JP2017528475A - Rafキナーゼ阻害剤としての化合物および組成物 - Google Patents
Rafキナーゼ阻害剤としての化合物および組成物 Download PDFInfo
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- JP2017528475A JP2017528475A JP2017513759A JP2017513759A JP2017528475A JP 2017528475 A JP2017528475 A JP 2017528475A JP 2017513759 A JP2017513759 A JP 2017513759A JP 2017513759 A JP2017513759 A JP 2017513759A JP 2017528475 A JP2017528475 A JP 2017528475A
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- raf
- compounds
- pharmaceutically acceptable
- compound
- cancer
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- 235000019260 propionic acid Nutrition 0.000 description 1
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 201000000849 skin cancer Diseases 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- JJGWLCLUQNFDIS-GTSONSFRSA-M sodium;1-[6-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCCCCNC(=O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1 JJGWLCLUQNFDIS-GTSONSFRSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000007921 solubility assay Methods 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 231100001274 therapeutic index Toxicity 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 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
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
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- 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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Abstract
Description
a)賦形剤、例えば、ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロースおよび/またはグリシン、
b)やはり錠剤のための、滑沢剤、例えば、シリカ、タルカム、ステアリン酸、そのマグネシウム塩もしくはカルシウム塩、および/またはポリエチレングリコール、
c)必要に応じて、結合剤、例えば、ケイ酸アルミニウムマグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロースナトリウム、および/またはポリビニルピロリドン、
d)崩壊剤、例えば、デンプン、寒天、アルギン酸もしくはそのナトリウム塩、または発泡混合物、ならびに/あるいは
e)吸収剤、着色剤、着香剤および甘味剤。
本発明は、本発明の化合物を調製するための方法も含む。記載されている反応において、反応性官能基、例えば、ヒドロキシ、アミノ、イミノ、チオまたはカルボキシ基を保護する必要となり得、この場合、これらの官能基は、最終生成物において、反応においてそれらが望ましくない関与をするのを回避することが望ましいものである。従来の保護基は、慣例に従って使用することができ、例えば、T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991を参照されたい。
本発明の化合物は、遊離塩基の形態の本化合物を薬学的に許容される無機酸または有機酸と反応させることにより、薬学的に許容される酸付加塩として調製することができる。あるいは、本発明の化合物の薬学的に許容される塩基付加塩は、遊離酸形態の本化合物を薬学的に許容される無機塩基または有機塩基と反応させることにより調製することができる。
本発明は、以下に限定されないが、以下の中間体、および本発明による式Iの化合物の調製を例示している実施例によりさらに例示される。
N−(3−(6−(2−ヒドロキシエトキシ)−5−モルホリノピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミドの合成
(R)−N−(3−(2−(2−ヒドロキシエトキシ)−6−(3−メチルモルホリノ)ピリジン−4−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミドの合成
本発明による化合物の活性は、周知のインビトロ法およびインビボ法によって評価することができる。本明細書において提示されているRaf阻害データは、以下の手順を使用して得た。
Claims (11)
- 式I:
R1は、水素およびメチルから選択され、
R2は、ピリジニルおよびフェニルから選択され、ここで、フェニルまたはピリジニルは、トリフルオロメチル、1,1−ジフルオロエチルおよび2−フルオロプロパン−2−イルから選択される基により置換されていてよく、
XおよびYは、Nおよび−OCH2CHR3R4から独立して選択され、ここで、R3は、水素およびOHから選択され、R4は、2−(ホスホノオキシ)メチルおよびホスホノオキシから選択され、ただし、XがNである場合、Yは−OCH2CHR3R4であり、YがNである場合、Xは−OCH2CHR3R4であり、
Zは、NおよびCHから選択される)
の化合物または薬学的に許容されるその塩。 - 式Ia:
R1は、水素およびメチルから選択され、
R2は、ピリジニルおよびフェニルから選択され、ここで、フェニルまたはピリジニルは、トリフルオロメチル、1,1−ジフルオロエチルおよび2−フルオロプロパン−2−イルから選択される基により置換されていてよく、
R3は、水素およびOHから選択され、
R4は、2−(ホスホノオキシ)メチルおよびホスホノオキシから選択され、
Zは、NおよびCHから選択される)の、請求項1に記載の化合物または薬学的に許容されるその塩。 -
- 式Ib:
R1は、水素およびメチルから選択され、
R2は、ピリジニルおよびフェニルから選択され、ここで、フェニルまたはピリジニルは、トリフルオロメチル、1,1−ジフルオロエチルおよび2−フルオロプロパン−2−イルから選択される基により置換されていてよく、
R3は、水素およびOHから選択され、
R4は、2−(ホスホノオキシ)メチルおよびホスホノオキシから選択され、
Zは、NおよびCHから選択される)の、請求項1に記載の化合物または薬学的に許容されるその塩。 -
- 次式:
- 請求項1に記載の化合物または薬学的に許容されるその塩、および1種または複数の薬学的に許容される担体を含む、医薬組成物。
- 治療有効量の請求項1に記載の化合物または薬学的に許容されるその塩、および1種または複数の治療上活性な共剤を含む、組合せ。
- 卵巣がん、非小細胞肺がん、およびRas変異によって推進されるがんから選択される増殖性障害を処置する方法であって、それを必要とする対象に治療有効量の請求項1に記載の化合物または薬学的に許容されるその塩を投与するステップを含む、方法。
- 医薬として使用するための、請求項1に記載の化合物または薬学的に許容されるその塩。
- がんの処置において使用するための、請求項1に記載の化合物または薬学的に許容されるその塩。
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