CA2274063C - Composes pyrimidines substitues et leur utilisation - Google Patents

Composes pyrimidines substitues et leur utilisation Download PDF

Info

Publication number: CA2274063C
Authority: CA; Canada
Prior art keywords: amino; radicals; alkyl; alkoxy; radical
Prior art date: 1996-12-05
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA002274063A

Other languages

English (en)

Other versions

CA2274063A1 (fr

Inventor

Ulrike D. Spohr

Michael J. Malone

Nathan B. Mantlo

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Amgen Inc

Original Assignee

Amgen 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.)

1996-12-05

Filing date

1997-12-04

Publication date

2007-09-04

1997-12-04 Application filed by Amgen Inc filed Critical Amgen Inc

1997-12-04 Priority claimed from PCT/US1997/022390 external-priority patent/WO1998024782A2/fr

1998-06-11 Publication of CA2274063A1 publication Critical patent/CA2274063A1/fr

2007-09-04 Application granted granted Critical

2007-09-04 Publication of CA2274063C publication Critical patent/CA2274063C/fr

2017-12-04 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

150000003230 pyrimidines Chemical class 0.000 title abstract description 14
150000001875 compounds Chemical class 0.000 claims abstract description 147
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
108090001007 Interleukin-8 Proteins 0.000 claims abstract description 25
108090001005 Interleukin-6 Proteins 0.000 claims abstract description 22
238000011282 treatment Methods 0.000 claims abstract description 22
150000003839 salts Chemical class 0.000 claims abstract description 20
238000011321 prophylaxis Methods 0.000 claims abstract description 17
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
206010061218 Inflammation Diseases 0.000 claims abstract description 10
230000004054 inflammatory process Effects 0.000 claims abstract description 10
-1 heterocyclyl radicals Chemical class 0.000 claims description 1095
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 370
150000003254 radicals Chemical class 0.000 claims description 364
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 253
125000004414 alkyl thio group Chemical group 0.000 claims description 171
125000003118 aryl group Chemical group 0.000 claims description 154
125000003282 alkyl amino group Chemical group 0.000 claims description 143
125000005236 alkanoylamino group Chemical group 0.000 claims description 128
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 120
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 117
YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 105
125000000217 alkyl group Chemical group 0.000 claims description 95
125000003545 alkoxy group Chemical group 0.000 claims description 85
125000000623 heterocyclic group Chemical group 0.000 claims description 83
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 80
125000004093 cyano group Chemical group *C#N 0.000 claims description 78
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 76
125000001072 heteroaryl group Chemical group 0.000 claims description 67
239000000203 mixture Substances 0.000 claims description 64
125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 63
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
229910052739 hydrogen Inorganic materials 0.000 claims description 53
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 51
239000001257 hydrogen Substances 0.000 claims description 51
125000001188 haloalkyl group Chemical group 0.000 claims description 44
125000000753 cycloalkyl group Chemical group 0.000 claims description 34
BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 claims description 34
108010002352 Interleukin-1 Proteins 0.000 claims description 27
125000004663 dialkyl amino group Chemical group 0.000 claims description 27
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 24
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 23
238000004519 manufacturing process Methods 0.000 claims description 23
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
229910052717 sulfur Inorganic materials 0.000 claims description 22
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
229910052757 nitrogen Inorganic materials 0.000 claims description 18
229910052760 oxygen Inorganic materials 0.000 claims description 18
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 17
239000003814 drug Substances 0.000 claims description 16
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 15
150000005840 aryl radicals Chemical group 0.000 claims description 14
230000000694 effects Effects 0.000 claims description 14
125000002950 monocyclic group Chemical group 0.000 claims description 14
239000001301 oxygen Substances 0.000 claims description 14
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 13
125000001589 carboacyl group Chemical group 0.000 claims description 13
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
229960004666 glucagon Drugs 0.000 claims description 11
239000011593 sulfur Substances 0.000 claims description 11
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
102000051325 Glucagon Human genes 0.000 claims description 9
108060003199 Glucagon Proteins 0.000 claims description 9
230000003247 decreasing effect Effects 0.000 claims description 9
MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 9
125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 8
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 8
125000001624 naphthyl group Chemical group 0.000 claims description 8
102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims description 7
108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims description 7
125000002619 bicyclic group Chemical group 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims description 6
229910006069 SO3H Inorganic materials 0.000 claims description 6
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 6
229920006395 saturated elastomer Polymers 0.000 claims description 6
125000006598 aminocarbonylamino group Chemical group 0.000 claims description 5
239000005557 antagonist Substances 0.000 claims description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 4
108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 4
125000003107 substituted aryl group Chemical group 0.000 claims description 4
HAOYRMOYPXUUBE-UHFFFAOYSA-N 2-[(2,6-dichlorophenyl)methyl]-5-(4-fluorophenyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1CC1=C(Cl)C=CC=C1Cl HAOYRMOYPXUUBE-UHFFFAOYSA-N 0.000 claims description 3
AQASPACMJACZAD-UHFFFAOYSA-N 2-[2-(2-chlorophenyl)ethylamino]-5-(4-fluorophenyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound N=1C(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)C(O)=NC=1NCCC1=CC=CC=C1Cl AQASPACMJACZAD-UHFFFAOYSA-N 0.000 claims description 3
125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 3
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
DAMZFIYOEBDWLN-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(3-phenylpropylamino)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1NCCCC1=CC=CC=C1 DAMZFIYOEBDWLN-UHFFFAOYSA-N 0.000 claims description 2
XSGRYEKOYIWSTG-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(3-phenylpropylsulfanyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1SCCCC1=CC=CC=C1 XSGRYEKOYIWSTG-UHFFFAOYSA-N 0.000 claims description 2
SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 2
125000001475 halogen functional group Chemical group 0.000 claims 87
241000124008 Mammalia Species 0.000 claims 16
230000036470 plasma concentration Effects 0.000 claims 8
150000001356 alkyl thiols Chemical class 0.000 claims 5
208000027520 Somatoform disease Diseases 0.000 claims 4
229940094443 oxytocics prostaglandins Drugs 0.000 claims 4
208000027753 pain disease Diseases 0.000 claims 4
150000003180 prostaglandins Chemical class 0.000 claims 4
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
HJHGQAVUFBUUKT-UHFFFAOYSA-N 2-(2-anilinoethylsulfanyl)-5-(4-fluorophenyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1SCCNC1=CC=CC=C1 HJHGQAVUFBUUKT-UHFFFAOYSA-N 0.000 claims 1
CTZFGEUKZGVDSP-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(2-phenoxyethylsulfanyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1SCCOC1=CC=CC=C1 CTZFGEUKZGVDSP-UHFFFAOYSA-N 0.000 claims 1
PUFINCKHIDBOBP-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(2-phenylethylsulfanyl)-6-pyridin-4-yl-1h-pyrimidin-4-one Chemical compound C1=CC(F)=CC=C1C(C(N1)=O)=C(C=2C=CN=CC=2)N=C1SCCC1=CC=CC=C1 PUFINCKHIDBOBP-UHFFFAOYSA-N 0.000 claims 1
102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 1
101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
238000000034 method Methods 0.000 abstract description 87
201000010099 disease Diseases 0.000 abstract description 24
102000004890 Interleukin-8 Human genes 0.000 abstract description 21
239000000543 intermediate Substances 0.000 abstract description 10
230000001404 mediated effect Effects 0.000 abstract description 10
229940002612 prodrug Drugs 0.000 abstract description 9
239000000651 prodrug Substances 0.000 abstract description 9
208000002193 Pain Diseases 0.000 abstract description 5
230000008569 process Effects 0.000 abstract description 5
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
238000005160 1H NMR spectroscopy Methods 0.000 description 100
125000002887 hydroxy group Chemical group [H]O* 0.000 description 94
125000005843 halogen group Chemical group 0.000 description 93
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
239000000243 solution Substances 0.000 description 44
238000002360 preparation method Methods 0.000 description 40
102100040247 Tumor necrosis factor Human genes 0.000 description 39
101150041968 CDC13 gene Proteins 0.000 description 38
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
239000012458 free base Substances 0.000 description 36
125000004076 pyridyl group Chemical group 0.000 description 35
238000006243 chemical reaction Methods 0.000 description 34
238000001704 evaporation Methods 0.000 description 34
230000008020 evaporation Effects 0.000 description 34
TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 34
125000000714 pyrimidinyl group Chemical group 0.000 description 32
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
125000004656 alkyl sulfonylamino group Chemical group 0.000 description 31
239000000741 silica gel Substances 0.000 description 31
229910002027 silica gel Inorganic materials 0.000 description 31
YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 30
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 29
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
108060008682 Tumor Necrosis Factor Proteins 0.000 description 26
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 25
102000000589 Interleukin-1 Human genes 0.000 description 23
239000007787 solid Substances 0.000 description 23
NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 22
238000010992 reflux Methods 0.000 description 22
125000004466 alkoxycarbonylamino group Chemical group 0.000 description 21
125000003963 dichloro group Chemical group Cl* 0.000 description 21
XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 20
229940096397 interleukin-8 Drugs 0.000 description 20
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 20
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 19
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 19
DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 19
125000004432 carbon atom Chemical group C* 0.000 description 19
210000004027 cell Anatomy 0.000 description 19
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
102000004889 Interleukin-6 Human genes 0.000 description 17
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 17
229940100601 interleukin-6 Drugs 0.000 description 17
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 17
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 17
238000003756 stirring Methods 0.000 description 17
229960003887 dichlorophen Drugs 0.000 description 16
238000001035 drying Methods 0.000 description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
150000001412 amines Chemical class 0.000 description 15
125000003710 aryl alkyl group Chemical group 0.000 description 15
238000004440 column chromatography Methods 0.000 description 15
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 14
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 14
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 14
239000002158 endotoxin Substances 0.000 description 14
229920006008 lipopolysaccharide Polymers 0.000 description 14
210000001616 monocyte Anatomy 0.000 description 14
239000000047 product Substances 0.000 description 14
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 14
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 13
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 13
239000000908 ammonium hydroxide Substances 0.000 description 13
235000011114 ammonium hydroxide Nutrition 0.000 description 13
229940043379 ammonium hydroxide Drugs 0.000 description 13
238000003556 assay Methods 0.000 description 13
102000004127 Cytokines Human genes 0.000 description 12
108090000695 Cytokines Proteins 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
229940093499 ethyl acetate Drugs 0.000 description 12
235000019439 ethyl acetate Nutrition 0.000 description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 12
238000012360 testing method Methods 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 11
238000013459 approach Methods 0.000 description 11
125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 11
239000002904 solvent Substances 0.000 description 11
239000007858 starting material Substances 0.000 description 11
LHLSGSPSOSTKCH-UHFFFAOYSA-N 2-chloro-5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C1=CN=C(Cl)N=C1C1=CC=NC=C1 LHLSGSPSOSTKCH-UHFFFAOYSA-N 0.000 description 10
229960000583 acetic acid Drugs 0.000 description 10
235000011054 acetic acid Nutrition 0.000 description 10
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
239000000463 material Substances 0.000 description 10
239000003921 oil Substances 0.000 description 10
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LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
229960003732 tyramine Drugs 0.000 description 1
241000701161 unidentified adenovirus Species 0.000 description 1
241001529453 unidentified herpesvirus Species 0.000 description 1
230000003827 upregulation Effects 0.000 description 1
238000011144 upstream manufacturing Methods 0.000 description 1
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
238000010792 warming Methods 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1
UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1

Classifications

- 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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
- 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
- C07D401/14—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 three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

CA002274063A 1996-12-05 1997-12-04 Composes pyrimidines substitues et leur utilisation Expired - Fee Related CA2274063C (fr)

Applications Claiming Priority (7)

Application Number	Priority Date	Filing Date	Title
US3212896P	1996-12-05	1996-12-05
US60/032,128		1996-12-05
US5095097P	1997-06-13	1997-06-13
US60/050,950		1997-06-13
US97605497A	1997-11-21	1997-11-21
US08/976,054		1997-11-21
PCT/US1997/022390 WO1998024782A2 (fr)	1996-12-05	1997-12-04	Composes pyrimidines substitues et leur utilisation

Publications (2)

Publication Number	Publication Date
CA2274063A1 CA2274063A1 (fr)	1998-06-11
CA2274063C true CA2274063C (fr)	2007-09-04

Family

ID=27364030

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002274063A Expired - Fee Related CA2274063C (fr)	1996-12-05	1997-12-04	Composes pyrimidines substitues et leur utilisation

Country Status (11)

Country	Link
EP (1)	EP0948497A2 (fr)
CN (1)	CN1246858A (fr)
AR (1)	AR048564A1 (fr)
AU (1)	AU733877C (fr)
BG (1)	BG65128B1 (fr)
BR (1)	BR9713850A (fr)
CA (1)	CA2274063C (fr)
CZ (1)	CZ296911B6 (fr)
HU (1)	HUP0001698A3 (fr)
IL (1)	IL130180A0 (fr)
NZ (1)	NZ335997A (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2002020495A2 (fr) *	2000-09-06	2002-03-14	Chiron Corporation	Inhibiteurs de glycogene-synthase kinase 3
IL160701A0 (en)	2001-09-21	2004-08-31	Mitsubishi Pharma Corp	3-substituted-4-pyrimidone derivatives
EP1427720B1 (fr)	2001-09-21	2009-03-04	Mitsubishi Tanabe Pharma Corporation	Derives de 3-substitue-4-pyrimidone
TWI330183B (fr) *	2001-10-22	2010-09-11	Eisai R&D Man Co Ltd
EP1340759A1 (fr) *	2002-02-28	2003-09-03	Sanofi-Synthelabo	Dérivés de la 1-alkyl, 1-(hétéroalkyl)alkyl et 1-(aryl)alkyl-7-pyrimidin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one
JP4616003B2 (ja)	2002-12-16	2011-01-19	田辺三菱製薬株式会社	３−置換−４−ピリミドン誘導体
TWI357408B (en)	2003-03-26	2012-02-01	Mitsubishi Tanabe Pharma Corp	3-substituted-4-pyrimidone derivatives
HRP20171587T1 (hr) *	2010-10-18	2017-12-01	Cerenis Therapeutics Holding Sa	Spojevi, pripravci i postupci pogodni za mobilizaciju kolesterola
TWI651310B (zh) *	2014-02-20	2019-02-21	日商日本煙草產業股份有限公司	三化合物及其醫藥用途
EP3372589B1 (fr) *	2015-10-29	2021-10-20	ASKA Pharmaceutical Co., Ltd.	Dérivé pyrimidine

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
BE759176A (fr) *	1969-11-20	1971-05-19	Sandoz Sa	Derives de la pyrimidine, leur preparation et medicaments contenant cesderives
US4438117A (en) *	1980-09-03	1984-03-20	E. I. Du Pont De Nemours And Company	2-Substituted thio-4,5-diarylpyrimidines
DE3319843A1 (de) *	1983-06-01	1984-12-06	Ali-Akbar Dipl.-Chem. Dr. 4300 Mülheim Pourzal	Verfahren zur herstellung von pyrimidinen aus nitrilen und alkinen
US4500533A (en) *	1983-06-22	1985-02-19	Eli Lilly And Company	2,4,5-Triaryl pyrimidines and a method of treating pain, fever, thrombosis, inflammation and arthritis
US5077142A (en) *	1989-04-20	1991-12-31	Ricoh Company, Ltd.	Electroluminescent devices
US5620999A (en) *	1994-07-28	1997-04-15	Weier; Richard M.	Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation

1997
- 1997-12-04 AR ARP970105689A patent/AR048564A1/es not_active Application Discontinuation
- 1997-12-04 CZ CZ0201599A patent/CZ296911B6/cs not_active IP Right Cessation
- 1997-12-04 CA CA002274063A patent/CA2274063C/fr not_active Expired - Fee Related
- 1997-12-04 NZ NZ335997A patent/NZ335997A/xx unknown
- 1997-12-04 AU AU60120/98A patent/AU733877C/en not_active Ceased
- 1997-12-04 CN CN97181563A patent/CN1246858A/zh active Pending
- 1997-12-04 IL IL13018097A patent/IL130180A0/xx unknown
- 1997-12-04 BR BR9713850-9A patent/BR9713850A/pt not_active Application Discontinuation
- 1997-12-04 HU HU0001698A patent/HUP0001698A3/hu unknown
- 1997-12-04 EP EP97954778A patent/EP0948497A2/fr not_active Withdrawn
1999
- 1999-06-22 BG BG103512A patent/BG65128B1/bg unknown

Also Published As

Publication number	Publication date
AU733877B2 (en)	2001-05-31
HUP0001698A2 (hu)	2001-04-28
BG65128B1 (bg)	2007-03-30
AR048564A1 (es)	2006-05-10
BR9713850A (pt)	2000-02-29
CN1246858A (zh)	2000-03-08
HUP0001698A3 (en)	2002-07-29
CZ9902015A3 (cs)	1999-11-17
EP0948497A2 (fr)	1999-10-13
NZ335997A (en)	2001-08-31
IL130180A0 (en)	2000-06-01
CA2274063A1 (fr)	1998-06-11
CZ296911B6 (cs)	2006-07-12
AU6012098A (en)	1998-06-29
AU733877C (en)	2003-05-08
BG103512A (en)	2000-07-31

Legal Events

Date	Code	Title	Description
1999-06-03	EEER	Examination request
2010-12-06	MKLA	Lapsed

Publication	Publication Date	Title
US6610698B2 (en)	2003-08-26	Substituted pyrimidine compounds and methods of use
CA2274093C (fr)	2006-11-07	Composes substitues a base de pyrimidone et de pyridone et procedes d'utilisation
US6420385B1 (en)	2002-07-16	Substituted pyrimidinone and pyridone compounds and methods of use
WO1998024782A2 (fr)	1998-06-11	Composes pyrimidines substitues et leur utilisation
CA2315827C (fr)	2007-08-21	Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques
US6174901B1 (en)	2001-01-16	Substituted pyridine and pyridazine compounds and methods of use
CA2271767A1 (fr)	1998-05-28	Agents anti-inflammatoires a base de pyrrole condense a substitution aryle et heteroaryle
CA2466072A1 (fr)	2003-05-30	Composes de type indolizine substitues et leurs methodes d'utilisation
AU733877C (en)	2003-05-08	Substituted pyrimidine compounds and their use
CA2535644A1 (fr)	2005-03-03	Derives de pyrimdinone substitues et leurs procedes d'utilisation
EP1314732A2 (fr)	2003-05-28	Composés de pyrimidine substitués et leur utilisation
MXPA99005168A (en)	2000-04-24	Substituted pyrimidine compounds and their use
KR20000069328A (ko)	2000-11-25	치환된 피리미딘 화합물과 그것의 용도
AU8142901A (en)	2002-01-03	Substituted pyrimidinone and pyridone compounds and methods of use