TW520362B

TW520362B - Substituted pyrimidine compounds and pharmaceutical composition comprising same

Substituted pyrimidine compounds and pharmaceutical composition comprising same Download PDF

Info

Publication number: TW520362B
Authority: TW; Taiwan
Prior art keywords: amino; fluorophenyl; pyridyl; group; phenyl
Prior art date: 1996-12-05

Application number

TW086118244A

Other languages

English (en)

Chinese (zh)

Inventor

Ulrike D Spohr

Michael J Malone

Nathan B Mantlo

Original Assignee

Amgen Inc

Priority date

1996-12-05

Filing date

1997-12-04

Publication date

2003-02-11

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

2003-02-11 Application granted granted Critical

2003-02-11 Publication of TW520362B publication Critical patent/TW520362B/zh

Links

239000008194 pharmaceutical composition Chemical class 0.000 title claims abstract description 15
150000003230 pyrimidines Chemical class 0.000 title description 6
150000001875 compounds Chemical class 0.000 claims abstract description 149
238000000034 method Methods 0.000 claims abstract description 78
201000010099 disease Diseases 0.000 claims abstract description 38
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
150000003839 salts Chemical class 0.000 claims abstract description 23
238000011282 treatment Methods 0.000 claims abstract description 18
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
206010061218 Inflammation Diseases 0.000 claims abstract description 6
230000004054 inflammatory process Effects 0.000 claims abstract description 6
-1 Phenylthiomethyl Chemical group 0.000 claims description 746
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 256
125000000217 alkyl group Chemical group 0.000 claims description 203
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 164
125000003282 alkyl amino group Chemical group 0.000 claims description 110
150000001412 amines Chemical class 0.000 claims description 101
125000003277 amino group Chemical group 0.000 claims description 96
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 87
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 79
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 76
239000000203 mixture Substances 0.000 claims description 65
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 43
125000004076 pyridyl group Chemical group 0.000 claims description 40
125000001207 fluorophenyl group Chemical group 0.000 claims description 23
229910052736 halogen Inorganic materials 0.000 claims description 18
150000002367 halogens Chemical class 0.000 claims description 18
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
238000006467 substitution reaction Methods 0.000 claims description 14
229960004666 glucagon Drugs 0.000 claims description 13
230000000694 effects Effects 0.000 claims description 12
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 11
206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 10
102000051325 Glucagon Human genes 0.000 claims description 10
108060003199 Glucagon Proteins 0.000 claims description 10
208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 10
208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 10
201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 10
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 10
238000004519 manufacturing process Methods 0.000 claims description 10
206010040070 Septic Shock Diseases 0.000 claims description 9
VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 9
241000701022 Cytomegalovirus Species 0.000 claims description 8
206010006895 Cachexia Diseases 0.000 claims description 7
206010028289 Muscle atrophy Diseases 0.000 claims description 7
230000006378 damage Effects 0.000 claims description 7
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
210000002237 B-cell of pancreatic islet Anatomy 0.000 claims description 6
208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
241000124008 Mammalia Species 0.000 claims description 6
102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 6
108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 6
102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims description 6
108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims description 6
206010063837 Reperfusion injury Diseases 0.000 claims description 6
208000006011 Stroke Diseases 0.000 claims description 6
230000001154 acute effect Effects 0.000 claims description 6
201000008482 osteoarthritis Diseases 0.000 claims description 6
239000000126 substance Substances 0.000 claims description 6
208000011580 syndromic disease Diseases 0.000 claims description 6
206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
206010009900 Colitis ulcerative Diseases 0.000 claims description 5
206010020751 Hypersensitivity Diseases 0.000 claims description 5
206010040047 Sepsis Diseases 0.000 claims description 5
208000030886 Traumatic Brain injury Diseases 0.000 claims description 5
201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
241000700605 Viruses Species 0.000 claims description 5
208000006673 asthma Diseases 0.000 claims description 5
210000004369 blood Anatomy 0.000 claims description 5
239000008280 blood Substances 0.000 claims description 5
208000019664 bone resorption disease Diseases 0.000 claims description 5
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
201000006417 multiple sclerosis Diseases 0.000 claims description 5
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
125000006308 propyl amino group Chemical group 0.000 claims description 5
150000003180 prostaglandins Chemical class 0.000 claims description 5
230000036303 septic shock Effects 0.000 claims description 5
208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
206010012442 Dermatitis contact Diseases 0.000 claims description 4
208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
208000001132 Osteoporosis Diseases 0.000 claims description 4
206010037660 Pyrexia Diseases 0.000 claims description 4
206010039085 Rhinitis allergic Diseases 0.000 claims description 4
206010044248 Toxic shock syndrome Diseases 0.000 claims description 4
231100000650 Toxic shock syndrome Toxicity 0.000 claims description 4
201000010105 allergic rhinitis Diseases 0.000 claims description 4
230000007815 allergy Effects 0.000 claims description 4
206010003246 arthritis Diseases 0.000 claims description 4
208000010247 contact dermatitis Diseases 0.000 claims description 4
208000015181 infectious disease Diseases 0.000 claims description 4
230000000302 ischemic effect Effects 0.000 claims description 4
230000002265 prevention Effects 0.000 claims description 4
230000017702 response to host Effects 0.000 claims description 4
241000701161 unidentified adenovirus Species 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 3
208000024827 Alzheimer disease Diseases 0.000 claims description 3
241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 3
208000034578 Multiple myelomas Diseases 0.000 claims description 3
206010033557 Palpitations Diseases 0.000 claims description 3
206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
201000004681 Psoriasis Diseases 0.000 claims description 3
239000012528 membrane Substances 0.000 claims description 3
PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 3
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 3
208000010125 myocardial infarction Diseases 0.000 claims description 3
125000004344 phenylpropyl group Chemical group 0.000 claims description 3
241001529453 unidentified herpesvirus Species 0.000 claims description 3
YJVKLLJCUMQBHN-UHFFFAOYSA-N 2-pyridin-2-ylpyrimidine Chemical compound N1=CC=CC=C1C1=NC=CC=N1 YJVKLLJCUMQBHN-UHFFFAOYSA-N 0.000 claims description 2
LNPMZQXEPNWCMG-UHFFFAOYSA-N 4-(2-aminoethyl)aniline Chemical compound NCCC1=CC=C(N)C=C1 LNPMZQXEPNWCMG-UHFFFAOYSA-N 0.000 claims description 2
206010028980 Neoplasm Diseases 0.000 claims description 2
206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
208000026935 allergic disease Diseases 0.000 claims description 2
239000005557 antagonist Substances 0.000 claims description 2
125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
230000002490 cerebral effect Effects 0.000 claims description 2
229960005181 morphine Drugs 0.000 claims description 2
PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims 1
VHJKDOLGYMULOP-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)ethanamine Chemical compound NCCC1=CC=C(Cl)C=C1Cl VHJKDOLGYMULOP-UHFFFAOYSA-N 0.000 claims 1
125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
DLUYDWMBZSEZCU-UHFFFAOYSA-N 2-[(2,6-dichlorophenyl)methyl]-5-(4-fluorophenyl)-4-pyridin-4-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1CC1=C(Cl)C=CC=C1Cl DLUYDWMBZSEZCU-UHFFFAOYSA-N 0.000 claims 1
125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
AYUVXKSTUTVAMO-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-(phenylsulfanylmethyl)-4-pyridin-4-ylpyrimidine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1CSC1=CC=CC=C1 AYUVXKSTUTVAMO-UHFFFAOYSA-N 0.000 claims 1
CWEMLTMVMPIHTR-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(2-methoxyphenyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound COC1=CC=CC=C1NC(N=C1C=2C=CN=CC=2)=NC=C1C1=CC=C(F)C=C1 CWEMLTMVMPIHTR-UHFFFAOYSA-N 0.000 claims 1
WAUSKYGFULPCPY-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-(2-phenylethyl)-4-pyridin-4-ylpyrimidin-2-amine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN=C1NCCC1=CC=CC=C1 WAUSKYGFULPCPY-UHFFFAOYSA-N 0.000 claims 1
206010003210 Arteriosclerosis Diseases 0.000 claims 1
208000037260 Atherosclerotic Plaque Diseases 0.000 claims 1
206010014978 Epidemic pleurodynia Diseases 0.000 claims 1
240000005708 Eugenia stipitata Species 0.000 claims 1
235000006149 Eugenia stipitata Nutrition 0.000 claims 1
206010020772 Hypertension Diseases 0.000 claims 1
GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims 1
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HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims 1
229940094443 oxytocics prostaglandins Drugs 0.000 claims 1
125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 39
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102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 abstract description 2
150000003222 pyridines Chemical class 0.000 abstract description 2
238000011321 prophylaxis Methods 0.000 abstract 2
MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 abstract 1
238000011049 filling Methods 0.000 description 169
125000001424 substituent group Chemical group 0.000 description 121
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 120
125000003545 alkoxy group Chemical group 0.000 description 118
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
125000003118 aryl group Chemical group 0.000 description 102
230000002079 cooperative effect Effects 0.000 description 97
125000001072 heteroaryl group Chemical group 0.000 description 92
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
125000005843 halogen group Chemical group 0.000 description 80
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 79
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
238000005481 NMR spectroscopy Methods 0.000 description 72
125000000623 heterocyclic group Chemical group 0.000 description 71
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 65
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238000006243 chemical reaction Methods 0.000 description 56
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102100040247 Tumor necrosis factor Human genes 0.000 description 51
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239000000243 solution Substances 0.000 description 50
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
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229910052739 hydrogen Inorganic materials 0.000 description 38
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UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 32
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