AU2001250570A1 - Dihydropyrimidine derivatives as cysteine protease inhibitors - Google Patents
Dihydropyrimidine derivatives as cysteine protease inhibitorsInfo
- Publication number
- AU2001250570A1 AU2001250570A1 AU2001250570A AU5057001A AU2001250570A1 AU 2001250570 A1 AU2001250570 A1 AU 2001250570A1 AU 2001250570 A AU2001250570 A AU 2001250570A AU 5057001 A AU5057001 A AU 5057001A AU 2001250570 A1 AU2001250570 A1 AU 2001250570A1
- Authority
- AU
- Australia
- Prior art keywords
- amino
- alkyl
- phenyl
- methyl
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title claims description 9
- 239000002852 cysteine proteinase inhibitor Substances 0.000 title description 5
- -1 benzyloxy, methylenedioxy, ethylenedioxy Chemical group 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 16
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 15
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 15
- 102000005600 Cathepsins Human genes 0.000 claims description 14
- 108010084457 Cathepsins Proteins 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 239000004305 biphenyl Substances 0.000 claims description 8
- 235000010290 biphenyl Nutrition 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 230000000172 allergic effect Effects 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000028993 immune response Effects 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 230000001537 neural effect Effects 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 201000006938 muscular dystrophy Diseases 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 claims description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 2
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 2
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 claims 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 32
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- 239000003112 inhibitor Substances 0.000 description 23
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
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- 238000004364 calculation method Methods 0.000 description 4
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- JLPJFSCQKHRSQR-UHFFFAOYSA-N oxolan-3-one Chemical compound O=C1CCOC1 JLPJFSCQKHRSQR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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Description
DIHYDROPYRIMIDINE DERIVATIVES AS CYSTEINE PROTEASE INHIBITORS
[0001] This invention relates to novel derivatives of dihydropyrimidine, to pharmaceutical compositions containing such compounds, and to their use in medicine as inhibitors of lysosomal cysteine proteases, particularly the cathepsins and more particularly Cathepsins B, L, K and S.
BACKGROUND OF THE INVENTION
[0002] Cysteine proteinases contain a highly reactive cysteine sulfhydryl group and a histidine imidazole group within the active site of the enzyme and are known to play an important role in a number of disease states.
[0003] Cathepsin K can be secreted into the extracellular space and is involved in bone and cartilage remodelling. Cathepsin K is implicated in the pathogenesis of osteoporosis. Cathepsin K inhibitors can prevent osteoporosis in animal models (PNAS.1997. 94:14249-14254). Cathepsin L inhibitors have also been shown to inhibit osteoporosis (Bone, 1997. 20:465- 471 ).
[0004] Cathepsin B and others have also been shown to be released extracelluiarly by various tumour cells and are thought to play a role in tumour invasion (Journal of cellular Physiology. 1992. 150:534-544).
[0005] The cathepsins have also been shown to play a role in rheumatoid arthritis (Arthritis and Rheumatism 1994. 37:236-247) and neuronal and cardiac ischaemia (European Journal of Neuroscience. 1998. 10.1723-1733).
[0006] Cathepsins S and L both play a role in the generation of free MHC class II molecules capable of binding antigenic peptides in the endosomes. These class ll/peptide complexes move to the cell membrane and are involved in T lymphocyte activation. Inhibitors of Cathepsin S have been shown to inhibit allergic immune responses (Journal of Clinical Investigation. 1998. 101 :2351 -2363).
[0007] In addition to their role in the above diseases, cathepsins play a major role in the pathogenesis of infectious diseases. For example, cathepsins are used by the protozoal parasites Plasmodium (malaria) and Trypanosoma (Chagas Disease) to invade the human host and cathepsin inhibitors can inhibit experimental disease in both cases (Antimicrobial agents and chemotherapy. 1998. 42:2254-2258; Journal of Experimental Medicine. 1998. 188:725-734). Cysteine proteases are also virulence factors for some pathogenic bacteria (J. Biochem. 1998, 123:305-312, Biochimica et Biophysica Acta 2000, 1477:35-50).
[0008] Cysteine proteinase are inhibited by several types of peptide derived inhibitors such as peptidyl aldehydes (Eur. J. Biochem. 1982, 129, 33- 41 ), chloromethyl ketones (Acta. Biol. Med. Ger. 1981 , 40, 1503-151 1 ), diazomethyl ketones (Biochemistry 1977,16, 5857-5861 ), monofluoromethyl ketones (Biochemical Pharmacology 1992 44, 1201 -1207), acyloxy methyl ketones (J. Med. Chem. 1994, 37, 1833-1840), O-acyl hydroxamates (Biochem. Biophy. Research Communications 1988, 155, 1201 -1206), methyl sulphonium salts (J. Biol. Chem. 1988, 263, 2768-2772), epoxy succinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527), tetrahydrofuran-3-one (WO-50533, 1998), monobactams (USP-5986108, 1999; USP-5916887, 1999; USP-5959123, 1999) and oxapenams (USP-5905076, 1999; USP- 5925633, 1999) without significantly inhibiting other classes of proteinases.
[0009] These inhibitors, in general, have a natural peptidyl affinity group and a reactive group towards the thiol of the cysteine residue of cysteine proteinase. Natural peptidyl affinity groups are an attractive starting point for drug discovery because they are essential to virtually every biochemical process. Unfortunately, the in vivo effectiveness of such compounds is not reflected as expected on the basis of in vitro inhibitory activity, which may be due to the specificity towards other proteinases and poor pharmacokinetics. However, there exists a continuing need to develop new cysteine proteinase inhibitors with high selectivity and lower toxicity.
[0010] In an effort to find more effective low molecular weight cysteine protease inhibitors for therapeutic uses, we have focused our attention on a
novel dihydropyrimidine class of compounds having substitutions at positions 2, 3 and 5 and inhibitors of cysteine proteinase particularly cathepsins, which is reported in the present invention. The novel route using appropriately substituted monobactams as starting material for synthesis of these compounds is also described.
SUMMARY OF THE INVENTION
[0011] The present invention provides the certain derivatives of novel dihydropyrimidine, to pharmaceutical compositions containing such compounds, and to their use in medicine as inhibitors of lysosomal cysteine proteases, particularly the cathepsins and more particularly Cathepsins B, L, K and S.
[0012] In accordance with the present invention, there is provided novel dihydropyrimidine derivatives having the formula (I):
or the pharmaceutically acceptable salts, hydrate or solvate thereof.
[0013] The present invention makes available a new class of cysteine protease inhibitors, which are significantly different from those, reported earlier and with improved in vivo potency in laboratory rodents. These compounds are useful for the treatment of diseases mediated by cysteine protease activity, for example muscular dystrophy, osteoporosis, tumour metastasis, rheumatoid arthritis, neuronal or cardiac ischaemia, allergic immune response, and protozoal or bacterial disease.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In accordance with the present invention, there is provided dihydropyrimidine derivatives of general formula (I):
or a pharmaceutical acceptable salt, hydrate or solvate thereof.
[0015] Wherein:
[0016] Y represents -C(O)-, -OC(O)-, -NHC(O)- or -S(O2)-;
[0017] Ri represents hydrogen or an optionally substituted CrC6alkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group.
[0018] R2 represents hydrogen or an optionally substituted Ci-Cealkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group.
[0019] R3 represents H, R6 and OR6, wherein R6 is CrC3alkyl, C2- C3alkenyl, C2-C3alkynyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic group.
[0020] R and R5 individually represent H or an optionally substituted d- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclic group.
[0021] R and R5 together represents an oxo group or a C3-C6 cyclic ring system, which may be further, substituted with hydroxyl, halogen, and amino and substituted amino groups.
[0022] The derivative of formula I having asymmetric carbon atoms represents both R and S diastereoisomers.
[0023] The derivative of formula I having double bonds represents both E and Z geometrical isomers.
[0024] Pharmaceutically acceptable salts of the compounds of this invention include the sodium, potassium, magnesium, calcium, hydrogen chloride, tartaric acid, succinic acid, fumaric acid, methanesulfonic acid and p- toluenesulfonic acid salts.
[0025] As used herein the term "(Cι-C6) alkyl" or "lower alkyl" means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 - methylpropyl, 2-methylprop-1 -yl, 2-methylprop-2-yl, pentyl, 3-methylbutyl, and hexyl. Similar terms such as "(CrC3) alkyl" are to be interpreted similarly.
[0026] As used herein the term "C2-C6alkenyl" means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1 - and 2-butenyl and 2-methyl-2- propenyl. Similar terms such as "(C2-C3)alkenyl" are to be interpreted similarly.
[0027] As used herein the term "C2-C6 alkynyl" means a straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1 -propynyl, 1 - and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Similar terms such as "(C2-C3)alkynyf are to be interpreted similarly.
[0028] As used herein the term "cycloalkyl" means a saturated alicyclic moiety having from 3-7 carbon atoms and includes, for example, cyclohexyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
[0029] As used herein the term "halogen" means fluoro, chloro, bromo or iodo.
[0030] As used herein the term "aryl" refers to a mono-, bi- or tri-cyclic, substituted or unsubstituted, carbocyclic aromatic group, and to groups consisting of two covalently linked substituted or unsubstituted monocyclic carbocyclic aromatic groups. Illustrative of such groups is phenyl, biphenyl and napthyl, tetrahydronaphthyl, dihydronaphthyl, and cyclohexyl phenyl.
[0031] As used herein the unqualified term "heterocyclic" means a 5-7 membered heterocyclic ring, which may be aromatic or non-aromatic, containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene or hetero-atom containing ring. The term therefore includes d-Cn heterocyclic groups containing 1 -4 heteroatoms selected from N, S or O. Examples include 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3,4-tetrazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, indolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyridylphenyl and pyrimidylphenyl groups.
[0032] As used herein, the unqualified term "substituted" as applied to a group means substituted with 1 , 2, or 3 substituents selected from
(d-C3)alkyl; phenyl;
C3-C6cycloalkyl; heterocyclic; hydroxy or mercapto;
(d-C3)alkoxy or (C C3)alkylthio; phenoxy or phenylthio; benzyloxy, methylenedioxy, ethylenedioxy; halogen; trifluoromethyl; nitro;
cyano (-CN); carboxyl, esterified or protected carboxyl; amino, mono- or di-(d-C3)alkylamino, or protected amino;
(d-C3)alkylcarbonyl- or (d-d)alkylcarbonylamino-;
-CONH(d-C3)alkyl or -CON[(C C3)alkyl] [(d-C3)alkyl]; and
-NH-C(=NR7)R8 wherein R7 is hydrogen, (Cι-C3)alkyl, or an N- protecting group and R8 is amino, mono- or di-(Cι-C6)alkylamino, protected amino, or (d-C3)alky!.
[0033] As used herein the term "protecting group" when used in relation to an amino or carboxylic acid moeity in the compounds of this invention means a group which is used to render the amino or carboxylic acid moeity substantially non reactive, ie to neutralise its amino or carboxylic acid functionality. In this context, protected amino groups include amido and acylamino, protected hydroxy or mercapto groups include ethers and thioethers, protected carboxyl groups include esters, and imidazolyl, indolyl or guanidyl groups may be protected as t-butoxycarbonyl derivatives. These are only examples of the many protecting derivatives known in the art and the others known to a skilled person. Such protecting groups are of course well known, eg from the art of peptide synthesis, and are discussed in the widely used handbook by T.W. Greene and P.G.M. Wuts, Protective groups in Organic Synthesis, 2nd Edition, Wiley, New York 1991 , and elsewhere in the chemical literature.
[0034] In accordance with the preferred embodiment of the second aspect of the present invention there is provided a derivatives of dihydropyrimidines of formula I
or a pharmaceutical acceptable salt, hydrate or solvate thereof
[0035] Wherein:
[0036] Y is selected from -C(O)-, -OC(O)-, or -S(O2)_;
[0037] Ri is selected from isopropyl, cyclohexyl, phenyl, tert-butylphenyl, isopropylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-pyhdinyl, naphthyl, biphenyl, 3,4-methylenedioxy-phenyl, benzothienyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydronaphthyl; aminonaphthyl; or acetamidonaphthyl.
[0038] R2 is selected from 2-fluoroethyl, cyclohexyl, phenyl, benzyloxyphenyl, t-butylphenyl, biphenyl, benzyl, phenethyl, guanidinobenzyl, amidinobenzyl, guanidinophenethyl, amidinophenethyl, benzyloxyphenyl, naphthyl, naphthylmethyl, naphthylethyl, morpholinophenyl, morpholinobenzyl, morpholinophenethyl, 4-(2-carboxy-2-amino ethyl)-phenyl, 4-(2-carboxy-2-amino ethyl)-phenethyl, 3-pyridyl-phenyl, 3-pyridyl-phenethyl, 3-tetrazolyl-phenyl; 3,4-methylenedioxy-phenyl; 3,4-ethylenedioxy-phenyl; tetrahydroquinolinyl; dihydroquinolinyl; benzothiophen-2-yl; 5-cloro- benzothiophen-2-yl; benzothiophen-2-yl-methyl, quinoline-2-yl; quinoline-2-yl- methyl, benzofuran-2-yl; 5-chloro-benzofuran-2-yl or benzofuran-2-yl-methyl.
[0039] R3 is selected from hydrogen, methyl, ethyl, 2-fluoroethyl, methoxy, ethoxy, cyclopropyl,
[0040] R4 and R5 individually is selected from hydrogen, methyl, 2- fluoroethyl, t-butyl, t-butylmethyl, phenyl, fluorophenyl, cyclopentyl, cyclohexyl, pyridyl, carboxyphenyl, methylphenyl or furanyl.
[0041] R4 and R5 together are selected from oxo, cyclopentyl or cyclohexyl.
[0042] The derivative of formula I having asymmetric carbon atoms represents both R and S diastereoisomers.
[0043] The derivative of formula I having double bonds represents both E and Z geometrical isomers.
[0044] Pharmaceutically acceptable salts of the compounds of formula (I) are selected from sodium, potassium, magnesium or calcium salt of carboxylic group and hydrogen chloride, tartaric acid, succinic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid salt of amino group.
[0045] More specifically, the most preferred embodiments of the present invention include the following compounds:
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-phenyl-2, 3- dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(2-fluorophenyl)-2,
3-dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(3-fluorophenyl)-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(4-fluorophenyl)-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(2,4-difluorophenyl)-
2, 3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-benzyl-2, 3- dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2,2-spirocyclopentyl-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2,2-spirocyclohexyl-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2,2-spirocyclohexyl-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl l]-acetamido-2-(pyridin-4-yl)-2, 3- dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(2-carboxyphenyl)-
2, 3-dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(4-carboxyphenyl)-
2, 3-dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-methyl-2,3- dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2,2-dimethyl-2, 3- dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-tert-butylmethyl-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(Benzyloxy carbonyl)-amino-2-benzyl]-acetamidopyrimidin-2,6-dione.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamidopyrimidin-2,6-dione.
5-[2-(Benzyloxy carbonyl)-amino-2-cyclohexylmethyl]-acetamidopyrimidin-2,6- dione.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(2,4- dimethylphenyl)-2, 3-dihydopyrimidine-6-(1 H)one
5-[2-(3-Phenylpropionyl)-amino-2-isobutyl]-acetamido-2,2-spirocyclopentyl-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(3-Phenylpropionyl)-amino-2-isobutyl]-acetamido-2-(furan-2-yl)-2, 3- dihydopyrimidine-6-(1 H)one
5-[2-(3-Phenylpropionyl)-amino-2-isobutyl]-acetamido-2,2-spirocycloheptyl-2,
3-dihydopyrimidine-6-(1 H)one.
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]-acetamido-2-(furan-2-yl)-2, 3- dihydopyrimidine-6-(1 H)one
5-[2-(Benzothiophene-2-yl)-amino-2-isobutyl]-acetamido-2-(2-fluorophenyl)-2,
3-dihydopyrimidine-6-(1 H)one
5-[2-(4-Benzyloxybenzoyl)-amino-2-isobutyl]-acetamido-2-(furan-2-yl)-2, 3- dihydopyrimidine-6-(1 H)one
[0046] In accordance with the preferred embodiment of the third aspect of the present invention there is provided a derivatives of dihydropyrimidines of formula I
or a pharmaceutical acceptable salt, hydrate or solvate thereof
[0047] Wherein:
[0048] Y is selected from -C(O)-;
[0049] Ri is isopropyl, cyclohexyl and phenyl.
[0050] R2 is t-butylphenyl, biphenyl, phenethyl, morpholinoethyl, benzothiophen-2-yl or benzofuran-2-yl.
[0051] R3 is selected from hydrogen or methyl,
[0052] R and R5 individually is fluorophenyl, pyridyl, or furanyl.
[0053] R and R5 together is cyclopentyl or cyclohexyl.
[0054] The derivative of formula I having asymmetric carbon atoms represents both R and S diastereoisomers.
[0055] The derivative of formula I having double bonds represents both E and Z geometrical isomers.
[0056] Pharmaceutically acceptable salts of the compounds of formula (I) is sodium salt of carboxylic acid and hydrogen chloride salt of amino group.
[0057] As stated, the compounds of the invention are inhibitors of cysteine proteases, for example cathepsins B, L and S or K. The invention therefore also provides a pharmaceutical composition containing a compound of formula (I) as defined above, and a pharmaceutically acceptable carrier. Also provided is the use of such a compound in the preparation of a composition for inhibiting cysteine protease activity in the body of a mammal suffering a disease mediated by such activity, and a method of treatment of an animal suffering from a disease mediated by cysteine protease activity, which method comprises administering to the mammal a sufficient amount of a compound of formula (I) as defined above to inhibit such activity.
[0058] Diseases mediated by cysteine protease activity include muscular dystrophy, osteoporosis, tumour metastasis, rheumatoid arthritis, neuronal or cardiac ischaemia, allergic immune response, and protozoal or bacterial disease.
[0059] Compositions with which the invention is concerned may be prepared for administration by any route consistent with the pharmacokinetic properties of the active ingredient(s).
[0060] Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions,
solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
[0061] For topical application to the skin, the active ingredient(s) may be made up into a cream, lotion or ointment. Cream or ointment formulations, which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
[0062] The active ingredient(s) may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. Intravenous infusion is another route of administration for the compounds.
[0063] Safe and effective dosages for different classes of patient and for different disease states will be determined by clinical trial as is required in the art. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0064] The present invention provides certain novel derivatives of dihydropyrimidine having excellent cysteine protease inhibitory activity particularily to cathepsins. The compounds of this invention are characterized by having a substitution at position 2, 3, and 5 of dihydropyhmidin-6-one.
[0065] Compounds of general formula I, reported in the present invention are prepared by the reaction of compound (II) with various aldehydes or ketones in appropriate solvents, which fall within the art of chemistry, as shown in the Scheme-1 .
Scheme-1
Alternatively, the derivatives of general formula I was also prepared by the general synthetic route as represented in scheme II
Scheme-2
[0066] The compound III was treated with amines followed by a reaction with substituted aldehyde or ketones gave protected compound V. The benzyloxycarbonyl protected compound V was deprotected by hydrogenation in the presence of a metal catalyst, such as Pd, Pt, or Rh, under normal pressure to high pressure to give compound VI. Further, compound VI was reacted with substituted carboxylic acid VII in the presence of DCC, or with acid chlorides in the presence of base, or with anhydride in the presence of base or the activated ester, gave compound I.
[0067] The preparation of compound II was carried out by the synthetic procedure as described in Scheme-3.
Scheme-3
[0068] Alternatively compound II can also be prepared by following the synthetic scheme-4.
Scheme-4
[0069] The compound VII residue is defined as substitution at position-5 of 5-amino-dihydropyrimidin-6-one. The compound VII was coupled with aminoacetamide either in the presence of DCC, or with its acid chloride in the presence of base, or with its anhydride in the presence of base or with its activated ester.
[0070] In the above processes, the reactants are reacted together with solvent at elevated or low temperatures for sufficient time to allow the reaction to proceed to completion. The reaction conditions will depend upon the nature and reactivity of the reactants. Wherever a base is used in a reaction, it is selected from the group consisting of triethyl amine, pyridine, 4- dimethylaminopyridine, diisopropylamine, 1 ,5-diazabicyclo [4,3,0] non-5-ene, 1 ,8-diazabicyclo [5,4,0] undec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide. Depending on the reactants, a solvent will generally be selected from the group consisting of benzene, toluene, acetonit le, tetrahydrofuran, ethanol, methanol, chloroform, ethyl acetate, methylene chloride, dimethyl formamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, water, pyridine, acetone and the like, solvent mixtures may also be utilized. Reaction temperatures generally range from between -70 °C to 150 °C. The preferred molar ratio of reactants is 1 :1 to 5. The reaction time range from 0.5 to 72 hours, depending on the reactants.
[0071] The following examples illustrate embodiments of the invention.
Example-KNPI-3243)
5-[2-(Benzylox.v carbonyl)amino-2-isobutyllacetamido-2-phenyl-2, 3- dihydopyrimidine-6-( lH)one.
[0072] A solution of 2-(2S-2-benzyloxycarbonylamino-2-isopropylmethyl- acetamido)-3-amino-acry!amide (1 .78g ) in methanol(I OOml) was treated with benzaldehyde (5g) and refluxed for 10h. The solvent was removed in vacuo
and the residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (5%) as to give the title compound.
Yield: 0.268g, 12% m.p.: 76-78
1HNMR(DMSO-d6): δ 0.85(m, 6H), 1 .40-1 .70(m, 3H), 4.00-4.20(m, 1 H),
5.05(s, 2H), 5.62(s, 1 H), 7.06(d, 1 H, J=6.0Hz), 7.20-7.50(m, 10H), 7.60-
7.70(m, 2H), 7.78(s, 1 H), 8.43(s, 1 H).
Example-2(NPI-3392
5-[2-(Benzyloxy carbonyl)amino-2-isobutyl1acetamido-2-(2-fluorophenyl)-2, 3- dihydopyrimidine-6-(1 H)one.
[0073] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 2-fluorobanzaldehyde.
Yield: 8% m.p.: 78-81 °C
1HNMR(DMSO-d6): δ 0.83-0.89(m, 6H), 1 .44-1 .70(m, 3H), 4.06-4.18(m, 1 H),
5.05(s, 2H), 5.91 (s, 1 H), 7.01 -7.67(m, 12H), 7.79(s, 1 H), 8.43(s, 1 H).
Example-3fNPI-3474l
5-[2-(Benzyloxy carbonyl)amino-2-isobUtyl]acetamido-2-(3-fluorophenyl)-2, 3- dihydopyrimidine-6-(t H)one
[0074] The title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-benzyloxycarbonylamino-2- isopropylmethyl-acetamido)-3-amino-acrylamide and 3-fluorobanzaldehyde.
Yield: 17% m.p.: 84-86 °C
1HNMR(DMSO-d6): δ 0.82-0.88(m, 6H), 1.41 -1.73(m, 3H), 4.02-4.15(m, 1 H),
5.04(s, 2H), 5.66(s, 1 H), 7.19-7.70(m, 12H), 7.97(s, 1 H), 8.39(s, 1 H).
Example-4(NPI-3470)
5-[2-(Benzyloxy carbonyl)amino-2-isobutyl]acetamido-2-(4-fluorophenyl)-2, 3- dihydopyrimidine-6-(1 H)one
[0075] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 4-fluorobanzaldehyde.
Yield: 23%
m.p.: 87-91 °C
1HNMR(DMSO-d6): δ 0.82-0.88(m, 6H), 1.33-1.74(m, 3H), 4.02-4.17(m, 1 H),
5.05(s, 2H), 5.64(s, 1 H), 7.07-7.72(m, 12H), 7.87(s, 1 H), 8.39(s, 1 H).
Example-5(NPI-3490)
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]acetamido-2-(2,4-difluorophenyl)- 2, 3-dihydopyrimidine-6-(l H)one
[0076] The title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-benzyloxycarbonylamino-2- isopropylmethyl-acetamido)-3-amino-acrylamide and 2,4- difluorobanzaldehyde.
Yield: 9% m.p.: 87-90 °C
1HNMR(DMSO-d6): δ 0.83-0.89(m, 6H), 1 .45-1 .74(m, 3H), 4.03-4.16(m, 1 H),
5.05(s, 2H), 5.88(s, 1 H), 7.00-7.35(m, 8H), 7.59-7.69(m, 2H), 7.81 (s, 1 H),
8.44(s, 1 H).
Example-6(NPI-3469^
5-[2-(Benzyloxy carbonyl)amino-2-isobutyl]acetamido-2,2-spirocvclopentyl-2. 3-dihydopyrimidine-6-(1 H)one
[0077] The above title compound was synthesized by the procedure described for step-2 of example-1 and Using the 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and cyclopentanone.
Yield: 3.4% m.p.: 80-82 °C
1HNMR(DMSO-d6): δ 0.80-0.88(m, 6H, 1 .41 -1 .92(m, 11 H), 4.02-4.15(m, 2H),
5.05(s, 2H), 6.80(d, 1 H, J=6.0Hz), 7.35(s, 5H), 7.56(d, 1 H, J=6.0Hz), 7.58(s,
1 H), 7.67(d, 1 H, J=9.0Hz), 8.32(s, 1 H).
Example-7(NPI-3481 )
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl1acetamido-2,2-spirocvclohexyl-2, 3-dihydopyrimidine-6-(1 H)one.
[0078] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-
11
benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and cyclohexanone.
Yield: 4.5% m.p.: 83-85 °C.
1HNMR(DMSO-d6): δ 0.83-0.88(m, 6H), 1 .15-1 .94(m, 13H), 3.90-4.18(m, 2H),
5.02 and 5.05(2s, 2H), 6.68(d, 1 H, J=6.0Hz), 7.35(s, 6H), 7.54(d, 1 H,
J=6.0Hz), 7.66(d, 1 H, J=8.3Hz), 8.31 (s, 1 H).
Example-8(NPI-3479)
5-[2-(Benzyloxy carbonvD-amino -2-isobutvπacetamido-2-tert-butyl-2, 3- dihydopyrimidine-6-(1 H)one
[0079] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and trimethyl acetaldehyde.
Yield: 4.5% m.p.: 87-88 °C.
1HNMR(DMSO-d6): δ 0.83-0.90(m, 15H), 1 .40-1.72(m, 3H), 3.99-4.15(m, 1 H),
4.20(s, 1 H), 5.05(s, 2H), 6.54(d, 1 H, J=5.0Hz), 7.25-7.71 (m, 8H), 8.35(d, 1 H,
J=2.5Hz).
Example-9(NPI-3468)
5-[2-(Benzyloxy carbonyl)-amino-2-isobutvnacetamido-2-(pyridin-4-yl)-2, 3- dihydopyrimidine-6-(1 H)one
[0080] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and pyridine-4-carboxaldehyde.
Yield: 20.4% m.p.: 97-99 °C
1HNMR(DMSO-d6): δ 0.84-0.88(m, 6H), 1 .44-1 .71 (m, 3H), 3.90-4.00(m, 1 H),
5.01 (s, 2H, ), 5.47(d, 1 H, J=8.1 Hz), 6.37(br, s, 1 H), 6.67-6.75(m, 2H), 7.36(s,
6H), 7.60-7.65(m, 1 H), 8.59(s, 1 H), 8.62(s, 1 H), 8.71 -8.90(m, 2H).
Example-10(NPI-3400)
5-[2-(Benzyloxy carbonvD-amino -2-isobutyl]acetamido-2-tert-butylmethyl-2, 3- dihydopyrimidine-6-(1 H)one
[0081] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 3,3-dimethylbutyraldehyde.
Yield: 13% m.p.: 84-86 °C
1HNMR(DMSO-d6): δ 0.83-0.98(m, 15H), 1 .45-1 .64(m, 5H), 4.05-4.15(m, 1 H),
4.54(s, 1 H), 5.05(s, 2H), 6.45(d, 1 H, J=4.3Hz), 7.26-7.35(m, 7H), 7.62-7.72(m,
2H), 8.35(m, 1 H).
Example-1 KNPI-3398)
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]acetamido-2-(2-carboxyphenyl)-2, 3-dihydopyrimidine-6-(1 H)one.
[0082] The title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-benzyloxycarbonylamino-2- isopropylmethyl-acetamido)-3-amino-acrylamide and 3-carboxy benzaldehyde.
Yield: 3% m.p.: 221 -223 °C
1HNMR(DMSO-d6): δ 0.82-0.92(m, 6H), 1 .43-1 .76(m, 3H), 4.05-4.l 7(m, 1 H),
5.05(s, 2H), 6.39(s, 1 H), 6.80-6.88(m, 1 H), 7.36-7.67(m, 10H), 7.96(d, 1 H,
J=7.6Hz), 8.41 (s, 1 H), 13.35(s, 1 H).
Example-12(NPI-3397)
5-[2-(Benzyloxy carbonyl)-amino-2-isobutvnacetamido-2-(4-carboxyphenyl)-2, 3-dihydopyrimidine-6-(1 H)one.
[0083] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 4-carboxy benzaldehyde.
Yield: 13% m.p.: 139-145 °C
1HNMR(DMSO-d6): δ 0.82-0.88(m, 6H), 1.35-1.80(m, 3H), 3.98-4.18(m, 1 H),
5.04(s, 2H), 5.71 (s, 1 H), 7.20-7.98(m, 13H), 8.39(s, 1 H), 13.04(s, 1 H).
Example-13(NPI-3267)
5-[2-(Benzyloxy carbonvQamino-2-benzvπacetamido pyhmidin-2,6-dione
[0084] A mixture of N-benzyloxycarbonylamino-phenylalanine (0.429g, 1.433 mmol), DCC (0.296g, 1 .433 mmol), 1 -HBT (0. 94g, 1 .433 mmol) and 5- amino uracil (0.182g, 1 .433 mmol) in dry DMF (10ml) was stirred at RT for 6 hrs and diluted with ethyl acetate. The ethyl acetate solution was washed with water, aq. sat. NaHCO3 solution followed by brine solution, dried over MgSO , filtered and evaporated. The crude product obtained was treated with isopropanol and the solid separated was filtered and dried to give the title compound.
Yield: 90.1 % m.p.: 229-230 °C
1HNMR(DMSO-d6): δ 2.76-3.06(m, 2H), 4.50-4.60(m, 1 H), 4.94(s, 2H), 7.23-
7.40(m, 10H), 7.72(d, 1 H, J=8.4Hz), 8.10(s, 1 H), 9.35(s, 1 H), 1 1.l 5(br, s, 2H).
Example-14(NPl-3268
5-[2-(Benzyloxy carbonyl)-amino-2-isobutyl]acetamido pyrimidin-2,6-dione.
[0085] The above compound was prepared by the procedure described in example-13 and by using N-(benzyloxycarbonyl)amino leucine (0.51 1 g, 1 .93 mmol), DCC (0.397g, 1 .93 mmol), 1 -HBT (0.261 g, 1 .93 mmol) and 5-amino uracil (0.245, 1.93 mmol) in DMF (12ml).
Yield: 52.4% m.p.: 205-206 °C
1HNMR(DMSO-d6): δ 0.84-0.89(m, 6H), 1.35-1.70(m, 3H), 4.22-4.32(m, 1H), 5.04(s, 2H ), 7.35(s, 5H), 7.70(d, 1H, J=8.1Hz), 8.06(s, 1H), 9.06(s, 1H), 10.67(br, s, 1H), 11.50(br, s, 1H).
Example-15(NPI-3269)
5-[2-(Benzyloxy carbonyl)-amino-2-cvclohexylmethvn-acetamido pyrimidin- 2,6-dione
[0086] The above compound was prepared by the procedure described in example-13 and by using N-(benzyloxycarbonyl)amino cyclohexylalanine (0.505g, 1.654 mmol), DCC (0.341 g, 1.654 mmol), 1-HBT (0.224g, 1.654 mmol) and 5-amino uracil (0.105, 1.654 mmol) in DMF (15ml).
Yield: 45% m.p.: 204-205 °C
1HNMR(DMSO-d6): δ 0.74-1.76(m, 13H), 4.25-4.35(m, 1H-), 5.05(s, 2H),
7.35(s, 5H), 7.69(d, 1H, J=8.0Hz), 8.05(s, 1H), 9.04(s, 1H), 10.66(br , s, 1H),
11.51(brs, 2H).
Example-16(NPl-3497)
5-[2-(Benzyloχy carbonyl)-amino-2-isobutyl1acetamido-2-(2,4-dimethylphenyl)- 2, 3-dihydopyrimidine-6-(lH)one
[0087] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 2,4-dimethyl benzaldehyde.
Yield: 5.1 % m.p.: 101 -106 °C
1HNMR(DMSO-d6): δ 0.84-0.89(m, 6H), 1 .45-1.70(m, 3H), 2.27 and 2.34(2s,
6H), 4.06-4.20(m, 1 H), 5.06(s, 2H), 5.76(s, 1 H), 6.79(d, 1 H, J=5.0Hz), 7.03-
7.42(m, 9H), 7.56(s, 1 H), 7.71 (d, 1 H, J=6.2Hz), 8.42(s, 1 H).
Example-17(NPI-4769)
5-[2-(3-Phenylpropionyl)-amino-2-isobutvπacetamido-2,2-spirocyclopentyl-2, 3-dihydopyrimidine-6-(1 H)one
[0088] The above title compound was synthesized by the procedure described for step-2 of example-1 and Using 2-[2S-2-(3-phenylpropionoyl)-
amino-2-isopropylmethyl-acetamido]-3-amino-acrylamide and cyclopentanone.
Yield: 3.4 % m.p.: 95 °C
1HNMR(DMSO-d6): δ 0.78-0.87(m, 6H), 1 .39-1.94(m, 1 1 H), 2.43-2.50(m, 2H),
2.80-2.90(m, 2H), 4.24-4.37(m, 1 H), 6.82(d, 1 H, J=6.5Hz), 7.13-7.33(m, 6H),
7.54(d, 1 H, J=6.5Hz), 8.17(d, 1 H, J=6.5Hz), 8.28(s, 1 H).
Example-18(NPI-4772)
5-[2-(3-Phenylpropionyl)-amino-2-isobutvπacetamido-2-(furan-2-yl)-2, 3- dihydopyrimidine-6-(1 H)one
[0089] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-(3-phenylpropionoyl)- amino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and furan-2- carboxaldehyde.
Yield: 4.4% m.p.: 124 °C
1HNMR(DMSO-d6): δ 0.79-0.90(m, 6H), 1 .40-1 .50(m, 3H), 2.40-2.50(m, 2H),
2.77-2.88(m, 2H), 4.27-4.40(m, 1 H), 5.67(s, 1 H), 6.35-6.47(m, 2H), 7.10-
7.30(m, 7H), 7.60(d, 1 H, J=5.83Hz), 7.66(s, 1 H), 7.91 (s, 1 H), 8.16(d, 1 H,
J=8.5Hz), 8.35(s, 1 H).
Example-19(NPI-4774)
5-[2-(3-Phenylpropionoyl)-amino-2-isobutvnacetamido-2,2-spirocvcloheptyl-2, 3-dihydopyrimidine-6-(1 H)one.
[0090] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-(3-phenylpropionoyl)- amino)-2-isopropylmethyl-acetamido)-3-amino-acrylamide and cycloheptanone.
Yield: 6.3% m.p.: 125 °C
1HNMR(DMSO-d6): δ 0.80-0.90(m, 6H), 1 .30-1.62(m, 10H), 1.74-2.00(m, 3H),
2.39-2.48(m, 2H), 2.78-2.89(m, 2H), 4.25-4.41 (m, 1 H), 6.74(d, 1 H, J=6.3Hz),
7.10-7.51 (m, 7H), 8.14(d, 1 H, J=8.3Hz).
Example-20(NPI-3510)
5-[2-(Benzyloxy carbonyl)amino-2-isobutyl1acetamido- 2-(furan-2-yl)-2, 3- dihydopyrimidine-6-(1 H)one
[0091] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2- benzyloxycarbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and furan-2-carboxaldehyde.
Yield: 4.8% m.p.: 75-80° C
1HNMR(DMSO-d6): δ 0.85-0.90(m, 6H), 1 .42-1 .72(m, 3H), 4.03-4.17(m, 1 H),
5.05(s, 2H), 5.68(s, 1 H), 6.36(s, 1 H), 6.43(s, 1 H), 7.10(s, 1 H), 7.35(s, 6H),
7.66(s, 2H), 7.92(s, 1 H), 8.38(s, 1 H).
Example-21 (NPI-3493)
5-[2-(Benzothiophene-2-yl)amino-2-isobutyl]acetamido-2-(2-fluorophenyl)-2, 3-dihydopyrimidine-6-(1 H)one
[0092] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-(2S-2-benzothein-2yl- carbonylamino-2-isopropylmethyl-acetamido)-3-amino-acrylamide and 2- fluorobenzaldehyde.
Yield: 1 1 .3% m.p.: 1 19-123 °C
1HNMR(DMSO-d6): δ 0.90-0.94(m, 6H), 1 .58-1 .85(m, 3H), 4.56-4.68(m, 1 H, ),
5.91 (s, 1 H), 7.08(d, 1 H, J=5.0Hz), 7.20-7.65 (m, 8H), 7.75(s, 1 H), 7.97-
8.09(m, 2H), 8.27(s, 1 H), 8.57(s, 1 H), 8.93(d, 1 H, J=8.4Hz).
Example-22(NPI-3522)
5-[2-(4-Benzyloxybenzoyl)amino-2-isobutyl]acetamido-2-(furan-2-yl)-2, 3- dihvdopyrimidine-6-(1 H)one
[0093] The above title compound was synthesized by the procedure described for step-2 of example-1 and using 2-[2S-2-(4- benzyloxybenzoylamino)-2-isopropylmethyl-acetamido]-3-amino-acrylamide and furan-2-carboxaldehyde.
Yield: 28% m.p.: 103-105 ° C
1HNMR(DMSO-d6): δ 0.90-0.97(m, 6H), 1 .54-1 .79(m, 3H), 4.50-4.62(m, 1 H),
5.19(s, 2H), 5.66(s, 1 H), 6.35-6.44(m, 2H), 7.08-7.12(m, 3H), 7.33-7.49(m,
6H), 7.67(s, 1 H), 7.86-7.90(m, 3H), 8.40(s, 1 H), 8.50(d, 1 H, J=6.5Hz).
Biological Testing
[0094] Testing of inhibitors for inhibition of cathepsin B, L, K and S.
In vitro assay procedure for cathepsin B
[0095] The compounds of formula I were tested for inhibition of cathepsin B using the known method (A.J. Barret et al., Biochem. J. 1982, 201 , 189- 198). To a 170μl of enzyme-buffer mixture (enzyme: r rat cathepsin B, diluted to give approximate 10 F units/min, buffer: 56mM sodium acetate, 1 .124mM EDTA, 10mM DTT, pH 5.1 ) a 10μl of inhibitor (dissolved in DMSO) was added. After 10min of incubation at room temperature, a 20μl of 5mM substrate (N-CBZ-Phe-Arg-AMC, dissolved in DMSO) was added to initiate reaction. Reading is followed up for 10 min at the fluoroscan reader (excitation at 380nm emission at 460nm).
[0096] A plot of percentage of inhibition vs inhibitor concentration is obtained, and IC50 is determined using a linear regression calculations (concentration of inhibitor which will give 50% inhibition).
In vitro assay procedure for cathepsin L
[0097] To a 170μl of enzyme-buffer mixture (enzyme: r rat cathepsin L, diluted to give approximate 15 F units/min, buffer: 58.8mM sodium citrate, 1 .18mM EDTA, 235mM sodium chloride, 5mM DTT, pH 5.0) a 10μl of inhibitor (dissolved in DMSO) was added. After 10 min of incubation at room temperature, a 20μl of 1 mM substrate (N-CBZ-Phe-Arg-AMC, dissolved in DMSO) was added to initiate reaction. Reading is followed up for 10 min at the fluoroscan reader (excitation at 380nm emission at 460nm).
[0098] A plot of percentage of inhibition vs inhibitor concentration is obtained, and IC50 is determined using a linear regression calculations (concentration of inhibitor which will give 50% inhibition).
In vitro assay procedure for cathepsin K
[0099] To a 170μl of enzyme-buffer mixture (enzyme: r cathepsin K, diluted to give approximate 30 F units/min, buffer: 100mM sodium acetate, 5mM EDTA, 20mM L-cysteine, 0.01 % Brij, pH 5.5) a 10μl of inhibitor
(dissolved in DMSO) was added. After 10 min of incubation at room temperature, a 20μl of 2.7mM substrate (N-CBZ-Phe-Arg-AMC, dissolved in DMSO) was added to initiate reaction. Reading is followed up for 10 min at the fluoroscan II plate reader (excitation at 380nm emission at 460nm).
[00100] A plot of percentage of inhibition vs inhibitor concentration is obtained, and IC50 is determined using a linear regression calculations (concentration of inhibitor which will give 50% inhibition).
In vitro assay procedure for cathepsin S
[00101] To a 170μl of enzyme-buffer mixture (enzyme: r cathepsin S, diluted to give approximate 30 F units/min, buffer: 100mM sodium phosphate, 1 mM EDTA, 5mM DTT, 0.01 % Brij, pH 6.5) a 10μl of inhibitor (dissolved in DMSO) was added. After 10 min of incubation at room temperature a 20μl of 1 .2mM substrate (N-CBZ-Val-Val-Arg-AMC, dissolved in DMSO) was added to initiate reaction. Reading is followed up for 10 min at the fluoroscan II plate reader (excitation at 380nm emission at 460nm).
[00102] A plot of percentage of inhibition vs inhibitor concentration is obtained, and IC50 is determined using a linear regression calculations (concentration of inhibitor which will give 50% inhibition).
Table-1 : In vitro inhibitory activity of compounds with Cathepsins
[00103] Selected compounds of present invention were tested in rodents. This class of compound has favorable pharmacokinetics at the oral dose of 5 mg/kg. The bioavailability is about 60-70%. The data is summarized in Table- 2.
Table-2: Pharmacokinetic parameters of selected examples with mice after single oral dose of 5mg/kg
Claims (18)
- Claims:. In accordance with the present invention, there is provided novel dihydropyrimidine derivatives of general formula (I):Wherein:Y represents -C(O)-, -OC(O)-, -NHC(O)- or -S(O2)-;R-t represents hydrogen or an optionally substituted Cι-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group.R2 represents hydrogen or an optionally substituted d-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group.R3 represents H, R6 and OR6, wherein R6 is d-C3alkyl, C2-C3alkenyl, C2-C3alkynyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic group.R4 and R5 individually represent H or an optionally substituted d- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclic group.R4 and R5 together represents an oxo group or a C3-C6 cyclic ring system, which may be further, substituted with hydroxyl, halogen, and amino and substituted amino groups. or a pharmaceutically acceptable salt, hydrate or solvate thereof
- 2. A compound according to claim 1 wherein the unqualified term "substituted" as applied to a group means substituted with 1 , 2, or 3 substituents selected from(d-C3)alkyl; phenyl;C3-C6cycloalkyl; heterocyclic; hydroxy or mercapto;(d-C3)alkoxy or (d-C3)alkylthio; phenoxy or phenylthio; benzyloxy, methylenedioxy, ethylenedioxy; halogen; trifluoromethyl; nitro; cyano (-CN); carboxyl, esterified or protected carboxyl; amino, mono- or di-(d-C3)alkylamino, or protected amino;(d-C3)alkylcarbonyl- or (Cι-C3)alkylcarbonylamino-;-CONH(d-C3)alkyl or -CON[(Cι-C3)alkyl] [(C C3)alkyl]; and-NH-C(=NR7)R8 wherein R7 is hydrogen, (C C3)alkyl, or an N- protecting group and R8 is amino, mono- or di-(d-C6)alkylamino, protected amino, or (Cι-C3)alkyl.
- 3. A compound according to claim 1 wherein the term "(CrC6) alkyl" or "lower alkyl" means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylprop-1 -yl, 2-methylprop- 2-yl, pentyl, 3-methylbutyl, and hexyl. Similar terms such as "(d~C3) alkyl" are to be interpreted similarly.
- 4. A compound according to claim 1 wherein the term "C2-C6alkenyl" means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond, for example, vinyl, ally! , 1 - and 2-butenyl and 2-methyl-2-propenyl. Similar terms such as "(C2- C3)alkenyl" are to be interpreted similarly.
- 5. A compound according to claim 1 wherein the term "C2-C6 alkynyl" means a straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond, for example, ethynyl, 1 -propynyl, 1 - and 2-butynyl, 2-methyl-2-propynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Similar terms such as "(C2-C3)alkynyl" are to be interpreted similarly.
- 6. A compound according to claim 1 wherein the term "cycloalkyl" means a saturated alicyclic moiety having from 3-7 carbon atoms and includes, for example, cyclohexyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
- 7. A compound according to claim 1 wherein the term "aryl" refers to a mono-, bi- or tri-cyclic, substituted or unsubstituted, carbocyclic aromatic group, and to groups consisting of two covalently linked substituted or unsubstituted monocyclic carbocyclic aromatic groups, for example phenyl, biphenyl and napthyl, tetrahydronaphthyl, dihydronaphthyl, and cyclohexyl phenyl.
- 8. A compound according to claim 1 wherein the unqualified term "heterocyclic" means a 5-7 membered heterocyclic ring, which may be aromatic or non-aromatic, containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene or hetero- atom containing ring, for examples 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3,4-tetrazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, indolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyridylphenyl and pyrimidylphenyl groups.
- 9. In accordance with the preferred embodiment of the second aspect of the present invention there is provided a derivatives ofdihydropyrimidines of formula IWherein:Y is selected from -C(O)-, -OC(O)-, or -S(O2)_;Ri is selected from isopropyl, cyclohexyl, phenyl, tert-butylphenyl, isopropylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-pyridinyl, naphthyl, biphenyl, 3,4-methylenedioxy-phenyl, benzothienyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydronaphthyl; aminonaphthyl; or acetamidonaphthyl.R2 is selected from 2-fluoroethyl, cyclohexyl, phenyl, benzyloxyphenyl, t-butylphenyl, biphenyl, benzyl, phenethyl, guanidinobenzyl, amidinobenzyl, guanidinophenethyl, amidinophenethyl, benzyloxyphenyl, naphthyl, naphthylmethyl, naphthylethyl, morpholinophenyl, morpholinobenzyl, morpholinophenethyl, 4-(2- carboxy-2-amino ethyl)-phenyl, 4-(2-carboxy-2-amino ethyl)-phenethyl, 3-pyridyl-phenyl, 3-pyridyl-phenethyl, 3-tetrazolyl-phenyl; 3,4- methylenedioxy-phenyl; 3,4-ethylenedioxy-phenyl; tetrahydroquinolinyl; dihydroquinolinyl; benzothiophen-2-yl; 5-cloro-benzothiophen-2-yl; benzothiophen-2-yl-methyl, quinoline-2-yl; quinoline-2-yl-methyl, benzofuran-2-yl; 5-chloro-benzofuran-2-yl or benzofuran-2-yl-methyl.R3 is selected from hydrogen, methyl, ethyl, 2-fluoroethyl, methoxy, ethoxy, cyclopropyl,R4 and R5 individually is selected from hydrogen, methyl, 2-fluoroethyl, t-butyl, t-butylmethyl, phenyl, fluorophenyl, cyclopentyl, cyclohexyl, pyridyl, carboxyphenyl, methylphenyl or furanyl.R and R5 together are selected from oxo, cyclopentyl or cyclohexyl.or a pharmaceutically acceptable salt, hydrate or solvate thereof
- 10. In accordance with the preferred embodiment of the third aspect of the present invention there is provided a derivatives of dihydropyrimidines of formula IWherein:Y is selected from -C(O)-R-i is isopropyl, cyclohexyl and phenyl.R2 is t-butylphenyl, biphenyl, phenethyl, morpholinoethyl, benzothiophen-2-yl or benzofuran-2-yl. R3 is selected from hydrogen or methyl,R4 and R5 individually is fluorophenyl, pyridyl, or furanyl.R4 and R5 together is cyclopentyl or cyclohexyl.or a pharmaceutical acceptable salt, hydrate or solvate thereof
- 1 1. As used herein the term "halogen" means fluoro, chloro, bromo or iodo
- 12. A compound according to claim 1 wherein the derivative of formula I having asymmetric carbon atoms represents both R and S diastereoisomers.
- 13. A compound according to claim 1 wherein the derivative of formula I having double bonds represents both E and Z geometrical isomers.
- 14. A compound according to claim 1 wherein pharmaceutically acceptable salts of the compounds of formula (I) are selected from sodium, potassium, magnesium or calcium salt of carboxylic group and hydrogen chloride, tartaric acid, succinic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid salt of amino group.
- 15. A pharmaceutical composition containing a compound as claimed in any of the preceding claims and a pharmaceutically acceptable carrier.
- 16. The use of a compound as claimed in any of claims 1 to 14 in the preparation of a composition for inhibiting cysteine protease activity particularly cathepsins in the body of a mammal suffering a disease mediated by such activity.
- 17. A method of treatment of an animal suffering from a disease mediated by cysteine protease activity, which method comprises administering to the mammal a sufficient amount of a compound as claimed in any of claims 1 to 14 to inhibit such activity.
- 18. The use as claimed in claim 16 or a method as claimed in claim 17 wherein the disease is muscular dystrophy, osteoporosis, tumour metastasis, rheumatoid arthritis, neuronal or cardiac ischaemia, allergic immune response, and protozoal or bacterial diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24136000P | 2000-10-19 | 2000-10-19 | |
| US60241360 | 2000-10-19 | ||
| PCT/IB2001/000707 WO2002032879A1 (en) | 2000-10-19 | 2001-04-30 | Dihydropyrimidine derivatives as cysteine protease inhibitors |
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| Publication Number | Publication Date |
|---|---|
| AU2001250570A1 true AU2001250570A1 (en) | 2002-04-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001250570A Abandoned AU2001250570A1 (en) | 2000-10-19 | 2001-04-30 | Dihydropyrimidine derivatives as cysteine protease inhibitors |
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|---|---|
| US (1) | US20040024000A1 (en) |
| EP (1) | EP1326848A1 (en) |
| JP (1) | JP2004511549A (en) |
| AU (1) | AU2001250570A1 (en) |
| CA (1) | CA2426271A1 (en) |
| WO (1) | WO2002032879A1 (en) |
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| SE0201976D0 (en) | 2002-06-24 | 2002-06-24 | Astrazeneca Ab | Novel compounds |
| SE0201980D0 (en) | 2002-06-24 | 2002-06-24 | Astrazeneca Ab | Novel compounds |
| NZ538961A (en) | 2002-09-24 | 2008-02-29 | Novartis Ag | Sphingosine-1-phosphate receptor agonists in the treatment of demyelinating disorders |
| US8012950B2 (en) * | 2003-08-29 | 2011-09-06 | Wisconsin Alumni Research Foundation | Method to diagnose and treat degenerative joint disease |
| JP5587790B2 (en) | 2008-01-09 | 2014-09-10 | アミュラ セラピューティクス リミティド | Compound |
| BRPI0914139A2 (en) | 2008-06-20 | 2015-10-20 | Novartis Ag | Pediatric compositions for the treatment of multiple sclerosis |
| EA023259B1 (en) | 2011-01-04 | 2016-05-31 | Новартис Аг | Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) |
| WO2014002051A2 (en) | 2012-06-28 | 2014-01-03 | Novartis Ag | Complement pathway modulators and uses thereof |
| US9388199B2 (en) | 2012-06-28 | 2016-07-12 | Novartis Ag | Pyrrolidine derivatives and their use as complement pathway modulators |
| WO2014002054A1 (en) | 2012-06-28 | 2014-01-03 | Novartis Ag | Pyrrolidine derivatives and their use as complement pathway modulators |
| JP6154897B2 (en) | 2012-06-28 | 2017-06-28 | ノバルティス アーゲー | Pyrrolidine derivatives and their use as complement pathway regulators |
| EP2867227B1 (en) | 2012-06-28 | 2018-11-21 | Novartis AG | Complement pathway modulators and uses thereof |
| EA201590200A1 (en) | 2012-07-12 | 2015-08-31 | Новартис Аг | MODULATORS OF THE COMPLEMENT ACTIVATION WAY AND THEIR APPLICATION |
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| US3853845A (en) * | 1971-08-18 | 1974-12-10 | Icn Pharmaceuticals | 5-n-aminoacyl-5-aminouridines |
| US5916887A (en) * | 1996-09-23 | 1999-06-29 | National Research Council Of Canada | 4-substituted-3-(2-amino-2-cycloalkyl methyl)-acetamido azetidin-2-one derivatives as cysteine proteinase regulators |
| AR013079A1 (en) * | 1997-05-06 | 2000-12-13 | Smithkline Beecham Corp | SUBSTITUTED DERIVATIVES OF TETRAHIDROFURANO-3-ONAS, TETRAHIDROPIRANO-3- ONAS AND TETRAHIDROTIOFEN-3-ONAS, A PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION OF A MEDICINAL PRODUCT USEFUL AS INTERMEDIATE PROTEIN INHIBITORS |
| GB9907683D0 (en) * | 1999-04-06 | 1999-05-26 | Synphar Lab Inc | Substituted azetidin-2-ones as cysteine protease inhibitors |
| GB9917909D0 (en) * | 1999-07-31 | 1999-09-29 | Synphar Lab Inc | Cysteine protease inhibitors |
| JP2001139534A (en) * | 1999-11-16 | 2001-05-22 | Yoshimitsu Nagao | Valine derivative and its use |
-
2001
- 2001-04-30 AU AU2001250570A patent/AU2001250570A1/en not_active Abandoned
- 2001-04-30 WO PCT/IB2001/000707 patent/WO2002032879A1/en not_active Ceased
- 2001-04-30 US US10/398,938 patent/US20040024000A1/en not_active Abandoned
- 2001-04-30 EP EP01923889A patent/EP1326848A1/en not_active Withdrawn
- 2001-04-30 CA CA002426271A patent/CA2426271A1/en not_active Abandoned
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| CA2426271A1 (en) | 2002-04-25 |
| US20040024000A1 (en) | 2004-02-05 |
| EP1326848A1 (en) | 2003-07-16 |
| WO2002032879A1 (en) | 2002-04-25 |
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