WO1998056788B1 - Imidazolyl-cyclic acetals - Google Patents
Imidazolyl-cyclic acetalsInfo
- Publication number
- WO1998056788B1 WO1998056788B1 PCT/GB1998/001711 GB9801711W WO9856788B1 WO 1998056788 B1 WO1998056788 B1 WO 1998056788B1 GB 9801711 W GB9801711 W GB 9801711W WO 9856788 B1 WO9856788 B1 WO 9856788B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- formula
- compound
- optionally substituted
- deflned
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 9
- 239000001257 hydrogen Substances 0.000 claims abstract 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract 7
- 150000002431 hydrogen Chemical group 0.000 claims abstract 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 4
- 239000003814 drug Substances 0.000 claims abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 3
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 claims 3
- 230000001668 ameliorated Effects 0.000 claims 3
- 239000003112 inhibitor Substances 0.000 claims 3
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 claims 1
- 239000005695 Ammonium acetate Substances 0.000 claims 1
- 206010003246 Arthritis Diseases 0.000 claims 1
- 208000006673 Asthma Diseases 0.000 claims 1
- 230000002378 acidificating Effects 0.000 claims 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims 1
- 229940043376 ammonium acetate Drugs 0.000 claims 1
- 235000019257 ammonium acetate Nutrition 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutic aid Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract 3
- 125000004432 carbon atoms Chemical group C* 0.000 abstract 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 3
- 150000001204 N-oxides Chemical class 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000002947 alkylene group Chemical group 0.000 abstract 2
- -1 azido, hydroxy Chemical group 0.000 abstract 2
- 229910052799 carbon Inorganic materials 0.000 abstract 2
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
- 239000000651 prodrug Substances 0.000 abstract 2
- 229940002612 prodrugs Drugs 0.000 abstract 2
- 101700079793 NR13 Proteins 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 abstract 1
- 125000004104 aryloxy group Chemical group 0.000 abstract 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 abstract 1
- 125000005553 heteroaryloxy group Chemical group 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 abstract 1
Abstract
Compounds of formula (I) are described in which R1 is optionally substituted heteroaryl; R2 is optionally substituted aryl or optionally substituted heteroaryl; R3 is a group -L?1-R7 or -L2-R8¿ [where L1 is an optionally substituted alkylene linkage; R7 is hydrogen, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, nitro, -S(O)¿nR?9, -NHSO¿2R?9, -C(=Z)0R10, -C(=Z)R?10, -N(R11¿)-C(=Z)R?9, -NY1Y2, -SO¿2-NY1Y2,-C(=Z)-NY?1Y2, -N(R11¿)-C(=Z)-NY?1Y2, -N(OR10¿)-C(=Z)-NY?1Y2, -N(OR10¿)-C(=Z)R10, -C(=NOR10)R10, -C(=Z)NR?10OR12, -N(R11)-C(=NR13)-NY1Y2¿ or -N(R11)-C(=Z)OR11; L2 is a direct bond or a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond; and R8 is hydrogen, aryl, cycloalkenyl, cycloalkyl, heteroaryl or heterocycloalky]; R4 is a group -L3-R14 [where L3 is a direct bond or an optionally substituted alkylene linkage and R14 is hydrogen, alkyl, azido, hydroxy, alkoxy, aryl, arylalkyloxy, aryloxy, carboxy (or an acid bioisostere) cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, nitro, -NY?4Y5, -N(R10¿)-C(=Z)-R?15; -N(R10¿)-C(=Z)-L4-R16, -NH-C(=Z)-NH-R15, -NH-C(=Z)-NH-L?4-R16, -N(R10)-SO¿2-R?15, -N(R10)-SO¿2-L4-R16, -S(O)¿nR?9, -C(=Z)-NY4Y5 or -C(=Z)-OR9); R5 is hydrogen, alkyl or hydroxyalkyl; or R?4 and R5¿, when attached to the same carbon atom, may form with the said carbon atom a cycloalkyl, cycloalkenyl or heterocycloalkyl ring or a group C=CH¿2; R?6 is hydrogen or alkyl; and m is zero or an integer 1 or 2; and N-oxides thereof, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (I) and N-oxides thereof, and their prodrugs. The compounds are TNF inhibitors and are useful as pharmaceuticals.
Claims
285
AMENDED CLAIMS
[received by the International Bureau on 3 December 1998 (03.12.98); original claims 37-43 replaced by new claims 37-46; remaining claims unchanged (4 pages)]
pharmaceutically acceptable carrier or excipient.
31. A pharmaceutical composition for use in the treatment of a condition which can be ameliorated by the administration of an inhibitor of TNF-alpha comprising an effective amount of the compound according to Claim 1.
32. A compound according to Claim 1 for use in therapy.
33. Use of a compound according to Claim 1 for the manufacture of a medicament for the treatment of a condition which can be ameliorated by the administration of an inhibitor of
TNF-alpha.
34. Use according to Claim 33 for the treatment of asthma.
35. Use according to claim 33 for the treatment of joint inflammation.
36. Method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF-alpha, which comprises the administration to said patient of an effective amount of a compound of claim 1.
37. Compounds of formula (II)
38. Compounds of formula (V)
AMENDED SHEET ARTICL E 1
wherein R^, R^, R4, R5? R6 and m are as deflned in claim 1.
39. Resin C
R< as in C
wherein R^, R3, R4, R5? R6 and m are as deflned in claim 1.
40. Resin D.
Resin D
wherein R^, R3, R4? R5? R6 and m are as deflned in claim 1.
41. Process for the preparation of a compound of formula (I), wherein Rl, R^, R4, R5, R6 and m are as deflned in Claim 1 and R-3 is hydrogen, comprising reacting a compound of formula (II)
wherein R* and R^ are as defined in Claim 1, R^ is hydrogen or a protecting group and R^O is -CHO or -CH(OMe)2, with a compound of formula (III)
wherein R^, R^, R^ and m are as defined in Claim 1 under acidic conditions.
42. Process for the preparation of a compound of formula (II)
wherein Rl and R^ are as deflned in Claim 1, R*9 is hydrogen and R^O is -CH(OMe)2, comprising reacting a compound of formula (2)
wherein R* and R^ are as deflned in Claim 1, with glyoxal 1,1-dimethylacetal and ammonium acetate.
43. A compound substantially as hereinbefore described with reference to the Examples.
44. A process as claimed in Claim 38 substantially as herein described and illustrated.
45. A pharmaceutical composition as claimed in Claim 30 substantially as herein described and illustrated.
46. Use as claimed in Claim 33 substantially as herein described and illustrated.
Priority Applications (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9830850T SI0988301T1 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| AU79259/98A AU742293B2 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| SK3-2009A SK286940B6 (en) | 1997-06-12 | 1998-06-12 | Method for the preparation of imidazole derivative |
| EP98929548A EP0988301B1 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| CA2293436A CA2293436C (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals as tnf inhibitors |
| KR1019997011695A KR100704059B1 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| JP50190899A JP4380803B2 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetal |
| DE69835518T DE69835518T2 (en) | 1997-06-12 | 1998-06-12 | IMIDAZOLYL-CYCLIC ACETALE |
| IL13331198A IL133311A0 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| PL337314A PL199893B1 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| BRPI9810007-6A BR9810007B1 (en) | 1997-06-12 | 1998-06-12 | compounds, and derivatives of merrifield resin. |
| TR1999/03098T TR199903098T2 (en) | 1997-06-12 | 1998-06-12 | �midosyl-cyclic acetals |
| HU0003309A HUP0003309A3 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals, process for producing them and pharmaceutical compositions containing the same |
| SK1710-99A SK171099A3 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
| NZ501714A NZ501714A (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetal derivatives, resins and intermediates thereof and use as TNF inhibitors |
| TW087112466A TWI235751B (en) | 1997-06-12 | 1998-07-29 | Imidazolyl-cyclic acetals and the composition and preparation thereof |
| IL133311A IL133311A (en) | 1997-06-12 | 1999-12-05 | Imidazolyl-cyclic acetals, their preparation and pharmaceutical compositions comprising them |
| US09/456,360 US6602877B1 (en) | 1997-06-12 | 1999-12-08 | Imidazolyl-cyclic acetals |
| NO996120A NO326660B1 (en) | 1997-06-12 | 1999-12-10 | Imidazolyl-cyclic acetal compounds, pharmaceutical compositions containing these compounds and use of the compounds |
| US10/436,609 US6989395B2 (en) | 1997-06-12 | 2003-05-13 | Imidazolyl-cyclic acetals |
| CY20061101365T CY1105238T1 (en) | 1997-06-12 | 2006-09-21 | IMIDAZOLYL-CYCLIC ACETALS |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9712270.9 | 1997-06-12 | ||
| GBGB9712270.9A GB9712270D0 (en) | 1997-06-12 | 1997-06-12 | Chemical compounds |
| US5218597P | 1997-07-10 | 1997-07-10 | |
| US60/052,185 | 1997-07-10 | ||
| GBGB9724678.9A GB9724678D0 (en) | 1997-11-21 | 1997-11-21 | Chemical compounds |
| GB9724678.9 | 1997-11-21 | ||
| US8549998P | 1998-05-14 | 1998-05-14 | |
| US60/085,499 | 1998-05-14 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/456,360 Continuation US6602877B1 (en) | 1997-06-12 | 1999-12-08 | Imidazolyl-cyclic acetals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998056788A1 WO1998056788A1 (en) | 1998-12-17 |
| WO1998056788B1 true WO1998056788B1 (en) | 1999-01-21 |
Family
ID=27451664
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1998/001711 WO1998056788A1 (en) | 1997-06-12 | 1998-06-12 | Imidazolyl-cyclic acetals |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US6602877B1 (en) |
| EP (1) | EP0988301B1 (en) |
| JP (1) | JP4380803B2 (en) |
| KR (1) | KR100704059B1 (en) |
| CN (1) | CN100443481C (en) |
| AT (1) | ATE335735T1 (en) |
| AU (1) | AU742293B2 (en) |
| BR (1) | BR9810007B1 (en) |
| CA (1) | CA2293436C (en) |
| CY (1) | CY1105238T1 (en) |
| CZ (1) | CZ9904452A3 (en) |
| DE (1) | DE69835518T2 (en) |
| DK (1) | DK0988301T3 (en) |
| ES (1) | ES2270520T3 (en) |
| HK (1) | HK1032586A1 (en) |
| HU (1) | HUP0003309A3 (en) |
| IL (2) | IL133311A0 (en) |
| NO (1) | NO326660B1 (en) |
| NZ (1) | NZ501714A (en) |
| PL (1) | PL199893B1 (en) |
| PT (1) | PT988301E (en) |
| RU (1) | RU2221795C2 (en) |
| SK (2) | SK171099A3 (en) |
| TR (1) | TR199903098T2 (en) |
| TW (1) | TWI235751B (en) |
| WO (1) | WO1998056788A1 (en) |
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| KR19990064117A (en) | 1995-10-06 | 1999-07-26 | 폴락 돈나 엘. | Substituted imidazole with anticancer activity and cytokine inhibitory activity |
| GB2306108A (en) | 1995-10-13 | 1997-04-30 | Merck & Co Inc | Treatment of Raf-mediated cancers with imidazole derivatives |
| EP0859771A4 (en) | 1995-10-31 | 2000-03-15 | Merck & Co Inc | Substituted pyridyl pyrroles, compositions containing such compounds and methods of use |
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| AU7529096A (en) | 1995-10-31 | 1997-05-22 | Merck & Co., Inc. | Substituted aryl pyrroles, compositions containing such compounds and methods of use |
| JP3912758B2 (en) | 1996-02-16 | 2007-05-09 | 富士フイルム株式会社 | Method for producing 1,1-disubstituted-1H-benzo [e] indole compound and 4- to 9-position hydroxy group-substituted compound |
| EP0889887A4 (en) | 1996-03-25 | 2003-06-11 | Smithkline Beecham Corp | Novel treatment for cns injuries |
| GB0515625D0 (en) | 2005-07-29 | 2005-09-07 | Univ Manchester | Hydrogel particle |
-
1998
- 1998-06-12 EP EP98929548A patent/EP0988301B1/en not_active Expired - Lifetime
- 1998-06-12 JP JP50190899A patent/JP4380803B2/en not_active Expired - Lifetime
- 1998-06-12 AT AT98929548T patent/ATE335735T1/en active
- 1998-06-12 DE DE69835518T patent/DE69835518T2/en not_active Expired - Lifetime
- 1998-06-12 HU HU0003309A patent/HUP0003309A3/en unknown
- 1998-06-12 TR TR1999/03098T patent/TR199903098T2/en unknown
- 1998-06-12 WO PCT/GB1998/001711 patent/WO1998056788A1/en active Application Filing
- 1998-06-12 RU RU2000100951/04A patent/RU2221795C2/en not_active IP Right Cessation
- 1998-06-12 PL PL337314A patent/PL199893B1/en not_active IP Right Cessation
- 1998-06-12 NZ NZ501714A patent/NZ501714A/en not_active IP Right Cessation
- 1998-06-12 SK SK1710-99A patent/SK171099A3/en unknown
- 1998-06-12 CN CNB988079119A patent/CN100443481C/en not_active Expired - Fee Related
- 1998-06-12 SK SK3-2009A patent/SK286940B6/en not_active IP Right Cessation
- 1998-06-12 ES ES98929548T patent/ES2270520T3/en not_active Expired - Lifetime
- 1998-06-12 PT PT98929548T patent/PT988301E/en unknown
- 1998-06-12 KR KR1019997011695A patent/KR100704059B1/en not_active IP Right Cessation
- 1998-06-12 CA CA2293436A patent/CA2293436C/en not_active Expired - Fee Related
- 1998-06-12 IL IL13331198A patent/IL133311A0/en active IP Right Grant
- 1998-06-12 BR BRPI9810007-6A patent/BR9810007B1/en not_active IP Right Cessation
- 1998-06-12 AU AU79259/98A patent/AU742293B2/en not_active Ceased
- 1998-06-12 DK DK98929548T patent/DK0988301T3/en active
- 1998-06-12 CZ CZ19994452A patent/CZ9904452A3/en unknown
- 1998-07-29 TW TW087112466A patent/TWI235751B/en not_active IP Right Cessation
-
1999
- 1999-12-05 IL IL133311A patent/IL133311A/en not_active IP Right Cessation
- 1999-12-08 US US09/456,360 patent/US6602877B1/en not_active Expired - Lifetime
- 1999-12-10 NO NO996120A patent/NO326660B1/en not_active IP Right Cessation
-
2001
- 2001-05-09 HK HK01103260.6A patent/HK1032586A1/en not_active IP Right Cessation
-
2003
- 2003-05-13 US US10/436,609 patent/US6989395B2/en not_active Expired - Lifetime
-
2006
- 2006-09-21 CY CY20061101365T patent/CY1105238T1/en unknown
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