JP2006502236A - 形質転換成長因子（ｔｇｆ）阻害剤としてのトリアゾール誘導体 - Google Patents
形質転換成長因子（ｔｇｆ）阻害剤としてのトリアゾール誘導体 Download PDFInfo
- Publication number
- JP2006502236A JP2006502236A JP2004568900A JP2004568900A JP2006502236A JP 2006502236 A JP2006502236 A JP 2006502236A JP 2004568900 A JP2004568900 A JP 2004568900A JP 2004568900 A JP2004568900 A JP 2004568900A JP 2006502236 A JP2006502236 A JP 2006502236A
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- JP
- Japan
- Prior art keywords
- alkyl
- phenyl
- heteroaryl
- cycloalkyl
- heterocyclic
- Prior art date
- 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.)
- Abandoned
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- 102000009618 Transforming Growth Factors Human genes 0.000 title abstract description 20
- 108010009583 Transforming Growth Factors Proteins 0.000 title abstract description 20
- 239000003112 inhibitor Substances 0.000 title abstract description 11
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 138
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
- -1 hydroxy, oxo, mercapto Chemical class 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 33
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 27
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 206010039580 Scar Diseases 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 230000019491 signal transduction Effects 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 3
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 206010016654 Fibrosis Diseases 0.000 abstract description 2
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- 239000000126 substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
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- 229940079593 drug Drugs 0.000 description 9
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- 0 CC(C)C1(C)C=C(C(C=*)*=*2)C2=CC=C1 Chemical compound CC(C)C1(C)C=C(C(C=*)*=*2)C2=CC=C1 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 7
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
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- 239000000047 product Substances 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- 150000007513 acids Chemical class 0.000 description 4
- 150000001447 alkali salts Chemical class 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
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- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 3
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
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| PCT/IB2003/003825 WO2004026307A1 (en) | 2002-09-18 | 2003-09-08 | Triazole derivatives as transforming growth factor (tgf) inhibitors |
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| MY140679A (en) | 2001-05-24 | 2010-01-15 | Avanir Pharmaceuticals | Inhibitors of macrohage migration inhibitory factor and methods for identifying the same |
| AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
| CN1681805A (zh) * | 2002-09-18 | 2005-10-12 | 辉瑞产品公司 | 作为转化生长因子(tgf)抑制剂的新的咪唑类化合物 |
| AU2003259475A1 (en) * | 2002-09-18 | 2004-04-08 | Pfizer Products Inc. | Pyrazole derivatives as transforming growth factor (TGF) inhibitors |
| CA2499429C (en) | 2002-09-18 | 2010-09-21 | Pfizer Products Inc. | Novel oxazole and thiazole compounds as transforming growth factor (tgf) inhibitors |
| PA8595001A1 (es) | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
| WO2006090717A1 (ja) | 2005-02-23 | 2006-08-31 | Shionogi & Co., Ltd. | チロシンキナーゼ阻害作用を有するキナゾリン誘導体 |
| EP1919881B1 (en) | 2005-07-25 | 2013-04-10 | Synta Pharmaceuticals Corp. | 1, 2, 3 -triazoles inhibitors of tubulin polymerization for the treatment of poliferative disorders |
| AU2006325706B2 (en) * | 2005-12-16 | 2012-03-29 | Novartis Ag | Control of intraocular pressure using ALK5 modulation agents |
| DE102005061840A1 (de) | 2005-12-23 | 2007-06-28 | Merck Patent Gmbh | Triazolderivate |
| US8673929B2 (en) | 2006-07-20 | 2014-03-18 | Gilead Sciences, Inc. | 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives and pharmaceutical compositions useful for treating viral infections |
| WO2008009078A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| US8871744B2 (en) | 2010-07-21 | 2014-10-28 | B & G Partyers, LLC | Compounds and methods for selectively targeting tumor-associated mucins |
| WO2013078286A1 (en) | 2011-11-22 | 2013-05-30 | Cornell University | Methods for stimulating hematopoietic recovery by inhibiting tgf beta signaling |
| ES2966030T3 (es) | 2012-10-05 | 2024-04-18 | Kadmon Corp Llc | Anticuerpos anti-VEGFR-2/KDR humanos |
| PT3702443T (pt) | 2013-03-14 | 2022-02-17 | Massachusetts Inst Technology | Composições e métodos para expansão e cultura de células estaminais epiteliais |
| EP3089971B1 (en) | 2014-01-01 | 2020-07-29 | Medivation Technologies LLC | Compounds and methods of use |
| CA2959404A1 (en) | 2014-09-03 | 2016-03-10 | The Brigham And Women's Hospital, Inc. | Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss |
| MY199988A (en) | 2015-03-04 | 2023-12-02 | Gilead Sciences Inc | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
| WO2017120543A1 (en) | 2016-01-08 | 2017-07-13 | Massachusetts Institute Of Technology | Production of differentiated enteroendocrine cells and insulin producing cells |
| US11260130B2 (en) | 2016-03-02 | 2022-03-01 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV |
| US10213511B2 (en) | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
| ES2826748T3 (es) | 2016-09-02 | 2021-05-19 | Gilead Sciences Inc | Derivados de 4,6-diamino-pirido[3,2-d]pirimidina como moduladores de receptores de tipo Toll |
| MA46093A (fr) | 2016-09-02 | 2021-05-19 | Gilead Sciences Inc | Composés modulateurs du recepteur de type toll |
| SG10201910821XA (en) | 2016-12-30 | 2020-01-30 | Frequency Therapeutics Inc | 1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells |
| CN112135613A (zh) | 2018-03-20 | 2020-12-25 | 西奈山伊坎医学院 | 激酶抑制剂化合物和组合物及使用方法 |
| US12049475B2 (en) | 2018-07-23 | 2024-07-30 | Brise Pharmaceuticals Co., Ltd. | Bisphosphonate drug conjugates |
| US11162071B2 (en) | 2018-08-17 | 2021-11-02 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by upregulating JAG-1 |
| US11617745B2 (en) | 2018-08-17 | 2023-04-04 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by downregulating FOXO |
| CN113508111A (zh) | 2018-12-31 | 2021-10-15 | 西奈山伊坎医学院 | 激酶抑制剂化合物和组合物及使用方法 |
| TW202210480A (zh) | 2019-04-17 | 2022-03-16 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TW202212339A (zh) | 2019-04-17 | 2022-04-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TWI879779B (zh) | 2019-06-28 | 2025-04-11 | 美商基利科學股份有限公司 | 類鐸受體調節劑化合物的製備方法 |
| CN112694477B (zh) * | 2019-10-22 | 2024-02-06 | 四川科伦博泰生物医药股份有限公司 | 吡唑并环类化合物，包含其的药物组合物，其制备方法及其用途 |
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| JPS6058981A (ja) * | 1983-09-09 | 1985-04-05 | Takeda Chem Ind Ltd | ５−ピリジル−１，３−チアゾ−ル誘導体，その製造法およびそれを含んでなる医薬組成物 |
| JPS6025142A (ja) | 1983-07-21 | 1985-02-07 | Matsushita Electric Ind Co Ltd | 表示装置の電極製造方法 |
| EP0149884B1 (en) * | 1983-09-09 | 1992-12-16 | Takeda Chemical Industries, Ltd. | 5-pyridyl-1,3-thiazole derivatives, their production and use |
| GB9201692D0 (en) * | 1992-01-27 | 1992-03-11 | Smithkline Beecham Intercredit | Compounds |
| CN1264376A (zh) | 1997-05-22 | 2000-08-23 | G·D·瑟尔公司 | 作为p38激酶抑制剂的3(5)－杂芳基取代的吡唑化合物 |
| WO1998052941A1 (en) | 1997-05-22 | 1998-11-26 | G.D. Searle And Co. | PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS |
| US6514977B1 (en) | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
| JPH11193281A (ja) * | 1997-10-27 | 1999-07-21 | Takeda Chem Ind Ltd | アデノシンａ３受容体拮抗剤およびチアゾール化合物 |
| DE60001229T2 (de) | 1999-04-09 | 2003-10-30 | Smithkline Beecham Corp., Philadelphia | Triarylimidazole |
| JP2000302680A (ja) * | 1999-04-23 | 2000-10-31 | Takeda Chem Ind Ltd | 脳保護剤 |
| EP1205478A4 (en) * | 1999-08-06 | 2004-06-30 | Takeda Chemical Industries Ltd | P38MAP KINASE INHIBITORS |
| CO5271680A1 (es) | 2000-02-21 | 2003-04-30 | Smithkline Beecham Corp | Compuestos |
| GB0007405D0 (en) | 2000-03-27 | 2000-05-17 | Smithkline Beecham Corp | Compounds |
| PE20020506A1 (es) | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | Derivados de pirazol fusionados como inhibidores de la proteina cinasa |
| US20040039198A1 (en) | 2000-11-16 | 2004-02-26 | Bender Paul E. | Compounds |
| GB0027987D0 (en) | 2000-11-16 | 2001-01-03 | Smithkline Beecham Plc | Compounds |
| EP1354603A1 (en) * | 2000-12-26 | 2003-10-22 | Takeda Chemical Industries, Ltd. | Concomitant drugs |
| GB0100762D0 (en) | 2001-01-11 | 2001-02-21 | Smithkline Beecham Plc | Novel use |
| ES2237671T3 (es) | 2001-02-02 | 2005-08-01 | Smithkline Beecham Corporation | Derivados de pirazol contra la sobreexpresion de tgf. |
| GB0102673D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| GB0102665D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| GB0102668D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| WO2002062787A1 (en) | 2001-02-02 | 2002-08-15 | Glaxo Group Limited | Pyrazoles as tgf inhibitors |
| GB0102672D0 (en) | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| JPWO2002062775A1 (ja) * | 2001-02-02 | 2004-06-10 | 山之内製薬株式会社 | ２−アシルアミノチアゾール誘導体又はその塩 |
| US20050080113A1 (en) * | 2001-06-11 | 2005-04-14 | Shigenori Ohkawa | Medicinal compositions |
| AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
| GB0217780D0 (en) | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Compounds |
| WO2004013135A1 (en) | 2002-07-31 | 2004-02-12 | Smithkline Beecham Corporation | 2-phenylpyridin-4-yl derivatives as alk5 inhibitors |
-
2003
- 2003-09-08 KR KR1020057004575A patent/KR20050057393A/ko not_active Ceased
- 2003-09-08 AU AU2003260810A patent/AU2003260810A1/en not_active Abandoned
- 2003-09-08 CA CA002497971A patent/CA2497971A1/en not_active Abandoned
- 2003-09-08 MX MXPA05002982A patent/MXPA05002982A/es unknown
- 2003-09-08 CN CNA038221594A patent/CN1681502A/zh active Pending
- 2003-09-08 PL PL03375974A patent/PL375974A1/xx not_active Application Discontinuation
- 2003-09-08 EA EA200500376A patent/EA200500376A1/ru unknown
- 2003-09-08 BR BR0314577-8A patent/BR0314577A/pt not_active IP Right Cessation
- 2003-09-08 HR HR20050251A patent/HRP20050251A2/hr not_active Application Discontinuation
- 2003-09-08 JP JP2004568900A patent/JP2006502236A/ja not_active Abandoned
- 2003-09-08 EP EP03797428A patent/EP1542685A1/en not_active Withdrawn
- 2003-09-08 AP AP2005003260A patent/AP2005003260A0/xx unknown
- 2003-09-08 OA OA1200500076A patent/OA12927A/en unknown
- 2003-09-08 WO PCT/IB2003/003825 patent/WO2004026307A1/en not_active Ceased
- 2003-09-16 PE PE2003000947A patent/PE20050074A1/es not_active Application Discontinuation
- 2003-09-16 UY UY27981A patent/UY27981A1/es not_active Application Discontinuation
- 2003-09-16 AR ARP030103360A patent/AR041276A1/es unknown
- 2003-09-17 TW TW092125634A patent/TW200412346A/zh unknown
- 2003-09-17 PA PA20038583401A patent/PA8583401A1/es unknown
- 2003-09-17 US US10/667,183 patent/US7053095B2/en not_active Expired - Fee Related
-
2005
- 2005-02-24 IS IS7713A patent/IS7713A/is unknown
- 2005-02-24 NO NO20051010A patent/NO20051010L/no unknown
- 2005-03-16 CO CO05024528A patent/CO5540390A2/es not_active Application Discontinuation
- 2005-03-17 EC EC2005005681A patent/ECSP055681A/es unknown
- 2005-03-18 MA MA28156A patent/MA27442A1/fr unknown
-
2006
- 2006-02-07 US US11/349,481 patent/US20060128761A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| MA27442A1 (fr) | 2005-07-01 |
| BR0314577A (pt) | 2005-08-09 |
| IS7713A (is) | 2005-02-24 |
| AR041276A1 (es) | 2005-05-11 |
| PE20050074A1 (es) | 2005-03-21 |
| PA8583401A1 (es) | 2004-04-23 |
| AP2005003260A0 (en) | 2005-03-31 |
| CO5540390A2 (es) | 2005-07-29 |
| PL375974A1 (en) | 2005-12-12 |
| NO20051010L (no) | 2005-05-31 |
| WO2004026307A1 (en) | 2004-04-01 |
| MXPA05002982A (es) | 2005-06-22 |
| CN1681502A (zh) | 2005-10-12 |
| AU2003260810A1 (en) | 2004-04-08 |
| HRP20050251A2 (en) | 2005-10-31 |
| UY27981A1 (es) | 2004-04-30 |
| KR20050057393A (ko) | 2005-06-16 |
| US20060128761A1 (en) | 2006-06-15 |
| EP1542685A1 (en) | 2005-06-22 |
| EA200500376A1 (ru) | 2005-08-25 |
| OA12927A (en) | 2006-10-13 |
| US20040110798A1 (en) | 2004-06-10 |
| US7053095B2 (en) | 2006-05-30 |
| CA2497971A1 (en) | 2004-04-01 |
| TW200412346A (en) | 2004-07-16 |
| ECSP055681A (es) | 2005-05-30 |
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