JP5857211B2 - プロテインキナーゼ阻害活性を有する4−フェニルアミノ−ピリミジン誘導体 - Google Patents
プロテインキナーゼ阻害活性を有する4−フェニルアミノ−ピリミジン誘導体 Download PDFInfo
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- JP5857211B2 JP5857211B2 JP2012545455A JP2012545455A JP5857211B2 JP 5857211 B2 JP5857211 B2 JP 5857211B2 JP 2012545455 A JP2012545455 A JP 2012545455A JP 2012545455 A JP2012545455 A JP 2012545455A JP 5857211 B2 JP5857211 B2 JP 5857211B2
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- heteroaryl
- aryl
- phenyl
- pyrimidin
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- WYQPVNZYOQDBGD-UHFFFAOYSA-N n-[[4-[[6-[2-(2-methylpropoxy)phenyl]pyrimidin-4-yl]amino]phenyl]methyl]methanesulfonamide Chemical compound CC(C)COC1=CC=CC=C1C1=CC(NC=2C=CC(CNS(C)(=O)=O)=CC=2)=NC=N1 WYQPVNZYOQDBGD-UHFFFAOYSA-N 0.000 description 1
- KWBVXSYVCZTBBV-UHFFFAOYSA-N n-[[4-[[6-[2-(trifluoromethyl)phenyl]pyrimidin-4-yl]amino]phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CNS(=O)(=O)C)=CC=C1NC1=CC(C=2C(=CC=CC=2)C(F)(F)F)=NC=N1 KWBVXSYVCZTBBV-UHFFFAOYSA-N 0.000 description 1
- CMQGHDXEJNKNBD-UHFFFAOYSA-N n-[[4-[[6-[2-[(3-fluorophenyl)methoxy]phenyl]pyrimidin-4-yl]amino]phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CNS(=O)(=O)C)=CC=C1NC1=CC(C=2C(=CC=CC=2)OCC=2C=C(F)C=CC=2)=NC=N1 CMQGHDXEJNKNBD-UHFFFAOYSA-N 0.000 description 1
- JSOKFHBFBVVSHX-UHFFFAOYSA-N n-[[4-[[6-[2-[(4-fluorophenyl)methoxy]phenyl]pyrimidin-4-yl]amino]phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CNS(=O)(=O)C)=CC=C1NC1=CC(C=2C(=CC=CC=2)OCC=2C=CC(F)=CC=2)=NC=N1 JSOKFHBFBVVSHX-UHFFFAOYSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical class C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
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- 201000001119 neuropathy Diseases 0.000 description 1
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- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Chemical class 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- GTVPOLSIJWJJNY-UHFFFAOYSA-N olomoucine Chemical compound N1=C(NCCO)N=C2N(C)C=NC2=C1NCC1=CC=CC=C1 GTVPOLSIJWJJNY-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- KGCNHWXDPDPSBV-UHFFFAOYSA-N p-nitrobenzyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CCl)C=C1 KGCNHWXDPDPSBV-UHFFFAOYSA-N 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 229940075931 sodium dithionate Drugs 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LZOZLBFZGFLFBV-UHFFFAOYSA-N sulfene Chemical compound C=S(=O)=O LZOZLBFZGFLFBV-UHFFFAOYSA-N 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000006361 tethered spinal cord syndrome Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229910021516 thallium(I) hydroxide Inorganic materials 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- JQKHNBQZGUKYPX-UHFFFAOYSA-N tris(2,4,6-trimethoxyphenyl)phosphane Chemical compound COC1=CC(OC)=CC(OC)=C1P(C=1C(=CC(OC)=CC=1OC)OC)C1=C(OC)C=C(OC)C=C1OC JQKHNBQZGUKYPX-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
Description
本発明は4,6−ジ置換アミノピリミジンおよびその医薬上で許容される塩および溶媒和物、これらの誘導体の医薬活性成分としての使用、特にプロテインキナーゼ関連疾病、特にCDK9関連疾病、例えば細胞増殖性疾病、感染性疾病、痛み、心臓血管系疾病および炎症の予防および/または処置用の医薬活性成分としての使用に関する。さらに、本発明は少なくとも1種の4,6−ジ置換アミノピリミジンのメチレンスルホンまたはメチレンスルホンアミド誘導体および/またはその医薬上で許容される塩または溶媒和物を含有する医薬組成物および上記疾病の予防および/または処置用の医薬組成物の調製における本発明の化合物の使用に関する。
プロテインキナーゼはATPから基質タンパク質の1個または2個以上のOH基へのホスフェート基の転移に専念する。この過程において、これらは生きている細胞におけるリン酸化反応において触媒的役割を果たす。リン酸化は生体分子レベルにおける情報伝達モードであり、代表的には別種のプロテインキナーゼである或る種のタンパク質の活性を調節することができる。約1000種のプロテインキナーゼが知られている。細胞膜に位置するレセプタープロテインキナーゼおよび細胞プラズマに位置する非−レセプタープロテインキナーゼが存在する。我々はチロシンOHをリン酸化することができるチロシンプロテインキナーゼおよびセリンまたはトレオニンOH基をリン酸化することができるセリン−トレオニンプロテインキナーゼについて言及する。CDKはそれらの活動にサイクリンを必要とする非−レセプターセリン−トレオニンプロテインキナーゼ(サイクリン依存性プロテインキナーゼ)(Cycline Dependent protein Kinases)である。
(米国特許第6,107,305号およびWO02/100401)。
本発明の目的は、医薬活性剤として、特に細胞増殖性疾病、例えば癌;感染性疾病、例えばHIVを包含するレトロウイルス感染性疾病;痛み、例えば炎症性痛みおよび神経障害性痛み;心臓血管系疾病、例えば心臓肥大;および炎症から選択される1種または2種以上の疾病または医学的症状の予防および/または処置用の医薬活性剤として使用することができるプロテインキナーゼインヒビター活性、好ましくはサイクリン依存性プロテインキナーゼ(CDK)インヒビター活性を有する一般式(I)で表される化合物およびその医薬上で許容される塩および溶媒和物、上記疾病の処置方法、ならびに少なくとも1種の当該化合物および/またはその医薬上で許容される塩を医薬活性成分として含有する組成物を提供することにある。本発明はまた、一般式(I)で表される化合物およびその医薬上で許容される塩の上記疾病の予防および/または処置用の医薬組成物の調製における使用に関する。
R1は、*ハロゲン;
*ビニレン−アリール;
*アリール、この基は1個または2個以上の下記群から選択される置換基により置換されていてもよい、
−アルコキシ、この基は或る種の具体例において、1個または2個以上のハロゲンにより、またはアリールにより置換されており、このアリールは或る種の具体例において、1個または2個以上のハロゲンによりさらに置換されていてもよい;
−ハロゲン、
−アルキル、この基は任意に1個または2個以上のハロゲンまたはアルコキシ、好ましくはハロゲンにより置換されていてもよい、
−アルキルアリールオキシ、この基はアルコキシにより置換されていてもよく、このアルコキシは任意に1個または2個以上のハロゲンにより置換されていてもよい、
−アミノカルボニル、
−アミノ、この基は任意に1個または2個のアルキルにより置換されていてもよい、
−アルキルチオ、
−アルキルスルフィニルまたはアルキルスルホニル、
−アリールオキシ、
−ヒドロキシル;
*式(a)で表される基:
式中、mは1、2または3、好ましくは1であり、およびR’は水素、ハロゲン、アルキルまたはアルコキシである;
*ヘテロアリール;
であり;
式中、R2は、
−アルキル、アルコキシまたはアリール、これらの基は任意に1個または2個以上のハロゲンにより置換されていてもよい、
−ヘテロアリール、
−ベンジル、この基は任意に1個または2個以上のハロゲン、アルキルまたはアルコキシにより置換されていてもよい、
−アミノ、この基は任意に1個または2個のアルキルにより置換されていてもよい、
−ヘテロアリール基、この基は任意に、(CH2)k−ヘテロ環状アルキル基により置換されていてもよく、ここでkは0、1、2または3である、
−NH−R3、ここでR3は水素、アルキル、アルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、アミノアルキル、アミノアリールまたはアミノヘテロアリールである、であり、および
nは1、2、3または4である。
例1: N−[3−(6−クロロ−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例2: N−{3−[6−(2−ベンジルオキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例3: N−[3−(6−スチリル−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例4: N−{3−[6−(2−フェノキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例5: N−{3−[6−(2−エトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例6: N−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例7: N−{3−[6−(4−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例8: N−{3−[6−(2−イソプロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例9: N−{3−[6−(5−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例10:N−(3−{6−[2−(4−フルオロ−ベンジルオキシ)−フェニル]−ピリミジン−4−イルアミノ}−ベンジル)−メタンスルホンアミド
例12:N−{3−[6−(2−エチル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例13:N−{3−[6−(2−フルオロ−6−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例14:N−{3−[6−(4−フルオロ−2−イソプロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例15:N−{3−[6−(2−トリフルオロメトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例16:N−{3−[6−(2−フルオロ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例17:N−{3−[6−(2,4−ジフルオロ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例18:N−{3−[6−(2−トリフルオロメチル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例19:N−{3−[6−(4−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例20:3−{6−[3−(メタンスルホニルアミノ−メチル)−フェニルアミノ]−ピリミジン−4−イル}−ベンズアミド
例22:N−{3−[6−(3−アミノ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例23:N−{3−[6−(2,3−ジメトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例24:N−{3−[6−(2,4−ジメトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例25:N−{3−[6−(4−クロロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例26:N−{3−[6−(2−メトキシ−5−メチル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例27:N−[3−(6−ベンゾ[1,3]ジオキソール−4−イル−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例28:N−{3−[6−(2−メチルスルファニル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例29:N−{3−[6−(2−メタンスルフィニル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例30:N−(3−{6−[2−(4−トリフルオロメトキシ−フェノキシメチル)−フェニル]−ピリミジン−4−イルアミノ}−ベンジル)−メタンスルホンアミド
例32:N−{3−[6−(1H−ピラゾール−4−イル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例33:N−[4−(6−クロロ−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例34:N−{4−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例35:N−{4−[6−(2−ベンジルオキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例36:N−(4−{6−[2−(4−フルオロ−ベンジルオキシ)−フェニル]−ピリミジン−4−イルアミノ}−ベンジル)−メタンスルホンアミド
例37:N−{4−[6−(2−エトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例38:N−{4−[6−(5−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例39:N−{4−[6−(4−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例40:N−{4−[6−(2−フェノキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例42:N−{4−[6−(2,4−ジフルオロ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例43:N−{4−[6−(2−トリフルオロメチル−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例44:N−{4−[6−(2−フルオロ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例45:N−[4−(6−フェニル−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例46:N−{4−[6−(3−アミノ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例47:N−{4−[6−(3−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例48:N−{4−[6−(4−フルオロ−2−イソプロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例49:N−(4−{6−[2−(3−フルオロ−ベンジルオキシ)−フェニル]−ピリミジン−4−イルアミノ}−ベンジル)−メタンスルホンアミド
例50:N−(4−{6−[2−(4−メトキシ−ベンジルオキシ)−フェニル]−ピリミジン−4−イルアミノ}−ベンジル)−メタンスルホンアミド
例52:N−[4−(6−ピリジン−3−イル−ピリミジン−4−イルアミノ)−ベンジル]−メタンスルホンアミド
例53:N−{4−[6−(2−プロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例54:N−{4−[6−(4−クロロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例55:N−{4−[6−(2,3−ジメトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例56:N−{4−[6−(2−イソプロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例57:N−{4−[6−(4−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例58:N−{4−[6−(1H−ピラゾール−4−イル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例59:(1H−ベンゾイミダゾール−2−イル)−[3−(6−クロロ−ピリミジン−4−イルアミノ]−ベンジル}−アミン
例60:(1H−ベンゾイミダゾール−2−イル)−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−アミン
例62:(1H−ベンゾイミダゾール−2−イル)−{3−[6−(5−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−アミン
例63:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−(6−クロロ−ピリミジン−4−イル)−アミン
例64:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(2−メトキシ−フェニル)−ピリミジン−4−イル]−アミン
例65:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(4−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イル)−アミン
例66:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(5−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イル]−アミン
例67:2−[3−(6−クロロ−ピリミジン−4−イルアミノ)−ベンジル]−イソインドール−1,3−ジオン
例68:2−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−イソインドール−1,3−ジオン
例69:(3−アミノメチル−フェニル)−[6−(2−メトキシ−フェニル)−ピリミジン−4−イル]アミン塩酸塩
例70:2,6−ジクロロ−N−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−ベンゼンスルホンアミド
例72:4−フルオロ−N−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−ベンゼンスルホンアミド
例73:チオフェン−2−スルホン酸3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジルアミド
例74:N−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−C−フェニル−メタンスルホンアミド
例75:N−{3−[6−(4−ヒドロキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例76:N−{4−[6−(4−ヒドロキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−メタンスルホンアミド
例77:(1H−ベンゾイミダゾール−2−イル)−{3−[6−(4−フルオロ−2−イソプロポキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−アミン
例78:4−(6−{3−[(1H−ベンゾイミダゾール−2−イルアミノ)−メチル]−フェニルアミノ}−ピリミジン−4−イル)−フェノール
例79:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(2−フルオロ−6−メトキシ−フェニル)−ピリミジン−4−イル]−アミン
例80:(3−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(2−イソプロポキシ−フェニル)−ピリミジン−4−イル]−アミン
例82:4−[6−(3−ベンゾイミダゾール−1−イルメチル−フェニルアミノ)−ピリミジン−4−イル]−フェノール
例83:3−[6−(3−ベンゾイミダゾール−1−イルメチル−フェニルアミノ)−ピリミジン−4−イル]−フェノール
例84:4−フルオロ−N−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−ベンズアミド
例85:1−(4−フルオロ−フェニル)−3−{3−[6−(2−メトキシ−フェニル)−ピリミジン−4−イルアミノ]−ベンジル}−尿素
例86:(4−ベンゾイミダゾール−1−イルメチル−フェニル)−(6−クロロ−ピリミジン−4−イル)−アミン
例87:(4−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(2−メトキシ−フェニル)−ピリミジン−4−イル)−アミン
例88:(4−ベンゾイミダゾール−1−イルメチル−フェニル)−[6−(4−フルオロ−2−イソプロポキシ−フェニル)−ピリミジン−4−イル]−アミン
例89:4−[6−(4−ベンゾイミダゾール−1−イルメチル−フェニルアミノ)−ピリミジン−4−イル]−フェノール
例90:(6−クロロ−ピリミジン−4−イル)−(3−インドール−1−イルメチル−フェニル)−アミン
例92:(6−クロロ−ピリミジン−4−イル)−[3−(2−モルホリン−4−イルメチル−ベンゾイミダゾール−1−イルメチル)−フェニル]−アミン
例93:[6−(2−メトキシ−フェニル)−ピリミジン−4−イル]−[3−(2−モルホリン−4−イルメチル−ベンゾイミダゾール−1−イルメチル)−フェニル]−アミン
例94:[6−(4−フルオロ−2−メトキシ−フェニル)−ピリミジン−4−イル]−[3−(2−モルホリン−4−イルメチル−ベンゾイミダゾール−1−イルメチル)−フェニル]−アミン
記号nは好ましくは、1〜3、さらに好ましくは1または2、最も好ましくは1である。
a)式(b)において、R2がC1−4アルキル、好ましくはC1−2アルキル、最も好ましくはメチルである基(すなわち、−(CH2)n−W部分がメタンスルホンアミド基である化合物)。
もう一つの好適な具体例において、R2はヘテロアリールを表し、この基は好ましくは、N、OおよびSの群から選択されるヘテロ原子、さらに好ましくは1個または2個のS−原子を含有する5−または6−員のヘテロアリールである。この場合、R2は最も好ましくは、チオフェン基である。
A.ウイルス B、細菌
II. 非感染原因
III. 慢性(肉芽腫性)疾病
A.細菌 B.スピロヘータ
C.真菌(カビ) D. 特発性
IV. アレルギー性、免疫性および特発性障害
A.過敏反応
B.免疫性および特発性障害
V. 多様な炎症状態
A.寄生体感染
B.吸入抗原原因 −急性(熱的)損傷
−花粉および吸入抗原
−発がん性物質
C.放射線性損傷 −放射線壊死
A1)一般的合成スキーム
本発明による4,6−ジ置換ピリミジンの誘導体の合成は第一工程におけるスズキ反応に従うピリミジン環のアミノ化または逆の順序の反応工程を包含するスキーム1に示されている一般的合成順序に従い行うと好ましい。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例2に記載の方法と同一の方法に従い製造した。収率は15〜70%であり、いくつかの場合、生成物の精製にカラムクロマトグラフィを使用した。分析結果および化合物同定については表1参照。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例33に記載の方法と同一の方法に従い製造した。収率は15〜70%であり、いくつかの場合、生成物の精製にカラムクロマトグラフィを使用した。分析結果および化合物同定については表1参照。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例60に記載の方法と同一の方法に従い製造した。収率は50〜70%である。分析結果および化合物同定については表1参照。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例64に記載の方法と同一の方法に従い製造した。収率は50〜70%である。分析結果および化合物同定については表1参照。
化合物は対応する酸クロライドまたはイソシアネートおよび反応時間(TLCが反応の完了を示すまで)を使用し、例70に記載の方法と同一の方法に従い製造した。収率は10〜60%であり、いくつかの場合、カラムクロマトグラフィを使用し、生成物を精製した。分析結果および化合物同定については表1参照。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例87に記載の方法と同一の方法に従い製造した。収率は50〜70%であった。分析結果および化合物同定については表1参照。
化合物は対応するボロン酸および反応時間(TLCが反応の完了を示すまで)を使用し、例93に記載の方法と同一の方法に従い製造した。収率は19%であった。分析結果および化合物同定については表1参照。
分析方法(HPLC−MS、NMR)
Waters HPLC/MS
MS検出計:Waters SQD
UV検出計:Waters 996DAD
分離モジュール:Waters Alliance2795
カラム:Waters XBridge C18、5cmx4.6mm、3.5μm
溶媒A:水/0.1%HCOOH
溶媒B:AcCN
アセトニトリル:Riedel−deHaen;G Chromasolv(34998)
水:Mill−Q Academic
ギ酸:Riedel−deHaen;エキストラビュア(27001)
流動速度:2ml/分
0.00 5
0,50 5
5.50 95
6.00 95
6.50 5
7.00 5
注入:5μg
イオン化:ES+/ES−
原始ブロック温度:110℃
脱溶媒和(desolvation)温度:250℃
脱溶媒和ガス:500L/時間
コーンガス:80L/時間
毛管:3000V
コーン:30V
抽出装置:6V
Rf レンズ:0.1V
スキャン:1秒で80〜1000m/z
内部スキャン遅延:0.1秒
本発明で開示されている化合物の活性は下記キナーゼ分析によって測定することができる。この分析は市販のIMAP Screening Express Assay Kit(Molecular devices)を用いる蛍光偏光によってヒトCDK9/サイクリンTキナーゼ複合体による蛍光標識したペプチドのホスホリル化を測定するものである。
A: <0.1μM(IC50)
B: <1μM(IC50)
C: <10μM(IC50)
D: 10μM(IC50)<
Claims (14)
- 一般式(I)で表される化合物およびその医薬上で許容される塩および溶媒和物:
式中、
R1は *ハロゲン;
* ビニレン−アリール;
*アリール、この基は1個または2個以上の下記群から選択される置換基により置換されている、
−アルコキシ、この基は任意に1個または2個以上のハロゲンにより、またはアリールにより置換されていてもよく、このアリールは任意に1個または2個以上のハロゲン、アルキルまたはアルコキシにより置換されていてもよい;
−ハロゲン、
−アルキル、この基は任意に1個または2個以上のハロゲンまたはアルコキシにより置換されていてもよい、
−アルキルアリールオキシ、この基は任意にアルコキシにより置換されていてもよく、このアルコキシは任意に1個または2個以上のハロゲンにより置換されていてもよい、
−アミノカルボニル、
−アミノ、この基は任意に1個または2個のアルキルにより置換されていてもよい、
−アルキルチオ、
−アルキルスルフィニルまたはアルキルスルホニル、
−アリールオキシ、
−ヒドロキシル;
*式(a)で表される基:
式中、mは1、2または3であり、およびR’は水素、ハロゲン、アルキルまたはアルコキシである;
*ヘテロアリールであり、
ピリミジン環の6位にあり;
Wは、
*式(b)で表される基:
式中、R2は、
−アルキル、アルコキシまたはアリール、これらの基は任意に1個または2個以上のハロゲンにより置換されていてもよい、
−ヘテロアリール、
−ベンジル、この基は任意に1個または2個以上のハロゲン、アルキルまたはアルコキシにより置換されていてもよい、
−アミノ、この基は任意に1個または2個のアルキルにより置換されていてもよい、
*ヘテロアリール基、この基は任意に(CH2)k−ヘテロ環状アルキル基により置換されていてもよく、ここでkは0、1、2または3である、
*NH−R3、ここでR3は水素、アルキル、アルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、アミノアルキル、アミノアリール、アミノヘテロアリール、−CO−アリールまたは−CO−NH−アリールであり、ここで−CO−アリールまたは−CO−NH−アリールのアリール基は任意に、1個または2個以上のハロゲンにより置換されていてもよい;
であり;および
nは1、2、3または4である。 - R1の意味中のヘテロアリールが、1個または2個のN−原子を含有する5−または6−員のヘテロアリールである、請求項1に記載の化合物。
- R2の意味中のヘテロアリールが、1個または2個のS−原子を含有する5−または6−員のヘテロアリールである、請求項1または2に記載の化合物。
- Wの意味中のヘテロアリールが、一方の環にN、OおよびSの群から選択される少なくとも1個のヘテロ原子を含有し、他方の環がベンゼン環である縮合二環状ヘテロアリール基であって、この基は任意に窒素含有環が1個または2個のオキソ基により置換されていてもよく、およびベンゼン環が任意に1個または2個以上のハロゲン、アルキルまたはアルコキシにより置換されていてもよい縮合二環状ヘテロアリール基である、請求項1〜3のいずれかに記載の化合物。
- Wの意味中のヘテロアリールが1−ベンゾイミダゾリル基である、請求項1〜3のいずれかに記載の化合物。
- Wの意味中のヘテロアリールのヘテロ環状アルキル置換基が、4〜7個の原子の飽和環であって、1個または2個の環員がO、SおよびNRxからなる群から選択され、ここでRxは水素またはアルキルである、請求項1〜3のいずれかに記載の化合物。
- R3の意味中のヘテロアリールが一方の環中にN、OおよびSからなる群から選択される少なくとも1個のヘテロ原子を含有し、および他方の環がベンゼン環である二環状縮合ヘテロアリール基である、請求項1〜3のいずれかに記載の化合物。
- R 3 が−CO−アリールまたは−CO−NH−アリールであり、ここでこのアリール基は任意に、1個または2個以上のハロゲンにより置換されていてもよい、請求項1〜3のいずれかに記載の化合物。
- 1種または2種以上の請求項1〜3のいずれかに記載の化合物を活性成分として、1種または2種以上医薬上で許容される補助物質とともに含有する医薬組成物。
- 細胞増殖性疾病、感染性疾病、痛み、心臓血管系疾病および炎症の予防および/または処置用の医薬の調製における請求項1〜8のいずれかに記載の一般式(I)で表される化合物の使用
- 細胞増殖性疾病、感染性疾病、痛み、心臓血管系疾病および炎症の予防および/または処置に使用される請求項1〜8のいずれかに記載の一般式(I)で表される化合物。
- 請求項1〜8のいずれかに記載の一般式(I)で表される化合物をこれを必要とする各対象に投与する、細胞増殖性疾病、感染性疾病、痛み、心臓血管系疾病および炎症の予防および/または処置のための請求項9に記載の医薬組成物。
- R 1 がピリジンまたはピラゾール基であり、R 2 がチオフェン基である、請求項1に記載の化合物。
- R 3 の意味中のヘテロアリールが2−ベンズイミダゾール基である、請求項7に記載の化合物。
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PCT/HU2010/000145 WO2011077171A1 (en) | 2009-12-21 | 2010-12-17 | 4-phenylamino-pyrimidine derivatives having protein kinase inhibitor activity |
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US9498471B2 (en) | 2011-10-20 | 2016-11-22 | The Regents Of The University Of California | Use of CDK9 inhibitors to reduce cartilage degradation |
US9617225B2 (en) * | 2012-08-23 | 2017-04-11 | Virostatics Srl | 4,6-disubstituted aminopyrimidine derivatives have anti-HIV activity |
EP2769722A1 (en) * | 2013-02-22 | 2014-08-27 | Ruprecht-Karls-Universität Heidelberg | Compounds for use in inhibiting HIV capsid assembly |
CA3000633C (en) | 2014-10-14 | 2023-10-03 | The Regents Of The University Of California | Use of cdk9 and brd4 inhibitors to inhibit inflammation |
CN107207475A (zh) | 2014-10-16 | 2017-09-26 | 拜耳医药股份有限公司 | 含有砜基团的氟化苯并呋喃基‑嘧啶衍生物 |
CN108290903B (zh) | 2015-09-29 | 2021-09-03 | 拜耳医药股份有限公司 | 新的大环磺酰二亚胺化合物 |
CN108368129B (zh) | 2015-10-08 | 2021-08-17 | 拜耳医药股份有限公司 | 改性大环化合物 |
WO2017060322A2 (en) | 2015-10-10 | 2017-04-13 | Bayer Pharma Aktiengesellschaft | Ptefb-inhibitor-adc |
US20180015153A1 (en) | 2016-07-16 | 2018-01-18 | Florida State University Research Foundation, Inc. | Compounds and methods for treatment and prevention of flavivirus infection |
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WO2019075011A1 (en) | 2017-10-10 | 2019-04-18 | Florida State University Research Foundation, Inc. | EMETIC COMPOUNDS FOR THE TREATMENT AND PREVENTION OF FLAVIVIRUS INFECTION |
IT201900004737A1 (it) | 2019-03-29 | 2020-09-29 | Virostatics Srl | Composti aventi attività enzimatica anti-CDK4/6 e anti-CDK9 per l’inibizione della proliferazione del cancro e relativi metodi di screening per la loro identificazione. |
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