Benzimidazole derivatives as therapeutic agents
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/4184
A61K-031/4164
C07D-235/14
C07D-235/00
출원번호
US-0225277
(2005-09-13)
등록번호
US-7329684
(2008-02-12)
발명자
/ 주소
Mjalli,Adnan M. M.
Gopalaswamy,Ramesh
출원인 / 주소
TransTech Pharma, Inc.
대리인 / 주소
Rollins,Samuel B.
인용정보
피인용 횟수 :
40인용 특허 :
15
초록▼
This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated en
This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.
대표청구항▼
We claim: 1. A pharmaceutical composition comprising the compound of Formula (II) wherein m is an integer of from 0 to 3; R1 is an aryl group; R2 is a group of the formula--N(R9R10),--NHC(O)R9, or--NHC(O)OR9; wherein R9 and R10 are independently selected from the group consisting of 1)--H; 2)-Ary
We claim: 1. A pharmaceutical composition comprising the compound of Formula (II) wherein m is an integer of from 0 to 3; R1 is an aryl group; R2 is a group of the formula--N(R9R10),--NHC(O)R9, or--NHC(O)OR9; wherein R9 and R10 are independently selected from the group consisting of 1)--H; 2)-Aryl; 3)--C1-6 alkyl; and 4)--C1-6 alkylaryl; R4 is a) H; b)-aryl; c)--C1-6 alkyl; d)--C1-6 alkylaryl; or e)--C1-6 alkoxyaryl; R5, R6, R7, and R8 are independently selected from the group consisting of a)--H; b)--C1-6 alkyl; c)-aryl; d)--C1-6 alkylaryl; e)--C(O)--O--C1-6 alkyl; f)--C(O)--O--C1-6 alkylaryl; g)--C(O)--NH--C1-6 alkyl; h)--C(O)--NH--C1-6 alkylaryl; i)--SO2--C1-6 alkyl; j)--SO2--C1-6 alkylaryl; k)--SO2-aryl; l)--SO2--NH--C1-6 alkyl; m)--SO2--NH--C1-6 alkylaryl; n)--C(O)--C1-6 alkyl; o)--C(O)--C1-6 alkylary; p)--Y--C1-6 alkyl; q)--Y-aryl; r)--Y--C-1-6 alkylaryl; s)--Y--C1-6 alkylene-NR13R14; t)--Y--C1-6 alklene-W--R15; wherein Y and W are independently selected from the group consisting of--CH2--,--O--,--N(H),--S--,--SO2--,--CON(H)--,--NHC(O)--,--NHCON(H)--,--NHSO2--,--SO2N(H)--,--C(O)--O--,--NHSO2NH--,--O--CO--, wherein R16 and R17 are independently selected from the group consisting of aryl, C1-C6alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6alkoxyaryl, R15 is aryl, C1-C6 alkyl, or C1-C6 alkylaryl, and u) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein at least one of R5, R6, R7, and R8 is--Y--C1-6 alkylene-N--R13R14, R13, and R14 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl; or R13 and R14 are taken together to form a ring having the formula--(CH2)o--X--(CH2)p--bonded to the nitrogen atom to which R13 and R14 are attached, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond,--CH2--,--O--,--S--,--SO 2--,--C(O)--,--CON(H)--,--NHC(O)--,--NHCON(H)--,--NHSO2--,--SO2N(H)--,--C(O)--O--,--O--C(O)--,--NHSO2NH--, wherein R18 and R19 are alkyl or aryl; and wherein the aryl and/or alkyl group(s) in R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16, R17, R18, and R19 may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups selected from the group consisting of: a)--H; b)--Z--C1-6 alkyl; --Z-aryl; --Z--C-1-6 alkylaryl; --Z--C1-6-alkyl-NR20R21; --Z--C1-6-alkyl-W--R22; wherein Z and W are independently selected from the group consisting of--CH2--,--O--,--N(H),--S--,--SO2--,--CON(H)--,--NHC(O)--,--NHCON(H)--,--NHSO2--,--SO2N(H)--,--C(O)--O--,--NHSO2NH--,--O--CO--, wherein, R22, R23, and R24 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl, c) halogen, hydroxyl, cyano, and carbamoyl, and wherein R20 and R21 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl; or R20 and R21 are taken together to form a ring having the formula--(CH2)q--X--(CH2)r--bonded to the nitrogen atom to which R20 and R21 are attached wherein q and r are, independently, 1, 2, 3, or 4; X is a direct bond,--CH2--,--O--,--S--,--SO2--,--C(O)--,--CON(H)--,--NHC(O)--,--NHCON(H)--,--NHSO2--,--SO2N(H)--,--C(O)--O--,--O--C(O)--,--NHSO2NH--, R25 and R26 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. 2. The pharmaceutical composition of to claim 1, in the form of an oral dosage or parenteral dosage unit. 3. The pharmaceutical composition of claim 1, wherein said compound is administered as a dose in a range from about 0.01 to 500 mg/kg of body weight per day. 4. The pharmaceutical composition of claim 1, wherein said compound is administered as a dose in a range from about 0.1 to 200 mg/kg of body weight per day. 5. The pharmaceutical composition of claim 1, wherein said compound is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day. 6. The pharmaceutical composition of claim 1, further comprising one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants. 7. The pharmaceutical composition of claim 1, wherein R4 is a) aryl; b)--C1-6 alkyl; c)--C1-6 alkylaryl; or d)--C1-6 alkylaryl. 8. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-tert-butoxycarbonylamino-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 9. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 10. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-tert-butoxycarbonylamino-1-ethyl]-3-butyl-6-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 11. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1ethyl]-3-butyl-6-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 12. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-tert-butoxycarbonylamino-1-ethyl]-6-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 13. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-6-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 14. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[2-(3-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3butyl-5 (3-diethlamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 15. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Ethoxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 16. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-(4-Chloro)phenethoxy)phenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 17. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-(3-diethylamino-1-propyl)-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 18. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-ethyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 19. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-(3-diethylamino-1-propyl)-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 20. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1ethyl]-3-benzyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 21. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxphenyl)-1amino-1-ethyl]-3-benzyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 22. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1ehtyl]-3-propyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 23. The pharmaceutical composition of claim 1, wherein the compound of Formula (II) is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-propyl-5-(3-diethylamino-1-propoxy)benzimidazole, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
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Bonsen Pieter (Los Altos CA) Wong Patrick S. (Kowloon CA HKX) Theeuwes Felix (Los Altos CA), Method of delivering drug with aid of effervescent activity generated in environment of use.
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deLong, Mitchell A.; Sturdivant, Jill Marie; Royalty, Susan M., Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds.
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