WO2006073973A2 - Novel benzylamine derivatives as cetp inhibitors - Google Patents
Novel benzylamine derivatives as cetp inhibitors Download PDFInfo
- Publication number
- WO2006073973A2 WO2006073973A2 PCT/US2005/047203 US2005047203W WO2006073973A2 WO 2006073973 A2 WO2006073973 A2 WO 2006073973A2 US 2005047203 W US2005047203 W US 2005047203W WO 2006073973 A2 WO2006073973 A2 WO 2006073973A2
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- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- selected independently
- alkyl
- methyl
- substituted
- Prior art date
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- 150000003939 benzylamines Chemical class 0.000 title abstract description 103
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 323
- 125000004432 carbon atom Chemical group C* 0.000 claims description 659
- 125000005842 heteroatom Chemical group 0.000 claims description 546
- 125000000217 alkyl group Chemical group 0.000 claims description 501
- 125000000623 heterocyclic group Chemical group 0.000 claims description 372
- 125000001072 heteroaryl group Chemical group 0.000 claims description 370
- 150000001875 compounds Chemical class 0.000 claims description 322
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 278
- 125000003118 aryl group Chemical group 0.000 claims description 227
- 125000001188 haloalkyl group Chemical group 0.000 claims description 210
- 239000001257 hydrogen Substances 0.000 claims description 205
- 229910052739 hydrogen Inorganic materials 0.000 claims description 205
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 194
- 125000001424 substituent group Chemical group 0.000 claims description 191
- 150000003839 salts Chemical class 0.000 claims description 189
- -1 4,5-dihydro-oxazolyl Chemical group 0.000 claims description 134
- 239000000651 prodrug Substances 0.000 claims description 127
- 229940002612 prodrug Drugs 0.000 claims description 127
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 108
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 71
- 150000002367 halogens Chemical class 0.000 claims description 71
- 125000003545 alkoxy group Chemical group 0.000 claims description 66
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 66
- 239000008194 pharmaceutical composition Substances 0.000 claims description 48
- 125000004122 cyclic group Chemical group 0.000 claims description 37
- 125000002950 monocyclic group Chemical group 0.000 claims description 34
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 33
- 125000002619 bicyclic group Chemical group 0.000 claims description 30
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 30
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 27
- 229910052702 rhenium Inorganic materials 0.000 claims description 27
- 229910052705 radium Inorganic materials 0.000 claims description 26
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 26
- 125000002971 oxazolyl group Chemical group 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 23
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 22
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 21
- 125000000335 thiazolyl group Chemical group 0.000 claims description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 16
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 150000004820 halides Chemical class 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000003755 preservative agent Substances 0.000 claims description 10
- 230000002335 preservative effect Effects 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000006071 cream Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 239000000443 aerosol Substances 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 239000006260 foam Substances 0.000 claims description 4
- 239000002502 liposome Substances 0.000 claims description 4
- 239000007937 lozenge Substances 0.000 claims description 4
- 239000003094 microcapsule Substances 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 4
- OBHZXRGXOPEZJM-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-(cyclopentylmethyl)-n-ethylquinolin-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NN(C)N=N2)C=1N(CC)CC1CCCC1 OBHZXRGXOPEZJM-UHFFFAOYSA-N 0.000 claims description 3
- KCCLGUJGEIEOKR-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-[(2-methyltetrazol-5-yl)methyl]amino]methyl]-n-(cyclopentylmethyl)-n-ethylquinolin-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC2=NN(C)N=N2)CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=1N(CC)CC1CCCC1 KCCLGUJGEIEOKR-UHFFFAOYSA-N 0.000 claims description 3
- KLBBMLPMDFMOEE-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-pyridin-2-ylamino]methyl]-n-(cyclopentylmethyl)-n-ethylquinolin-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2N=CC=CC=2)C=1N(CC)CC1CCCC1 KLBBMLPMDFMOEE-UHFFFAOYSA-N 0.000 claims description 3
- HETSCGCAPKPTCI-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-pyrimidin-2-ylamino]methyl]-n-(cyclopentylmethyl)-n-ethylquinolin-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2N=CC=CN=2)C=1N(CC)CC1CCCC1 HETSCGCAPKPTCI-UHFFFAOYSA-N 0.000 claims description 3
- DQKOOKBZNRFUOC-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n,n-bis(cyclopropylmethyl)-1-methylpyrazolo[3,4-b]pyridin-6-amine Chemical compound CN1N=NC(N(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CC=2C(=NC=3N(C)N=CC=3C=2)N(CC2CC2)CC2CC2)=N1 DQKOOKBZNRFUOC-UHFFFAOYSA-N 0.000 claims description 3
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- ZROXYHJBYVUARA-UHFFFAOYSA-N ethyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(propyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OCC)C=1N(CCC)CC1CCCC1 ZROXYHJBYVUARA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- ZOXYUUHHWCTUMB-UHFFFAOYSA-N methyl n-[[2-[bis(cyclopropylmethyl)amino]-8-methylquinolin-3-yl]methyl]-n-[[3,5-bis(trifluoromethyl)phenyl]methyl]carbamate Chemical compound C=1C2=CC=CC(C)=C2N=C(N(CC2CC2)CC2CC2)C=1CN(C(=O)OC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZOXYUUHHWCTUMB-UHFFFAOYSA-N 0.000 claims description 3
- DZPFMXMFURUVJM-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclobutylmethyl(ethyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OC)C=1N(CC)CC1CCC1 DZPFMXMFURUVJM-UHFFFAOYSA-N 0.000 claims description 3
- GFLMCDHUEGRHMC-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]-5,6,7,8-tetrahydroquinolin-3-yl]methyl]carbamate Chemical compound N=1C=2CCCCC=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OC)C=1N(CC)CC1CCCC1 GFLMCDHUEGRHMC-UHFFFAOYSA-N 0.000 claims description 3
- FUERTWOVMCBAIC-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]-6-methylquinolin-3-yl]methyl]carbamate Chemical compound N=1C2=CC=C(C)C=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OC)C=1N(CC)CC1CCCC1 FUERTWOVMCBAIC-UHFFFAOYSA-N 0.000 claims description 3
- FLLCZARJBRSAFA-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OC)C=1N(CC)CC1CCCC1 FLLCZARJBRSAFA-UHFFFAOYSA-N 0.000 claims description 3
- BMZPGSKGYSPIQY-UHFFFAOYSA-N n-[5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl]-3-chloro-n-(cyclopropylmethyl)propanamide Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(C(=O)CCCl)CC1CC1 BMZPGSKGYSPIQY-UHFFFAOYSA-N 0.000 claims description 3
- HTSCAXMNTICSAZ-UHFFFAOYSA-N n-[5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl]-n-(cyclopropylmethyl)acetamide Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NN(C)N=N2)C=1N(C(=O)C)CC1CC1 HTSCAXMNTICSAZ-UHFFFAOYSA-N 0.000 claims description 3
- GUOMATWHRCHEQV-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]quinolin-3-yl]methyl]-4-methyl-1,3-oxazol-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2OC=C(C)N=2)C=1N(CC)CC1CCCC1 GUOMATWHRCHEQV-UHFFFAOYSA-N 0.000 claims description 3
- BCEGIOWPDPPWLU-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[6-[cyclobutylmethyl(ethyl)amino]-1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl]methyl]-5-methyl-1,2-oxazol-3-amine Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NOC(C)=C2)C=1N(CC)CC1CCC1 BCEGIOWPDPPWLU-UHFFFAOYSA-N 0.000 claims description 3
- 125000006413 ring segment Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- VAEDBVAEPNYHQP-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-[(1-methyltetrazol-5-yl)methyl]amino]methyl]-n-(cyclopentylmethyl)-n-ethylquinolin-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2N(N=NN=2)C)CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=1N(CC)CC1CCCC1 VAEDBVAEPNYHQP-UHFFFAOYSA-N 0.000 claims description 2
- HEDBZMCYFDHDTM-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n,n-bis(cyclopropylmethyl)-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(CC1CC1)CC1CC1 HEDBZMCYFDHDTM-UHFFFAOYSA-N 0.000 claims description 2
- LWMZJLFWWVYRLR-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-(cyclobutylmethyl)-n-(cyclopropylmethyl)-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(CC1CCC1)CC1CC1 LWMZJLFWWVYRLR-UHFFFAOYSA-N 0.000 claims description 2
- PFHGFFXODPRKKQ-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-(cyclobutylmethyl)-n-ethyl-1-methylpyrazolo[3,4-b]pyridin-6-amine Chemical compound N=1C=2N(C)N=CC=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NN(C)N=N2)C=1N(CC)CC1CCC1 PFHGFFXODPRKKQ-UHFFFAOYSA-N 0.000 claims description 2
- WFTKEUZYJNWKBI-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-cyclopentyl-n-ethyl-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NN(C)N=N2)C=1N(CC)C1CCCC1 WFTKEUZYJNWKBI-UHFFFAOYSA-N 0.000 claims description 2
- BTDIMGSRLPOWKK-UHFFFAOYSA-N ethyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[butyl(ethyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound CCCCN(CC)C1=NC2=CC=CC=C2C=C1CN(C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 BTDIMGSRLPOWKK-UHFFFAOYSA-N 0.000 claims description 2
- PENFZVSMRPVDDO-UHFFFAOYSA-N ethyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclohexylmethyl(ethyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound C=1C2=CC=CC=C2N=C(N(CC)CC2CCCCC2)C=1CN(C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PENFZVSMRPVDDO-UHFFFAOYSA-N 0.000 claims description 2
- FHGLFNAQIFGIIA-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopropylmethyl(ethyl)amino]quinolin-3-yl]methyl]carbamate Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=O)OC)C=1N(CC)CC1CC1 FHGLFNAQIFGIIA-UHFFFAOYSA-N 0.000 claims description 2
- GXQNOHASRMTPED-UHFFFAOYSA-N n,n-bis(cyclopropylmethyl)-5-[[(3,5-dichlorophenyl)methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound C=1C(Cl)=CC(Cl)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(CC1CC1)CC1CC1 GXQNOHASRMTPED-UHFFFAOYSA-N 0.000 claims description 2
- IWYCJJJQXVVZIW-UHFFFAOYSA-N n-(cyclopentylmethyl)-n-ethyl-1,3-dimethyl-5-[[(2-methyltetrazol-5-yl)-[(3,4,5-trifluorophenyl)methyl]amino]methyl]pyrazolo[3,4-b]pyridin-6-amine Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(F)C(F)=C(F)C=2)C2=NN(C)N=N2)C=1N(CC)CC1CCCC1 IWYCJJJQXVVZIW-UHFFFAOYSA-N 0.000 claims description 2
- RCHSXIMOQLCWIJ-UHFFFAOYSA-N n-[5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl]-n-(cyclopropylmethyl)cyclohexanecarboxamide Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(C(=O)C1CCCCC1)CC1CC1 RCHSXIMOQLCWIJ-UHFFFAOYSA-N 0.000 claims description 2
- PGJUQBSZYJREHD-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclobutylmethyl(ethyl)amino]quinolin-3-yl]methyl]-5-methyl-1,2-oxazol-3-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NOC(C)=C2)C=1N(CC)CC1CCC1 PGJUQBSZYJREHD-UHFFFAOYSA-N 0.000 claims description 2
- USLSEQBDVKFJJT-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]quinolin-3-yl]methyl]-4,5-dihydro-1,3-oxazol-2-amine Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2OCCN=2)C=1N(CC)CC1CCCC1 USLSEQBDVKFJJT-UHFFFAOYSA-N 0.000 claims description 2
- QNAXOUMUKZDEGB-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n,n-bis(cyclopropylmethyl)-4,6-dimethylpyridin-2-amine Chemical compound C1CC1CN(CC1CC1)C1=NC(C)=CC(C)=C1CN(C1=NN(C)N=N1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 QNAXOUMUKZDEGB-UHFFFAOYSA-N 0.000 claims 2
- ZNOTTYXVTJLPFD-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethyl-n,n-bis(2-methylpropyl)pyrazolo[3,4-b]pyridin-6-amine Chemical compound CC(C)CN(CC(C)C)C1=NC=2N(C)N=C(C)C=2C=C1CN(C1=NN(C)N=N1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZNOTTYXVTJLPFD-UHFFFAOYSA-N 0.000 claims 2
- XTTVYHYMQBJFKZ-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-(2,2-dimethylpropyl)-n-ethyl-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound CC(C)(C)CN(CC)C1=NC=2N(C)N=C(C)C=2C=C1CN(C1=NN(C)N=N1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 XTTVYHYMQBJFKZ-UHFFFAOYSA-N 0.000 claims 2
- SRDYLXFAHFAOQH-UHFFFAOYSA-N 5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-(cyclopropylmethyl)-1,3-dimethyl-n-(2-methylpropyl)pyrazolo[3,4-b]pyridin-6-amine Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C2=NN(C)N=N2)C=1N(CC(C)C)CC1CC1 SRDYLXFAHFAOQH-UHFFFAOYSA-N 0.000 claims 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims 2
- GITHBSDJZHOKKF-UHFFFAOYSA-N methyl n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-[[2-[cyclopentylmethyl(ethyl)amino]quinolin-3-yl]methyl]carbamodithioate Chemical compound N=1C2=CC=CC=C2C=C(CN(CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C(=S)SC)C=1N(CC)CC1CCCC1 GITHBSDJZHOKKF-UHFFFAOYSA-N 0.000 claims 2
- 239000002324 mouth wash Substances 0.000 claims 2
- 229940051866 mouthwash Drugs 0.000 claims 2
- XLAURLHVQSVZOF-UHFFFAOYSA-N n-(cyclopentylmethyl)-5-[[(3,5-difluorophenyl)methyl-(2-methyltetrazol-5-yl)amino]methyl]-n-ethyl-1,3-dimethylpyrazolo[3,4-b]pyridin-6-amine Chemical compound N=1C=2N(C)N=C(C)C=2C=C(CN(CC=2C=C(F)C=C(F)C=2)C2=NN(C)N=N2)C=1N(CC)CC1CCCC1 XLAURLHVQSVZOF-UHFFFAOYSA-N 0.000 claims 2
- YLRWKOANWWCEME-UHFFFAOYSA-N n-[5-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl]-n-(cyclopropylmethyl)cyclopentanecarboxamide Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1CN(C1=NN(C)N=N1)CC=1C=C2C(C)=NN(C)C2=NC=1N(C(=O)C1CCCC1)CC1CC1 YLRWKOANWWCEME-UHFFFAOYSA-N 0.000 claims 2
- 235000010603 pastilles Nutrition 0.000 claims 2
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to benzylamine compounds, methods and compositions for making and using the benzylamine compounds, and compositions and methods for treating or preventing conditions or diseases associated with lipoprotein metabolism.
- CETP Cholesteryl ester-transfer protein
- HDL high density lipoprotein
- CETP is a 70 kDa plasma glycoprotein that is physically associated with HDL particles. It facilitates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. This transfer is accompanied by transfer of triglycerides in the opposite direction.
- VLDL very low density lipoprotein
- LDL very low density lipoprotein
- LDL very low density lipoprotein
- LDL very low density lipoprotein
- LDL very low density lipoprotein
- HDL-C high-density lipoprotein cholesterol
- CAD coronary artery disease
- HDL-C levels >40 mg/dl be considered as a therapeutic target in primary and secondary prevention. This goal appears to be particularly important in patients with low serum HDL-C levels and ischemic heart disease (IHD) or its equivalents, even if the therapeutic target for serum low-density lipoprotein cholesterol (LDL-C) levels ( ⁇ 100 mg/dl) has been achieved. It is believed that the anti-atherogenic role of HDL is in part due its ability to promote the efflux of free cholesterol from cells and to transport it to the liver, a process termed reverse cholesterol transport. HDL could protect against atherosclerosis by several other mechanisms. For example, several studies showed HDL to have antioxidant and anti-inflammatory effects.
- IHD ischemic heart disease
- HDL particles carry enzymes that retard LDL oxidation, including paraoxonase, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase. These enzymes degrade pro-inflammatory, oxidized phospholipids, limiting their accumulation in LDL.
- apoA-I can bind oxidized lipids and remove them from LDL.
- HDL also can act as a carrier vehicle for small molecules, including bacterial lipopolysaccharide (LPS) thus regulating the inflammatory effects of LPS.
- LPS bacterial lipopolysaccharide
- elevating HDL is not only anti-atherogenic but it could also potentially be anti-inflammatory.
- Existing therapies such as, for example, HDL-elevating therapies and anti- atherosclerosis therapies have limitations including serious toleration issues.
- alternative therapies including methods of preventing or treating conditions or diseases associated with lipoprotein metabolism such as, for example, atherosclerosis.
- the present invention is directed to novel benzylamine compounds, novel compositions comprising these benzylamine compounds, and novel methods employing such benzylamine compounds and their compositions.
- Disclosed herein are methods for making benzylamine compounds compounds, compositions comprising these benzylamines, and methods and compositions for using these benzylamines.
- the benzylamine compounds and compositions comprising these compounds have utility in treatment of a variety of diseases. Certain aspects of benzylamine compounds have been disclosed in PCT Publication WO 2004/020393, and in U.S. Patent Numbers 6,710,089 and 6,723,753.
- the present invention provides for compounds and compositions comprising these compounds, in which the compounds have the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- A is a substituted or an unsubstituted, monocyclic or bicyclic, heterocyclic moiety, comprising from 5 to 10 ring atoms, inclusive, and comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R and R are selected independently from: 1) hydrogen; 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; 3) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; or 4) (CHR x ) n R 5 or (CH 2 )
- R is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , C(S)NR 6 R 7 , C(S)NC(O)OR 8 , or C(S)SR 8 ; wherein when R 3 is an alkyl, an aryl, a heterocyclyl, or a heteroaryl, R 3 is optionally substituted with up to three substituents selected independently from
- R 4 in each occurrence, is selected independently from: 1) halogen, cyano, or hydroxy; 2) an alkyl, a cycloalkyl, a cycloalkoxy, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, aralkyl, aryloxy, heteroaryl, or heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, or >NR 10 ; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , or (CH 2 ) q NR 6 R 7 , wherein q is an integer from O to 5, inclusive; m is an integer from O to 3, inclusive; or R 4
- R 5 in each occurrence, is selected independently from: 1) an alkoxy, a haloalkoxy, or a cycloalkyl, any of which having up to 12 carbon atoms; 2) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; 3) hydroxyl, NR 6 R 7 , CO 2 R 6 , COR 8 , or SO 2 R 8 ; or 4) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from >0, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 6 and R 7 in each occurrence, are selected independently from: 1) hydrogen;
- R and R together form a substituted or an unsubstituted cyclic moiety having from 3 to 7 ring carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms in addition to the nitrogen atom to which R 6 and R 7 are bonded, selected independently from >O, >N-, >S, or >NR 10 ;
- R 8 in each occurrence, is selected independently from: 1) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms; or 2) a substituted of an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or
- R in each occurrence, is selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- Z is N or CH; or the ZR 1 moiety is S, CO, or SO 2 ; or the ZR 1 R 2 moiety is - C ⁇ CR 2 ;
- R 1 ' is selected independently from:
- R 13 in each occurrence, is independently 1, 2, or 3;
- R 12 in each occurrence, is independently selected from a substituted or an unsubstituted heterocyclyl having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >SO 2 , or >C0, wherein any substituted heterocyclyl is substituted with up to three substituents selected independently from an acyl, an alkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms, or -COOH;
- R 13 in each occurrence, is independently selected from: 1) hydrogen; or 2) a cycloalkyl, an aryl, a haloalkyl, a heterocyclyl, or an alkyl group optionally substituted with at least one hydroxyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0;
- R 14 in each occurrence, is independently selected from a heterocyclyl, a cycloalkyl, or an aryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- Z 2 in each occurrence, is selected independently from >NR 10 or O; R' and R", in each occurrence, are independently selected from hydrogen or an alkyl having up to 12 carbon atoms; and
- R 15 and R 16 are independently selected from: 1) hydrogen; 2) an alkyl having up to 12 carbon atoms; or 3) -(CH 2 )r-O-R 13 , -(CH 2 )r-R 14 ,
- R 15 and R 16 together form a substituted or an unsubstituted cyclic moiety comprising up to 12 carbon atoms, optionally comprising at least one additional heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >SO 2 , or >C0; wherein any substituted cyclic moiety is substituted with up to three substituents selected independently from: 1) hydroxyl; 2) an alkyl or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heteroaryl comprises at least one heteroatom or heterogroup selected independently from
- A is optionally substituted with 1 , 2, or 3 substituents selected independently from: 1) halogen, cyano, or hydroxyl; 2) an alkyl, an alkenyl, an alkynyl, a haloalkyl, a cycloalkyl, an alkoxy, a cycloalkoxy, a haloalkoxy, an aryl, an aryloxy, an aralkyl, a heteroaryl, a heterocyclyl, or a heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl, heterocyclyl, or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or
- R 1 and R 2 are optionally and independently substituted with 1 or 2 substituents selected independently from: 1) an alkyl, a cycloalkyl, a haloalkyl, an alkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2
- R 4 , R 5 , R 6 , R 7 , and R 8 are optionally and independently substituted with at least one substituent selected independently from: 1) halide, hydroxy, cyano, or NR 6 R 7 ; or 2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms.
- substituents selected independently from: 1) halide, hydroxy, cyano, or NR 6 R 7 ; or 2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms.
- R a when a substituent such as R a is represented as bonded to any position on the carbocyclic ring of a quinoline moiety, such a representation is intended to encompass regioisomers in which R a is bonded to the heterocyclic ring as well.
- any heterocyclyl, any heterocycloalkyl, any heteroaryl, and any heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO, as the context allows or requires.
- R 1 are selected independently from substituents on R 2 .
- R 1 and R 2 form a cyclic moiety
- any subsitutent selected constitutes a subsitutent on the cyclic R 1 -A-R 2 moiety or core.
- each substituent is selected independently of any other substituent.
- the present invention is also directed to methods or processes for the preparation of the benzylamine compounds disclosed herein, including compounds of the general formula (I).
- this invention is also directed to compositions comprising the benzylamine compounds disclosed herein, including compounds of the general formula (I).
- the composition is a pharmaceutical compositions
- the composition also comprises a pharmaceutically acceptable carrier and at least one compound according to this invention, and further comprises: optionally, a pharmaceutically acceptable auxiliary; optionally, a pharmaceutically acceptable preservative; optionally, a pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable diluent; and optionally, a pharmaceutically acceptable solvate.
- the present invention also is directed to a method for treating a condition or disease in a mammalian subject, including a human.
- the method comprises administering to the subject a composition comprising a therapeutically- effective amount of at least one compound disclosed herein, or their pharmaceutically- acceptable salts thereof.
- the methods and compositions of the present invention are useful for treating a variety of mammals such as, for example, companion animals such as cats or dogs, primates, ruminant animals, and rodents.
- the present invention also is directed to a method for treating or preventing a condition or disease in a human or an animal subject, the method comprising administering to the subject a composition comprising a prophylactically- or therapeutically-effective amount of at least one compound disclosed herein, or their pharmaceutically-acceptable salts thereof.
- this invention provides methods for the treatment and/or prevention of conditions or disease states in a human or anminal, such as dyslipidemia, atherosclerosis, peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipo- proteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic retinopathy, and endotoxemia, comprising administering a therapeutically-effective amount of at least one compound disclosed herein.
- a human or anminal such as dyslipidemia, atherosclerosis, peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipo- proteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic
- novel benzylamine compounds and novel compositions comprising these benzylamine compounds are described.
- compounds in accordance with the present invention can comprise benzylamine compounds having the following formula:
- R and R are selected independently from: hydrogen; a Cl to C6 alkyl, that is, an alkyl having up to 6 carbon atoms; a C3 to C6 cycloalkyl, that is, a cycloalkyl having up to 6 carbon atoms; COR 8 ; or (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1 or 2; or R and R together form a substituted or an unsubstituted monocyclic or bi cyclic moiety comprising up to 12 carbon atoms, and optionally comprising 1 or 2 heteroatoms or heterogroups selected independently from >O, >N-, or >NR 10 ; wherein any optional substituent on the cyclic moiety selected from: 1) a C3 to C6 cycloalkyl, that is, a cycloalkyl having up to 6 carbon atoms; or 2) a Cl to C2 alkyl, that is, an
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO, any of which having up to 12 carbon atoms; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , C(S)NR 6 R 7 , C(S)NC(O)OR 8 , or C(S)SR 8 ; wherein when R 3 is an alkyl, an aryl, a heterocyclyl, or a heteroaryl, R 3 is optionally substituted with up to three substituents selected independently from
- R 12 in each occurrence, is independently selected from a substituted or an unsubstituted heterocyclyl having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO, wherein any substituted heterocyclyl is substituted with up to three substituents selected independently from an acyl, an alkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms, or -COOH;
- R 13 in each occurrence, is independently selected from: 1) hydrogen; or 2) a cycloalkyl, an aryl, a haloalkyl, a heterocyclyl, or an alkyl group optionally substituted with at least one hydroxyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R in each occurrence, is independently selected from a heterocyclyl, a cycloalkyl, or an aryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- Z 2 in each occurrence, is selected independently from >NR 10 or O; R' and R", in each occurrence, are independently selected from hydrogen or an alkyl having up to 12 carbon atoms; and
- R 15 and R 16 are independently selected from: 1) hydrogen; 2) an alkyl having up to 12 carbon atoms; or 3) -(CH 2 )r-O-R 13 , -(CH 2 )r-R 14 , -COR 13 , -(CH 2 )r-CO-Z 2 -R 13 , -CO 2 R 13 , -CO 2 -(CH 2 )r-R 13 , -CO 2 -(CH 2 )r-R 12 , -CO 2 -
- R 15 and R 16 together form a substituted or an unsubstituted cyclic moiety comprising up to 12 carbon atoms, optionally comprising at least one additional heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or
- any substituted cyclic moiety is substituted with up to three substituents selected independently from: 1) hydroxyl; 2) an alkyl or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, or >NR 10 ; or 3) COOR 13 , -Z 2 -(CH 2 )r-R 13 , -COR 13 , -CO 2 -(CH 2 )r-R 13 , -CO(CH 2 )r-O-R 13 , -(CH 2 )r-CO 2 -
- R 4 in each occurrence, is selected independently from: 1) a halogen or cyano; or 2) an alkyl or a haloalkyl, either of which having up to 4 carbon atoms; and m is 2 or 3.
- compounds in accordance with the present invention can comprise benzylamine compounds according to formula (I), having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- A is selected from a substituted or an unsubstituted, monocyclic or bicyclic
- R 1 and R 2 are selected independently from: 1) hydrogen; 2) a Cl to C6 alkyl, that is, an alkyl having up to 6 carbon atoms; 3) a C3 to C6 cycloalkyl, that is, a cycloalkyl having up to 6 carbon atoms; 4) COR 8 ; or 5) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1 or 2; R , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO, any of which having up to 12 carbon atoms; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , C(S)NR 6 R 7 , C(S)NC(O)OR 8 , or C(S)SR 8 ; wherein when R 3 is a heterocyclyl or a heteroaryl, R 3 is optionally substituted with up to three substituents selected independently from a halide, a hydroxyl
- R in each occurrence, is independently selected from a substituted or an unsubstituted heterocyclyl having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0, wherein any substituted heterocyclyl is substituted with up to three substituents selected independently from an acyl, an alkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms, or -COOH;
- R 13 in each occurrence, is independently selected from: 1) hydrogen; or 2) a cycloalkyl, an aryl, a haloalkyl, a heterocyclyl, or an alkyl group optionally substituted with at least one hydroxyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0;
- R in each occurrence, is independently selected from a heterocyclyl, a cycloalkyl, or an aryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0;
- Z in each occurrence, is selected independently from >NR or O; R' and R", in each occurrence, are independently selected from hydrogen or an alkyl having up to 12 carbon atoms; and
- R 15 and R 16 are independently selected from: 1) hydrogen; 2) an alkyl having up to 12 carbon atoms; or 3) -(CH 2 )r-O-R 13 , -(CH 2 )r-R 14 , -COR 13 , -(CH 2 )r-CO-Z 2 -R 13 , -CO 2 R 13 , -CO 2 -(CH 2 )r-R 13 , -CO 2 -(CH 2 )r-R 12 , -CO 2 -
- R 15 and R 16 together form a substituted or an unsubstituted cyclic moiety comprising up to 12 carbon atoms, optionally comprising at least one additional heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or
- any substituted cyclic moiety is substituted with up to three substituents selected independently from: 1) hydroxyl; 2) an alkyl or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, or >NR 10 ; or 3) COOR 13 , -Z 2 -(CH 2 )r-R 13 , -COR 13 , -CO 2 -(CH 2 )r-R 13 , -CO(CH 2 )r-O-R 13 , -(CH 2 )r-CO 2 -
- R in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, any of which having up to 4 carbon atoms; and m is 2 or 3.
- compounds in accordance with the present invention can comprise benzylamine compounds according to formula (I), having the following formula: da'); or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- A is selected from a substituted or an unsubstituted, monocyclic or bicyclic
- R a in each occurrence, is selected independently from: 1) a halogen; a hydroxyl, or a cyano; 2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ; and p is an integer from 0 to 3, inclusive, as the structure of A allows or requires.
- R a groups as substituents on any portion of the bicyclic moieties is intended to denote all possible regioisomers, including regioisomers in which R a groups are bonded to either ring or both rings of the bicyclic moieties.
- substituents of the formula can be selected as indicated here, while unspecified substitutents are selected as disclosed above for this formula:
- substituents of the formula can be selected as indicated here, while unspecified substitutents are selected as disclosed above for this formula:
- R 1 and R 2 are selected independently from: 1) hydrogen; 2) a Cl to C6 alkyl, that is, an alkyl having up to 6 carbon atoms; 3) a C3 to C6 cycloalkyl, that is, a cycloalkyl having up to 6 carbon atoms; 4) COR 8 ; or 5) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R ⁇ , wherein n, in each occurrence, is 1 or 2; R , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O,
- R 1 l is selected independently from:
- a substituted or an unsubstituted heteroaryl or heterocyclyl any of which having up to 12 carbon atoms, comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0, wherein any substituted heteroaryl or heterocyclyl is substituted with up to three substituents selected independently from an alkyl having up to 12 carbon atoms or a hydroxyl; or 3) -CO-Z 2 -R 13 , -CO-R 12 , -CO-Z 2 -(CH 2 )r-CO-Z 2 -R 13 , -NR 15 R 16 , -Z 2 -
- R 13 in each occurrence, is independently 1, 2, or 3;
- R 12 in each occurrence, is independently selected from a substituted or an unsubstituted heterocyclyl having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0, wherein any substituted heterocyclyl is substituted with up to three substituents selected independently from an acyl, an alkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms, or -COOH;
- R 13 in each occurrence, is independently selected from: 1) hydrogen; or 2) a cycloalkyl, an aryl, a haloalkyl, a heterocyclyl, or an alkyl group optionally substituted with at least one hydroxyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or
- R 14 in each occurrence, is independently selected from a heterocyclyl, a cycloalkyl, or an aryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- Z 2 in each occurrence, is selected independently from >NR 10 or O;
- R' and R" in each occurrence, are independently selected from hydrogen or an alkyl having up to 12 carbon atoms;
- R 15 and R 16 are independently selected from: 1) hydrogen; 2) an alkyl having up to 12 carbon atoms; or 3) -(CH 2 )r-O-R 13 , -(CH 2 )r-R 14 , -COR 13 , -(CH 2 )r-CO-Z 2 -R 13 , -CO 2 R 13 , -CO 2 -(CH 2 )r-R 13 , -CO 2 -(CH 2 ) ⁇ R 12 , -CO 2 -
- R 15 and R 16 together form a substituted or an unsubstituted cyclic moiety comprising up to 12 carbon atoms, optionally comprising at least one additional heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or
- any substituted cyclic moiety is substituted with up to three substituents selected independently from: 1) hydroxyl; 2) an alkyl or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, or >NR 10 ; or 3) COOR 13 , -Z 2 -(CH 2 )r-R 13 , -COR 13 , -CO 2 -(CH 2 )r-R 13 , -CO(CH 2 )r-O-R 13 , -(CH 2 )r-CO 2 -
- R 4 in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, any of which having up to 4 carbon atoms; and m is 2 or 3.
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture thereof, or any combination thereof, wherein:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1 or 2; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted, 5-, 6-, or 7- membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 , C(S)SR 8 , or C(S)NC(O)OR 8 ;
- R 4 in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, either of which having up to 12 carbon atoms; m is an integer from O to 3, inclusive;
- R 5 in each occurrence, is selected independently from: 1) a substituted or an unsubstituted aryl, cycloalkyl, heterocyclyl, or heteroaryl, any of which having up to
- any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >CO;
- R 6 is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R in each occurrence, is selected independently from a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from: 1) halogen, hydroxyl, or cyano; 2) an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, or an aryl, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ; p is an integer from 0 to 3, inclusive;
- R is optionally substituted with at least one substituent selected independently from 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R b is selected independently from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R 3 is selected from a substituted or an unsubstituted group selected from tetrazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R a is selected from methyl, ethyl, or methoxy; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I),
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1 or 2; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted, 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 ;
- R 4 in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, either of which having up to 12 carbon atoms; m is an integer from 0 to 3, inclusive;
- R 5 in each occurrence, is selected independently from: 1) a substituted or an unsubstituted aryl, cycloalkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 2) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 6 is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 8 in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is an selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from: 1) a hydrogen; 2) an alkyl, a haloalkyl, an aryl, or an alkoxy, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ;
- p is an integer from 0 to 2, inclusive;
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention affords benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R a is selected from: 1) hydrogen; or 2) an alkyl or an aryl, either of which having up to 12 carbon atoms;
- R a2 is selected from hydrogen or an alkyl having up to 12 carbon atoms
- R b is selected from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- R a is selected from: 1) hydrogen, or 2) an alkyl or an aryl, either of which having up to 12 carbon atoms;
- R a2 is selected from hydrogen or an alkyl having up to 12 carbon atoms
- R 3 is selected from a substituted or an unsubstituted group selected from tetrazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substituted on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still a further aspect of this invention affords benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e ,
- R d in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms, or hydrogen;
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted, 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or3) CO 2 R 6 ;
- R 6 is selected from: 1) hydrogen; or 2) a substituted of an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from hydrogen or an alkyl having up to 12 carbon atoms; p is an integer from 0 to 3, inclusive;
- R 3 is optionally substituted with at least one substituent selected independently from 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R b is selected independently from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this disclosure affords benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from a substituted or an unsubstituted group selected from tetrazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1 or 2; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up
- heterocyclyl or heteroaryl any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 ;
- R in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; m is an integer from 0 to 3, inclusive; R 5 , in each occurrence, is selected independently from; 1) a substituted or an unsubstituted aryl, cycloalkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 2) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 6 is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or
- R in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N- S >S, >NR 10 , >SO 2 , or >CO;
- R in each occurrence, is an selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms; R a , in each occurrence, is selected independently from hydrogen or an alkyl having up to 12 carbon atoms; p is an integer from 0 to 3, inclusive;
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- benzylamine compounds according to formula (I) and compositions comprising benzylamine compounds, having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R b is selected independently from; 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- a further aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from a substituted or an unsubstituted tetrazolyl, 1,3,4- oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R and R are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up to
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted, 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 ;
- R 4 in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; m is an integer from 0 to 3, inclusive;
- R 5 in each occurrence, is selected independently from: 1) a substituted or an unsubstituted aryl, cycloalkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 2) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 6 is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or
- R in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is an selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from: 1) halogen, hydroxyl, or cyano; or 2) an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ; p is an integer from 0 to 3, inclusive;
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R b is selected independently from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I),
- a further aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from a substituted or an unsubstituted tetrazolyl, 1,3,4- oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- (Vic) or a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one
- heterocyclyl or heteroaryl any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 ;
- R 6 is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or
- R in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is an selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from: 1) halogen, hydroxyl, or cyano; or 2) an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ;
- p is an integer from 0 to 3, inclusive;
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- benzylamine compounds according to formula (I) and compositions comprising benzylamine compounds, having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R b is selected independently from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- a further aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from a substituted or an unsubstituted tetrazolyl, 1,3,4- oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted alkyl or a substituted or an unsubstituted cycloalkyl, either of which having up to 12 carbon atoms; 2) COR 8 or CO 2 R 6 ; or 3) (CH 2 ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having
- R 3 is selected from: 1) hydrogen or cyano; 2) a substituted or an unsubstituted, 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1 , 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 4) CO 2 R 6 ;
- R 4 in each occurrence, is selected independently from: 1) halogen or cyano; or 2) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; m is an integer from 0 to 3, inclusive;
- R in each occurrence, is selected independently from: 1) a substituted or an unsubstituted aryl, cycloalkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; or 2) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R is selected from: 1) hydrogen; or 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R in each occurrence, is selected independently from an alkyl, a cycloalkyl, a haloalkyl, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO;
- R 10 in each occurrence, is an selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
- R a in each occurrence, is selected independently from: 1) halogen, hydroxyl, or cyano; or 2) an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ;
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R is an alkyl having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I). Any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R b is selected independently from: 1) hydrogen; or 2) an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- a further aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R 3 is selected from a substituted or an unsubstituted tetrazolyl, 1,3,4- oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substitutent on R 3 is selected independently from an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R a is hydrogen or an alkyl having up to 2 carbon atoms
- R 3 is selected from: 1) CO 2 R 6 or 2) a substituted or an unsubstituted 5-, 6-, or 7-membered heteroaryl having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from >O, >N-, >S, or >NR 10 ; and any group or substituent that is not specified, is selected according to the substituents disclosed herein for structure (I).
- the present invention provides several benzylamine compound genera, each of which is a subgenus of formula (I) disclosed herein. These genera are represented by the formulas (II-l), (IIa-1), (Hb-I), (HI-I), (IIIa-1), (IIIb-1), (IV-I), (IVa-I), (IVb-I), (V-I) 5 (Va-I), (Vb-I), (VI-I), (VIa-I), (VIb-I), (VII-I), (VIIa-I), (VIb-I), (VII-I), (VIIa-I), (VIIb-I), (VIII-I), (VIIIa-I), and (VIIIb-I), as illustrated below, and each is characterized by various substituents including, but not limited to, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R
- the possible selections for these substituent in each instance are provided in the listing below, and definitions of each of these possible selections, for example, the definitions of R 1A , R 1B , R 1C , and R 1D which are possible selections for R 1 , are further provided below.
- formulas (A-Ol) through (A-384) in Table A are applicable to the compounds associated with that table, in this case, (II-l), (HI-I), (IIIb-1), (IV-I), (V-I), (VI-I), (VII-I), and (VIII-I), and provide 384 differenet subgenera for each formula (II-l), (HI-I), (IIIb-1), (IV-I), (V-I), (VI-I), (VII-I), and (VIII-I).
- This present invention provides for each of these compounds, methods of making each of these compounds, and methods of using each compound.
- substituent selections are as follows. To the extent that any group or substituent is not specified in any of these formulas, the definition of that group of or substituent provided for formula (I) is applicable.
- Z can be selected from Z A , Z B , or Z c .
- R 1 can be selected from R 1A , R 1B , R 1C , or R ID .
- R 2 can be selected from R 2A , R 2B , R 2C , or R 2D .
- R 3 can be selected from R 3A , R 3B , R 3C , or R 3D .
- R 4 can be selected from R 4A , R 4B , or R 4C .
- R 5 can be selected from R 5A , R 5B , or R 5C .
- R 6 can be selected from R 6A , R 6B , R 6C , R 6D , or R 6E .
- R 7 can be selected from R 7A , R 7B , R 7C , R 7D , or R 7E .
- R 8 can be selected from R 8A , R 8B , or R 8C .
- R 9 can be selected from R 9A , R 9B , R 9C , or R 9D .
- R 10 can be selected from R 10A , R 10B , or R 10C .
- R a can be selected from R al or R a2 .
- R b can be selected from R bl or R b2 .
- R x can be selected from R xl , R x2 , R x3 , or R x4 .
- Z A is N or CH.
- Z B is N.
- Z c is CH.
- R 1A is: a) hydrogen; or b) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, monoalkylamino, dialkylamino, alkoxyalkyl, haloalkoxyalkyl, or aminoalkyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 1B is a substituted or an unsubstituted heterocyclyl or heteroaryl, any of which having up to 12 parbon atoms, comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 1C is: a) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; or b) (CHR x ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R x , in each occurrence, is selected independently from an alkyl or an alkoxy, either of which having up to 12 carbon atoms, or hydrogen; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO; and R e , in each occurrence, is selected independently from an alky
- R 1D and R 2D together form a substituted or an unsubstituted monocyclic or bi cyclic moiety comprising up to 12 carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms or heterogroups in addition to Z, selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 2A is: a) hydrogen; or b) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, monoalkylamino, dialkylamino, alkoxyalkyl, haloalkoxyalkyl, or aminoalkyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 2B is a substituted or an unsubstituted heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 2C is: a) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; or b) (CHR x ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R x , in each occurrence, is selected independently from an alkyl or an alkoxy, either of which having up to 12 carbon atoms, or hydrogen; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >CO; and R e , in each occurrence, is selected independently from an al
- R 2D and R 1D together form a substituted or an unsubstituted monocyclic or bicyclic moiety comprising up to 12 carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms or heterogroups in addition to Z, selected independently from >O, >N-,
- R 3A is: a) hydrogen or cyano; or 2) a substituted or an unsubstituted alkyl having up to 12 carbon atoms.
- R 3B is a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or hetero groups selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 3C is a substituted or an unsubstituted group selected from CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , C(S)NR 6 R 7 , C(S)NC(O)OR 8 , or C(S)SR 8 .
- R 3D is a substituted or an unsubstituted group selected from 4,5-dihydro- oxazolyl, tetrazolyl, isooxazolyl, pyridyl, pyrimidinyl, oxadiazolyl, thiazoyl, or oxazolyl; wherein any optional substitutent on R 3D is selected independently from: a) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or b) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms.
- R 4 ⁇ is: a) halogen, cyano, or hydroxy; or b) an alkyl, a cycloalkyl, a cycloalkoxy, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 12 carbon atoms.
- R 4B is a substituted or an unsubstituted aryl, aralkyl, aryloxy, heteroaryl, or heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, or >NR 10 .
- R 4C is: a) a substituted or an unsubstituted group selected from CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; or b) (CH 2 ) q NR 6 R 7 , wherein q is an integer from O to 5, inclusive.
- R 5 is a substituted or an unsubstituted an alkoxy, a haloalkoxy, or a cycloalkyl, any of which having up to 12 carbon atoms.
- R is: a) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >0,
- R 5C is hydroxyl, NR 6 R 7 , CO 2 R 6 , COR 8 , or SO 2 R 8 .
- R 6A hydrogen, R 6B is an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms.
- R 6C is a substituted or an unsubstituted aryl, or a substituted or an unsubstituted aralkyl, any of which having up to 12 carbon atoms.
- R 6D is a substituted or an unsubstituted heterocyclyl, or a substituted or an unsubstituted heteroaryl, any of which having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 6E and R 7E together form a substituted or an unsubstituted cyclic moiety having from 3 to 7 ring carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms in addition to the nitrogen atom to which R 6E and R 7E are bonded, selected independently from >O, >N-, >S, or >NR 10 .
- R 7A hydrogen.
- R 7B is an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms.
- R is a substituted or an unsubstituted aryl, or a substituted or an unsubstituted aralkyl, any of which having up to 12 carbon atoms.
- R is a substituted or an unsubstituted heterocyclyl, or a substituted or an unsubstituted heteroaryl, any of which having up to 12 carbon atoms, comprising at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R 7E and R 6B together form a substituted or an unsubstituted cyclic moiety having from 3 to 7 ring carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms in addition to the nitrogen atom to which R 6E and R 7E are bonded, selected independently from >O, >N-, >S, or >NR 10 .
- R 8A is: a) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms; or b) a substituted of an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R is an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms.
- R 8C is a substituted of an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >S, >NR 10 , >SO 2 , or >CO.
- R is an alkyl having up to 12 carbon atoms.
- R 9B is an alkyl having up to 8 carbon atoms.
- R 9C is an alkyl having up to 6 carbon atoms.
- R 9D is an alkyl having up to 4 carbon atoms.
- R 10A is hydrogen. ; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms.
- R 10B is an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms.
- R 10C is an aryl or an aralkyl, any of which having up to 12 carbon atoms.
- R al is a halogen.
- R a2 is an alkyl or an alkoxy, any of which having up to 12 carbon atoms.
- R bl is an alkyl having up to 12 carbon atoms.
- R b2 is an alkyl having up to 6 carbon atoms.
- R xl is independently: 1) an alkyl or an alkoxy, either of which having up to 12 carbon atoms; or 2) hydrogen.
- R x2 is an alkyl having up to 12 carbon atoms.
- R x3 is an alkoxy having up to 12 carbon atoms.
- R x4 is hydrogen.
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as specified herein for formula (I).
- any of substituents on substituted or optionally substituted groups can be selected as follows:
- Ring A is optionally substituted with 1, 2, or 3 substituents selected independently from: 1) halogen, cyano, or hydroxyl; 2) an alkyl, an alkenyl, an alkynyl, a haloalkyl, a cycloalkyl, an alkoxy, a cycloalkoxy, a haloalkoxy, an aryl, an aryloxy, an aralkyl, a heteroaryl, or a heteroarylaoxy, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; 4) (CH 2 ) q NR 6 R 7 , wherein q is an integer from O to 5, inclusive; or 5) (CH 2 ) q CO 2 (CH 2 ) q , wherein q is an integer from O to 3, inclusive;
- R and R are optionally and independently substituted with 1 or 2 substituents selected independently from: 1) an alkyl, a cycloalkyl, a haloalkyl, an alkoxy, an aryl, a heteroaryl, or a heterocyclyl, any of which having up to 12 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected independently from >0, >N-, >S, >NR 10 , >S0 2 , or >C0; or 2) halogen, cyano, or hydroxyl; when R 1 and R 2 together form a monocyclic or a bicyclic moiety, the cylic moiety is optionally substituted with at least one substituent selected independently from: 1) halogen, cyano, or hydroxyl; 2) an alkyl, an alkenyl, an alkynyl, a haloalkyl
- R 3 is optionally substituted with at least one substituent selected independently from: 1) an alkyl, a haloalkyl, an aryl, or a cycloalkyl, any of which having up to 12 carbon atoms; or 2) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms; R 4 and R 5 are optionally and independently substituted with at least one substituent selected independently from: 1) halide, hydroxy, cyano, amino, or oxo; or 2) an alkyl, an alkenyl, a carboxy, a cycloalkyl, an aryl, a heterocyclyl, a heteroaryl, an alkoxy, an alkylthio, an alkyloxycarbonyl, a monoalkylamino, or a dialkylamino, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from >O, >N-, >
- R 6 , R 7 , and R 8 are optionally and independently substituted with 1 or 2 substituents selected independently from an alkyl, a haloalkyl, or an aryl, any of which having up to 12 carbon atoms; and m and p are intergers from 0 to the maximum number allowed by the structure of the moiety to which R and R a are bonded, respectively.
- m can be an integer from 0 to 3, inclusive.
- p can be an integer from 0 to 3, inclusive.
- the number of carbon atoms on the substituents refers to the carbon atoms on the base chemical moiety, and does not include the carbon atoms in any optional substituent.
- substituent size is listed in the definitions of the substitutents.
- R b is present in a given molecule, the selection in the table refers to one of the occurrences of that substituent, wherein any further occurrences of that substituent are selected independently according to the definitions provided herein.
- R a when more than one R a occurs in formula (H-I), according to formula A-Ol in table below, at least one occurrence of R a is R a , and any other occurrences of R a are selected independently from R al and R a2 .
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds have following formula:
- R 1 , R 2 , R 3 , R 4 , and R a can be selected according to the following table, to provide formulas (A-Ol) through (A-384), that are applicable to the compounds (H-I) 3 (III-l), (HIb-I), (IV-I), (V-I), (VI-I), (VII-I), and (VIII-I) illustrated above.
- Table 1 Substituent selections for compounds according to this invention, having substituents R 1 , R 2 , R 3 , R 4 , and R a .
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds have
- R 5 R , R a , and R can be selected according to the following table, to provide formulas (B-Ol) through (B-64), that are applicable to the compounds (IIa-1), (VIa-I), (VIIa-I), and (VIIIa-I) illustrated above.
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds have
- R 1 , R 2 , R 3 , and R a can be selected according to the following table, to provide formulas (C-Ol) through (C-128), that are applicable to the compounds (IIb-1), (VIb-I), (VIIb-I), and (VIIIb-I) illustrated above.
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds have
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds
- this disclosure provides benzylamine compounds according to formula (I), wherein the compounds
- this disclosure provides benzylamine compounds, wherein the compound is selected from any of the compounds in the following tables, including any combination of the compounds provided in these tables.
- the disclosure of these specific compounds it is intended to include any salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, any prodrug, and any stereoisomer, including diastereomeric mixtures, enantiomers, tautomers, racemic mixtures, or any combinations thereof, of the disclosed compounds.
- the Example number (Ex. No.) is provided for the preparation of that specific compound.
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R al is Me or Et;
- R > a a 3 i is H, Me, or Et;
- Another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R al is Me or Et
- R a3 is H, Me, or Et
- R 1 is Me, Et, & ⁇ ; or tf ⁇ ;
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R a is H, Me, or Et;
- R 1 is Me, Et, or *A
- Still a further aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R a6 is H, Me, or Et
- R a8 is H, Me, or Et
- R 1 is Me, Et, Pr, Bu, or *A
- R b is Me or Et.
- benzylamine compounds according to formula (I) and compositions comprising benzylamine compounds, having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R a6 is H, Me, or Et
- R a8 is H, Me, or Et
- R 1 is Me, Et, or
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- R a4 is H, Me, or Et;
- R , a a 6 o is H, Me, or Et;
- R is Me, Et, Pr, Bu, * ⁇ . *J 3 . *&.« or*£ ⁇ .. ;
- R is Me, Et, Pr, Bu, i * ⁇ ⁇ "A , i ⁇ JO ⁇ ⁇ , * r ⁇ £ ⁇ > , radical or*£ )
- Still another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds, having the following formula:
- a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 is Me, Et, Pr, Bu, and
- R z is Me, Et, Pr, Bu, and
- benzylamine compounds according to formula (I) and compositions comprising benzylamine compounds, having the following formula: or a salt, including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
- R 1 is Me, Et, Pr, Bu, i ⁇ A a ⁇ O iJO m or i J ⁇ ;.
- R 2 is Me, Et, Pr, Bu, *A *A * ⁇ 0 n orriX>
- Another aspect of this invention provides benzylamine compounds according to formula (I), and compositions comprising benzylamine compounds wherein the compound is:
- the present invention also encompasses any combination of compounds provided herein, including any salts, including pharmaceutically acceptable and non- pharmaceutically acceptable salts, or any mixture thereof.
- the present invention also encompasses any stereoisomers of compounds provided herein, including any combination of stereoisomers.
- compounds provided herein can be chiral or achiral, or they may exist as racemic mixtures, diastereomers, pure enantiomers, a prodrug, a tautomer or any mixture thereof.
- chiral compounds separate enantiomers, separate diastereomers, and any mixture of enantiomers, diastereomers, or both are encompassed herein, such as, for example, (R), (S), or a mixture of (R) and (S) isomers.
- any compound illustrated herein, including any compound of formula (I), is intended to include all possible positional isomers or regioisomers that could be encompassed by a given formula, including all possible positional isomers that arise from the position of a heteroatom or heterogroup within a heterocyclic ring.
- ring A of formula (I) is pyridine
- positional isomers include , , and s an d eacn o f these isomers is intended to be included in formula (I) when ring A is pyridine.
- the possible positional isomers include
- methods for the resolution of racemic compounds include, but are not limited to: using microbial resolution; resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable; or resolving the diastereomeric salts formed with chiral bases such as brucine, cinchona alkaloids and their derivatives; and the like.
- chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable
- resolving the diastereomeric salts formed with chiral bases such as brucine, cinchona alkaloids and their derivatives
- compounds of formula (I) can be resolved by treating with chiral amines, aminoacids, or aminoalcohols derived from aminoacids; by using conventional reaction conditions to convert an acid into an amide; by separation of diastereomers by fractional crystallization or by chromatography; or by preparing the stereoisomers of formula (I) by hydrolyzing the pure diastereomeric amide,
- pharmacologically acceptable salt or pharmaceutically acceptable salt refers generally to a salt or complex of the compound or compounds in which the compound can be either anionic or cationic, and have associated with it a counter cation or anion, respectively, that is generally considered suitable for human or animal consumption.
- a pharmaceutically acceptable salt can refer to a salt of a compound disclosed herein that forms upon reaction or complexation with an acid whose anion is generally considered suitable for human or animal consumption.
- pharmacologically acceptable salts include salts with organic acids or inorganic acids.
- salts examples include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartarate, and the like. Salts may also be formed by deprotonating an acid moiety of the compound, such as a carboxylic acid moiety, OH, or NH, and the like, using a base such as an organic base, an inorganic base, an organometallic base, a Lewis base, a Br ⁇ nsted base, or any combination thereof.
- a base such as an organic base, an inorganic base, an organometallic base, a Lewis base, a Br ⁇ nsted base, or any combination thereof.
- suitable pharmaceutically acceptable salts can include alkali metal salts, alkaline earth metal salts, or salts with organic basis, and the like.
- alkali metal salts include, but are not limited to, sodium and potassium salts
- examples of salts with organic basis include, but are not limited to, meglumine salts, and the like.
- the pharmacologically acceptable salts can be prepared by conventional means. Additional examples of pharmaceutically acceptable salts, and methods of preparing such salts, are found, for example, in Berg et.al., J. Pharma. Sci, 66, 1-19 (1977).
- this invention also provides a composition comprising at least one compound as disclosed herein, including a composition comprising a pharmaceutically acceptable carrier and at least one compound as disclosed herein.
- the at least one compound can be present as a neutral compound, as a salt, or as any combination thereof.
- This invention also encompasses a composition comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof,
- this invention encompasses a pharmaceutical composition comprising at least one compound as disclosed herein, and optionally further comprising an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory agent, an antidyspilidemic agent, an antirheumatic agent, a cardiovascular agent, or any combination thereof.
- this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
- a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule,
- the compounds can be formulated and administered in a prodrug form.
- prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form.
- administering encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc. Trans.
- prodrugs of the compounds disclosed herein refers to species that have chemically- or metabolically-cleavable groups wherein, under physiological conditions, the species become, provide, release, or are transformed into the compounds disclosed herein. In this manner, prodrugs can release the pharmaceutically in vivo active compounds disclosed herein.
- prodrugs of present invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam- containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine or other 5-fluorouridine prodrugs which may be converted into the more active species, and the like.
- prodrugs of present invention include, but are not limited to derivatives of carboxylic acid, sulfonamide, amine, hydroxyl, and the like, including other functional groups and including any combination thereof.
- this invention provides a pharmaceutical composition, comprising one or more compounds of any formula in any combination described above and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, • a preservative, a solvate, or any combination thereof.
- this invention affords a method of treating a condition or disease state such as dyslipidemia, atherosclerosis, peripheral vascular disease, hypertriglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic retinopathy, and endotoxemia, comprising administering an effective amount of at least one compound as disclosed herein.
- a condition or disease state such as dyslipidemia, atherosclerosis, peripheral vascular disease, hypertriglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, hypoalphalipoprotenemia, cardiovascular disorders such as angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis and hypertension, and diabetic vascular diseases such as diabetic retinopathy, and endotoxemia
- Halogenation could be carried out by using reagents such as phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ), and the like, for example, at a temperature from about 80°C to about 120°C, for about 4 to about 8 hours, followed by pH adjustment of resultant mixture to a pH from about 6 to about 7.
- reagents such as phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ), and the like, for example, at a temperature from about 80°C to about 120°C, for about 4 to about 8 hours, followed by pH adjustment of resultant mixture to a pH from about 6 to about 7.
- Amination could be carried out by using amines in presence of a solvent chosen from acetone, acetonitrile, dimethylformamide, dimethylacetamide and the like, with or with out a base.
- Suitable bases include triethylamine, N,N-diisopropyl ethyl amine, potassium carbonate, sodium carbonate, sodium hydride, and the like.
- the reaction temperature was typically from about 20°C to about 12O 0 C, and the duration of the reaction was typically in the range of from about 4 hours to about 20 hours.
- any compound of any formula disclosed herein can be obtained using procedures provided in the reaction Schemes, as well as procedures provided in the Examples, by selecting suitable starting materials and following analogous procedures.
- any compound of any formula disclosed or exemplified herein can be obtained by using the appropriate starting materials and appropriate reagents, with the desired substitutions, and following procedures analogous to those described herein. Therefore, it will be readily understood by one of ordinary skill, that the reaction schemes disclosed herein can be adapted to prepare any compound of this disclosure, therefore any discussion of a particular step in a reaction scheme is intended to reflect one method or one set of considitions that can be used to carry out that step. This discussion of a particular step is not intended to be limiting, but rather exemplary, of one particular method and set of conditions by which that step can be effected.
- compounds of formula (I) according to this invention could be prepared as illustrated in at least one of the following Schemes 1-5.
- the relevant reagents and starting materials were commercially available.
- the relevant reagents and starting materials were made by standard synthetic procedures in organic and heterocyclic chemistry, and known by one of ordinary skill in the relevant art. These techniques were analogous to the synthesis of known structurally similar intermediates or starting materials and the procedures described in preparations and examples below.
- Scheme 1 Representative steps of Scheme 1 include the following.
- the compound of formula (Ia) could be converted to a compound of formula (Ib) by an amination reaction using HNR 1 R 2 , in a polar solvent such as N,N-dimethylformamide (DMF) and a base such as sodium carbonate or potassium carbonate.
- a polar solvent such as N,N-dimethylformamide (DMF)
- a base such as sodium carbonate or potassium carbonate.
- the reaction could also be carried out in the presence of a solvent such as acetonitrile, tetrahydrofuran, or toluene.
- the base could also be selected from cesium carbonate, potassium tertiary butoxide, and the like.
- the temperature of the reaction could be maintained from about 25 0 C to about 35 0 C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours.
- the compound of formula (I), where R 3 is hydrogen, could be converted to a compound of formula (I), wherein R 3 is typically CO 2 R 6 or COR 8 , wherein R 6 and R 8 are as defined herein, by reacting with a compound of formula X CO 2 R or X COR , where X 1 can be halogen, in the presence of a base such as potassium carbonate in a solvent such as tetrahydrofuran.
- the reaction could also be carried out in the presence of acetone, acetonitrile, and the like.
- the temperature of the reaction could be maintained from about 25 0 C to about 55 0 C, and the duration of the reaction typically could range from about 20 minutes to about 5 hours.
- the temperature of the reaction could be maintained from about 25 0 C to about 35 0 C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours.
- the compound of formula (Ie) could be reacted with a compound of formula (If) wherein X 1 can be leaving group such as halogen, mesyloxy, tosyl, and the like, to obtain a compound of formula (I), where R 3 can be akyl, heteroaryl, heterocyclyl, in the presence of a base like sodium hydride or potassium hydride.
- the reaction could be carried in a solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, toluene and the like.
- the temperature of the reaction could be maintained from about 25 0 C to about 55 0 C, and the duration of the reaction typically could range from about 20 minutes to about 5 hours.
- compounds according to the present invention could be prepared according to the following scheme. Scheme 2
- the compound of formula (I), where R 3 can be hydrogen could be converted to a compound of formula (I), where R 3 can be CN group, in the presence of cyanogen bromide (CNBr), by using a suitable solvent such as dimethylformamide, acetonitrile, a (Ci-Ci 0 ) alcohol, or the like, along with a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and the like.
- a suitable solvent such as dimethylformamide, acetonitrile, a (Ci-Ci 0 ) alcohol, or the like
- a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and the like.
- the temperature of the reaction could be maintained from about 25 0 C to about 55 0 C, and the duration of the reaction typically could range from about 20 minutes to about 5 hours.
- the compound of formula (I), where R 3 can be a cyano (CN) group can be converted to a compound of formula (I), where R 3 is a tetrazoloyl group by reacting the cyano compound with sodium azide or potassium azide, in the presence zinc salts such as ZnBr 2 .
- Suitable solvents for this reaction include N,N-dimethylformamide, acetonitrile, (C 1 -C 10 ) alcohols, and the like.
- R 3 can be a CONH 2 group
- R 3 can be a CONH 2 group
- R d can be hydrogen, alkyl, or haloalkyl
- X 1 can be a leaving group such as halogen, in the presence of an alcoholic solvent such as tert-butanol, isopropanol, and the like.
- the temperature of the reaction could be maintained from about 60 0 C to about 120 0 C, to yield a compound of formula (I) where R 3 can be an R d -substituted oxazolyl group
- R 3 can be an R d -substituted oxazolyl group
- Compounds of formula (I) wherein R 3 is a cyano (CN) group could be reacted with hydroxyl amine in a solvent such as 1 ,4-dioxane, toluene, and the like, followed by the addition of a compound of general formula R 0 COX 1 , wherein R d can be an alkyl and X 1 can be halogen, along with a base such as pyridine, to yield a compound of formula (I), wherein R 3 can be an R d -substituted 1,2,4-oxadiazolyl group.
- compounds according to the present invention could be prepared according to the following scheme.
- syntheses can begin with a compound of formula (Ig) wherein Z 1 can be .an aldehyde, acetal, or CN, and X 2 can be a halogen, which could be reacted with a nucleophile of formula (Ih), wherein R 1 can be alkyl, to obtain a compound of formula (Ii), by using the methodology known to one of ordinary skill from the literature (see below).
- formation of a secondary amine from a substituted chloropyridine and the primary amine (ethylamine hydrochloride) could be carried out in the presence of a base such as N,N-diisopropyl-N-ethylamine, and a solvent such as ethanol.
- the base could also be selected from other tertiary amines such as triethyl amine (TEA), tributyl amine, and the like.
- TAA triethyl amine
- the reaction could also be carried out in the presence of a solvent which includes, but is not limited to, n- butanol, tertiary butanol, N,N-dimethylformamide (DMF), dimethoxyethane, and the like.
- the temperature of the reaction could be maintained from about 50 0 C to the boiling point of the solvent used.
- the duration of the reaction could be in the range from about 3 to about 16 hours [Cappelli, A. et. al. Journal of Medicinal Chemistry, 47(10): pp. 2574-2586 (2004); Izumi, T., et.
- the compound of formula (Ik) could be obtained by the alkylation or acylation of a compound of formula (Ii) with a compound of formula (Ij), wherein R 2 can be an alkyl, a haloalkyl, or COR , in the presence of a base such as potassium carbonate, in a polar solvent such as tetrahydrofuran, diethyl ether, and the like.
- a base such as potassium carbonate
- a polar solvent such as tetrahydrofuran, diethyl ether, and the like.
- the temperature of the reaction could be maintained from about 0 0 C to about 100 0 C, and the duration of the reaction typically could range from about 1 hour to about 8 hours.
- the compound of formula (Ip) could be prepared by reducing a compound of formula (Ik), wherein Z 1 can be a cyano (CN) group, by using an appropriate reducing agent such as lithium aluminium hydride (LAH), sodium bis(2-methoxy- ethoxy)aluminumhydride (Red-Al®), and the like, which could be carried out in an appropriate solvent such as tetrahydrofuran, diethylether, and the like.
- LAH lithium aluminium hydride
- Red-Al® sodium bis(2-methoxy- ethoxy)aluminumhydride
- the temperature of the reaction could be maintained from about 0 0 C to about 60 0 C, and the duration of the reaction typically could range from about 1 hour to about 14 hours.
- the compound of formula (Ip) could be converted to a compound of formula (Im) by reductive animation with a compound of formula (Iq).
- the reaction could be conducted in the presence of acetic acid, a solvent such as methanol, and a reducing agent such as sodium cyanoborohydride.
- the reaction could also be carried out in the presence of diluted hydrochloric acid.
- the solvent used could also be selected from (Ci-Cio) alcohols such as ethanol, propanol, isopropanol, and the like, or mixtures thereof.
- the reaction could also be conducted using other reducing agents such as sodium triacetoxyborohydride, and the like,
- the temperature of the reaction could be maintained from about 25 0 C to about 35 0 C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours.
- the compound of formula (Ik), an aldehyde or acetal could be converted to a compound of formula (Im) by reductive amination with a compound of formula (Ic).
- the reaction could be conducted in the presence of acetic acid, a solvent such as methanol, and a reducing agent such as sodium cyanoborohydride.
- the reaction could also be carried out in the presence of diluted hydrochloric acid.
- the solvent used could also be selected from a (Q-Cio) alcohol such as ethanol, propanol, isopropanol, and the like, or mixtures thereof.
- the reaction could also be conducted using other reducing agents such as sodium triacetoxyborohydride, and similar reducing agents.
- the temperature of the reaction could be maintained between about 25 0 C and about 35 0 C, and the duration of the reaction typically could be from about 30 minutes to about 5 hours.
- the compound of formula (Im) is converted to a compound of formula (I) wherein typically, R 3 can be CO 2 R 6 , COR 8 , SO 2 R 8 , CONR 6 R 7 , or alkyl, by acylation with a compound of formula (In), wherein X can be a leaving group such as halogen, mesyloxy and the like.
- compound (Im) could be reacted with ethyl chloroformate in the presence of a base such as potassium carbonate and a solvent such as tetrahydrofuran at ambient temperature. The reaction could also be carried out with other acylating agent such as methyl chloroformate, and the like.
- the reaction could also be carried out in the presence of different solvents, including but not limited to, acetone, acetonitrile, and the like.
- the temperature of the reaction could be maintained from about 22 0 C to about 50 0 C, and the duration of the reaction typically could range from about 4 hours to about 12 hours.
- the compound of formula (Ik) wherein Z 1 can be an aldehyde or acetal could also be converted to a compound of formula (Io) by reductive amination with a compound of formula (Id) wherein R 3 can be alkyl, heteroaryl, heterocyclyl, in the presence of acetic acid, a solvent such as methanol, and an appropriate reducing agent such as sodium cyanoborohydride.
- the reaction could also be carried out in the presence of diluted hydrochloric acid.
- the solvent used could also be selected from (Ci-C 10 ) alcohols such as ethanol, propanol, isopropanol, and the like or their mixtures thereof.
- the temperature of the reaction could be maintained from about 25 0 C to about 50 0 C, and the duration of the reaction typically could range from about 1 hour to about 6 hours.
- the compound of formula (Io) could be converted to a compound of formula (I) wherein R 3 can be a 5-7 membered heteroaryl group, by a benzylation reaction with a compound of formula (If), wherein X 1 can be a leaving group such as halogen, mesyloxy, and the like, in the presence of a base such as sodium hydride and a solvent such as N,N-dimethylformamide.
- the base could also be selected from bases including potassium hydride, and the like.
- the reaction could also be carried out in the presence of a solvent, including for example, acetonitrile, tetrahydrofuran, toluene, and the like.
- the temperature of the reaction could be in the range from about 25 0 C to about 60 0 C.
- R 1 , R 8 are independently H, alkyl, R 1 , R 8 are independently H, alkyl, aryl, heteroaryl, or haloalkyl; aryl, heteroaryl, or haloalkyl; R 3 is alkyl, H, CO 2 R 6 , COR 8 , R 3 is a 5-7 membered heteroaryl SO 2 R 8 , CONR 6 R 7 , or CSNR 6 R 7
- a palladium catalyzed cross-coupling amidation reaction could be used to produce compound of formula (It).
- formation of compound of formula (It) from the heteroaryl halide (Ir), wherein X 1 can be halogen, and amide (Is), wherein R and R can be alkyl or aryl could be accomplished in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, a phosphorus ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantphosTM), and a base such as cesium carbonate, in a suitable solvent, such as toluene.
- a palladium catalyst such as tris(dibenzylideneacetone)dipalladium
- a phosphorus ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantphosTM
- the reaction could also be carried out in the presence of a solvent including toluene, xylene, dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like, as well as mixtures thereof. Further, the reaction could be carried out in the presence of from about 1 mol % to about 10 mol % of a suitable Pd catalyst such as Pd(OAc) 2 , Pd(DIPHOS) 2 , Pd(PPh 3 ) 4 and the like.
- a suitable Pd catalyst such as Pd(OAc) 2 , Pd(DIPHOS) 2 , Pd(PPh 3 ) 4 and the like.
- the reaction could also be carried out in the presence of a ligand, such as 2-dicyclohexylphoshino-2',4',6'-tri-i-propyl-l,r-biphenyl (XPHOS), 1 , 1 -bis(diphenylphosphine)ferrocene (DPPF), 2,2 ' -bis(diphenylphosphanyl)- 1 , 1 ' - biphenyl (BINAP), l,2-bis(diphenyl ⁇ hosphine)ethane (DIPHOS), and the like.
- a ligand such as 2-dicyclohexylphoshino-2',4',6'-tri-i-propyl-l,r-biphenyl (XPHOS), 1 , 1 -bis(diphenylphosphine)ferrocene (DPPF), 2,2 ' -bis(diphenylphosphanyl)- 1 , 1 '
- the temperature of the reaction could typically be in the range from about 50 0 C to about 125 0 C [see: Yin, J; Buchwald, S. L. Organic Letters, 2 (8): pp. 1101-1104 (2000)].
- the compound of formula (It) could be converted to a compound of formula
- the reaction could also be carried out in the presence of diluted hydrochloric acid.
- the solvent used could also be selected from (Cj-Cio) alcohols such as ethanol, propanol, isopropanol and the like or mixtures thereof.
- the temperature of the reaction could be maintained from about 25 0 C to about 35 0 C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours.
- the compound of formula (Iv) could be converted to a compound of formula (I) wherein R 3 can be CO 2 R 6 , COR 8 , SO 2 R 8 , CONR 6 R 7 , or an alkyl, and Y can be N, by acylation with a compound of formula (In), wherein X 1 can be halogen, in the presence of a base such as potassium carbonate, and a solvent such as terahydrofuran.
- the reaction could also be carried out in the presence of other suitable solvents, including acetone, acetonitrile, and the like.
- the temperature of the reaction could be maintained from about 22 0 C to about 50 0 C, and the duration of the reaction typically could range from about 4 hours to about 12 hours.
- the compound of formula (It) is converted to a compound of formula (Iu) by reductive animation with a compound of formula (Id) wherein R can be a 5-7 membered heteroaryl group, in the presence of acetic acid, a solvent such as methanol, and a reducing agent such as sodium cyanoborohydride.
- the reaction could also be carried out in the presence of diluted hychloric acid.
- the solvent used could also be selected from (Ci-C 10 ) alcohols such as ethanol, propanol, isopropanol, and the like, or mixtures thereof.
- the temperature of the reaction could be maintained from about 25 0 C to about 50 0 C, and the duration of the reaction typically could range from about 1 hour to about 6 hours.
- the compound of formula (Iu) could be converted to a compound of formula
- X 1 can be a leaving group such as halogen, mesyloxy, and the like, in the presence of a base such as sodium hydride and a solvent such as dimethylformamide.
- the base could also be selected from potassium hydride, other hydrides, and the like.
- the reaction could also be conducted in the presence of a solvent, which includes acetonitrile, tetrahydrofuran, toluene and the like.
- the temperature of the reaction could be in the range from about 25 °C to about 60 0 C.
- the present invention provides a general process for the preparation of compound of formula (I), wherein R 1 can be (CHR x ) n R 5 , wherein n is i and all other substituents are as defined above.
- R 1 can be (CHR x ) n R 5 , wherein n is i and all other substituents are as defined above.
- This general process is depicted in the following scheme.
- the compound of formula (Up) could be converted to a compound of formula (Hq) by reductive animation with a compound of formula (Ic) in the presence of acetic acid, a solvent such as methanol, and a reducing agent such as sodium cyanoborohydride.
- the reaction could also be carried out in the presence of diluted hydrochloric acid.
- the solvent used could also be selected from (C 1 -C 1 O) alcohol such as ethanol, propanol, isopropanol, and the like, or their mixtures thereof.
- the temperature of the reaction could be maintained from about 25 0 C to about 35 0 C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours.
- the compound of formula (Hq) could be converted to a compound of formula (Hr), wherein R 3 can be CO 2 R , by acylation with a compound of formula (IXh), in the presence of a base such as potassium carbonate, and a solvent such as tetrahydrofuran.
- the reaction could also be carried out in the presence of other suitable solvents, such as tetrahydrofuran, acetone, acetonitrile, and the like.
- the temperature of the reaction could be maintained from about 22 0 C to about 50 0 C, and the duration of the reaction typically could range from about 4 hours to about 12 hours.
- the Heck-type carbon-carbon bond formation reaction could be conducted between a compound of formula (Hr) and a compound of formula (Us), wherein R x , R 2 , and R 5 , indepdently can be selected from hydrogen, alkyl, aryl, heteroaryl, cyano, carbalkoxy, or alkoxy.
- Synthetic methods include, for example, formation of compound of formula (lit) from the heteroaryl halide (Hr) and an olefin (Hs) in the presence of a palladium catalyst such as palladium acetate, a phosphorus ligand such as triphenylphosphine, a base such as triethylamine (TEA), and a suitable solvent, such as tetrahydrofuran.
- a palladium catalyst such as palladium acetate
- a phosphorus ligand such as triphenylphosphine
- a base such as triethylamine (TEA)
- TAA triethylamine
- suitable solvent such as tetrahydrofuran.
- suitable solvents such as toluene, xylene, N,N-dimethylformamide, diethyl ether, 1,4-dioxane, and the like.
- this reaction could be carried out in the presence of from about 1 mol % to about 10 mol % of palladium catalyst, which include but are not limited to, PdCl 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , and the like.
- the reaction could also be accomplished in the presence of a ligand, which includes tributylphosphine, triarylphosphine, DPPF, BINAP, DIPHOS, and the like.
- the reaction could be carried out in the presence of other bases, which include sodium carbonate, potassium carbonate, sodium acetate, and the like.
- the temperature of the reaction could be in the range from about 50 0 C to about 125 0 C [see: Franzen, R., Canadian Journal of Chemistry, 78: pp. 957-962 (2000); Negishi, E. et al, Chemical Review, Vol. 96: pp. 365-394 (1996)].
- the compound of formula (I), wherein R 1 can be (CHR x ) n R 5 , where n is 1, and all other substituents and abbreviations are as defined herein, could be obtained by reduction of a compound of formula (lit).
- Synthetic methods of reduction include, but are not lmited to, catalytic hydrogenation, wherein catalyst include approximately a 5-10% palladium on carbon, Raney-nickel, sodium (or other appropriate metal(s)) amalgam, in the presence of hydrogen (typically from about 1 psi to about 50 psi), in a polar solvent such as ethanol, tetrahydrofuran, and the like.
- the temperature of the reaction could be in the range of about 25 0 C to about 60 0 C.
- compounds of formula (I) wherein R 1 is (CH 2 ) n R d C ⁇ 2 R e and R is alkyl, and unspecified substitutents are selected as disclosed above for formula (I), can be prepared by following an analogous procedure as described in Schemes 1 through 5, using precursors, starting materials, and reagents having the appropriate substitutions.
- compounds of formula (Hy) could be prepared by starting from a compound of formula (Hu), wherein Z is: (CH 2 ) r and r is an integer from 0 to 2, inclusive, N, or O; and R e is defined according to formula (I); by procedures known to one of ordinary skill.
- the applicable synthetic methods include, for example, the following sequence of reaction steps: 1) Wittig reaction; 2) reduction; 3) hydrolysis of the ester; and 4) conversion to the amine.
- Compound of formula (Hy) could be reacted with a compound of formula (Ia) or (Ig) of Scheme 1 or Scheme 3 to obtain the corresponding compound of formula
- compounds of the formulas provided herein including, but not limited to, compounds of formula (I), (Ia), (Ia'), (II), (Ha), (lib), (Hc), (III), (HIa), (HIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), (Vc), (VI), (Via), (VIb), (VIc),
- CETP activity can affect the level of circulating cholesterol-containing HDL.
- Increased CETP can produce a decrease in HDL-C levels relative to LDL-C and/or VLDL-C levels.
- CETP plays a role in transferring cholesteryl ester from HDL to VLDL and LDL, and thereby in altering the relative profile of circulating lipoproteins to one which is associated with an increased risk of cardiovascular disease (for example, decreased levels of HDL-C and increased levels of VLDL-C and LDL-C).
- CETP activity can be predictive of increased risk of cardiovascular disease.
- Modulation or inhibition of CETP activity therefore, can be a prophylactic or therapeutic method for modulating the relative levels of lipoproteins to reduce or prevent the progression of, to induce regression of, or reduce risk of development of a variety of conditions or diseases including cardiovascular diseases, such as atherosclerosis.
- compositions comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts, can be used in conjunction with other prophylactic or therapeutic agents or in methods optionally comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet.
- the present invention provides a method of treating or preventing a condition or disease in a mammalian subject, the method comprising administering to the subject a composition comprising a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts.
- the condition or disease is dyslipidemia, atherosclerosis, a peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, hypoalphalipoprotenemia, a cardiovascular disorder (i.e., angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis, hypertension) or diabetic vascular diseases (i.e., diabetic retinopathy, endotoxemia).
- a cardiovascular disorder i.e., angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis, hypertension
- diabetic vascular diseases i.e., diabetic retinopathy, endotoxemia
- the present invention provides a method of decreasing or inhibiting CETP activity in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically- acceptable salts, wherein the amount is sufficient to decrease or inhibit CETP activity in the subject.
- the present invention provides a method of increasing high density lipoprotein (HDL) in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically- acceptable salts, wherein the amount is sufficient to increase high density lipoprotein (HDL) in the subject.
- HDL high density lipoprotein
- the present invention provides a method of elevating the ratio of circulating HDL to circulating LDL, VLDL, or total cholesterol in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts.
- the present invention provides a method of altering catabolism of HDL-cholesterol to decrease development of atherosclerotic lesions in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts, wherein the amount is sufficient to alter the catabolism of HDL-cholesterol thereby leading to decreased development of atherosclerotic lesions.
- the present invention provides a method of decreasing low density lipoprotein (LDL) in a mammalian subject, the method comprising administering to the subject an amount of a composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically- acceptable salts, wherein the amount is sufficient to decrease low density lipoprotein (LDL).
- LDL low density lipoprotein
- the present invention provides a method of treating or preventing atherosclerosis in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts.
- the present invention provides a method of treating or preventing hyperlipidemia in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts.
- this invention provides a method of treating or preventing a CETP -mediated disorder in a mammalian subject, the method comprising administering to the subject a prophylactically- or therapeutically-effective amount of at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts.
- the present invention provides a method of treating or preventing dyslipidemia, atherosclerosis, a peripheral vascular disease, hypertryglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, hypoalphalipoprotenemia, a cardiovascular disorder, a diabetic vascular disease, or endotoxemia.
- the cardiovascular disorder is angina, ischemia, stroke, myocardial infarction (MI), reperfusion injury, restenosis or hypertension.
- the compounds of the present invention are useful in the treatment and / or prophylaxis of the above said diseases in combination / concomittant with one or more LDL-cholesterol lowering agents such as HMG CoA reductase inhibitors; cholesterol absorption inhibitors; antiobesity drugs; lipoprotein disorder treatment drugs; hypoglycemic agents: insulin; biguanides; sulfonylureas; thiazolidinediones; dual PPAR agonists; and/or mixtures thereof.
- LDL-cholesterol lowering agents such as HMG CoA reductase inhibitors; cholesterol absorption inhibitors; antiobesity drugs; lipoprotein disorder treatment drugs; hypoglycemic agents: insulin; biguanides; sulfonylureas; thiazolidinediones; dual PPAR agonists; and/or mixtures thereof.
- the compounds of the present invention in combination with HMG CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP) /ApoB secretion inhibitors, cholesterol absorption inhibitors, antiobesity drugs, hypoglycemic agents can be administered together or within in such a period of time so as to act synergistically.
- MTP microsomal triglyceride transfer protein
- the present invention provides a prophylactic or therapeutic composition
- a prophylactic or therapeutic composition comprising at least one compound having a formula as disclosed herein, and/or their pharmaceutically-acceptable salts and, optionally an antihypertensive agent.
- Hypertension can be characterized as persistently high blood pressure.
- an adult having a systolic blood pressure that is persistently at least about 140 mmHg or a diastolic blood pressure that is at least about 90 mmHg can be classified as hypertensive.
- Hyperlipidemic conditions such as atherosclerosis can have an affect on hypertension.
- the dosage regimen utilizing, the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
- An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Compounds and compositions of the present invention can be administered by any appropriate route, including, for example, orally, parenterally, intravenously, intradermally, intramuscularly, subcutaneously, sublingually, transdermally, bronchially, pharyngolaryngeal, intranasally, topically such as by a cream or ointment, rectally, intraarticular, intracisternally, intrathecally, intravaginally, intraperitoneally, intraocularly, by inhalation, bucally or as an oral or nasal spray.
- Oral dosages of compositions of the present invention when used for the indicated effects, will range from about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day.
- compounds of the present invention can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
- the dosage administration will, of course, be substantially continuous rather than intermittent throughout the dosage regimen.
- the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- suitable pharmaceutical diluents, excipients or carriers collectively referred to herein as 'carrier' materials
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the present invention provides a composition comprising at least one compound as disclosed herein.
- this invention provides a pharmaceutical composition, comprising: at least one compound as disclosed herein; and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
- this invention provides a pharmaceutical composition, comprising: at least one compound as disclosed herein; and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; wherein the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
- a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; wherein the pharmaceutical composition is in the form of a tablet, a capsule, a
- this invention provides a pharmaceutical composition, comprising: at least one compound as disclosed herein; optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; and further comprising an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory agent, an antirheumatic agent, an antidyspilidemic agent, a cardiovascular agent, or any combination thereof.
- a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof
- the pharmaceutical compositions of the present invention can further comprise at least one of any suitable auxiliary such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like.
- suitable auxiliaries are employed. Examples and methods of preparing such sterile solutions are well known in the art and can be found in well known texts such as, but not limited to, REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)).
- Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the compound.
- a compound for oral administration in the form of a tablet or capsule, can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture.
- suitable binders include, without limitation, starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes; and the like.
- Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
- the pharmaceutical preparations contain at least one compound of the present invention represented by any formula disclosed herein, and/or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit CETP activity and prevent or treat the various conditions or diseases attributable to CETP activity.
- One skilled in the art can easily determine such an effective amount.
- the preparations optionally can contain other ingredients including, for example, an antihypertensive drug.
- Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, and the like.
- the invention further relates to the administration of at least one compound disclosed herein by the following routes, including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means.
- routes including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabron
- a composition comprising at least one compound of the present invention can be administered at a frequency and for a period of time effective to achieve a therapeutic effect, which should be understood in the context of a regimen of repeated administration at such a frequency and over such a period.
- a composition is administered at a frequency and for a period of time effective to increase a HSPG expression.
- a composition can be administered in a single daily dose, or a total daily dosage can be administered in divided doses of two, three, or four times daily.
- a composition is administered at least once daily, but in certain situations less frequent, e.g., twice weekly or weekly, administration can be effective.
- administration should continue for a prolonged period, for example at least about 3 months, or at least about 6 months, or at least about 1 year, or at least about 2 years, or at least about 3 years. In one aspect, administration continues from a time of initiation for substantially the remainder of the mammal's life.
- the selection and/or amounts of individual compounds can, if desired vary over the period of administration.
- a single composition of this invention is administered to a mammal for the entire period of administration. In other aspects, different compositions comprising at least one compound are administered to the mammal at different times.
- the dosages of compounds can be adjusted on a per body weight basis and may thus be suitable for any subject regardless of the subject's size.
- daily oral dose comprises a total compound amount of at least about 0.0001 mg per kg body weight, illustratively about 0.0001 mg to about 1000 mg, about 0.001 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 5 mg, or about 1 to about 3 mg per kg body weight.
- a daily intravenous injection comprises a total compound amount of at least about 0.0001 mg per kg body weight, illustratively about 0.0001 mg to about 0.5 mg, about 0.001 mg to about 0.25, or about 0.01 to about 0.03 mg per kg body weight.
- a tablet for oral administration can be manufactured to comprise a total compound amount of about 0,001 mg, about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.
- a composition comprises an active ingredient content of at least about 0.01% by weight of the composition, illustratively about 0.01% to about 99%, about 0.05% to about 90%, about 0.1% to about 80%, about 0.5% to about 50% by weight of the composition.
- the amount of active ingredient that can be combined with other materials to produce a single dosage form varies depending upon the subject treated and the particular mode of administration.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. In one aspect, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day. In another aspect, the range is from about 0.5 mg/kg to about 10 mg/kg of body weight per day.
- the compounds can be administered on a regimen of about 1 to about 10 times per day.
- Co-administration or sequential administration of the compounds of the present invention and other therapeutic agents can be employed, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, and pro-drug activating enzymes, which can be naturally occurring or produced by recombinant methods.
- the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities. It is to be understood that this invention is not limited to the particular methodology, syntheses, formulations, protocols, cell lines, constructs, and reagents described herein and as such can vary.
- any substituent recited on a base group is described by its own definition, including its own limitation of the number of carbon atoms.
- all structural isomers of a given structure for example, all enantiomers, diasteriomers, and regioisomers, are included within this definition.
- halogen or “halo” includes fluorine, chlorine, bromine, or iodine.
- alkyl group is used to refer to both linear and branched alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, and the like. Unless otherwise specified, an alkyl group has from 1 to 12 carbon atoms. Also unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition.
- propyl is meant to include n-propyl and wo-propyl
- butyl is meant to include n-butyl, fco-butyl, t-butyl, sec-butyl, and so forth.
- aryl refers to an optionally substituted monocylic or polycyclic aromatic ring system of 6 to 14 carbon atoms.
- exemplary groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indane, fluorene, and the like. Unless otherwise specified, an aryl group typically has from 6 to 14 carbon atoms.
- Alkyl refers to an aryl substituted alkyl group, wherein the aryl group and the alkyl group are defined herein. Typically, the aryl group can have from 6 to 14 carbon atoms, and the alkyl group can have up to 10 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl, propyl -2 -phenylethyl and the like.
- haloalkyl refers to a group containing at least one halogen and an alkyl portion as define above, that is, a haloalkyl is a substituted alkyl group that is substituted with one or more halogens. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trifluoromethyl, and the like. Unless otherwise specified, a haloalkyl group has from 1 to 12 carbon atoms.
- a "cycloalkyl” group refers to a cyclic alkyl group which can be mono or polycyclic.
- exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
- a cycloalkyl group has from 3 to 12 carbon atoms.
- alkoxy refers to an -O(alkyl) group, where alkyl is as defined herein. Therefore, unless otherwise specified, all isomers of a given structure are included within a definition. Exemplary alkyl groups include methoxy, ethoxy, n- propoxy, z ' so-propoxy, «-butoxy, wo-butoxy, t-butoxy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 12 carbon atoms. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. For example, unless otherwise specified, the term propoxy is meant to include n-propoxy and wo-propoxy.
- aryloxy group refers to an -O(aryl) group, where aryl is as defined herein.
- aryl is as defined herein.
- the aryl portion of an aryloxy group can be substituted or unsubstituted.
- aryloxy groups include, but are not limited to, phenoxy, naphthyl, and the like. Unless otherwise specified, an aryloxy group typically has from 6 to 14 carbon atoms.
- Haloalkoxy refers to an alkoxy group with a halo substituent, where alkoxy and halo groups are as defined above.
- exemplary haloalkoxy groups include fiuoromethoxy, chloromethoxy, trifluoromethoxy, trichloroethoxy, fiuoroethoxy, chloroethoxy, trifloroethoxy, perfiuoroethoxy (-OCF 2 CF 3 ), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy (-OC(CF 3 ) 3 ), and the like.
- an haloalkoxy group typically has from 1 to 12 carbon atoms.
- Alkylthio refers to an -S(alkyl) goup, where alkyl group is as defined above.
- alkyl groups include methylthio, ethylthio, propylthio, butylthio, iso- propylthio, wo-butylthio, and the like. Unless otherwise specified, an alkylthio group typically has from 1 to 12 carbon atoms.
- Heteroaryl is an aromatic monocyclic or polycyclic ring system of 4 to 10 carbon atoms, having at least one heteroatom or heterogroup selected from -O-, >N-, - S-, >NH or NR, and the like, wherein R is a substituted or unsubstituted alkyl, aryl, or acyl, as defined herein.
- >NH or NR are considered to be included when the heteroatom or heterogroup can be >N-.
- heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, oxatriazolyl, oxadiazolyl, pyridazinyl, thienopyrimidyl, furanyl, indolyl, isoindolyl, benzo[l,3]dioxolyl, 1,3-benzoxathiole, quinazolinyl, isoquinolinyl, quinolinyl, pyridyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl pyridyl, thiophenyl, and the like.
- a heteroaryl group typically has from 4 to 10 carbon atoms.
- the heteroaryl group can be bonded to the heterocyclic core structure at a ring carbon atom, or, if applicable for a N-substituted heteroaryl such as pyrrole, can be bonded to the heterocyclic core structure through the heteroatom that is formally deprotonated to form a direct heteroatom-pyrimdine ring bond.
- ⁇ eterocyclyl is a non-aromatic, saturated or unsaturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from -O-, >N-, -S-, >NR, >SO 2 , >CO, and the like, wherein R is hydrogen or a substituted or an unstubstituted alkyl, aryl, or acyl, as defined herein.
- heterocyclyl groups include aziridinyl, imidazolidinyl, 2,5-dihydro- [l,2,4]oxadiazolenyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1 ,4-dioxanyl, 2,5-dihydro-lH-imidazolyl, and the like.
- a heterocyclyl group typically has from 2 to 10 carbon atoms.
- a heterocyclyl group can be bonded through a heteroatom that is formally deprotonated or a heterocyclyl group can be bonded through a carbon atom of the heterocyclyl group.
- Heterocycloalkyl refers to the saturated subset of a heterocyclyl, that is, a non-aromatic, saturated monocyclic or polycyclic ring system of 3 to 10 members having at least one heteroatom or heterogroup selected from -O-, >N-, -S-, >NR, >SO 2 , >CO, and the like, wherein R is hydrogen or a substituted or an unstubstituted alkyl, aryl, or acyl, as defined herein.
- heterocycloalkyl groups include aziridinyl, piperdinyl, piperazinyl, morpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4- dioxanyl, and the like.
- a heterocycloalkyl group typically has from 2 to 10 carbon atoms, or in another aspect, from 2 to 6 carbon atoms.
- a heterocycloalkyl group can be bonded through a heteroatom that is formally deprotonated or a heterocycloalkyl group can be bonded through a carbon atom of the heterocycloalkyl group.
- a "heteroaryloxy” group refers to an aryloxy-type analog of a heteroaryl group.
- a heteroaryloxy group is intended to describe a heteroaryl group as defined herein, that is bonded to an oxygen atom, to form a formal [O-heteroaryl] moiety. Unless otherwise specified, a heteroaryloxy group typically comprises from 4 to 10 carbon atoms.
- alkoxycarbonyl refers to a -C(O)O(alkyl) group, wherein the alkyl portion of the alkoxycarbonyl group is defined as herein.
- alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t- butoxycarbonyl and the like.
- alkenyl is an aliphatic hydrocarbon group comprising an alkene functionality, regardless of the regiochemistry of the alkene functionality within the aliphatic hydrocarbon group. Unless otherwise specified, an alkenyl group typically has from 2 to 12 carbon atoms, and in another aspect, is a C 2 -C 10 alkenyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, and the like, including all regiochemistries, thus, "butenyl” includes 1 -butenyl, 2-butenyl, and 3-butenyl.
- alkynyl is an aliphatic hydrocarbon group comprising an alkyne functionality, regardless of the regiochemistry of the alkyne functionality within the aliphatic hydrocarbon group. Unless otherwise specified, an alkynyl group typically has from 2 to 12 carbon atoms, and in another aspect, is a C 2 -C 10 alkynyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, and the like, including all regiochemistries. Thus, “butynyl” includes 1 -butynyl, 2-butynyl, and 3-butynyl.
- an "alkoxyalkyl” group is an alkoxy-substituted alkyl group, wherein an alkoxy group and an alkyl group are defined herein. Unless otherwise specified, an alkoxyalkyl group typically has from 2 to 20 carbon atoms. In one aspect, an alkoxyalkyl group can be a (Ci-Ci 0 ) alkoxy group bonded to a (Ci-Ci 0 ) alkyl group, where alkoxy and alkyl groups are as defined here, including all stereochemistries and all regiochemistries.
- alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methoxyisopropyl, ethoxyisobutyl, and the like.
- aminoalkyl refers to an amino-substituted alkyl group, wherein an alkyl is defined herein. Unless otherwise specified, an aminoalkyl group can typically have from 1 to 12 carbon atoms, therefore, a typical aminoalkyl group can be an amino (Ci-C 12 ) alkyl, including all regiochemistries. Exemplary aminoalkyl groups include, but are not limited to, aminomethyl, aminoetbyl, aminopropyl, and the like.
- a "cycloalkyl-substitued alkyl” group also termed a “cycloalkylalkyl” group, refers to an alkyl group that is substituted with a cycloalkyl substituent, wherein alkyl and cycloalkyl are defined herein.
- the cycloalkyl group portion can be a mono or polycyclic alkyl group.
- a cycloalkylalkyl group can have up to 20 carbon atoms, regardless of how the carbon atoms are distributed between the alkyl portion and the cycloalkyl portion of the group, and including all possible sterochemistries and all regiochemistries.
- a cycloalkyl-substitued alkyl can comprise a (C 3 -C 1O ) cycloalkyl bonded to a C 1 -C 10 alkyl group, wherein the cycloalkyl portion can be mono or polycyclic.
- Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl, cyclooctylethyl, cyclooctylpropyl, and the like.
- a “cycloalkoxy” group also refered to as a “cycloalkyloxy” group, refers herein to an -O(cycloalkyl) substituent, that is, an alkoxide-type moiety comprising a cycloalkyl group, wherein a cycloalkyl is defined herein.
- the cycloalkyl group portion can be a mono or polycyclic alkyl group, and unless otherwise specifed, a cycloalkylalkyl group can have up to 20 carbon atoms.
- a cycloalkoxy group can be a (C 3 -C 1O ) cycloalkyl-O- group.
- Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like.
- acyl refers to a (Ci-Cio)alkyl-CO- group, wherein the (C 1 - Cjo)alkyl group is used in this structure to refer to the alkyl-linker moiety bonded both to the CO group, and to another chemical group.
- acyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, and the like.
- an alkenylene group has from 2 to 10 carbon atoms.
- haloalkoxyalkyl refers to a haloalkyl-O-(C 1 -Ci 0 )alkyl group, that is, a haloalkoxy-substituted alkyl group, wherein haloalkoxy and alkyl are defined herein.
- a cycloalkylalkyl group can have up to 20 carbon atoms, regardless of how the carbon atoms are distributed between the haloalkoxy portion and the alkyl portion of the group, and including all possible sterochemistries and all regiochemistries.
- a haloalkoxyalkyl is haloalkyl-O-(Ci-
- Cio)alkyl where group can be (C 1 -Ci 0 ) haloalkyl group bonded to a (Ci-Cio) alkyl moiety.
- exemplary haloalkoxyalkyl groups include trifluoromethoxymethyl, chloromethoxyethyl, flouroethoxyethyl, chloroethoxyethyl, trilfluoromethoxypropyl, hexafluoroethoxyethyl and the like.
- a "monoalkylamino” group refers to an amino group that is substituted with a single alkyl group, that is, a mono(Ci-C 20 )alkylamino group. Unless otherewise specified, a monoalkylamino group can have up to 20 carbon atoms, hi one aspect, a monoalkylamino group can be a (Ci-Cio)alkyl-substitued amino group. Exemplary monoalkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, and the like.
- dialkylamino refers to an amino group that is substituted with two, independently-selected, alkyl groups, that is, a di(Ci-Ci 0 )alkylamino group. Unless otherewise specified, a dialkylamino group can have up to 20 carbon atoms. Exemplary dialkylamino groups include dimethylamino, diethylamino, and the like.
- the term “substance” refers broadly to any material of a particular kind or constitution.
- a “substance” can include, without limitation, a chemical element, a molecule, a compound, a mixture, a composition, an emulsion, a chemotherapeutic agent, a pharmacological agent, a hormone, an antibody, a growth factor, a cellular factor, a nucleic acid, a protein, a peptide, a peptidomimetic, a nucleotide, a carbohydrate, and combinations, fragments, analogs or derivatives of such entities.
- treatment refers generally to any process, application, therapy, etc., wherein a mammal is subject to medical attention with the object of obtaining a desired pharmacological and/or physiological effect for improving the mammal's condition or disease, directly or indirectly.
- the effect can be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
- the effect also can include, for example, inhibition of disease symptom (i.e., arresting its development) or relieving disease symptom (i.e., causing regression of the disease or symptom).
- the term "therapeutically-effective amount” refers to that amount of at least one compound as disclosed herein, or their pharmaceutically- acceptable salts thereof, that is sufficient to bring about the biological or medical effect that is being sought in a mammal, system, tissue, or cell.
- preventing refer generally to any process, application, therapy, etc., wherein a mammal is subject to medical attention with the object of obtaining a desired pharmacological and/or physiological effect for preventing onset of clinically evident condition or disease or preventing onset of a preclinically evident stage of a condition or disease.
- the effect can be prophylactic in terms of completely or partially preventing or reducing the risk of occurance of a condition or disease or symptom thereof.
- prophylactically-effective amount refers to that amount of a drug or pha ⁇ naceutical agent that will prevent or reduce the risk of occurrence of the biological or medical effect that is sought to be prevented in the cell, tissue, system, or mammal.
- activation refers to any alteration of a signaling pathway or biological response including, for example, increases above basal levels, restoration to basal levels from an inhibited state, and stimulation of the pathway above basal levels.
- valance must be conserved for all the stable molecules. Therefore, the necessary implication that hydrogen atoms are necessary and available to complete the valance in all structures including Formula I unless expressly indicated otherwise.
- Publications and patents mentioned herein are disclosed for the purpose of describing, for example, the constructs and methodologies that are provided in the publications and patents, which might be used in connection with the present invention. None herein is to be construed as an admission that the inventors are not entitled to antedate such publications, patents, or other disclosure by virtue of prior invention.
- Applicants' intent is to disclose or claim individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of subranges encompassed therein.
- Applicants disclose or claim a chemical moiety having a certain number of carbon atoms Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein.
- R is selected independently from an alkyl group having up to 12 carbon atoms, or in alternative language a Cj to C 12 alkyl group, as used herein, refers to an R group that can be selected independently from a hydrocarbyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, as well as any range between these two numbers for example a C 3 to C 8 alkyl group, and also including any combination of ranges between these two numbers for example a C 3 to C 5 and C 7 to C 10 hydrocarbyl group.
- the molar ratio typically spans the range from about 0.1 to about 1.1
- NMR abbreviations br (broad), apt (apparent), s (singlet), d (doublet), t (triplet), q (quartet), dq (doublet of quartets), dd (doublet of doublets), dt (doublet of triplets), m (multiplet).
- Room temperature is defined as an ambient temperature range, typically from about 20°C to about 35 0 C.
- An ice bath (crushed ice and water) temperature is defined as a range, typically from about -5°C to about 0 0 C.
- Temperature at reflux is defined as +15 0 C of the boiling point of the primary reaction solvent. Overnight is defined as a time range of from about 8 to about 16 hours.
- Vacuum filtration water aspirator
- Dried under vacuum is defined as using a high vacuum pump at a range of pressures, typically from about 0.1 mm Hg to about 5 mm Hg.
- Neutralization is defined as a typical acid-based neutralization method and measured to a pH range of from about pH 6 to about pH 8, using pH-indicating paper.
- Brine is defined as a saturated aqueous sodium chloride.
- Nitrogen atmosphere is defined as positive static pressure of nitrogen gas passed through a DrieriteTM column with an oil bubbler system.
- Concentrated ammonium hydroxide is defined as an approximately 15 M solution. Melting points were measured against a mercury thermometer and are not corrected.
- crushed ice quantity typically ranged from about 10 g to about 1000 g depending on reaction scale
- silica gel quantity used in column chromatography depended on material quantity, complexity of mixture, and size of chromatography column employed and typically ranged from about 5 g to about 1000 g
- extraction solvent volume typically ranged from about 10 mL to about 500 mL, depending upon the reaction size
- washes employed in compound isolation ranged from about 10 mL to about 100 mL of solvent or aqueous reagent, depending on scale of reaction
- drying reagents potassium carbonate, sodium carbonate or magnesium sulfate
- the title compound was obtained as a colorless thick liquid following the procedure as described in Example 1, using cyclobutylmethyl-rnethyl-amine (obtained as a colorless liquid following the procedure as described in Example 1, step (ii), using methylamine, instead of ethylamine), instead of cyclobutylmethyl-ethyl-amine in step (iii) (0.23 g), yield: 31%.
- the combined organic extracts were dried over sodium sulfate and concentrated to afford the crude product.
- the crude product was purified by column chromatography over 100-200 mesh silica gel, using 10% ethyl acetate and petroleum ether to yield the title compound as an oil (59%).
- Example 1 The title compound was prepared following the experimental procedure for Example 1, except using bis-cyclopropylmethyl-ethylamine, instead of cyclobutyl methyl ethylamine in step (iii) of Example 1, and 3,5-dichlorobenzylamine, instead of bis- trifluoromethyl-benzylamine in step (iv) of Example 1.
- IR (neat) cm “1 3447, 2955, 2866, 1610, 1582, 1563, 1403, 1361, 1281, 1170, 1131, 900, 706, 682.
- IR (neat) cm- 1 2959, 2871, 1612, 1582, 1563, 1514, 1466, 1404, 1380, 1279, 1175, 1138, 1050, 758.
- a mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-l,3-dimethyl-lH- pyrazolo[3,4- ⁇ ]pyridin-5-ylmethyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.5 g, 0.9 mmol), potassium tertiary butoxide (0.43 g, 3 mmol), cyclopropylmethyl amine (0.275 g, 3 mmol), and Pd(OAc) 2 (0.01 g, 0.004 mmol), BINAP (0.03 g, 0.04 mmol) was prepared in a 10 mL pressure vial.
- the pressure vial was placed in the focused microwave oven (CEM Discovery) and irradiated for 20 min at 110 0 C by using 250 Watt microwave power. After this mixture was cooled to RT, ethyl acetate (100 mL) was added to the vial. The organic layer was washed with water (3 x 100 mL) and dried and concentrated. The resultant oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 10% ethyl acetate in hexane afforded a colorless solid (0.485 g), yield: 90%.
- the vessel was cooled to RT and the reaction mixture was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (3 x 100 mL), the organic layer was separated out, dried over sodium sulfate, and concentrated. The resulting oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 1% methanol in dichloromethane afforded a colorless solid (0.147 g), yield: 52.5%, mp 120- 122 0 C. Purity: 98%.
- IR (neat) cm '1 2927, 2361, 1664, 1579, 1403, 1380, 1279, 1174, 1135, 1021, 903, 756, 682.
- the title compound was prepared following the experimental procedure for Example 24 except using ⁇ 5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-3-methyl- isoxazolo[5,4- ⁇ ]pyridine-6-yl ⁇ -cyclopentylmethyl-ethyl-amine, instead of ⁇ 5-[(3,5-bis- trifluoromethyl-benzylamino)-methyl]-l,3-dimethyl-lH-pyrazolo[3,4- ⁇ ]pyridine-6-yl ⁇ - cyclopentylmethyl-ethyl-amine (60%).
- iV-Cyclopentenoyl-ethylamine was prepared from cyclopentenoic acid (2 grams, 17.5 mmol) and oxallyl chloride (2.2 grams, 17.5 mmol) after stirring at 25-35 0 C for 8- 12 hours. To this was added a benzene solution of ethylamine (2,1 grams, 48.7 mmol) at 0 0 C 3 and this reaction mixture was stirred for 3 hours at 25-35 0 C, after which time the solvent was evaporated under vacuum to yield N-cyclopentenoyl-ethylamine (1.7 grams), yield: 68.9 %.
- step (iv) ⁇ 3-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-quinolin-2-yl ⁇ -cyclopentyl- methyl-ethyl-amine (0.155 g, 0.304 mmol), obtained in step (iv), and K 2 CO 3 (0.126 g, 0.913 mmol) were added to a two-necked round-bottomed flask under a nitrogen atmosphere. Dry tetrahydrofuran (3 to 4 mL) was added to the flask, and the mixture was stirred at room temperature for 30 minutes.
- Methylchloroformate (0.035 grams, 0.456 mmol) was then added dropwise, and the reaction mixture was stirred at 25-35 0 C for 8- 12 hours. After this time, the solvent was removed in vacuo, water added to it, and the mixture extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum to get the crude title compound, which was purified over silica gel (100-200 mesh ASTM) using 3% ethyl acetate/petroleum ether. The desired compound was obtained as a yellow sticky compound having purity of 96.70%. Yield: 115 mg (90%);
- step (iii) The title compound was obtained as an oil following the procedure as described in Example 35, using pyrrolidine instead of cyclopentyl methyl ethylamine in step (iii) (0.25 g, 59%) of 95.12% purity (HPLC: Inertsil ODS 3V, [0.01M KH 2 PO 4 : CH 3 CN], 215 nM, R t 12.410 min).
- 3,5-Bis(trifluoromethyl)benzylamine (0.305 g, 1.25 mmol) was added to a solution of 2-(4-cyclohexylmethyl-piperazin-l-yl)-quinoline-3-carbaldehyde (0.4 g, 1.23 mmol) in methanol followed by acetic acid (0.15 mL) at ambient temperature under nitrogen atmosphere. After stirring 1 h, sodium cyanoborohydride (0.237 g, 3.77 mmol) was added carefully, and the reaction was stirred at RT for overnight.
- the target compound was prepared following the experimental procedure for Example 39, except using iV-ethyl-butylamine instead of l-(cyclohexylmethyl)piperazine in Step (i) and obtained as a viscous liquid (0.223 g), yield: 97.4%. Purity 98.83 % (HPLC: 30:70 [KH 2 PO 4 (0.01 M, pH 3.2):CH 3 CN], R t 52.25 min).
- Acetyl chloride (1.1 mL, 15.4 mmol) was added slowly to an ice cooled solution of cyclohexylmethyl amine (1.3 mL, 10 mmol) in pyridine (4 mL) under a nitrogen atmosphere. After stirring at 0-5° C for 1 h, the reaction mixture was maintained at ambient temperature for 6 h. This mixture was then poured into water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with IN HCl (2 x 10 mL) and then with a saturated sodium bicarbonate solution (10 mL).
- iV-acetyl-cyclohexyl-ethyl-amine (1.50 g), yield: 98%.
- a solution of iV-acetyl- cylohexyl-ethyl-amine (0.8 g, 5.0 mmol) in anhydrous THF (10 niL) was prepared under nitrogen, and lithium aluminum hydride (1.0 M solution in ether, 10 mmol) was added to the solution. After stirring for 6 h at RT, the reaction mixture was poured into water (30 mL) and stirred for 1 h.
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ES05855717.4T ES2644450T3 (en) | 2004-12-31 | 2005-12-28 | New benzylamine derivatives as CETP inhibitors |
KR1020077017632A KR101238525B1 (en) | 2004-12-31 | 2005-12-28 | Novel benzylamine derivatives as cetp inhibitors |
CA2605214A CA2605214C (en) | 2004-12-31 | 2005-12-28 | Benzylamine derivatives as cetp inhibitors |
DK05855717.4T DK1848430T3 (en) | 2004-12-31 | 2005-12-28 | NEW BENZYLAMINE DERIVATIVES AS CETP INHIBITORS |
MX2007007919A MX2007007919A (en) | 2004-12-31 | 2005-12-28 | Novel benzylamine derivatives as cetp inhibitors. |
JP2007549577A JP5096927B2 (en) | 2004-12-31 | 2005-12-28 | Novel benzylamine derivatives as CETP inhibitors |
EP05855717.4A EP1848430B1 (en) | 2004-12-31 | 2005-12-28 | Novel benzylamine derivatives as cetp inhibitors |
CN200580048913XA CN101443006B (en) | 2004-12-31 | 2005-12-28 | Novel benzylamine derivatives as CETP inhibitors |
CA2642130A CA2642130C (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors |
ES06774300.5T ES2615340T3 (en) | 2004-12-31 | 2006-06-29 | Selective benzylamine derivatives and their usefulness as cholesterol ester transfer protein inhibitors |
EP06774300.5A EP1981342B1 (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors |
AU2006330072A AU2006330072B2 (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors |
CN2006800535289A CN101448397B (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors |
PCT/US2006/025427 WO2007075194A1 (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors |
JP2008548498A JP4981814B2 (en) | 2005-12-28 | 2006-06-29 | Selective benzylamine derivatives and their usefulness as cholesterol ester transcription protein inhibitors |
HK09110597.7A HK1131055A1 (en) | 2004-12-31 | 2009-11-13 | Novel benzylamine derivatives as cetp inhibitors |
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WO2014128564A3 (en) * | 2013-02-21 | 2015-03-12 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical compositions of cetp inhibitors |
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US20060178514A1 (en) | 2006-08-10 |
ES2644450T3 (en) | 2017-11-29 |
ES2615340T3 (en) | 2017-06-06 |
CA2605214A1 (en) | 2006-07-13 |
JP2008528447A (en) | 2008-07-31 |
US9040558B2 (en) | 2015-05-26 |
KR101238525B1 (en) | 2013-02-28 |
US20150216866A1 (en) | 2015-08-06 |
CN103102303A (en) | 2013-05-15 |
MX2007007919A (en) | 2008-01-22 |
CN101443006A (en) | 2009-05-27 |
CN101443006B (en) | 2012-10-10 |
WO2006073973A3 (en) | 2008-12-04 |
KR20070102696A (en) | 2007-10-19 |
CN103102303B (en) | 2015-10-28 |
EP1848430A2 (en) | 2007-10-31 |
HK1131055A1 (en) | 2010-01-15 |
EP1848430A4 (en) | 2011-12-28 |
JP5096927B2 (en) | 2012-12-12 |
CA2605214C (en) | 2016-07-12 |
US9782407B2 (en) | 2017-10-10 |
DK1848430T3 (en) | 2017-11-06 |
EP1848430B1 (en) | 2017-08-02 |
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