HRP970031A2 - Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation - Google Patents

Info

Publication number

HRP970031A2

HRP970031A2 HR96/019,328A HRP970031A HRP970031A2 HR P970031 A2 HRP970031 A2 HR P970031A2 HR P970031 A HRP970031 A HR P970031A HR P970031 A2 HRP970031 A2 HR P970031A2

Authority

HR

Croatia

Prior art keywords

group

salt

formula

compound

image

Prior art date

1995-12-08

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• 238000000034 method Methods 0.000 title claims description 104
• 238000002360 preparation method Methods 0.000 title description 21
• 239000000543 intermediate Substances 0.000 title description 18
• 239000008194 pharmaceutical composition Substances 0.000 title description 9
• 239000003475 metalloproteinase inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 356
• 150000003839 salts Chemical class 0.000 claims description 333
• 125000003118 aryl group Chemical group 0.000 claims description 141
• 125000000217 alkyl group Chemical group 0.000 claims description 127
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 100
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 99
• 125000001072 heteroaryl group Chemical group 0.000 claims description 93
• 238000006243 chemical reaction Methods 0.000 claims description 89
• 239000000203 mixture Substances 0.000 claims description 77
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• 229910052760 oxygen Inorganic materials 0.000 claims description 48
• 229940002612 prodrug Drugs 0.000 claims description 43
• 239000000651 prodrug Substances 0.000 claims description 43
• 229910052799 carbon Inorganic materials 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 41
• 230000015572 biosynthetic process Effects 0.000 claims description 40
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
• 229910052717 sulfur Inorganic materials 0.000 claims description 39
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 38
• 125000001424 substituent group Chemical group 0.000 claims description 36
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 230000002349 favourable effect Effects 0.000 claims description 28
• 229910052739 hydrogen Inorganic materials 0.000 claims description 22
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 21
• 125000002950 monocyclic group Chemical group 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
• 102000005741 Metalloproteases Human genes 0.000 claims description 16
• 108010006035 Metalloproteases Proteins 0.000 claims description 16
• 206010028980 Neoplasm Diseases 0.000 claims description 16
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
• 239000000460 chlorine Substances 0.000 claims description 14
• 230000000694 effects Effects 0.000 claims description 14
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 12
• 229910052710 silicon Inorganic materials 0.000 claims description 12
• 125000006413 ring segment Chemical group 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 5
• 206010003246 arthritis Diseases 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical group 0.000 claims description 5
• 239000003981 vehicle Substances 0.000 claims description 5
• 206010027476 Metastases Diseases 0.000 claims description 4
• 230000009471 action Effects 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 125000004432 carbon atom Chemical group C* 0.000 claims description 4
• 150000005690 diesters Chemical class 0.000 claims description 4
• 230000009401 metastasis Effects 0.000 claims description 4
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• 238000005859 coupling reaction Methods 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 2
• 206010010904 Convulsion Diseases 0.000 claims 2
• 125000000962 organic group Chemical group 0.000 claims 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• 230000008878 coupling Effects 0.000 claims 1
• 238000010168 coupling process Methods 0.000 claims 1
• 239000011737 fluorine Substances 0.000 claims 1
• 229910052740 iodine Inorganic materials 0.000 claims 1
• 239000012453 solvate Substances 0.000 claims 1
• 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 330
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
• 239000000243 solution Substances 0.000 description 156
• 235000002639 sodium chloride Nutrition 0.000 description 145
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 140
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• 239000007787 solid Substances 0.000 description 82
• 239000012071 phase Substances 0.000 description 81
• 235000019439 ethyl acetate Nutrition 0.000 description 77
• -1 tetralin-1-yl Chemical group 0.000 description 71
• 239000002904 solvent Substances 0.000 description 61
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
• 239000012044 organic layer Substances 0.000 description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 56
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
• 229910052938 sodium sulfate Inorganic materials 0.000 description 49
• 235000011152 sodium sulphate Nutrition 0.000 description 49
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
• 238000002844 melting Methods 0.000 description 36
• 230000008018 melting Effects 0.000 description 36
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 35
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
• 239000012267 brine Substances 0.000 description 31
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
• 239000011541 reaction mixture Substances 0.000 description 30
• 238000001914 filtration Methods 0.000 description 29
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
• 238000005160 1H NMR spectroscopy Methods 0.000 description 27
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 26
• 150000003254 radicals Chemical class 0.000 description 25
• 239000002253 acid Substances 0.000 description 24
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
• 239000010410 layer Substances 0.000 description 23
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
• 239000002585 base Substances 0.000 description 22
• 235000019441 ethanol Nutrition 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 20
• 238000004587 chromatography analysis Methods 0.000 description 19
• JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 19
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 19
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 19
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
• NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 18
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 18
• 239000000047 product Substances 0.000 description 18
• 102000002274 Matrix Metalloproteinases Human genes 0.000 description 17
• 108010000684 Matrix Metalloproteinases Proteins 0.000 description 17
• 150000002148 esters Chemical class 0.000 description 17
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 17
• 239000002244 precipitate Substances 0.000 description 16
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 14
• IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
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• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
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• MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 7
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