Pyrazole compounds and pharmaceutical compositions comprising the compound
First Claim
Patent Images
1. A compound represented by the formula (I), a salt thereof or a hydrate of them.
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Accused Products
Abstract
The present invention provides a novel compound having an excellent JNK inhibitory effect. That is, it provides a compound represented by the following formula, a salt thereof or a hydrate of them.
Wherein R1 designates —(COh—(NRa)j—(CRb═CRc)k—Ar (wherein Ra, Rb and Rc each independently designate a hydrogen atom, a halogen atom, hydroxyl group, an optionally substituted C1-6 alkyl group or the like; Cy designates a 5- or 6-membered heteroaryl; and
- V each independently designate the formula -L-X—Y (wherein L designates a single bond, an optionally substituted C1-6 alkylene group or the like; X designates a single bond or the formula -A- (wherein A designates NR2, O, CO, S, SO or SO2) and so on; and Y designates a hydrogen atom, a halogen atom, nitro group or the like).
182 Citations
61 Claims
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1. A compound represented by the formula (I), a salt thereof or a hydrate of them.
- View Dependent Claims (2, 3, 4, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
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2. The compound according to claim 1, a salt thereof or a hydrate of them, wherein Cy forms a 5-membered heteroaryl group.
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3. The compound according to claim 1, a salt thereof or a hydrate of them, wherein Cy forms a thiophene ring.
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4. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), the partial structure consisting of Cy and the pyrazole ring adjoining to the Cy is 1H-thieno[2,3-c]pyrazole.
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24. The compound according to any one of claims 1 to 22, a salt thereof or a hydrate of them, wherein at least either h or j is 1.
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25. The compound according to any one of claims 1 to 22, a salt thereof or a hydrate of them, wherein h and j are 0, and k is 1.
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26. The compound according to any one of claims 1 to 19, a salt thereof or a hydrate of them, wherein h, j and k are 0.
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27. The compound according to any one of claims 24 and 25, a salt thereof or a hydrate of them, wherein Rb and/or Rc are(is) a hydrogen atom.
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28. The compound according to claim 27, a salt thereof or a hydrate of them, wherein Rb and Rc are a hydrogen atom.
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29. The compound according to any one of claims 1 to 28, a salt thereof or a hydrate of them, wherein Ar is a C6-14 aryl group or a 5- to 14-membered heteroaryl group, and Ar is a group which may be substituted with 1 to 3 group(s) selected from the following substituent group (a):
<
Substituent group a>
the group consisting of (1) each optionally substituted (a) C1-6 alkyl groups, (b) C1-6 alkoxy groups, (c) C1-7 acyl groups, (d) amide group, (e) amino group, (f) C3-8 cycloalkyl groups, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group.
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30. The compound according to claim 29, a salt thereof or a hydrate of them, wherein Ar is a phenyl group, naphthyl group or a 5- to 10-membered heteroaryl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from Substituent group A described in claim 29.
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31. The compound according to claim 29, a salt thereof or a hydrate of them, wherein Ar is a phenyl group, 2-naphthyl group, pyridyl group, 2-thienyl group, 2-furyl group, 2-benzofuryl group, 2-quinolyl group or 2-benzothienyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from Substituent group A described in claim 29.
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32. The compound according to claim 29, a salt thereof or a hydrate of them, wherein Ar is a phenyl group, pyridyl group, 2-thienyl group or 2-furyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from Substituent group A described in claim 29.
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33. The compound according to claim 29, a salt thereof or a hydrate of them, wherein Ar is a 2-naphthyl group, 2-benzofuryl group, 2-quinolyl group or 2-benzothienyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from Substituent group a described in claim 29.
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34. The compound according to any one of claims 29 to 33, a salt thereof or a hydrate of them, wherein Substituent group A is the group consisting of (1) C1-6 alkyl groups each optionally substituted with 1 to 3 group(s) selected from the group consisting of a halogen atom, hydroxyl group and cyano group, (2) C1-6 alkoxy groups optionally substituted with 1 to 3 group(s) selected from the group consisting of a halogen atom, hydroxyl group and cyano group, (3) halogen atom, (4) hydroxyl group, (5) cyano group, and (6) C1-7 acyl groups.
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35. The compound according to any one of claims 29 to 33, a salt thereof or a hydrate of them, wherein Substituent group A is a halogen atom.
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36. The compound according to any one of claims 1 to 35, a salt thereof or a hydrate of them, wherein L is a single bond or methylene group.
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37. The compound according to claim 36, a salt thereof or a hydrate of them, wherein L is a single bond.
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38. The compound according to any one of claims 1 to 37, a salt thereof or a hydrate of them, wherein X is a group represented by —
- CO—
NR8-Z-, —
NR8—
CO-Z- or —
NR8—
SO2-Z- (wherein R8 and Z have the same meanings as defined for R8 and Z in claim
1).
- CO—
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39. The compound according to claim 38, a salt thereof or a hydrate of them, wherein R8 is a hydrogen atom.
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40. The compound according to claim 38, a salt thereof or a hydrate of them, wherein X is a group represented by —
- CO—
NH—
(CH2)t—
(wherein t designates 0 or
1).
- CO—
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41. The compound according to claim 38, a salt thereof or a hydrate of them, wherein X is a group represented by —
- NH—
CO—
(CH2)t—
(wherein t designates 0 or
1).
- NH—
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42. The compound according to any one of claims 1 to 37, a salt thereof or a hydrate of them, wherein X is a single bond.
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43. The compound according to any one of claims 1 to 42, a salt thereof or a hydrate of them, wherein Y is a C1-6 alkyl group, a C6-14 aryl group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, a 4- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from the following Substituent group a2:
<
Substituent group a2>
the group consisting of (1) each optionally substituted (a) C1-6 alkyl groups, (b) C2-6 alkenyl groups, (c) C2-6 alkynyl groups, (d) C1-6 alkoxy groups, (e) C2-7 acyl groups, (f) amide group, (g) amino group, (h) C3-8cycloalkyl groups, (i) C3-8 cycloalkenyl groups, (j) C6-14 aryl groups, (k) 5- to 14-membered heteroaryl groups, (1) C6-14 aryloxy groups, and (m) 4- to 14-membered non-aromatic heterocyclic groups, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group.
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44. The compound according to claim 43, a salt thereof or a hydrate of them, wherein Y is a C3-8 cycloalkyl group, phenyl group, a 5- or 6-membered non-aromatic heterocyclic group, or a 5- or 6-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from Substituent group a2 described in claim 43.
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45. The compound according to any one of claims 1 to 42, a salt thereof or a hydrate of them, wherein Y is a furyl group, thienyl group, pyrrolyl group, phenyl group, pyridyl group, C3-8 cycloalkyl group, tetrahydrofuran-yl group, tetrahydrothiophene-yl group, pyrrolidinyl group, tetrahydrofuran-2-on-yl group, pyrrolidine-2-on-yl group or a group represented by the formula:
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46. The compound according to claim 43, a salt thereof or a hydrate of them, wherein Y is a furyl group or thienyl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from Substituent group a2 described in claim 43.
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47. The compound according to any one of claims 43 to 46, a salt thereof or a hydrate of them, wherein Substituent group a2 is the group consisting of (1) (a) C1-6 alkyl groups, (b) C1-6 alkoxy groups, (C)C1-7 acyl groups, (d) amide group, (e) amino group, (f) C3-8cycloalkyl groups, each of which may be substituted with 1 to 3 group(s) selected from the following Substituent group b2, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group, and <
- Substituent group b2>
is the group consisting of C1-6 alkyl groups, halogen atom, hydroxyl group, nitro group, cyano group and carboxyl group.
- Substituent group b2>
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48. The compound according to any one of claims 43 to 46, a salt thereof or a hydrate of them, wherein Substituent group a2 is the group consisting of (1) C1-6 alkoxy groups, (2) halogen atoms and (3) cyano groups.
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50. A pharmaceutical composition comprising the compound according to anyone of claims 1 to 49, a salt thereof or a hydrate of them, and a pharmaceutically acceptable carrier.
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51. A c-Jun amino-terminal kinase (JNKs) inhibitor comprising the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them.
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52. A c-Jun amino-terminal kinase 1 (JNK 1), c-Jun amino-terminal kinase 2 (JNK 2) and/or c-Jun amino-terminal kinase 3 (JNK 3) inhibitor, comprising the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them.
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53. An agent for treating or preventing immunological diseases, inflammatory diseases or metabolic disorders, which comprises the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them.
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54. An agent for treating or preventing neurodegenerative diseases, which comprises the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them.
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55. An agent for treating or preventing Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration, which comprises the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them.
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56. Use of the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them for prevention or treatment of immunological diseases, inflammatory diseases, metabolic disorders and/or neurodegenerative diseases.
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57. Use of the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them, for producing an agent for treating or preventing a disease based on JNK action against which inhibition of a c-Jun amino-terminal kinase (JNK) is effective for prevention or treatment, immunological diseases, inflammatory diseases, metablic disorders or neurodegenerative diseases.
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58. The use according to claim 57, wherein the disease is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration.
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59. A method for treating or preventing a disease based on JNK 3 action against which inhibition of a c-Jun amino-terminal kinase 3 (JNK 3) is effective for prevention or treatment, immunological diseases, inflammatory diseases, metablic disorders and/or neurodegenerative diseases, which comprises adiministering a pharmacologically effective amount of the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them to a patient.
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60. A method for treating or preventing a disease based on JNK action against which inhibition of a c-Jun amino-terminal kinase (JNK) is effective for prevention or treatment, immunological diseases, inflammatory diseases, metablic disorders or neurodegenerative diseases, which comprises adiministering a pharmacologically effective amount of the compound according to any one of claims 1 to 49, a salt thereof or a hydrate of them to a patient.
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61. The method according to claim 60, wherein the disease is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration.
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2. The compound according to claim 1, a salt thereof or a hydrate of them, wherein Cy forms a 5-membered heteroaryl group.
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5. A compound represented by the formula (II), a salt thereof or a hydrate of them.
- View Dependent Claims (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
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6. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either one is —
- N═
, and the others are —
CV2═
.
- N═
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7. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either one of Q1, Q3 and Q4 is —
- N═
, and the others are —
CV2═
.
- N═
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8. The compound according to claim 6, a salt thereof or a hydrate of them, wherein Q1 is —
- N═
.
- N═
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9. The compound according to claim 6, a salt thereof or a hydrate of them, wherein Q2 is —
- N═
.
- N═
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10. The compound according to claim 6, a salt thereof or a hydrate of them, wherein Q3 is —
- N═
.
- N═
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11. The compound according to claim 6, a salt thereof or a hydrate of them, wherein Q4 is —
- N═
.
- N═
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12. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either two are —
- N═
, and the others are —
CV2═
.
- N═
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13. The compound according to claim 12, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either two of Q1, Q3 and Q4 are —
- N═
, and the others are —
CV2═
.
- N═
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14. The compound according to any one of claims 5 to 13, a salt thereof or a hydrate of them, wherein when either of Q1, Q3 and Q4 is —
- CV2═
, the —
CV2═
in Q1, Q3 or Q4 is —
CH═
.
- CV2═
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15. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either three are —
- N═
, and the other is —
CV2═
.
- N═
-
16. The compound according to claim 15, a salt thereof or a hydrate of them, wherein Q1, Q3 and Q4 are —
- N═
.
- N═
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17. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, at least one is —
- CO—
.
- CO—
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18. The compound according to claim 5, a slat thereof or a hydrate of them, wherein Q1 is —
- CO—
, Q2 is —
NV1—
, and Q3 and Q4 are —
CV2═
.
- CO—
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19. The compound according to claim 5, a slat thereof or a hydrate of them, wherein Q3 is —
- CO—
, Q2 is —
NV1—
, and Q1 and Q4 are —
CV2═
.
- CO—
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6. The compound according to claim 5, a salt thereof or a hydrate of them, wherein among Q1 to Q4, either one is —
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20. A compound represented by the formula (III), a salt thereof or a hydrate of them.
- View Dependent Claims (21, 22, 23, 49)
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21. The compound according to claim 20, a salt thereof or a hydrate of them, wherein at least one of Rd, Re and Rf is not a hydrogen atom.
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22. The compound according to claim 20, a salt threof or a hydrate of them, wherein either one of Rd, Re and Rf is a halogen atom or an optionally substituted C1-6 alkoxy group.
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23. The compound according to any one of claims 20 to 22, a salt thereof or a hydrate of them, wherein at least one of Rb and Rc is not a hydrogen atom, and L is a single bond, an optionally substituted C2-6 alkenylene group or an optionally substituted C2-6 alkynylene group, provided that, when L is a single bond, the case where X is a single bond, and Y is an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C3-8 cycloalkenyl group, an optionally substituted 4- to 14-membered non-aromatic heterocyclic group, an optionally substituted C6-14 aryl group or an optionally substituted 5- to 14-membered heteroaryl group is excluded.
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49. The compound according to any one of claims 20 to 35, a salt thereof or a hydrate of them, wherein L and X are a single bond, Y is a 5- to 6-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from Substituent group a2 described in claim 43.
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21. The compound according to claim 20, a salt thereof or a hydrate of them, wherein at least one of Rd, Re and Rf is not a hydrogen atom.
Specification
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Current AssigneeEisai R & D Management Company Limited (Eisai Medical Research Incorporated)
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Original AssigneeEisai R & D Management Company Limited (Eisai Medical Research Incorporated)
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InventorsOhi, Norihito, Doko, Takashi, Sato, Nobuaki, Soejima, Motohiro, Terauchi, Taro, Motoki, Takafumi, Naoe, Yoshimitsu
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Application NumberUS10/447,948Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current435/7.100CPC Class CodesA61K 31/407 condensed with other hetero...A61K 31/416 condensed with carbocyclic ...A61K 31/4162 condensed with heterocyclic...A61K 31/4178 not condensed 1,3-diazoles ...A61K 31/4184 condensed with carbocyclic ...A61K 31/4196 1,2,4-TriazolesA61K 31/42 OxazolesA61K 31/422 not condensed and containin...A61K 31/4245 OxadiazolesA61K 31/427 not condensed and containin...A61K 31/43 Compounds containing 4-thia...A61K 31/437 the heterocyclic ring syste...A61K 31/4439 containing a five-membered ...A61K 31/444 containing a six-membered r...A61K 31/454 containing a five-membered ...A61K 31/496 Non-condensed piperazines c...A61K 31/497 containing further heterocy...A61K 31/4985 Pyrazines or piperazines or...A61K 31/506 not condensed and containin...A61K 31/5377 not condensed and containin...A61K 31/55 : having seven-membered rings...A61P 21/00 : Drugs for disorders of the ...A61P 25/00 : Drugs for disorders of the ...A61P 25/02 : for peripheral neuropathiesA61P 25/14 : for treating abnormal movem...A61P 25/16 : Anti-Parkinson drugsA61P 25/28 : for treating neurodegenerat...A61P 29/00 : Non-central analgesic, anti...A61P 3/00 : Drugs for disorders of the ...A61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 43/00 : Drugs for specific purposes...C07D 231/56 : Benzopyrazoles; Hydrogenate...C07D 401/06 : linked by a carbon chain co...C07D 403/04 : directly linked by a ring-m...C07D 403/06 : linked by a carbon chain co...C07D 405/06 : linked by a carbon chain co...C07D 409/04 : directly linked by a ring-m...C07D 409/06 : linked by a carbon chain co...C07D 413/04 : directly linked by a ring-m...C07D 413/14 : containing three or more he...C07D 471/04 : Ortho-condensed systemsC07D 487/04 : Ortho-condensed systemsC07D 495/04 : Ortho-condensed systems