AP1368A - Metalloproteinase inhibitors, pharmaceutical compositisions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparations. - Google Patents

Info

Publication number

AP1368A

AP1368A APAP/P/1998/001284A AP9801284A AP1368A AP 1368 A AP1368 A AP 1368A AP 9801284 A AP9801284 A AP 9801284A AP 1368 A AP1368 A AP 1368A

Authority

AP

ARIPO

Prior art keywords

group

formula

salt

compound

solvate

Prior art date

1995-12-08

Links

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• 238000000034 method Methods 0.000 title claims abstract description 79
• 239000000543 intermediate Substances 0.000 title abstract description 17
• 238000002360 preparation method Methods 0.000 title description 13
• 239000003475 metalloproteinase inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 349
• 150000003839 salts Chemical class 0.000 claims abstract description 151
• 239000012453 solvate Substances 0.000 claims abstract description 115
• 125000003118 aryl group Chemical group 0.000 claims abstract description 80
• 239000000651 prodrug Substances 0.000 claims abstract description 49
• 229940002612 prodrug Drugs 0.000 claims abstract description 49
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 44
• 125000001424 substituent group Chemical group 0.000 claims abstract description 37
• 230000000694 effects Effects 0.000 claims abstract description 17
• 102000005741 Metalloproteases Human genes 0.000 claims abstract description 15
• 108010006035 Metalloproteases Proteins 0.000 claims abstract description 15
• 125000006413 ring segment Chemical group 0.000 claims abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
• -1 4-(4-chlorophenoxy)benzenesulfonyl Chemical group 0.000 claims description 90
• 125000000217 alkyl group Chemical group 0.000 claims description 87
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 32
• 229910052717 sulfur Inorganic materials 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 229910052739 hydrogen Inorganic materials 0.000 claims description 28
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
• 239000001257 hydrogen Substances 0.000 claims description 26
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 23
• 125000002950 monocyclic group Chemical group 0.000 claims description 20
• 229910052760 oxygen Inorganic materials 0.000 claims description 20
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
• 239000000460 chlorine Substances 0.000 claims description 13
• 230000015572 biosynthetic process Effects 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
• 238000003786 synthesis reaction Methods 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• 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 7
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 229910052710 silicon Inorganic materials 0.000 claims description 6
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 5
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
• 206010003246 arthritis Diseases 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 230000001404 mediated effect Effects 0.000 claims description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
• BRYCUMKDWMEGMK-UHFFFAOYSA-N piperazine-2-carboxamide Chemical compound NC(=O)C1CNCCN1 BRYCUMKDWMEGMK-UHFFFAOYSA-N 0.000 claims description 5
• 230000004614 tumor growth Effects 0.000 claims description 5
• 239000003981 vehicle Substances 0.000 claims description 5
• 206010027476 Metastases Diseases 0.000 claims description 4
• 150000001721 carbon Chemical group 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
• 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
• 230000009401 metastasis Effects 0.000 claims description 3
• AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
• 230000009400 cancer invasion Effects 0.000 claims 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 1
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 1
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• 101000986989 Naja kaouthia Acidic phospholipase A2 CM-II Proteins 0.000 claims 1
• 229910006069 SO3H Inorganic materials 0.000 claims 1
• IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 claims 1
• 239000011737 fluorine Substances 0.000 claims 1
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
• 230000002401 inhibitory effect Effects 0.000 abstract description 6
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 230
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 199
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 160
• 239000000243 solution Substances 0.000 description 148
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
• 238000006243 chemical reaction Methods 0.000 description 85
• 239000007787 solid Substances 0.000 description 74
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
• 229910001868 water Inorganic materials 0.000 description 71
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• 239000000203 mixture Substances 0.000 description 65
• 239000002904 solvent Substances 0.000 description 65
• 239000002253 acid Substances 0.000 description 64
• 235000019439 ethyl acetate Nutrition 0.000 description 62
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 54
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
• 239000012044 organic layer Substances 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 35
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• 229910052938 sodium sulfate Inorganic materials 0.000 description 35
• 239000012267 brine Substances 0.000 description 34
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
• 238000011282 treatment Methods 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
• 235000011152 sodium sulphate Nutrition 0.000 description 31
• 239000002585 base Substances 0.000 description 30
• 238000001914 filtration Methods 0.000 description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
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• 150000002148 esters Chemical class 0.000 description 25
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• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 23
• 150000003254 radicals Chemical class 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
• 238000004587 chromatography analysis Methods 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• 235000019441 ethanol Nutrition 0.000 description 21
• 239000010410 layer Substances 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 239000000725 suspension Substances 0.000 description 19
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 18
• NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 18
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
• JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 18
• 239000011734 sodium Substances 0.000 description 18
• 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 description 17
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 16
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• 125000006239 protecting group Chemical group 0.000 description 16
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• 125000003545 alkoxy group Chemical group 0.000 description 6
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• 150000007529 inorganic bases Chemical class 0.000 description 6
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