BG103586A - Сулфамидни металопротеазни инхибитори - Google Patents

Сулфамидни металопротеазни инхибитори Download PDF

Info

Publication number: BG103586A
Authority: BG; Bulgaria
Prior art keywords: alkyl; hydrogen; aryl; compound according; aralkyl
Prior art date: 1997-01-23

Application number

BG103586A

Other languages

Bulgarian (bg)

English (en)

Inventor

Chris Broka

Jeffrey Campbell

Arlindo Castelhano

Jian Chen

Robert HENDRICKS

Michael Melnick

Keith Walker

Original Assignee

F. Hoffmann- La Roche Ag

Agouron Pharmaceuticals, Inc.

Priority date (The priority date 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 date listed.)

1997-01-23

Filing date

1999-07-19

Publication date

2000-03-31

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26713422&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=BG103586(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1999-07-19 Application filed by F. Hoffmann- La Roche Ag, Agouron Pharmaceuticals, Inc. filed Critical F. Hoffmann- La Roche Ag

2000-03-31 Publication of BG103586A publication Critical patent/BG103586A/bg

Links

NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title abstract description 9
239000003475 metalloproteinase inhibitor Substances 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 265
238000000034 method Methods 0.000 claims abstract description 81
238000002360 preparation method Methods 0.000 claims abstract description 17
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
-1 amino, monosubstituted amino Chemical group 0.000 claims description 923
125000000217 alkyl group Chemical group 0.000 claims description 219
229910052739 hydrogen Inorganic materials 0.000 claims description 212
239000001257 hydrogen Substances 0.000 claims description 212
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 140
125000003118 aryl group Chemical group 0.000 claims description 122
125000003710 aryl alkyl group Chemical group 0.000 claims description 119
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 110
125000001072 heteroaryl group Chemical group 0.000 claims description 105
125000000753 cycloalkyl group Chemical group 0.000 claims description 98
125000004475 heteroaralkyl group Chemical group 0.000 claims description 95
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 76
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 74
229910052757 nitrogen Inorganic materials 0.000 claims description 68
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 68
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 64
125000001188 haloalkyl group Chemical group 0.000 claims description 63
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 59
125000001424 substituent group Chemical group 0.000 claims description 50
125000004404 heteroalkyl group Chemical group 0.000 claims description 49
125000002947 alkylene group Chemical group 0.000 claims description 46
125000004433 nitrogen atom Chemical group N* 0.000 claims description 45
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
125000004429 atom Chemical group 0.000 claims description 41
125000004476 heterocycloamino group Chemical group 0.000 claims description 40
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 39
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 36
239000000203 mixture Substances 0.000 claims description 35
125000003342 alkenyl group Chemical group 0.000 claims description 34
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
125000004193 piperazinyl group Chemical group 0.000 claims description 28
125000003386 piperidinyl group Chemical group 0.000 claims description 28
125000002252 acyl group Chemical group 0.000 claims description 26
229910052799 carbon Inorganic materials 0.000 claims description 25
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 24
125000000623 heterocyclic group Chemical group 0.000 claims description 24
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 23
150000001721 carbon Chemical group 0.000 claims description 17
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical group C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 16
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 15
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 15
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
230000005764 inhibitory process Effects 0.000 claims description 15
125000003545 alkoxy group Chemical group 0.000 claims description 14
201000010099 disease Diseases 0.000 claims description 14
102000004190 Enzymes Human genes 0.000 claims description 12
108090000790 Enzymes Proteins 0.000 claims description 12
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
239000000546 pharmaceutical excipient Substances 0.000 claims description 12
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 11
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 10
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
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 10
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
BRYCUMKDWMEGMK-BYPYZUCNSA-N (S)-piperazine-2-carboxamide Chemical compound NC(=O)[C@@H]1CNCCN1 BRYCUMKDWMEGMK-BYPYZUCNSA-N 0.000 claims description 9
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 9
125000004104 aryloxy group Chemical group 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 9
125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 9
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
206010003246 arthritis Diseases 0.000 claims description 8
229940079593 drug Drugs 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 8
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 7
125000004438 haloalkoxy group Chemical group 0.000 claims description 7
201000006417 multiple sclerosis Diseases 0.000 claims description 7
206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
HXEACLLIILLPRG-RXMQYKEDSA-N D-pipecolic acid Chemical compound OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims description 6
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
208000001132 Osteoporosis Diseases 0.000 claims description 6
150000003857 carboxamides Chemical class 0.000 claims description 6
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims description 6
125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 5
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
230000033115 angiogenesis Effects 0.000 claims description 5
239000002585 base Substances 0.000 claims description 5
125000002837 carbocyclic group Chemical group 0.000 claims description 5
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
201000008482 osteoarthritis Diseases 0.000 claims description 5
150000004885 piperazines Chemical group 0.000 claims description 5
229940002612 prodrug Drugs 0.000 claims description 5
239000000651 prodrug Substances 0.000 claims description 5
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
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
230000002159 abnormal effect Effects 0.000 claims description 4
ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical class C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 4
208000028169 periodontal disease Diseases 0.000 claims description 4
125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 4
208000037803 restenosis Diseases 0.000 claims description 4
BMQVWLIVQKJCOL-CQSZACIVSA-N (2r)-2-[[4-(5-chloropyridin-2-yl)oxypiperidin-1-yl]sulfonylamino]-n-hydroxy-3-methylbutanamide Chemical compound C1CN(S(=O)(=O)N[C@H](C(C)C)C(=O)NO)CCC1OC1=CC=C(Cl)C=N1 BMQVWLIVQKJCOL-CQSZACIVSA-N 0.000 claims description 3
125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 3
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
239000002207 metabolite Substances 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 3
125000005505 thiomorpholino group Chemical group 0.000 claims description 3
239000008096 xylene Substances 0.000 claims description 3
QKIHQFCYDKNBDP-QGZVFWFLSA-N (2r)-4-(dimethylcarbamoyl)-1-[4-(4-fluorophenyl)piperidin-1-yl]sulfonylpiperazine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CCC(C=2C=CC(F)=CC=2)CC1 QKIHQFCYDKNBDP-QGZVFWFLSA-N 0.000 claims description 2
WSZLRMUWTDAHFS-QGZVFWFLSA-N (2r)-4-(dimethylcarbamoyl)-1-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]piperazine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CC=C(C=2C=CC(F)=CC=2)CC1 WSZLRMUWTDAHFS-QGZVFWFLSA-N 0.000 claims description 2
239000013589 supplement Substances 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 39
FUGFMGKHXKOFDJ-UHFFFAOYSA-N 2,2-dimethylthiomorpholine Chemical group CC1(C)CNCCS1 FUGFMGKHXKOFDJ-UHFFFAOYSA-N 0.000 claims 3
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 2
LIKMQTVZSHGANU-OAHLLOKOSA-N (2r)-2-[[4-(4-fluorophenyl)piperidin-1-yl]sulfonylamino]-3-methylbutanoic acid Chemical compound C1CN(S(=O)(=O)N[C@H](C(C)C)C(O)=O)CCC1C1=CC=C(F)C=C1 LIKMQTVZSHGANU-OAHLLOKOSA-N 0.000 claims 1
PMBFZMBLMABGCK-QGZVFWFLSA-N (3r)-4-[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl-3-n-hydroxy-1-n,1-n-dimethylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CCC(C=2C=CC(F)=CC=2)CC1 PMBFZMBLMABGCK-QGZVFWFLSA-N 0.000 claims 1
150000008083 1,2,3,6-tetrahydropyridines Chemical class 0.000 claims 1
HYHRHELVUQEDFD-UHFFFAOYSA-N 4-thiomorpholin-4-yloxythiomorpholine Chemical compound C1CSCCN1ON1CCSCC1 HYHRHELVUQEDFD-UHFFFAOYSA-N 0.000 claims 1
125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
125000000068 chlorophenyl group Chemical group 0.000 claims 1
KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 1
125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
239000012458 free base Substances 0.000 claims 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
229960002317 succinimide Drugs 0.000 claims 1
DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims 1
102000005741 Metalloproteases Human genes 0.000 abstract description 13
108010006035 Metalloproteases Proteins 0.000 abstract description 13
239000003112 inhibitor Substances 0.000 abstract description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 175
239000011541 reaction mixture Substances 0.000 description 97
239000000243 solution Substances 0.000 description 94
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 93
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
238000006243 chemical reaction Methods 0.000 description 63
235000019439 ethyl acetate Nutrition 0.000 description 59
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
239000007787 solid Substances 0.000 description 46
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
238000003786 synthesis reaction Methods 0.000 description 32
230000015572 biosynthetic process Effects 0.000 description 31
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
239000012267 brine Substances 0.000 description 30
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
239000000047 product Substances 0.000 description 27
108060008682 Tumor Necrosis Factor Proteins 0.000 description 23
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
229910000041 hydrogen chloride Inorganic materials 0.000 description 21
239000012044 organic layer Substances 0.000 description 21
210000004027 cell Anatomy 0.000 description 20
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
125000003884 phenylalkyl group Chemical group 0.000 description 19
102000003390 tumor necrosis factor Human genes 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
239000011159 matrix material Substances 0.000 description 17
239000000725 suspension Substances 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
239000002904 solvent Substances 0.000 description 16
238000003756 stirring Methods 0.000 description 16
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 15
230000002401 inhibitory effect Effects 0.000 description 15
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 14
125000004432 carbon atom Chemical group C* 0.000 description 14
239000003921 oil Substances 0.000 description 14
235000019198 oils Nutrition 0.000 description 14
238000000746 purification Methods 0.000 description 14
210000000845 cartilage Anatomy 0.000 description 13
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
150000003254 radicals Chemical class 0.000 description 12
125000006413 ring segment Chemical group 0.000 description 12
238000012360 testing method Methods 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
102000008186 Collagen Human genes 0.000 description 10
108010035532 Collagen Proteins 0.000 description 10
102000029816 Collagenase Human genes 0.000 description 10
108060005980 Collagenase Proteins 0.000 description 10
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
229920001436 collagen Polymers 0.000 description 10
230000000694 effects Effects 0.000 description 10
229940088598 enzyme Drugs 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
239000002609 medium Substances 0.000 description 10
239000003960 organic solvent Substances 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
BRYCUMKDWMEGMK-SCSAIBSYSA-N (R)-piperazine-2-carboxamide Chemical compound NC(=O)[C@H]1CNCCN1 BRYCUMKDWMEGMK-SCSAIBSYSA-N 0.000 description 9
239000004215 Carbon black (E152) Substances 0.000 description 9
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
230000015556 catabolic process Effects 0.000 description 9
239000012230 colorless oil Substances 0.000 description 9
229930195733 hydrocarbon Natural products 0.000 description 9
239000000463 material Substances 0.000 description 9
UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 9
229920006395 saturated elastomer Polymers 0.000 description 9
210000001519 tissue Anatomy 0.000 description 9
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
239000004615 ingredient Substances 0.000 description 8
230000004048 modification Effects 0.000 description 8
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FFJHHJHPMZWVBU-LLVKDONJSA-N methyl (2r)-2-[[4-[(4-chlorophenyl)carbamoyl]piperazin-1-yl]sulfonylamino]propanoate Chemical compound C1CN(S(=O)(=O)N[C@H](C)C(=O)OC)CCN1C(=O)NC1=CC=C(Cl)C=C1 FFJHHJHPMZWVBU-LLVKDONJSA-N 0.000 description 1
YBQBWYUONUIEOA-LJQANCHMSA-N methyl (2r)-2-[[4-[2-[(4-chlorophenyl)methylamino]-2-oxoethyl]piperidin-1-yl]sulfonylamino]-3-methylbutanoate Chemical compound C1CN(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)CCC1CC(=O)NCC1=CC=C(Cl)C=C1 YBQBWYUONUIEOA-LJQANCHMSA-N 0.000 description 1
GKOGEYICOZZVOJ-QGZVFWFLSA-N methyl (2r)-2-[benzyl-[4-(4-chlorophenyl)piperazin-1-yl]sulfonylamino]propanoate Chemical compound C1CN(C=2C=CC(Cl)=CC=2)CCN1S(=O)(=O)N([C@H](C)C(=O)OC)CC1=CC=CC=C1 GKOGEYICOZZVOJ-QGZVFWFLSA-N 0.000 description 1
DWKPPFQULDPWHX-GSVOUGTGSA-N methyl (2r)-2-aminopropanoate Chemical compound COC(=O)[C@@H](C)N DWKPPFQULDPWHX-GSVOUGTGSA-N 0.000 description 1
LFUIOAXMANYSCA-LBPRGKRZSA-N methyl (2s)-2-(benzylamino)-3-methylbutanoate Chemical compound COC(=O)[C@H](C(C)C)NCC1=CC=CC=C1 LFUIOAXMANYSCA-LBPRGKRZSA-N 0.000 description 1
MTPXRXOMKRLUMU-UHFFFAOYSA-N methyl 1-aminocyclohexane-1-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1(N)CCCCC1 MTPXRXOMKRLUMU-UHFFFAOYSA-N 0.000 description 1
RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 description 1
125000006178 methyl benzyl group Chemical group 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
CXQTTWVBUDFUNO-UHFFFAOYSA-N methyl piperidine-2-carboxylate Chemical compound COC(=O)C1CCCCN1 CXQTTWVBUDFUNO-UHFFFAOYSA-N 0.000 description 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
230000011987 methylation Effects 0.000 description 1
238000007069 methylation reaction Methods 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000003607 modifier Substances 0.000 description 1
210000001616 monocyte Anatomy 0.000 description 1
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 1
DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
KOCUHZAYIXUHIT-CQSZACIVSA-N n-(4-chlorophenyl)-4-[[(2r)-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]sulfamoyl]piperazine-1-carboxamide Chemical compound C1CN(S(=O)(=O)N[C@H](C(C)C)C(=O)NO)CCN1C(=O)NC1=CC=C(Cl)C=C1 KOCUHZAYIXUHIT-CQSZACIVSA-N 0.000 description 1
RBMBUFMMNAPTJP-UHFFFAOYSA-N n-(dimethylamino)sulfamoyl chloride Chemical compound CN(C)NS(Cl)(=O)=O RBMBUFMMNAPTJP-UHFFFAOYSA-N 0.000 description 1
NBBNHGNCVGVVOG-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-2-piperidin-4-ylacetamide Chemical compound C1=CC(Cl)=CC=C1CNC(=O)CC1CCNCC1 NBBNHGNCVGVVOG-UHFFFAOYSA-N 0.000 description 1
YDLAQBRNNOLMIH-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]formamide Chemical group ClC1=CC=C(CNC=O)C=C1 YDLAQBRNNOLMIH-UHFFFAOYSA-N 0.000 description 1
FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
UJJUEJRWNWVHCM-UHFFFAOYSA-N n-methylsulfamoyl chloride Chemical compound CNS(Cl)(=O)=O UJJUEJRWNWVHCM-UHFFFAOYSA-N 0.000 description 1
239000002105 nanoparticle Substances 0.000 description 1
KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
ZBDXGNXNXXPKJI-UHFFFAOYSA-N o-tert-butylhydroxylamine;hydrochloride Chemical compound Cl.CC(C)(C)ON ZBDXGNXNXXPKJI-UHFFFAOYSA-N 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
229940100692 oral suspension Drugs 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
125000000962 organic group Chemical group 0.000 description 1
239000005416 organic matter Substances 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
238000006053 organic reaction Methods 0.000 description 1
230000008506 pathogenesis Effects 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
230000008447 perception Effects 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000012071 phase Substances 0.000 description 1
125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
229910052698 phosphorus Inorganic materials 0.000 description 1
239000011574 phosphorus Substances 0.000 description 1
229910000073 phosphorus hydride Inorganic materials 0.000 description 1
LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical class OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
229920000053 polysorbate 80 Polymers 0.000 description 1
229940068968 polysorbate 80 Drugs 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
108010048738 promatrilysin Proteins 0.000 description 1
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
235000004252 protein component Nutrition 0.000 description 1
230000002797 proteolythic effect Effects 0.000 description 1
125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
150000003233 pyrroles Chemical class 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
230000007017 scission Effects 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
235000012239 silicon dioxide Nutrition 0.000 description 1
235000020183 skimmed milk Nutrition 0.000 description 1
239000000779 smoke Substances 0.000 description 1
150000003385 sodium Chemical class 0.000 description 1
239000007974 sodium acetate buffer Substances 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
210000004872 soft tissue Anatomy 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
230000004936 stimulating effect Effects 0.000 description 1
229910052682 stishovite Inorganic materials 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
125000000547 substituted alkyl group Chemical group 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
229940124530 sulfonamide Drugs 0.000 description 1
150000003456 sulfonamides Chemical class 0.000 description 1
230000006103 sulfonylation Effects 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
210000002435 tendon Anatomy 0.000 description 1
MGIXROGOPVWNSH-LJQANCHMSA-N tert-butyl (2r)-2-[[4-(4-chlorobenzoyl)piperidin-1-yl]sulfonyl-methylamino]-3-methylbutanoate Chemical compound C1CN(S(=O)(=O)N(C)[C@H](C(C)C)C(=O)OC(C)(C)C)CCC1C(=O)C1=CC=C(Cl)C=C1 MGIXROGOPVWNSH-LJQANCHMSA-N 0.000 description 1
QJIDTHNWWRLAGC-XMMPIXPASA-N tert-butyl (2r)-2-[[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenylpropanoate Chemical compound C([C@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)S(=O)(=O)N1CCN(CC1)C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 QJIDTHNWWRLAGC-XMMPIXPASA-N 0.000 description 1
XAVMNYFVPOIBDF-OAQYLSRUSA-N tert-butyl (3r)-3-(phenylmethoxycarbamoyl)-4-[4-(4,5,6,7-tetrafluoro-1h-indol-3-yl)piperidin-1-yl]sulfonylpiperazine-1-carboxylate Chemical compound O=C([C@@H]1N(CCN(C1)C(=O)OC(C)(C)C)S(=O)(=O)N1CCC(CC1)C=1C2=C(F)C(F)=C(F)C(F)=C2NC=1)NOCC1=CC=CC=C1 XAVMNYFVPOIBDF-OAQYLSRUSA-N 0.000 description 1
KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 1
ATPCDGFSUJMMNO-SNVBAGLBSA-N tert-butyl 4-[[(2r)-1-methoxy-1-oxopropan-2-yl]sulfamoyl]piperazine-1-carboxylate Chemical compound COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1 ATPCDGFSUJMMNO-SNVBAGLBSA-N 0.000 description 1
PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
238000000844 transformation Methods 0.000 description 1
FBQURXLBJJNDBX-UHFFFAOYSA-N tri(propan-2-yl)-pyrrol-1-ylsilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)N1C=CC=C1 FBQURXLBJJNDBX-UHFFFAOYSA-N 0.000 description 1
229910052905 tridymite Inorganic materials 0.000 description 1
150000008648 triflates Chemical class 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
229960000281 trometamol Drugs 0.000 description 1
210000002993 trophoblast Anatomy 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
230000036269 ulceration Effects 0.000 description 1
210000004325 uterine smooth muscle cell Anatomy 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000005303 weighing Methods 0.000 description 1
AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/04—Antineoplastic agents specific for metastasis
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Physical Education & Sports Medicine (AREA)
Rheumatology (AREA)
Immunology (AREA)
Orthopedic Medicine & Surgery (AREA)
Diabetes (AREA)
Urology & Nephrology (AREA)
Hematology (AREA)
Heart & Thoracic Surgery (AREA)
Transplantation (AREA)
Pain & Pain Management (AREA)
Cardiology (AREA)
Vascular Medicine (AREA)
Oncology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Hydrogenated Pyridines (AREA)
Pyrane Compounds (AREA)
Detergent Compositions (AREA)

BG103586A 1997-01-23 1999-07-19 Сулфамидни металопротеазни инхибитори BG103586A (bg)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US3671497P	1997-01-23	1997-01-23
US6220997P	1997-10-16	1997-10-16
PCT/EP1998/000180 WO1998032748A1 (fr)	1997-01-23	1998-01-14	Inhibiteurs de sulfamide-metalloprotease

Publications (1)

Publication Number	Publication Date
BG103586A true BG103586A (bg)	2000-03-31

Family

ID=26713422

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG103586A BG103586A (bg)	1997-01-23	1999-07-19	Сулфамидни металопротеазни инхибитори

Country Status (35)

Country	Link
EP (1)	EP0958287B2 (fr)
JP (1)	JP3563411B2 (fr)
KR (1)	KR100377696B1 (fr)
CN (1)	CN1093125C (fr)
AR (1)	AR011425A1 (fr)
AT (1)	ATE223909T1 (fr)
AU (1)	AU730127B2 (fr)
BG (1)	BG103586A (fr)
BR (1)	BR9807508A (fr)
CA (1)	CA2278694C (fr)
DE (2)	DE69807845T2 (fr)
DK (1)	DK0958287T3 (fr)
EA (1)	EA002810B1 (fr)
ES (2)	ES2183331T3 (fr)
FR (1)	FR2758559A1 (fr)
GB (1)	GB2321641B (fr)
HR (1)	HRP980036A2 (fr)
HU (1)	HUP0000941A3 (fr)
ID (1)	ID22849A (fr)
IL (1)	IL130802A0 (fr)
IS (1)	IS5125A (fr)
IT (1)	IT1298163B1 (fr)
MA (1)	MA26467A1 (fr)
NO (1)	NO313635B1 (fr)
NZ (1)	NZ336625A (fr)
OA (1)	OA11078A (fr)
PA (1)	PA8445301A1 (fr)
PE (1)	PE57399A1 (fr)
PL (1)	PL334846A1 (fr)
PT (1)	PT958287E (fr)
TN (1)	TNSN98012A1 (fr)
TR (1)	TR199901765T2 (fr)
UY (1)	UY24854A1 (fr)
WO (1)	WO1998032748A1 (fr)
YU (1)	YU34599A (fr)

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CN101084211A (zh) *	2004-09-20	2007-12-05	泽农医药公司	杂环衍生物及其作为治疗剂的用途
DE102004060229A1 (de) *	2004-12-15	2006-06-29	Sanofi-Aventis Deutschland Gmbh	Neue zyklische Harnstoffe als Inhibitoren von Metallproteasen
WO2007102392A1 (fr) *	2006-03-03	2007-09-13	Shionogi & Co., Ltd.	Inhibiteur selectif de mmp-13
WO2008053913A1 (fr) *	2006-11-02	2008-05-08	Shionogi & Co., Ltd.	Dérivé de sulfonylurée capable d'inhiber sélectivement mmp-13
WO2008147764A1 (fr) *	2007-05-23	2008-12-04	Array Biopharma, Inc.	Inhibiteurs des métalloprotéases matricielles (mmp) et leurs méthodes d'utilisation
CN101821233B (zh) *	2007-10-12	2016-06-29	巴斯夫欧洲公司	生产磺酸二酰胺的方法
FR2947268B1 (fr)	2009-06-30	2011-08-26	Galderma Res & Dev	Nouveaux composes benzene-sulfonamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
ES2736200T3 (es) *	2009-07-22	2019-12-26	Univ Illinois	Inhibidores de HDAC y métodos terapéuticos que utilizan los mismos
CA2836487A1 (fr) *	2011-06-09	2012-12-13	Rhizen Pharmaceuticals Sa	Nouveaux composes utilises comme modulateurs de gpr-119
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1998
- 1998-01-14 PL PL98334846A patent/PL334846A1/xx unknown
- 1998-01-14 ID IDW990716A patent/ID22849A/id unknown
- 1998-01-14 TR TR1999/01765T patent/TR199901765T2/xx unknown
- 1998-01-14 AU AU66140/98A patent/AU730127B2/en not_active Ceased
- 1998-01-14 AT AT98907943T patent/ATE223909T1/de not_active IP Right Cessation
- 1998-01-14 YU YU34599A patent/YU34599A/sh unknown
- 1998-01-14 WO PCT/EP1998/000180 patent/WO1998032748A1/fr not_active Ceased
- 1998-01-14 EA EA199900643A patent/EA002810B1/ru not_active IP Right Cessation
- 1998-01-14 DE DE69807845T patent/DE69807845T2/de not_active Expired - Lifetime
- 1998-01-14 IL IL13080298A patent/IL130802A0/xx unknown
- 1998-01-14 BR BR9807508A patent/BR9807508A/pt not_active Application Discontinuation
- 1998-01-14 KR KR10-1999-7006632A patent/KR100377696B1/ko not_active Expired - Fee Related
- 1998-01-14 ES ES98907943T patent/ES2183331T3/es not_active Expired - Lifetime
- 1998-01-14 NZ NZ336625A patent/NZ336625A/en unknown
- 1998-01-14 PT PT98907943T patent/PT958287E/pt unknown
- 1998-01-14 JP JP53153798A patent/JP3563411B2/ja not_active Expired - Fee Related
- 1998-01-14 EP EP98907943A patent/EP0958287B2/fr not_active Expired - Lifetime
- 1998-01-14 HU HU0000941A patent/HUP0000941A3/hu unknown
- 1998-01-14 CA CA002278694A patent/CA2278694C/fr not_active Expired - Fee Related
- 1998-01-14 DK DK98907943T patent/DK0958287T3/da active
- 1998-01-14 CN CN98803233A patent/CN1093125C/zh not_active Expired - Fee Related
- 1998-01-20 PE PE1998000043A patent/PE57399A1/es not_active Application Discontinuation
- 1998-01-20 IT IT98MI000091A patent/IT1298163B1/it active IP Right Grant
- 1998-01-20 AR ARP980100227A patent/AR011425A1/es active IP Right Grant
- 1998-01-21 MA MA24932A patent/MA26467A1/fr unknown
- 1998-01-21 PA PA19988445301A patent/PA8445301A1/es unknown
- 1998-01-21 FR FR9800601A patent/FR2758559A1/fr not_active Withdrawn
- 1998-01-22 ES ES009800113A patent/ES2136037B1/es not_active Expired - Fee Related
- 1998-01-22 GB GB9801393A patent/GB2321641B/en not_active Expired - Fee Related
- 1998-01-22 UY UY24854A patent/UY24854A1/es not_active IP Right Cessation
- 1998-01-22 TN TNTNSN98012A patent/TNSN98012A1/fr unknown
- 1998-01-22 DE DE19802350A patent/DE19802350A1/de not_active Withdrawn
- 1998-01-23 HR HR60/062,209A patent/HRP980036A2/hr not_active Application Discontinuation
1999
- 1999-07-19 BG BG103586A patent/BG103586A/bg unknown
- 1999-07-22 IS IS5125A patent/IS5125A/is unknown
- 1999-07-22 NO NO19993587A patent/NO313635B1/no not_active IP Right Cessation
- 1999-07-23 OA OA9900162A patent/OA11078A/en unknown

Also Published As

Publication number	Publication date
AR011425A1 (es)	2000-08-16
GB2321641A (en)	1998-08-05
AU6614098A (en)	1998-08-18
JP3563411B2 (ja)	2004-09-08
DE69807845D1 (de)	2002-10-17
EA002810B1 (ru)	2002-10-31
DE69807845T2 (de)	2003-06-05
ES2136037B1 (es)	2000-11-16
CA2278694C (fr)	2006-09-26
KR20000070398A (ko)	2000-11-25
UY24854A1 (es)	2000-12-29
HRP980036A2 (en)	1998-12-31
OA11078A (en)	2003-03-17
PA8445301A1 (es)	2001-07-31
NO993587L (no)	1999-09-22
JP2001523222A (ja)	2001-11-20
EA199900643A1 (ru)	2000-04-24
KR100377696B1 (ko)	2003-03-29
EP0958287B2 (fr)	2008-04-09
WO1998032748A1 (fr)	1998-07-30
ES2183331T3 (es)	2003-03-16
PL334846A1 (en)	2000-03-27
MA26467A1 (fr)	2004-12-20
BR9807508A (pt)	2000-03-21
EP0958287A1 (fr)	1999-11-24
DE19802350A1 (de)	1998-07-30
TR199901765T2 (xx)	1999-10-21
EP0958287B1 (fr)	2002-09-11
CN1250445A (zh)	2000-04-12
ES2136037A1 (es)	1999-11-01
ITMI980091A1 (it)	1999-07-20
HUP0000941A2 (hu)	2001-04-28
AU730127B2 (en)	2001-02-22
NO313635B1 (no)	2002-11-04
GB2321641B (en)	2001-04-04
PE57399A1 (es)	1999-06-25
IL130802A0 (en)	2001-01-28
CN1093125C (zh)	2002-10-23
CA2278694A1 (fr)	1998-07-30
NZ336625A (en)	2001-04-27
HUP0000941A3 (en)	2002-06-28
YU34599A (sh)	2002-03-18
IS5125A (is)	1999-07-22
ATE223909T1 (de)	2002-09-15
GB9801393D0 (en)	1998-03-18
NO993587D0 (no)	1999-07-22
ID22849A (id)	1999-12-09
TNSN98012A1 (fr)	2005-03-15
DK0958287T3 (da)	2003-01-20
PT958287E (pt)	2002-12-31
FR2758559A1 (fr)	1998-07-24
IT1298163B1 (it)	1999-12-20

Publication	Publication Date	Title
US6143744A (en)	2000-11-07	Sulfamide-metalloprotease inhibitors
EP0958287B1 (fr)	2002-09-11	Inhibiteurs de sulfamide-metalloprotease
US6376506B1 (en)	2002-04-23	Sulfamide-metalloprotease inhibitors
US6130220A (en)	2000-10-10	Sulfamide-metalloprotease inhibitors
CN101528681B (zh)	2013-01-30	作为缓激肽拮抗剂的磺酰胺衍生物
EP1140903B1 (fr)	2004-08-04	Amides aromatiques
SK2702001A3 (en)	2001-08-06	ARYLPIPERAZINES AND THEIR USE AS METALLOPROTEINASE INHIBITINGì (54) AGENTS (MMP)
CZ374096A3 (cs)	1998-01-14	Matricové metalloproteasové inhibitory
WO2008068540A1 (fr)	2008-06-12	Nouveaux dérivés de benzamide utilisés comme antagonistes de la bradykinine
US20100298299A1 (en)	2010-11-25	non-peptide derivatives as bradykinin b1 antagonists
US8034827B2 (en)	2011-10-11	Phenanthridine derivatives as bradykinin antagonists
CZ255199A3 (cs)	2000-03-15	Derivát sulfamidu inhibující metaloproteázu, způsob jeho přípravy a jeho použití pro výrobu léčiv
HK1024915A (en)	2000-10-27	Sulfamide-metalloprotease inhibitors
HK1128157A (en)	2009-10-16	New phenanthridine derivatives as bradykinin antagonists