula 2d.

22. A method according to claim 1, wherein R¹⁶ represents the sidechain of a proteinogenic amino acid.

23. A method according to claim 22, wherein R¹⁶ represents H, methyl, —

CH₂OH, —

CH(Me)OH, CHMe₂, CH₂CHMe₂, CH(Me)CH₂Me, CH₂CH₂CONH₂, —

CH₂COOH, —

CH₂CONH₂ or CH₂CH₂COOH.

24. A method according to claim 23, wherein R¹⁶ represents alkyl.

25. A method according to claim 24, wherein R¹⁶ is methyl.

26. A method according to claim 1, wherein N—

Y—

CO represents a moiety of formula 2a, 2e, 2f or 2g.

27. A method according to claim 1, wherein N—

Y—

CO represents a moiety of formula 2b or 2c.

28. A method according to claim 1, wherein N—

Y—

CO represents a moiety of formula of 2h or 2i;

29. A method according to claim 28, wherein R⁷⁷ and R⁷⁸ independently are methyl.

30. A method according to claim 28, wherein R⁷⁷ and R⁷⁸ independently are CN.

31. A method according to claim 28, wherein R⁷⁷ and R⁷⁸ independently are H.

32. A method according to claim 1, wherein N—

Y—

CO represents a moiety of formula 2j or 2k;

33. A method according to claim 32, wherein R⁷⁷ and R⁷⁸ independently are methyl.

34. A method according to claim 32, wherein R⁷⁷ and R⁷⁸ independently are CN.

35. A method according to claim 32, wherein R⁷⁷ and R⁷⁸ independently are H.

36. A method according to claim 1, wherein X¹ represents CH₂.

37. A method according to claim 1, wherein Z represents a 5-membered heteroaryl ring optionally fused to a benzene ring

38. A method according to claim 37, wherein Z is selected from the group consisting of 2-furan, 2-imidazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-thiophene, 3-thiophene, 2-oxazole, 4-oxazole, 5-oxazole, 2-pyrrole, 3-pyrrole, 2-benzo[d]imidazole, 2-benzo[d]thiazole, 2-benzo[b]thiophene, 3-benzo[b]thiophene, 2-benzo[d]oxazole, 2-indole, 3-indole, or from a moiety of formula 3a, 3b, 3c, 3d or 3e:

39. A method according to claim 38, wherein R⁸², R⁸³, R⁸⁴, R⁸⁵ and R⁸⁶ are H or alkyl.

40. A method according to claim 39, wherein R⁸², R⁸³, R⁸⁴, R⁸⁵ and R⁸⁶ are H.

41. A method according to claim 1, wherein the compound is:

42. A method according to claim 1, wherein the compound of Formula (1) is selected from the group consisting of:

43. A method according to claim 1 wherein the compound of Formula (1) is selected from the group consisting of:

44. A method according to claim 1, wherein administering a compound of Formula (1) comprises administering a pharmaceutical composition comprising a compound of Formula (1) and one or more therapeutically acceptable diluents or carriers.

45. A method according to claim 44, wherein the pharmaceutical composition is formulated for parenteral, enteral or oral administration.

46. A method according to claim 44, wherein the pharmaceutical composition further comprises at least one compound selected from the group consisting of QC-inhibitors, LiCl, inhibitors of dipeptidyl aminopeptidases, preferably inhibitors of DP IV or DP IV-like enzymes, NPY-receptor ligands, NPY agonists, ACE inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, PDE-4 inhibitors, MAO inhibitors, TNFalpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors and histamine H3 antagonists.

47. A method according to claim 46, wherein the pharmaceutical composition is formulated for parenteral, enteral or oral administration.

48. A method according to claim 1, wherein the mammalian subject is diagnosed with a disease selected from the group consisting of:

Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff'"'"'s syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and blood coagulation disorders.

49. A method according to claim 1, wherein the mammalian subject is at risk for a disease selected from the group consisting of:

Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff'"'"'s syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and blood coagulation disorders.

50. A method according to claim 1, wherein the mammalian subject is diagnosed with or at risk for a neurodegenerative disorder.

51. A method according to claim 50, wherein the neurodegenerative disorder is selected from the group consisting of:

mild cognitive impairment (MCI), Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease, and Chorea Huntington.

52. A method according to claim 1, wherein the mammalian subject is diagnosed with or at risk for a pathogenic psychotic condition.

53. A method according to claim 52, wherein the pathogenic psychotic condition is selected from the group consisting of:

schizophrenia, impaired food intake, sleep-wakefulness, impaired autonomic function, anorexia, anxiety related disorders including depression, drug withdrawal and alcoholism, dementia, aphasia, apraxia, agnosia, and amnesia.

54. A method according to claim 1, wherein the mammalian subject is diagnosed with or at risk for restenosis, coronary arteriopathy, or atherosclerosis.

55. A method according to claim 1, wherein the mammalian subject is diagnosed with or at risk for reperfusion injury, hypoxia, ischemia, or a blood coagulation disorder.