SK14192000A3 - Dihydro-benzo(1,4)oxazíny a tetrahydrochinoxalíny, ich použitie a farmaceutický prostriedok obsahujúci tieto zlúčeniny - Google Patents

Dihydro-benzo(1,4)oxazíny a tetrahydrochinoxalíny, ich použitie a farmaceutický prostriedok obsahujúci tieto zlúčeniny Download PDF

Info

Publication number: SK14192000A3
Authority: SK; Slovakia
Prior art keywords: group; alkyl; substituted; optionally substituted; compound
Prior art date: 1998-12-23

Application number

SK1419-2000A

Other languages

English (en)

Slovak (sk)

Inventor

Jean-Dominique Bourzat

Alain Commercon

Bruno Jacques Christophe FILOCHE

Neil Harris

Thomas David Pallin

Keith Alfred James Stuttle

Original Assignee

Aventis Pharma Limited

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.)

1998-12-23

Filing date

1999-12-23

Publication date

2001-07-10

1998-12-23 Priority claimed from GBGB9828417.7A external-priority patent/GB9828417D0/en

1999-12-23 Application filed by Aventis Pharma Limited filed Critical Aventis Pharma Limited

2001-07-10 Publication of SK14192000A3 publication Critical patent/SK14192000A3/sk

Links

HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical class C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 title description 2
150000004893 oxazines Chemical class 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 468
-1 imino, oxo, thioxo Chemical group 0.000 claims abstract description 322
125000000217 alkyl group Chemical group 0.000 claims abstract description 264
125000003118 aryl group Chemical group 0.000 claims abstract description 117
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 112
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 102
239000000651 prodrug Substances 0.000 claims abstract description 84
229940002612 prodrug Drugs 0.000 claims abstract description 84
150000003839 salts Chemical class 0.000 claims abstract description 84
150000001204 N-oxides Chemical class 0.000 claims abstract description 82
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 72
239000001257 hydrogen Substances 0.000 claims abstract description 63
125000002947 alkylene group Chemical group 0.000 claims abstract description 60
230000002378 acidificating effect Effects 0.000 claims abstract description 48
239000012453 solvate Substances 0.000 claims abstract description 45
239000002253 acid Chemical group 0.000 claims abstract description 44
125000003545 alkoxy group Chemical group 0.000 claims abstract description 37
229910052736 halogen Inorganic materials 0.000 claims abstract description 33
150000002367 halogens Chemical class 0.000 claims abstract description 31
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 29
125000004450 alkenylene group Chemical group 0.000 claims abstract description 18
125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 17
125000004419 alkynylene group Chemical group 0.000 claims abstract description 16
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 13
125000002993 cycloalkylene group Chemical group 0.000 claims abstract description 12
125000005724 cycloalkenylene group Chemical group 0.000 claims abstract description 10
125000000524 functional group Chemical group 0.000 claims abstract description 10
125000006588 heterocycloalkylene group Chemical group 0.000 claims abstract description 10
125000004043 oxo group Chemical group O=* 0.000 claims abstract description 9
125000000732 arylene group Chemical group 0.000 claims abstract description 7
150000002431 hydrogen Chemical class 0.000 claims abstract 12
125000004432 carbon atom Chemical group C* 0.000 claims description 93
229910005965 SO 2 Inorganic materials 0.000 claims description 86
238000000034 method Methods 0.000 claims description 73
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 61
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 61
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
239000000203 mixture Substances 0.000 claims description 52
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 43
125000001424 substituent group Chemical group 0.000 claims description 40
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 38
229910052760 oxygen Inorganic materials 0.000 claims description 37
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 36
125000000753 cycloalkyl group Chemical group 0.000 claims description 33
229910052799 carbon Inorganic materials 0.000 claims description 29
150000004677 hydrates Chemical class 0.000 claims description 25
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 24
125000003342 alkenyl group Chemical group 0.000 claims description 22
229910052801 chlorine Inorganic materials 0.000 claims description 21
125000003107 substituted aryl group Chemical group 0.000 claims description 21
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
125000001309 chloro group Chemical group Cl* 0.000 claims description 19
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
239000001301 oxygen Substances 0.000 claims description 19
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 16
229910052717 sulfur Inorganic materials 0.000 claims description 16
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
238000011282 treatment Methods 0.000 claims description 15
125000000304 alkynyl group Chemical group 0.000 claims description 14
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 13
239000005977 Ethylene Substances 0.000 claims description 13
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
125000004414 alkyl thio group Chemical group 0.000 claims description 13
229910052757 nitrogen Inorganic materials 0.000 claims description 13
125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 11
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
125000004076 pyridyl group Chemical group 0.000 claims description 11
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
230000021164 cell adhesion Effects 0.000 claims description 10
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 9
125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 9
239000003112 inhibitor Substances 0.000 claims description 9
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
125000005156 substituted alkylene group Chemical group 0.000 claims description 9
125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
201000010099 disease Diseases 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 8
125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 8
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
150000001413 amino acids Chemical group 0.000 claims description 7
125000004104 aryloxy group Chemical group 0.000 claims description 7
229940079593 drug Drugs 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 7
230000001404 mediated effect Effects 0.000 claims description 7
125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
125000005018 aryl alkenyl group Chemical group 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 6
150000001721 carbon Chemical group 0.000 claims description 6
CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 6
125000004122 cyclic group Chemical group 0.000 claims description 6
125000000623 heterocyclic group Chemical group 0.000 claims description 6
125000000842 isoxazolyl group Chemical group 0.000 claims description 6
125000005650 substituted phenylene group Chemical group 0.000 claims description 6
125000000335 thiazolyl group Chemical group 0.000 claims description 6
125000001425 triazolyl group Chemical group 0.000 claims description 6
WHTCSRYJVJPELL-UHFFFAOYSA-N 3-[1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-3,4-dihydro-2h-quinoxalin-6-yl]butanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(C=C3NCC2)C(C)CC(O)=O)=CC=C1NC(=O)NC1=CC=CC=C1C WHTCSRYJVJPELL-UHFFFAOYSA-N 0.000 claims description 5
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
125000002619 bicyclic group Chemical group 0.000 claims description 5
125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 5
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 4
125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 4
RMFDRRVQFURRJY-UHFFFAOYSA-N 3-[1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-3,4-dihydro-2h-quinoxalin-6-yl]propanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(CCC(O)=O)C=C3NCC2)=CC=C1NC(=O)NC1=CC=CC=C1C RMFDRRVQFURRJY-UHFFFAOYSA-N 0.000 claims description 4
RJJFYUCWALUYHX-UHFFFAOYSA-N 3-[4-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydro-1,4-benzoxazin-7-yl]-3-(2-methylphenyl)propanoic acid Chemical compound C=1C=C(NC(=O)NC=2C(=CC=CC=2)C)C(OC)=CC=1CC(=O)N(C1=CC=2)CCOC1=CC=2C(CC(O)=O)C1=CC=CC=C1C RJJFYUCWALUYHX-UHFFFAOYSA-N 0.000 claims description 4
QPEXNWHAVZXPSX-UHFFFAOYSA-N 3-[4-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydro-1,4-benzoxazin-7-yl]-5-methylhexanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(C=C3OCC2)C(CC(C)C)CC(O)=O)=CC=C1NC(=O)NC1=CC=CC=C1C QPEXNWHAVZXPSX-UHFFFAOYSA-N 0.000 claims description 4
ZDGBRJZRAZJVFV-UHFFFAOYSA-N 3-[4-benzoyl-1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydroquinoxalin-6-yl]butanoic acid Chemical compound C=1C=C(NC(=O)NC=2C(=CC=CC=2)C)C(OC)=CC=1CC(=O)N(C1=CC=C(C=C11)C(C)CC(O)=O)CCN1C(=O)C1=CC=CC=C1 ZDGBRJZRAZJVFV-UHFFFAOYSA-N 0.000 claims description 4
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
208000006673 asthma Diseases 0.000 claims description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
125000004434 sulfur atom Chemical group 0.000 claims description 4
238000002560 therapeutic procedure Methods 0.000 claims description 4
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
KVDFGKHYSMBOQF-UHFFFAOYSA-N 3-[4-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydro-1,4-benzoxazin-7-yl]butanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(C=C3OCC2)C(C)CC(O)=O)=CC=C1NC(=O)NC1=CC=CC=C1C KVDFGKHYSMBOQF-UHFFFAOYSA-N 0.000 claims description 3
VSLZGGRNMWOBML-UHFFFAOYSA-N 3-[4-acetyl-1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydroquinoxalin-6-yl]propanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(CCC(O)=O)C=C3N(C(C)=O)CC2)=CC=C1NC(=O)NC1=CC=CC=C1C VSLZGGRNMWOBML-UHFFFAOYSA-N 0.000 claims description 3
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 3
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000004430 oxygen atom Chemical group O* 0.000 claims description 3
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
GDFDDGBASMUGEP-UHFFFAOYSA-N 3-[4-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydro-1,4-benzoxazin-7-yl]-3-phenylpropanoic acid Chemical compound C=1C=C(NC(=O)NC=2C(=CC=CC=2)C)C(OC)=CC=1CC(=O)N(C1=CC=2)CCOC1=CC=2C(CC(O)=O)C1=CC=CC=C1 GDFDDGBASMUGEP-UHFFFAOYSA-N 0.000 claims description 2
ISKPXJYUHLLVKX-UHFFFAOYSA-N 3-[4-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydro-1,4-benzoxazin-7-yl]-4-methylpentanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(C=C3OCC2)C(CC(O)=O)C(C)C)=CC=C1NC(=O)NC1=CC=CC=C1C ISKPXJYUHLLVKX-UHFFFAOYSA-N 0.000 claims description 2
LZOHEVXVSHTPMK-UHFFFAOYSA-N 3-[4-benzoyl-1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydroquinoxalin-6-yl]propanoic acid Chemical compound C=1C=C(NC(=O)NC=2C(=CC=CC=2)C)C(OC)=CC=1CC(=O)N(C1=CC=C(CCC(O)=O)C=C11)CCN1C(=O)C1=CC=CC=C1 LZOHEVXVSHTPMK-UHFFFAOYSA-N 0.000 claims description 2
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 2
208000027866 inflammatory disease Diseases 0.000 claims description 2
239000002243 precursor Substances 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims 2
XYLWSDWJYDAPRL-UHFFFAOYSA-N 2h-quinoxaline-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)CC=NC2=C1 XYLWSDWJYDAPRL-UHFFFAOYSA-N 0.000 claims 1
QUDDBXDLRYJAFV-UHFFFAOYSA-N 3-[4-[3-(dimethylamino)propanoyl]-1-[2-[3-methoxy-4-[(2-methylphenyl)carbamoylamino]phenyl]acetyl]-2,3-dihydroquinoxalin-6-yl]propanoic acid Chemical compound COC1=CC(CC(=O)N2C3=CC=C(CCC(O)=O)C=C3N(C(=O)CCN(C)C)CC2)=CC=C1NC(=O)NC1=CC=CC=C1C QUDDBXDLRYJAFV-UHFFFAOYSA-N 0.000 claims 1
125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims 1
125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
108010067306 Fibronectins Proteins 0.000 abstract description 12
102000016359 Fibronectins Human genes 0.000 abstract description 12
230000003993 interaction Effects 0.000 abstract description 10
108010008212 Integrin alpha4beta1 Proteins 0.000 abstract description 9
102100023543 Vascular cell adhesion protein 1 Human genes 0.000 abstract description 2
108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 101
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
238000006243 chemical reaction Methods 0.000 description 63
239000000243 solution Substances 0.000 description 63
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
239000011541 reaction mixture Substances 0.000 description 43
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
150000002148 esters Chemical class 0.000 description 33
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 31
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
230000008569 process Effects 0.000 description 29
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
239000002585 base Substances 0.000 description 25
210000004027 cell Anatomy 0.000 description 24
239000000460 chlorine Substances 0.000 description 23
239000007787 solid Substances 0.000 description 23
125000004494 ethyl ester group Chemical group 0.000 description 22
239000000377 silicon dioxide Substances 0.000 description 22
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
238000003756 stirring Methods 0.000 description 21
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
229910052943 magnesium sulfate Inorganic materials 0.000 description 19
235000019341 magnesium sulphate Nutrition 0.000 description 19
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 17
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 17
238000002360 preparation method Methods 0.000 description 17
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
125000006239 protecting group Chemical group 0.000 description 16
230000002829 reductive effect Effects 0.000 description 16
108010044426 integrins Proteins 0.000 description 15
102000006495 integrins Human genes 0.000 description 15
239000000047 product Substances 0.000 description 15
238000010992 reflux Methods 0.000 description 15
239000002904 solvent Substances 0.000 description 15
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
239000003921 oil Substances 0.000 description 13
235000019198 oils Nutrition 0.000 description 13
238000004587 chromatography analysis Methods 0.000 description 12
239000012442 inert solvent Substances 0.000 description 12
DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
239000012153 distilled water Substances 0.000 description 11
239000000284 extract Substances 0.000 description 11
239000006260 foam Substances 0.000 description 11
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
150000003254 radicals Chemical class 0.000 description 10
235000017557 sodium bicarbonate Nutrition 0.000 description 10
229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
238000005984 hydrogenation reaction Methods 0.000 description 9
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
241000699670 Mus sp. Species 0.000 description 8
241000700159 Rattus Species 0.000 description 8
125000001931 aliphatic group Chemical group 0.000 description 8
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
238000007796 conventional method Methods 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
239000003446 ligand Substances 0.000 description 8
239000000843 powder Substances 0.000 description 8
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
239000011737 fluorine Substances 0.000 description 7
229910052731 fluorine Inorganic materials 0.000 description 7
125000002950 monocyclic group Chemical group 0.000 description 7
125000004433 nitrogen atom Chemical group N* 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
229920006395 saturated elastomer Polymers 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
229940035024 thioglycerol Drugs 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
210000003437 trachea Anatomy 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
102000035160 transmembrane proteins Human genes 0.000 description 1
108091005703 transmembrane proteins Proteins 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
JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical class OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
KBMBVTRWEAAZEY-UHFFFAOYSA-N trisulfane Chemical class SSS KBMBVTRWEAAZEY-UHFFFAOYSA-N 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
230000002792 vascular Effects 0.000 description 1
230000006441 vascular event Effects 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
230000029663 wound healing Effects 0.000 description 1
UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
229910021511 zinc hydroxide Inorganic materials 0.000 description 1
229940007718 zinc hydroxide Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Pulmonology (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Rheumatology (AREA)
Pain & Pain Management (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

SK1419-2000A 1998-12-23 1999-12-23 Dihydro-benzo(1,4)oxazíny a tetrahydrochinoxalíny, ich použitie a farmaceutický prostriedok obsahujúci tieto zlúčeniny SK14192000A3 (sk)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GBGB9828417.7A GB9828417D0 (en)	1998-12-23	1998-12-23	Chemical compounds
US12608499P	1999-03-25	1999-03-25
PCT/GB1999/004430 WO2000039103A1 (en)	1998-12-23	1999-12-23	Dihydro-benzo(1,4)oxazines and tetrahydroquinoxalines

Publications (1)

Publication Number	Publication Date
SK14192000A3 true SK14192000A3 (sk)	2001-07-10

Family

ID=26314897

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK1419-2000A SK14192000A3 (sk)	1998-12-23	1999-12-23	Dihydro-benzo(1,4)oxazíny a tetrahydrochinoxalíny, ich použitie a farmaceutický prostriedok obsahujúci tieto zlúčeniny

Country Status (10)

Country	Link
US (1)	US6632814B1 (es)
EP (1)	EP1056728B1 (es)
AP (1)	AP2000001924A0 (es)
AU (1)	AU1881900A (es)
BG (1)	BG104786A (es)
DE (1)	DE69937603T2 (es)
ES (1)	ES2297943T3 (es)
HU (1)	HUP0200481A3 (es)
SK (1)	SK14192000A3 (es)
WO (1)	WO2000039103A1 (es)

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ATE263162T1 (de)	1999-05-05	2004-04-15	Aventis Pharma Ltd	Harnstoffderivate und ihr gebrauch als zell adhesion modulatoren
US6750215B2 (en)	2001-08-08	2004-06-15	Pharmacia & Upjohn, S.P.A.	Substituted benzoxazines as integrin antagonists
US6794385B2 (en)	2001-08-08	2004-09-21	Pharmacia & Upjohn, S.P.A.	Benzoxazine derivatives useful as integrin receptor antagonists
SG189019A1 (en)	2010-10-18	2013-05-31	Cerenis Therapeutics Holding Sa	Compounds, compositions and methods useful for cholesterol mobilisation
JO3398B1 (ar)	2011-12-22	2019-10-20	Novartis Ag	مشتقات 2،3- ثانى هيدرو- بنزو[1,4] أوكسازين والمركبات المتعلقة بها كمثبطات كيناز فسفواينوسيتيد-3 (pi3k) لمعالجة على سبيل المثال التهاب المفاصل الروماتيدي
CN103275021B (zh) *	2013-05-24	2015-05-20	东北农业大学	N-二氯乙酰基-6,7-二氯-1,2,3,4-四氢喹喔啉及其制备方法
CN110627770A (zh)	2013-11-18	2019-12-31	福马疗法公司	作为bet溴域抑制剂的四氢喹啉组成物
RU2720237C2 (ru)	2013-11-18	2020-04-28	Форма Терапеутикс, Инк.	Композиции, содержащие бензопиперазин, в качестве ингибиторов бромодоменов вет

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WO1995015973A1 (en) *	1993-12-06	1995-06-15	Cytel Corporation	Cs-1 peptidomimetics, compositions and methods of using the same
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DE19647381A1 (de) *	1996-11-15	1998-05-20	Hoechst Ag	Neue Heterocyclen als Inhibitoren der Leukozytenadhäsion und VLA-4-Antagonisten
EP1025857A4 (en)	1997-10-22	2003-11-12	Eisai Co Ltd	RETINOIC ACID AGONISTS, PREVENTIVE AND THERAPEUTIC AGENTS FOR NEPHRITES
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IL136584A (en) *	1997-12-23	2005-03-20	Aventis Pharma Ltd	SUBSTITUTED beta-ALANINES, PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AND USES THEREOF
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1999
- 1999-12-23 ES ES99962463T patent/ES2297943T3/es not_active Expired - Lifetime
- 1999-12-23 DE DE69937603T patent/DE69937603T2/de not_active Expired - Lifetime
- 1999-12-23 AU AU18819/00A patent/AU1881900A/en not_active Abandoned
- 1999-12-23 WO PCT/GB1999/004430 patent/WO2000039103A1/en not_active Ceased
- 1999-12-23 HU HU0200481A patent/HUP0200481A3/hu unknown
- 1999-12-23 AP APAP/P/2000/001924A patent/AP2000001924A0/en unknown
- 1999-12-23 EP EP99962463A patent/EP1056728B1/en not_active Expired - Lifetime
- 1999-12-23 SK SK1419-2000A patent/SK14192000A3/sk unknown
2000
- 2000-08-23 US US09/644,308 patent/US6632814B1/en not_active Expired - Fee Related
- 2000-09-20 BG BG104786A patent/BG104786A/xx unknown

Also Published As

Publication number	Publication date
US6632814B1 (en)	2003-10-14
WO2000039103A1 (en)	2000-07-06
BG104786A (en)	2001-04-30
AU1881900A (en)	2000-07-31
EP1056728B1 (en)	2007-11-21
DE69937603T2 (de)	2008-10-23
HUP0200481A2 (en)	2002-06-29
EP1056728A1 (en)	2000-12-06
ES2297943T3 (es)	2008-05-01
AP2000001924A0 (en)	2000-09-30
WO2000039103B1 (en)	2000-09-28
HUP0200481A3 (en)	2002-12-28
DE69937603D1 (de)	2008-01-03

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