JP2011527684A - Axl阻害剤として有用な架橋二環ヘテロアリール置換トリアゾール - Google Patents
Axl阻害剤として有用な架橋二環ヘテロアリール置換トリアゾール Download PDFInfo
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- JP2011527684A JP2011527684A JP2011517496A JP2011517496A JP2011527684A JP 2011527684 A JP2011527684 A JP 2011527684A JP 2011517496 A JP2011517496 A JP 2011517496A JP 2011517496 A JP2011517496 A JP 2011517496A JP 2011527684 A JP2011527684 A JP 2011527684A
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- triazole
- diamine
- ethano
- tetrahydro
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- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
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- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 201000008171 proliferative glomerulonephritis Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
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- 238000004659 sterilization and disinfection Methods 0.000 description 1
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- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000005891 transamination reaction Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 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
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
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Classifications
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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- C07D471/12—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 three hetero rings
- C07D471/18—Bridged systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Aは −C(R1)(H)−又は−N(R2)−であり;
R1は −N(R3)R4 及び −N(R3)C(O)−R5−N(R3)R4からなる群から選択され;
R2は水素、シクロアルキル及び−C(O)−R5−N(R3)R4からなる群から選択され;
R3及びR4は各々独立に水素及びアルキルからなる群から選択される。
Bは、直接結合又は−CH2−であり、
R6 は、水素、ハロ、ハロアルキル、アルコキシ及びアルキルからなる群から選択され、但し、式(I)の化合物は、1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(3−フルオロ−4−(4−(ピロリジン−1−イル)ピペリジン−1−イル)フェニル)−1H−1,2,4−トリアゾール−3,5−ジアミンではない。
R7 は、−N(R12)R13及び−N(R12)C(O)OR13からなる群から選択され、
R12及びR13は各々独立して、水素、アルキル及びシクロアルキルからなる群から選択される。
R8は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にシアノ及びアルキルからなる群から選択される置換基で置換されていてもよい。
R9は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にハロ及びアルキルからなる群から選択される置換基で置換されていてもよい。
R10はハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にハロ、シアノ、アルコキシ及びアルキルからなる群から選択される1又は複数の置換基で置換されていてもよい。
R11は、以下:
R7は、ニトロ、ハロまたは−C(O)OR2であり、
R2は、水素、アルキル、アルケニル、場合により置換されているアラルキル、場合により置換されているシクロアルキル、場合により置換されているシクロアルキルアルキルおよび場合により置換されているヘテロアリールである]
を調製する方法であって、
式(i)の化合物:
R7は、ニトロ、ハロまたは−C(O)OR2であり、
R2は、水素、アルキル、アルケニル、場合により置換されているアラルキル、場合により置換されているシクロアルキル、場合により置換されているシクロアルキルアルキルおよび場合により置換されているヘテロアリールである]
を、適切な条件下、触媒量の(S)−特異的トランスアミナーゼの存在下においてアミノ供与体分子で処理して、(S)−鏡像異性体を形成するステップを含む方法を提供する。
本明細書および添付の特許請求の範囲において使用される場合、そうでないと指定しない限り、下記の用語は示されている意味を有する。
(i)特に、哺乳動物が該状態にかかりやすいが未だ罹患しているとの診断が為されていない場合、そのような哺乳動物において該疾患または状態が発生するのを予防すること、
(ii)該疾患または状態を阻害すること、すなわちその発症を阻止すること、
(iii)該疾患または状態を軽減すること、すなわち該疾患または状態の後退を引き起こすこと、あるいは
(iv)該疾患または状態を安定させること
を含む。
「発明の概要」において上記で説明した通りの本発明の化合物の種々の態様のうち、ある特定の実施形態が好ましい。
R1は−N(R3)R4及び−N(R3)C(O)−R5−N(R3)R4からなる群から選択され、
R3及びR4 は各々独立に水素及びアルキルからなる群から選択される化合物であって、単離された立体異性体又はそれらの混合物、あるいはその製薬的に許容される塩である。
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−アミノ−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−[(((ジアミノ)アミノ)メチル)カルボニルアミノ]−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−(シクロペンチルアミノ)−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
R2は水素、シクロアルキル及び−C(O)−R5−N(R3)R4からなる群から選択され、
R3及びR4は各々独立に水素及びアルキルからなる群から選択される化合物であって、単離された立体異性体又はそれらの混合物、あるいはその製薬的に許容される塩である。
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−[((ジメチル)アミノ)メチルカルボニル]−5,6,7,8−テトラヒドロ−1,6−ナフチリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−(シクロペンチル)−5,6,7,8−テトラヒドロ−1,6−ナフチリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
1−(6,9−エタノ−4−フェニル−6,7,8,9−テトラヒドロ−5H−ピリド[3,2−c]アゼピン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジンイル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(4−フルオロフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−フルオロフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−トリフルオロメチルフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−メトキシフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(1,4−エタノ−8−(2−メチルフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(t−ブトキシカルボニルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジエチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジメチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(イソプロピルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(シクロブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジプロピルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(イソブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−yl)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジイソブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
R8は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にシアノ及びアルキルからなる群から選択される置換基で置換されていてもよい。
1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−シアノフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(ベンゾ[d][1,3]ジオキソル−5−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;及び
1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
R8は、ハロ、ピリジニル、ベンゾジオキソニル及びフェニルからなる群から選択され、それらはシアノ及びアルキルからなる群から選択される置換基で任意に置換れていてもよい。
1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N5−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
(3S)−1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−フェニル−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
(3S)−1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−フェニル−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−シアノフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−エトキシ−5−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(4−フルオロ−2−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
1−(4−フェニル−5,6,7,8−テトラヒドロキナゾリン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニルl)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;及び
1−(5,8−エタノ−4−フェニル−5,6,7,8−テトラヒドロピリド[3,2−d]ピリミジン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
発癌性RTKであるAxlは、レトロウイルスベースの機能的遺伝子スクリーニングプロトコールを使用し、血管新生における主要イベントである走触性移動の調節因子として最近同定された。RNAi媒介性サイレンシングによるAxl阻害は、内皮細胞移動、増殖およびインビトロ管形成を遮断した。American Association Cancer Research General Meeting、2005年4月16〜20日、Anaheim、Californiaおよび第7回Annual Symposium on Anti−Angiogenic Agents、2005年2月10〜13日、San Diego、California;(Requirement for The Receptor Tyrosine Kinase Axl in Angiogenesis and Tumor Growth、Holland,S.J.、Powell,M.J.、Franci,C.、Chan,E.、Friera,A.M.、Atchison,R.、Xu,W.、McLaughlin,J.、Swift,S.E.、Pali,E.、Yam,G.、Wong,S.、Xu,X.、Hu,Y.、Lasaga,J.、Shen,M.、Yu,S.、Daniel,R.、Hitoshi,Y.、Bogenberger,J.、Nor,J.E.、Payan,D.GおよびLorens,J.B)において開示されたこれらの知見は、安定なshRNAi媒介性Axlノックダウンが、ヒト血管新生のマウスモデルにおいて機能的ヒト血管の形成を損なうことを実証したインビボ研究によって立証された。これらの知見は、論文審査のある学術誌(Holland SJ、Powell MJ、Franci C、Chan EW、Friera AM、Atchison RE、McLaughlin J、Swift SE、Pali ES、Yam G、Wong S、Lasaga J、Shen MR、Yu S、Xu W、Hitoshi Y、Bogenberger J、Nor JE、Payan DG、Lorens JB、「Multiple roles for the receptor tyrosine kinase axl in tumor formation」、Cancer Res.(2005)、第65巻、9294〜303頁において公開された。これらの知見は、米国公開特許出願第2005/0118604号および欧州特許出願第1563094号においても開示されており、これらの開示は、参照により全体が組み込まれる。したがって、Axlシグナル伝達は、インビトロにおける新血管形成のために必要な複数の機能に影響を及ぼし、インビボにおける血管新生を調節する。これらの前血管新生過程の調節には、Axlの触媒活性が必要であった。このように、Axl媒介性血管新生刺激は、Axl触媒活性の小分子阻害剤による変調の影響を受けやすい。
本発明の化合物またはそれらの薬学的に許容できる塩の、純粋形態または適切な医薬組成物での投与は、同様の有用性をもたらす作用物質の認められている投与モードのいずれかによって行われ得る。本発明の医薬組成物は、本発明の化合物を、適切な薬学的に許容できる担体、賦形剤または添加剤と組み合わせることによって調製でき、錠剤、カプセル剤、散剤、顆粒剤、軟膏剤、液剤、坐剤、注射剤、吸入剤、ゲル剤、マイクロスフェア剤およびエアゾール剤等、固体、半固体、液体または気体形態の調製物に製剤化され得る。そのような医薬組成物を投与する典型的な経路は、経口、局所、経皮、吸入、非経口、舌下、口腔、直腸、膣内および鼻腔内を含むがこれらに限定されない。非経口という用語は、本明細書において使用される場合、皮下注射、静脈、筋肉内、胸骨内注射または注入技術を含む。本発明の医薬組成物は、その中に含有されている活性成分が、患者への組成物の投与時に生物学的に利用可能であるように製剤化される。対象または患者に投与される組成物は、1種または複数の投薬単位の形態をとり、ここで、例えば、錠剤は単一投薬単位であってよく、エアゾール剤形態の本発明の化合物の容器は複数の投薬単位を収納し得る。そのような剤形を調製する実際の方法は、当業者には既知であるか、または明白であろう。例えば、Remington:The Science and Practice of Pharmacy、第20版(Philadelphia College of Pharmacy and Science、2000)を参照されたい。投与される組成物は、いずれの場合も、本発明の教示に従う関心対象の疾患または状態の治療のための、治療有効量の本発明の化合物または薬学的に許容できるその塩を含有する。
下記の反応スキームは、前記の発明の概要に記載した本発明の化合物を、単離された立体異性体又はその混合物として、互変異性体又はその混合物として、あるいは製薬的に許容される塩又はN−オキサイドとして、製造するための方法を例示する。以下の反応スキームにおいて、置換基の組み合わせ及び/又は表示した式の変数は、そのような寄与(contributions)が安定な化合物をもたらす場合に限り許されると解される。
ホスホ−Akt細胞内ウエスタンアッセイ
本発明の化合物を、下記のアッセイにおいて、Axl活性を阻害するそれらの能力について試験した。
細胞培養プレート:96ウェルアッセイプレート(Corning3610)、白色、透明底、組織培養処理済。
細胞:Hela細胞
飢餓培地:Axl刺激用:DMEM中0.5%FCS(ウシ胎仔血清)、プラスAxl/Fc(免疫グロブリン(imunoglobulin)Fc領域と縮合したAXLの細胞外ドメイン)(R&D、154−AL)500ng/mL。
EGF(上皮成長因子)刺激用:DMEM(ダルベッコ変法イーグル培地)中0.5%FCS。
ポリ−L−リジン0.01%溶液(希釈標準溶液):10μg/ml、PBS(リン酸緩衝生理食塩水)中で希釈。
Axl抗体架橋:
第1:マウス抗Axl(R&D、MAB154)。
第2:ビオチン−SP共役アフィニピュアヤギ抗マウスIgG(H+L)(Jackson ImmunoResearch、115−065−003番)。
固定緩衝剤:PBS中4%ホルムアルデヒド。
洗浄緩衝剤:PBS中0.1%トリトンX−100。
クエンチ緩衝剤:洗浄緩衝剤中3%H2O2、0.1%アジド、アジドおよび過酸化水素(H2O2)は、新鮮なものを添加する。
ブロック緩衝剤:TBST(トリス緩衝生理食塩水プラス0.1%ツイン20)中5%BSA。
一次抗体:ウサギ抗ヒトホスホ−Akt抗体(Cell Signaling9271):ブロック緩衝剤中で1×250希釈。
二次抗体:HRP(西洋ワサビペルオキシダーゼ)共役ヤギ抗ウサギ二次、ストック溶液:Jackson ImmunoResearch(ヤギ抗ウサギHRP、111−035−144番)をグリセロール中1:1希釈、−20℃で保存する。希釈標準溶液:ストックのブロック緩衝剤中1×2000希釈物。
化学発光希釈標準溶液(Pierce、37030):スーパーシグナルELISA(酵素結合免疫吸着剤(immunosorbant)アッセイ)ピコ化学発光基質。
クリスタルバイオレット溶液:ストック:メタノール中2.5%クリスタルバイオレット、濾過し周囲温度で保つ。希釈標準溶液:使用直前にストックをPBSで1:20に希釈。
10%SDS:希釈標準溶液:5%SDS(ドデシル硫酸ナトリウム)、PBS中で希釈。
第1日目:
96ウェルTC(組織培養処理済)プレートを、10μg/mLポリ−L−リジンにより37℃で30分間コーティングし、PBSで2回洗浄し、5分間風乾させた後、細胞を添加した。Hela細胞を10,000細胞/ウェルで播種し、細胞を、Axl/Fcを含有する100μLの飢餓培地中で24時間飢餓させた。
細胞上の飢餓培地に100μLの2×試験化合物を添加することにより、細胞を試験化合物で前処理した。細胞を刺激前に37℃で1時間インキュベートした。
洗浄緩衝剤を除去し、希釈した二次抗体(100μL)を添加し、細胞を穏やかに振とうしながら周囲温度で1時間インキュベートした。インキュベーション中に、化学発光試薬を周囲温度にした。
Claims (20)
- 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(I):
Aは −C(R1)(H)−又は−N(R2)−であり;
R1は −N(R3)R4 及び −N(R3)C(O)−R5−N(R3)R4からなる群から選択され;
R2は水素、シクロアルキル及び−C(O)−R5−N(R3)R4からなる群から選択され;
R3及びR4は各々独立に水素及びアルキルからなる群から選択される)で表される化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(Ia):
R1は−N(R3)R4及び−N(R3)C(O)−R5−N(R3)R4からなる群から選択され、
R3及びR4は各々独立に水素及びアルキルからなる群から選択される)で表される、請求項1に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(Ib):
R2は水素、シクロアルキル及び−C(O)−R5−N(R3)R4からなる群から選択され、
R3及びR4は各々独立に水素及びアルキルからなる群から選択される)で表される、請求項1に記載の化合物。 - 1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−アミノ−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−[(((ジアミノ)アミノ)メチル)カルボニルアミノ]−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−(シクロペンチルアミノ)−5,6,7,8−テトラヒドロキノリン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン。
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(5,6,7,8−テトラヒドロ−1,6−ナフチリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−[((ジメチル)アミノ)メチルカルボニル]−5,6,7,8−テトラヒドロ−1,6−ナフチリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(6−(シクロペンチル)−5,6,7,8−テトラヒドロ−1,6−ナフチリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項1に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(Ia):
Bは、直接結合又は−CH2−であり、
R6 は、水素、ハロ、ハロアルキル、アルコキシ及びアルキルからなる群から選択され、但し、式(I)の化合物は、1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(3−フルオロ−4−(4−(ピロリジン−1−イル)ピペリジン−1−イル)フェニル)−1H−1,2,4−トリアゾール−3,5−ジアミンではない)で表される化合物。 - 1−(6,9−エタノ−4−フェニル−6,7,8,9−テトラヒドロ−5H−ピリド[3,2−c]アゼピン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジンイル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(4−フルオロフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−フルオロフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−トリフルオロメチルフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(1,4−エタノ−8−(3−メトキシフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(1,4−エタノ−8−(2−メチルフェニル)−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項5に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(III):
R7 は、−N(R12)R13及び−N(R12)C(O)OR13からなる群から選択され、
R12及びR13は各々独立して、水素、アルキル及びシクロアルキルからなる群から選択される)で表される化合物。 - (7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(t−ブトキシカルボニルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジエチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジメチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(イソプロピルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(シクロブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジプロピルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(イソブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−yl)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
(7S)−1−(1,4−エタノ−8−フェニル−1,2,3,4−テトラヒドロ−1,5−ナフチリジン−6−イル)−N3−(7−(ジイソブチルアミノ)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項7に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(IV):
R8は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にシアノ及びアルキルからなる群から選択される置換基で置換されていてもよい)で表される化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(IVa):
R8は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にシアノ及びアルキルからなる群から選択される置換基で置換されていてもよい)で表される、請求項9に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(IVb)
R8は、ハロ、ピリジニル、ベンゾジオキソニル及びフェニルからなる群から選択され、それらはシアノ及びアルキルからなる群から選択される置換基で任意に置換れていてもよい)で表される、請求項9に記載の化合物。 - 1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−シアノフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(ベンゾ[d][1,3]ジオキソル−5−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;及び
1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N5−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項9に記載の化合物 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(V):
R9は、ハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にハロ及びアルキルからなる群から選択される置換基で置換されていてもよい)で表される化合物。 - (3S)−1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−フェニル−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
(3S)−1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
(3S)−1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(6−(4−(シクロプロピルメチル)−3−メチルピペラジン−1−イル)ピリジン−3−イル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項13に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(VI):
R10はハロ、ピリジニル、ベンゾジオキソリル及びフェニルからなる群から選択され、それらは任意にハロ、シアノ、アルコキシ及びアルキルからなる群から選択される1又は複数の置換基で置換されていてもよい)で表される化合物。 - 1−(4−クロロ−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−フェニル−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−クロロフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(3−シアノフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(2−エトキシ−5−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン;
1−(4−(4−フルオロ−2−メチルフェニル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミン; 及び
1−(4−(ピリジン−4−イル)−5,8−エタノ−5,6,7,8−テトラヒドロフタラジン−1−イル)−N3−(7−(ピロリジン−1−イル)−6,7,8,9−テトラヒドロ−5H−ベンゾ[7]アヌレン−2−イル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項15に記載の化合物。 - 単離された立体異性体又はそれらの混合物あるいはそれらの製薬的に許容される塩としての、下記式(VII):
R11は、以下:
- 1−(4−フェニル−5,6,7,8−テトラヒドロキナゾリン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニルl)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン;及び
1−(5,8−エタノ−4−フェニル−5,6,7,8−テトラヒドロピリド[3,2−d]ピリミジン−2−イル)−N3−(4−(4−(ピロリジン−1−イル)ピペリジニル)−3−フルオロフェニル)−1H−1,2,4−トリアゾール−3,5−ジアミンからなる群から選択される、請求項17に記載の化合物。 - 薬学的に許容できる添加剤と、単離された立体異性体又はそれらの混合物あるいは薬学的に許容できる塩としての請求項1から10のいずれか一項に記載の化合物の有効量を含む医薬組成物。
- 哺乳動物において、Axl活性に関連する疾患または状態を治療する方法であって、該哺乳動物に、単離された立体異性体又はそれらの混合物あるいは薬学的に許容できる塩としての請求項1から10のいずれか一項に記載の化合物、あるいは請求項19に記載の医薬組成物の治療有効量を投与することを含む方法。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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