JP5331679B2 - c−fmsキナーゼの阻害剤 - Google Patents
c−fmsキナーゼの阻害剤 Download PDFInfo
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- JP5331679B2 JP5331679B2 JP2009506741A JP2009506741A JP5331679B2 JP 5331679 B2 JP5331679 B2 JP 5331679B2 JP 2009506741 A JP2009506741 A JP 2009506741A JP 2009506741 A JP2009506741 A JP 2009506741A JP 5331679 B2 JP5331679 B2 JP 5331679B2
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- Prior art keywords
- alkyl
- phenyl
- compound
- mmol
- carboxylic acid
- Prior art date
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- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 title abstract description 12
- 239000003112 inhibitor Substances 0.000 title description 6
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- 206010003246 arthritis Diseases 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 138
- -1 —OR a Chemical group 0.000 claims description 122
- 229910005965 SO 2 Inorganic materials 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000000623 heterocyclic group Chemical class 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 15
- 125000003386 piperidinyl group Chemical class 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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- 125000000392 cycloalkenyl group Chemical class 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
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- 125000001544 thienyl group Chemical class 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
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- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 124
- 239000000203 mixture Substances 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 73
- 238000001819 mass spectrum Methods 0.000 description 63
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
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- 239000011734 sodium Substances 0.000 description 44
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
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- 239000002904 solvent Substances 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 239000012267 brine Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- XTDRPNJABDWQFI-UHFFFAOYSA-N 5-cyano-1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC(C#N)=CN1 XTDRPNJABDWQFI-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
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- 239000000741 silica gel Substances 0.000 description 17
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- 238000005859 coupling reaction Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 0 *C(C(NC(N)=O)=CC(*)=C(*)I)=C Chemical compound *C(C(NC(N)=O)=CC(*)=C(*)I)=C 0.000 description 11
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- 125000006239 protecting group Chemical group 0.000 description 11
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- WUEVEAZIMNIMQX-UHFFFAOYSA-N n-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide Chemical compound C1C(C)(C)CCC(C=2C(=CC=C(Br)C=2)NC(=O)C=2NC=C(N=2)C#N)=C1 WUEVEAZIMNIMQX-UHFFFAOYSA-N 0.000 description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 10
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 9
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- 125000003277 amino group Chemical group 0.000 description 7
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
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- BNQGKHUEVQWESM-UHFFFAOYSA-M potassium;4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate Chemical compound [K+].C[Si](C)(C)CCOCN1C=C(C#N)N=C1C([O-])=O BNQGKHUEVQWESM-UHFFFAOYSA-M 0.000 description 6
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- 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
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
本出願は、2006年4月20日付けで出願した米国仮出願連続番号60/793,667(これの内容は引用することによって全体が本明細書に組み入れられる)による優先権を主張するものである。
本発明は、c−fmsキナーゼの効力のある阻害剤を提供することでそのような現在必要とされている効力のある選択的蛋白質チロシンキナーゼ阻害剤の必要性を取り扱うものである。本発明は式I:
Wは、
各R4は、独立して、H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1−4)アルキル、SOC(1−4)アルキル、SO2C(1−4)アルキル、−C(1−3)アルキル、CO2Rd、CONReRf、C≡CRgまたはCNであり;かつ
Rdは、Hまたは−C(1−3)アルキルであり;
Reは、Hまたは−C(1−3)アルキルであり;
Rfは、Hまたは−C(1−3)アルキルであり;そして
Rgは、H、−CH2OHまたは−CH2CH2OHであり;
R2は、シクロアルキル、スピロ置換シクロアルケニル、ヘテロシクリル、スピロ置換ピペリジニル、チオフェニル、ジヒドロスルホノピラニル、フェニル、フラニル、テトラヒドロピリジルまたはジヒドロピラニルであり、これらはいずれも独立して下記:クロロ、フルオロ、ヒドロキシ、C(1−3)アルキルおよびC(1−4)アルキルの各々の1または2個で置換されていてもよく;
Zは、H、FまたはCH3であり;
Jは、CHまたはNであり;
Xは、
R1は、−C(1−4)アルキル、−ORa、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−OC(1−4)アルキルORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NRaCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Ra、−CH2CO2Ra、−CH2CH2SO2C(1−4)アルキル、−SO2CH2CH2NA1A2、−SOCH2CH2NA1A2、−SCH2CH2NA1A2、−NHSO2CH2CH2NA1A2 、フェニル、イミダゾリル、チアゾリル、4H−[1,2,4]オキサジアゾール−5−オニル、4H−ピロロ[2,3−b]ピラジニル、ピリジニル、[1,3,4]オキサジアゾリル、4H−[1,2,4]トリアゾリル、テトラゾリル、ピラゾリル、[1,3,5]トリアジニルまたは[1,3,4]チアジアゾリルであり;
RzおよびRyは、独立して、Hまたは−C(1−4)アルキルであり、かつ両方のRzがシンまたはアンチ立体化学のいずれかを有していてもよいか;あるいは、シン関係にある両方のRzが一緒になって-(CH2)n−を形成していてもよく、かつnは2または3であり;
R3は、H、C(1−4)アルキル、C(1−3)アルキル−CF3、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
A1は、H、-C(1−4)アルキルまたはCH2CH2ORaであり;
A2は、H、-C(1−4)アルキル、CORa、CH2CON(CH3)2、−CH2CH2ORa、−CH2CH2SC(1−4)アルキル、−CH2CH2SOC(1−4)アルキルまたは−CH2CH2SO2C(1−4)アルキルであるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
Raは、HまたはC(1−4)アルキルであり;
Raaは、HまたはC(1−4)アルキルであり;
Rbbは、H、-C(1−4)アルキル、−CH2CH2OCH2CH2OCH3、−CH2CO2H、−C(O)C(1−4)アルキルまたは−CH2C(O)C(1−4)アルキルである]
で表される新規な化合物またはこれらの溶媒和物、水化物、互変異性体または製薬学的に許容される塩に向けたものである。
本発明は式I:
Wは、
各R4は、独立して、H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1−4)アルキル、SOC(1−4)アルキル、SO2C(1−4)アルキル、−C(1−3)アルキル、CO2Rd、CONReRf、C≡CRgまたはCNであり;かつ
Rdは、Hまたは−C(1−3)アルキルであり;
Reは、Hまたは−C(1−3)アルキルであり;
Rfは、Hまたは−C(1−3)アルキルであり;そして
Rgは、H、−CH2OHまたは−CH2CH2OHであり;
R2は、シクロアルキル(シクロヘキセニルおよびシクロヘプテニルを包含)、スピロ置換シクロアルケニル(スピロ[2.5]オクト−5−エニル、スピロ[3.5]ノノ−6−エニル、スピロ[4.5]デコ−7−エニルおよびスピロ[5.5]ウンデコ−2−エニルを包含)、ヘテロシクリル(ピペリジニルを包含)、スピロ置換ピペリジニル(3−アザ−スピロ[5.5]ウンデカニルおよび8−アザ−スピロ[4.5]デカニルを包含)、チオフェニル、ジヒドロスルホノピラニル、フェニル、フラニル、テトラヒドロピリジルまたはジヒドロピラニルであり、これらはいずれも独立して下記:クロロ、フルオロ、ヒドロキシ、C(1−3)アルキルおよびC(1−4)アルキルの中の各々の1または2個で置換されていてもよく(前記置換されているシクロアルキルには4,4−ジメチルシクロヘキセニル、4,4−ジエチルシクロヘキセニル、4−メチルシクロヘキセニル、4−エチルシクロヘキセニル、4−n−プロピルシクロヘキセニル、4−イソ−プロピルシクロヘキセニルおよび4−t−ブチルシクロヘキセニルが含まれ;前記置換されているピペリジニルには4−メチルピペリジニル、4−エチルピペリジニル、4−(1’ヒドロキシエト−2’イル)ピペリジニルおよび4,4ジメチルピペリジニルが含まれる);
Zは、H、FまたはCH3であり;
Jは、CHまたはNであり;
Xは、
R1は、−C(1−4)アルキル、−ORa、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−OC(1−4)アルキルORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NRaCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Ra、−CH2CO2Ra、−CH2CH2SO2C(1−4)アルキル、−SO2CH2CH2NA1A2、−SOCH2CH2NA1A2、−SCH2CH2NA1A2、−NHSO2CH2CH2NA1A2 、フェニル、イミダゾリル、チアゾリル、4H−[1,2,4]オキサジアゾール−5−オニル、4H−ピロロ[2,3−b]ピラジニル、ピリジニル、[1,3,4]オキサジアゾリル、4H−[1,2,4]トリアゾリル、テトラゾリル、ピラゾリル、[1,3,5]トリアジニルまたは[1,3,4]チアジアゾリルであり;
RzおよびRyは、独立して、Hまたは−C(1−4)アルキルであり、かつ両方のRzがシンまたはアンチ立体化学のいずれかを有していてもよいか;あるいは、シン関係にある両方のRzが一緒になって-(CH2)n−を形成していてもよく、かつnは2または3であり;
R3は、H、C(1−4)アルキル、C(1−3)アルキル−CF3(−CH2CF3を包含)、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
A1は、H、-C(1−4)アルキルまたはCH2CH2ORaであり;
A2は、H、-C(1−4)アルキル、CORa、CH2CON(CH3)2、−CH2CH2ORa(−CH2CH2OCH3を包含)、−CH2CH2SC(1−4)アルキル(−CH2CH2SCH3を包含)、−CH2CH2SOC(1−4)アルキル(−CH2CH2SOCH3を包含)または−CH2CH2SO2C(1−4)アルキル(−CH2CH2SO2CH3を包含)であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
Raは、HまたはC(1−4)アルキルであり;
Raaは、HまたはC(1−4)アルキルであり;
Rbbは、H、-C(1−4)アルキル、−CH2CH2OCH2CH2OCH3、−CH2CO2H、−C(O)C(1−4)アルキルまたは−CH2C(O)C(1−4)アルキルである]
で表される新規な化合物またはこれらの溶媒和物、水化物、互変異性体または製薬学的に許容される塩に向けたものである。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Raまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RaがHまたは−C(1−4)アルキルであり;
RaaがHまたは−C(1−4)アルキルであり;
RbbがH、-C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるかまたは-CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH2CF3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COOH、−CO2CH3、−CH2−NA1A2、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2CO2CH3、−NHCH2CH2OCH3、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Hまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RbbがH、-C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるか、または-CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH2CF3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COOH、−CO2CH3、−CH2−NA1A2、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2CO2CH3、−NHCH2CH2OCH3、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Hまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RbbがH、-C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるか、または-CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH2CF3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−NH2、−N(CH3)2、−SO2CH3、−COOH、−CO2CH3、−CH2−モルホリニル、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2OCH3、−OCH2CO2H、モルホリニル、ピペラジニル、N−メチルピペラジニル、ピペラジニル−CH2CO2Hまたはテトラゾリルであり;
RzがHまたは−CH3であり;
R3が−COCH3、−CH2CF3または−CO2Hである;
化合物およびこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
各R4が独立してH、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1−4)アルキル、SOC(1−4)アルキル、SO2C(1−4)アルキル、−C(1−3)アルキル、CO2Rd、CONReRf、C≡CRgまたはCNであり;かつ
RdがHまたは−C(1−3)アルキルであり;
ReがHまたは−C(1−3)アルキルであり;
RfがHまたは−C(1−3)アルキルであり;そして
RgがH、−CH2OHまたは−CH2CH2OHであり;
R2がシクロアルキル(シクロヘキセニルおよびシクロヘプテニルを包含)、スピロ置換シクロアルケニル(スピロ[2.5]オクト−5−エニル、スピロ[3.5]ノノ−6−エニル、スピロ[4.5]デコ−7−エニルおよびスピロ[5.5]ウンデコ−2−エニルを包含)、ヘテロシクリル(ピペリジニルを包含)、スピロ置換ピペリジニル(3−アザ−スピロ[5.5]ウンデカニルおよび8−アザ−スピロ[4.5]デカニルを包含)、チオフェニル、ジヒドロスルホノピラニル、フェニル、フラニル、テトラヒドロピリジルまたはジヒドロピラニルであり、これらはいずれも独立して下記:クロロ、フルオロ、ヒドロキシ、C(1−3)アルキルおよびC(1−4)アルキルの各々の1または2個で置換されていてもよく(前記置換されているシクロアルキルには4,4−ジメチルシクロヘキセニル、4,4−ジエチルシクロヘキセニル、4−メチルシクロヘキセニル、4−エチルシクロヘキセニル、4−n−プロピルシクロヘキセニル、4−イソ−プロピルシクロヘキセニルおよび4−t−ブチルシクロヘキセニルが含まれ;前記置換されているピペリジニルには4−メチルピペリジニル、4−エチルピペリジニル、4−(1’ヒドロキシエト−2’イル)ピペリジニルおよび4,4ジメチルピペリジニルが含まれる);
ZがH、FまたはCH3であり;
JがCHまたはNであり;
Xが
R1が−C(1−4)アルキル、−ORa、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−OC(1−4)アルキルORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NRaCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Ra、−CH2CO2Ra、−CH2CH2SO2C(1−4)アルキル、−SO2CH2CH2NA1A2、−SOCH2CH2NA1A2、−SCH2CH2NA1A2、−NHSO2CH2CH2NA1A2 、フェニル、イミダゾリル、チアゾリル、4H−[1,2,4]オキサジアゾール−5−オニル、4H−ピロロ[2,3−b]ピラジニル、ピリジニル、[1,3,4]オキサジアゾリル、4H−[1,2,4]トリアゾリル、テトラゾリル、ピラゾリル、[1,3,5]トリアジニルまたは[1,3,4]チアジアゾリルであり;
RzおよびRyが独立してHまたは−C(1−4)アルキルであり、かつ両方のRzがシンまたはアンチ立体化学のいずれかを有していてもよいか;あるいは、シン関係にある両方のRzが一緒になって-(CH2)n−を形成していてもよく、かつnが2または3であり;
R3がH、C(1−4)アルキル、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
A1がH、-C(1−4)アルキルまたはCH2CH2ORaであり;
A2がH、-C(1−4)アルキル、CORa、CH2CON(CH3)2、−CH2CH2ORa(−CH2CH2OCH3を包含)、−CH2CH2SC(1−4)アルキル(−CH2CH2SCH3を包含)、−CH2CH2SOC(1−4)アルキル(−CH2CH2SOCH3を包含)または−CH2CH2SO2C(1−4)アルキル(−CH2CH2SO2CH3を包含)であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RaがHまたはC(1−4)アルキルであり;
RaaがHまたはC(1−4)アルキルであり;
RbbがH、-C(1−4)アルキル、−CH2CH2OCH2CH2OCH3、−CH2CO2H、−C(O)C(1−4)アルキルまたは−CH2C(O)C(1−4)アルキルである。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Raまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RaがHまたは−C(1−4)アルキルであり;
RaaがHまたは−C(1−4)アルキルであり;
RbbがH、−C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるか、または−CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COOH、−CO2CH3、−CH2−NA1A2、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2CO2CH3、−NHCH2CH2OCH3、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Hまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RbbがH、-C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるかまたは-CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COOH、−CO2CH3、−CH2−NA1A2、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2CO2CH3、−NHCH2CH2OCH3、−NHCH2CH2NA1A2、−OC(1−4)アルキルNA1A2、−OCH2CO2Hまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらが結合している窒素と一緒になって下記:
RbbがH、−C(1−4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは−CH3であり;
RzがH、−CH3であるか、または−CH2CH2−として一緒になっていてもよく;
R3がH、−COCH3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
Wが
R2が
ZがHであり;
JがCHまたはNであり;
Xが
R1が−OH、−NH2、−N(CH3)2、−SO2CH3、−COOH、−CO2CH3、−CH2−モルホリニル、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2OCH3、−OCH2CO2H、モルホリニル、ピペラジニル、N−メチルピペラジニル、ピペラジニル−CH2CO2Hまたはテトラゾリルであり;
RzがHまたは−CH3であり;
R3が−COCH3または−CO2Hである;
化合物およびこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩である。
用語“アルキル”は、特に明記しない限り炭素原子数が12以下、好適には炭素原子数が6以下の直鎖および分枝鎖両方の基を指し、これには、これらに限定するものでないが、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、s−ブチル、t−ブチル、ペンチル、イソペンチル、ヘキシル、イソヘキシル、ヘプチル、オクチル、2,2,4−トリメチルペンチル、ノニル、デシル、ウンデシルおよびドデシルが含まれる。
前記式Iで表される化合物は蛋白質チロシンキナーゼ、例えばc−fmsなどの効力のある新規な阻害剤に相当し、そのようなキナーゼの作用が原因で生じる疾患の予防および治療で用いるに有用であり得る。
その上、本発明の化合物は1種以上の多形もしくは非晶形態も取り得、このように、それらを本発明の範囲に包含させることを意図する。加うるに、本化合物は溶媒和物、例えば水との溶媒和物(即ち水化物)または一般的有機溶媒との溶媒和物も形成する可能性がある。本明細書で用いる如き用語“溶媒和物”は、本発明の化合物と1種以上の溶媒分子の物理的結合を意味する。そのような物理的結合は、いろいろな度合のイオンおよび共有結合(水素結合を包含)を伴う。ある場合には、そのような溶媒和物を単離することができ、例えば1個以上の溶媒分子が結晶固体の結晶格子の中に取り込まれている場合などに単離可能である。用語“溶媒和物”に溶液相および単離可能溶媒和物の両方を包含させることを意図する。適切な溶媒和物の非限定例には、エタノラート、メタノラートなどが含まれる。
スキーム3
xが
[実施例1]
b)2−ブロモ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−4−カルボニトリル
c)4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸エチルエステル
d)4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸カリウム塩
e)4−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニルアミン
f)4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸[4−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
g)4−シアノ−1H−イミダゾール−2−カルボン酸[4−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
h)5−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(4−ヒドロキシ−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
4−シアノ−1H−イミダゾール−2−カルボン酸[4−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド(0.550g、1.38ミリモル)(この上に示した段階で調製した)を20mLのTHFに入れることで生じさせた-40℃の懸濁液にi−PrMgCl(1.40mL、2.80ミリモル、THF中2M)を加えた後、その溶液を0℃に温めて10分間撹拌した。次に、その溶液を-78℃に冷却し、t−BuLi(2.15mL、3.65ミリモル、ペンタン中1.7M)を5分かけて滴下した後直ちにテトラヒドロ−ピラン−4−オン(0.650mL、7.05ミリモル)を加えた。-78℃で5分後に飽和NH4Cl(20mL)で反応を消滅させ、EtOAc(3x20mL)を用いた抽出を実施した後、Na2SO4を用いた乾燥を実施した。表題の化合物をフラッシュクロマトグラフィー(Siゲル)にかけて50% EtOAc/DCMで溶離させて精製することで0.460g(79%)の白色固体を得た。1H−NMR(400MHz、DMSO−d6)δ14.28(s、1H)、9.77(s、1H)、8.21(s、1H)、7.98(d、J=8.5Hz、1H)、7.38(dd、J=8.5、2.2Hz、1H)、7.34(d、J=2.2Hz、1H)、5.67(m、1H)、5.03(s、1H)、3.83−3.66(m、4H)、2.31−2.22(m、2H)、2.04−1.92(m、4H)、1.58−1.46(m、4H)、1.01(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C24H28N4O3、421.2(M+H)、測定値:421.1.
[実施例2]
[実施例3]
[実施例4]
[実施例11]
[実施例12]
[実施例13]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(1−アセチル−4−アミノ−ピペリジン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミドの酢酸塩
4−シアノ−1H−イミダゾール−2−カルボン酸[4−(1−アセチル−4−アジド−ピペリジン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド(この上に示した段階で調製したまま、40.0mg、0.0822ミリモル)と亜鉛(54.0mg、0.822ミリモル)を1.6mLのTHFに入れることで生じさせた混合物に酢酸(0.40mL)を加えた。その結果として得た混合物をAr下室温で16時間撹拌した。セライトを用いた濾過で固体を除去した後、その濾液に濃縮を真空下で受けさせた。その残留物をシリカゲル使用フラッシュクロマトグラフィー(10% MeOH/DCM)で精製することで13mg(30%)の表題の化合物を白色の固体として得た。1H−NMR(CD3OD;400MHz):δ8.33(d、1H、J=8.6Hz)、7.91(s、1H)、7.52(dd、1H、J=8.6、2.3Hz)、7.40(s、1H)、5.77(m、1H)、3.76−3.98(m、2H)、3.42(m、2H)、2.46(m、2H)、2.32(m、2H)、2.13(s、3H)、2.07(m、2H)、1.86−2.03(m、2H)、1.93(s、6H)、1.59(t、2H、J=6.1Hz).質量スペクトル(ESI−neg、m/z):下記として計算した値:C26H32N6O2、459.3(M−H)、測定値:459.5.
[実施例14]
b) 4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸(4−ブロモ−2−シクロヘキソ−1−エニル−フェニル)−アミド
c) 4−シアノ−1H−イミダゾール−2−カルボン酸(4−ブロモ−2−シクロヘキソ−1−エニル−フェニル)−アミド
d) 4−シアノ−1H−イミダゾール−2−カルボン酸[2−シクロヘキソ−1−エニル−4−(4−ヒドロキシ−テトラヒドロ−チオピラン−4−イル)−フェニル]−アミド
[実施例15]
[実施例16]
b) 4−(4−アミノ−フェニル)−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
c) 4−(4−アミノ−3−ブロモ−フェニル)−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
d) 4−[4−アミノ−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
e) 4−[4−{[4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボニル]−アミノ}−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
f) 4−[4−[(4−シアノ−1H−イミダゾール−2−カルボニル)−アミノ]−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
[実施例17]
[実施例18]
b) 4−(4−{[4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボニル]−アミノ}−3−シクロヘキソ−1−エニル−フェニル)−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
c) 4−{4−[(4−シアノ−1H−イミダゾール−2−カルボニル)−アミノ]−3−シクロヘキソ−1−エニル−フェニル}−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
d) 4−{4−[(4−シアノ−1H−イミダゾール−2−カルボニル)−アミノ]−3−シクロヘキソ−1−エニル−フェニル}−テトラヒドロ−ピラン−4−カルボン酸
[実施例19]
[実施例20]
[実施例21]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸[2−シクロヘキソ−1−エニル−4−(4−モルホリン−4−イルメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
[実施例22]
b) 4−(4−ニトロ−フェニル)−テトラヒドロ−ピラン−4−カルボニトリル
c) 4−(4−アミノ−フェニル)−テトラヒドロ−ピラン−4−カルボニトリル
d) 4−(4−アミノ−3−ブロモ−フェニル)−テトラヒドロ−ピラン−4−カルボニトリル
e) 2−ブロモ−4−[4−(2H−テトラゾール−5−イル)−テトラヒドロ−ピラン−4−イル]−フェニルアミン
f) 4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸{2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−[4−(2H−テトラゾール−5−イル)−テトラヒドロ−ピラン−4−イル]−フェニル}−アミド
g) 4−シアノ−1H−イミダゾール−2−カルボン酸{2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−[4−(2H−テトラゾール−5−イル)−テトラヒドロ−ピラン−4−イル]−フェニル}−アミド
[実施例23]
b) 4−[4−[(4−シアノ−1H−ピロール−2−カルボニル)−アミノ]−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸
[実施例24]
[実施例25]
[実施例26]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(4−モルホリン−4−イルメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
下記の化合物の調製を示す如き実施例に従って実施した:
4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(シス−4−ヒドロキシ−シス−2,6−ジメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミドおよび4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(トランス−4−ヒドロキシ−シス−2,6−ジメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
31:質量スペクトル(ESI、m/z):下記として計算した値:C26H32N4O3、449.2(M+H)、測定値:449.2.
32:質量スペクトル(ESI、m/z):下記として計算した値:C26H32N4O3、449.2(M+H)、測定値:449.2.
[実施例32]
b) 6−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−ピリジン−3−イルアミン
c)4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸[6−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−ピリジン−3−イル]−アミド
d)5−シアノ−1H−イミダゾール−2−カルボン酸[6−ブロモ−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−ピリジン−3−イル]−アミド
e)4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−6−(4−ヒドロキシ−シス−2,6−ジメチル−テトラヒドロ−ピラン−4−イル)−ピリジン−3−イル]−アミド
質量スペクトル(ESI、m/z):下記として計算した値:C25H31N5O3、450.2(M+H)、測定値:450.2.
[実施例33]
[実施例34]
[実施例35]
b) C−[4−(4−ニトロ−フェニル)−テトラヒドロ−ピラン−4−イル]−メチルアミン
c) [4−(4−ニトロ−フェニル)−テトラヒドロ−ピラン−4−イルメチル]−カルバミン酸t−ブチルエステル
d) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−アミノメチル−テトラヒドロ−ピラン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
[実施例74]
b) 4−(4−ニトロ−フェニル)−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−カルボン酸アミド
c) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−カルバモイル−1,1−ジオキソ−ヘキサヒドロ−1λ6チオピラン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
[実施例75]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸(2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−{4−[(2−メトキシ−エチルアミノ)−メチル]−テトラヒドロ−ピラン−4−イル}−フェニル)−アミド
[実施例76]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(4−メチルアミノメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
[実施例77]
b) 1−アセチル−4−(4−ニトロ−フェニル)−ピペリジン−4−カルボニトリル
c) 1−アセチル−4−(4−ニトロ−フェニル)−ピペリジン−4−カルボン酸
d) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(1−アセチル−4−メチルアミノメチル−ピペリジン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
[実施例78]
b) 4−シアノ−4−[4−[(4−シアノ−1H−イミダゾール−2−カルボニル)−アミノ]−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−ピペリジン−1−カルボン酸アミド
b) 4−シアノ−1H−イミダゾール−2−カルボン酸{2−(4,4−ジメチル−シクロヘキソ−1−エニル)−6−[4−(4−メチル−ピペラジン−1−イル)−テトラヒドロ−ピラン−4−イル]−ピリジン−3−イル}−アミド
b) 4−[4−アミノ−3−(4−メチル−ピペリジン−1−イル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
c) 4−[4−{[4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボニル]−アミノ}−3−(4−メチル−ピペリジン−1−イル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
d) 4−[4−[(4−シアノ−1H−イミダゾール−2−カルボニル)−アミノ]−3−(4−メチル−ピペリジン−1−イル)−フェニル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
e) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−ヒドロキシメチル−テトラヒドロ−ピラン−4−イル)−2−(4−メチル−ピペリジン−1−イル)−フェニル]−アミド
f) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−ホルミル−テトラヒドロ−ピラン−4−イル)−2−(4−メチル−ピペリジン−1−イル)−フェニル]−アミド
g) 4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4−メチル−ピペリジン−1−イル)−4−(4−ピロリジン−1−イルメチル−テトラヒドロ−ピラン−4−イル)−フェニル]−アミド
[実施例87]
b) 4−(4−アミノ−フェニル)−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−カルボニトリル
c) 4−(4−アミノ−3−ブロモ−フェニル)−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−カルボニトリル
d) 4−[4−アミノ−3−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−カルボニトリル
e) 4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸[4−(4−シアノ−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
f) 4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−シアノ−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
4−シアノ−1−(2−トリメチルシラニル−エトキシメチル)−1H−イミダゾール−2−カルボン酸[4−(4−シアノ−1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド(193mg、0.318ミリモル、この上に示した段階で調製したまま)をCH2Cl2(10mL)に入れることで生じさせた溶液をTFA(2mL)で処理した後、室温で3時間撹拌した。EtOH(5mL)を加えた後の混合物に濃縮乾固を受けさせた。その残留物をCH2Cl2で取り上げた後、飽和NaHCO3水溶液(1x)で注意深く洗浄した。その水層にCH2Cl2(1x)を用いた抽出を受けさせ、その有機層を一緒にしてMgSO4で乾燥させた後、真空下で濃縮した。その残留物を20−g Isolute SPEカラム(FlashMaster装置)使用シリカゲルクロマトグラフィーにかけて25−50% EtOAc−ヘキサンを用いることで表題の化合物(50.4mg、33%)を白色の固体として得た。1H−NMR(CD3OD;400MHz):δ8.39(d、1H、J=8.8Hz)、8.01(s、1H)、7.53(dd、1H、J=8.8、2.0Hz)、7.42(d、1H、J=2.0Hz)、5.85−5.80(m、1H)、3.59−3.46(m、2H)、2.81−2.69(m、2H)、2.62−2.52(m、2H)、2.39−2.32(m、2H)、2.17−2.10(m、2H)、1.68−1.58(m、4H)、1.13(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C25H27N5O3S、478.2(M+H)、測定値:478.2.
[実施例88]
[実施例89]
[実施例90]
[実施例91]
b) 4−シアノ−1H−イミダゾール−2−カルボン酸{2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−[4−ヒドロキシ−2,2,6,6−テトラメチル−1−(2,2,2−トリフルオロ−エチル)−ピペリジン−4−イル]−フェニル}−アミド
[実施例92]
[実施例93]
[実施例94]
484.2(M+1)、測定値:484.0.
[実施例95]
蛍光偏光競合免疫測定法
式Iで表される選択した化合物が示すc−fms阻害能力を測定する目的で自己燐酸化蛍光偏光競合免疫測定法を用いた。この検定を黒色の96穴ミクロプレート(LJL BioSystems)を用いて実施した。用いた検定用緩衝液は100mMの4−(2−ヒドロキシエチル)ピペラジン1−エタンスルホン酸(HEPES)(pH7.5)、1mMの1,4−ジチオ−DL−トレイトール(DTT)、0.01%(体積/体積)のTween−20であった。検定を実施する直前に化合物をジメチルスルホキサイド(DMSO)を4%含有させておいた検定用緩衝液で希釈した。各穴に化合物を5μL加えた後、検定用緩衝液にc−fms(Johnson & Johnson PRD)を33nMとMgCl2(Sigma)を16.7mM入れることで生じさせた混合物を3μL添加した。検定用緩衝液中5mMのATP(Sigma)を2μL添加することでキナーゼ反応を開始させた。検定液中の最終濃度は10nMのc−fms、1mMのATP、5mM
のMgCl2、2%のDMSOであった。各プレート毎に対照反応を実施し、正および負対照の穴には当該化合物の代わりに検定用緩衝液(DMSO中4%になるように作成)を用いることに加えて正対照の穴には50mMのエチレンジアミンテトラ酢酸(EDTA)を1.2μL入れた。
FCSを10%と組換え型マウスCSF−1を50ng/ml補充しておいたアルファ−MEMを細菌学用皿に入れてその中でマウス骨髄を培養することを通してマクロファージを得る。6日目にマクロファージを皿から脱離させ、洗浄した後、FCS含有量が10%のアルファ−MEMに入れて細胞数が1mL当たり0.05百万個になるように再懸濁させる。細胞懸濁液を96穴培養プレートに穴1個当たり100ulになるように分配する。穴にCSF−1を15ng/mlとインドメタシンを3uMと試験化合物の一連の希釈液を3Xの量で入れておいた培地を50ul添加することによるさらなる補充を受けさせる。その細胞を37度において5%のCO2下で30時間培養する。最後の6時間の間に培養物にブロモデオキシウリジン(BrDU)の1:500希釈液を入れておいた培地を追加的に30ul用いた補充を受けさせる。この培養期間が終了した時点で前記プレートを1000 RPMで1分間回転させた後、ピペットで培地を130ul除去しそして150ulの定着用溶液を代わりに入れて室温に1時間置く。次に、その定着剤を前記プレートから除去した後、そのプレートを空気で乾燥させる。その定着させて乾燥させた細胞の中に取り込まれたBrDUを特異的ELISAで量化する。
Claims (10)
- 式I
Wは、
各R4は、独立して、H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1-4)アルキル、SOC(1-4)アルキル、SO2C(1-4)アルキル、−C(1-3)アルキル、CO2Rd、CONReRf、C≡CRgまたはCNであり;かつ
Rdは、Hまたは−C(1-3)アルキルであり;
Reは、Hまたは−C(1-3)アルキルであり;
Rfは、Hまたは−C(1-3)アルキルであり;そして
Rgは、H、−CH2OHまたは−CH2CH2OHであり;
R2は、シクロアルキル、スピロ置換シクロアルケニル、ヘテロシクリル、スピロ置換ピペリジニル、チオフェニル、ジヒドロスルホノピラニル、フェニル、フラニル、テトラヒドロピリジルまたはジヒドロピラニルであり、これらはいずれも独立して下記:クロロ、フルオロ、ヒドロキシ、C(1-3)アルキルおよびC(1-4)アルキルの各々の1または2個で置換されていてもよく;
Zは、H、FまたはCH3であり;
Jは、CHまたはNであり;
Xは、
R1は、−C(1-4)アルキル、−ORa、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−OC(1-4)アルキルORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NRaCH2CH2NA1A2、−OC(1-4)アルキルNA1A2、−OCH2CO2Ra、−CH2CO2Ra、−CH2CH2SO2C(1-4)アルキル、−SO2CH2CH2NA1A2、−SOCH2CH2NA1A2、−SCH2CH2NA1A2、−NHSO2CH2CH2NA1A2、フェニル、イミダゾリル、チアゾリル、4H−[1,2,4]オキサジアゾール−5−オニル、4H−ピロロ[2,3−b]ピラジニル、ピリジニル、[1,3,4]オキサジアゾリル、4H−[1,2,4]トリアゾリル、テトラゾリル、ピラゾリル、[1,3,5]トリアジニルまたは[1,3,4]チアジアゾリルであり;
RzおよびRyは、独立して、Hまたは−C(1-4)アルキルであり、かつ両方のRzがシンまたはアンチ立体化学のいずれかを有していてもよいか;あるいは、シン関係にある両方のRzが一緒になって-(CH2)n−を形成していてもよく、かつnは2または
3であり;
R3は、H、C(1-4)アルキル、C(1-3)アルキル−CF3、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
A1は、H、-C(1-4)アルキルまたはCH2CH2ORaであり;
A2は、H、-C(1-4)アルキル、CORa、CH2CON(CH3)2、−CH2CH2ORa、−CH2CH2SC(1-4)アルキル、−CH2CH2SOC(1-4)アルキルまたは−CH2CH2SO2C(1-4)アルキルであるか;あるいは
A1とA2がこれらの結合している窒素と一緒になって下記:
Raは、HまたはC(1-4)アルキルであり;
Raaは、HまたはC(1-4)アルキルであり;そして
Rbbは、H、-C(1-4)アルキル、−CH2CH2OCH2CH2OCH3、−CH2CO2H、−C(O)C(1-4)アルキルまたは−CH2C(O)C(1-4)アルキルである]
で表される新規な化合物または該化合物の溶媒和物、水化物、互変異性体もしくは製薬学的に許容される塩。 - Wが
R2が
ZがHであり;
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COORa、−CO2CH3、−CH2−NA1A2、−CONA1A2、−CH2ORa、−NHCH2CH2CO2Ra、−NHCH2CH2ORa、−NHCH2CH2NA1A2、−OC(1-4)アルキルNA1A2、−OCH2CO2Raまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらの結合している窒素と一緒になって下記:
RaがHまたは−C(1-4)アルキルであり;
RaaがHまたは−C(1-4)アルキルであり;
RbbがH、-C(1-4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるか、または-CH2CH2−として一緒になっていてもよく;
R3がH、−CH2CF3、−COCH3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
請求項1記載の化合物または該化合物の溶媒和物、水化物、互変異性体もしくは製薬学的に許容される塩。 - R2が
Xが
R1が−OH、−CN、−NA1A2、−SO2CH3、−COOH、−CO2CH3、−CH2−NA1A2、−CONH2、−CON(CH3)2、−CH2OH、−OCH2CH2N(CH3)2、−NHCH2CH2CO2CH3、−NHCH2CH2OCH3、−NHCH2CH2NA1A2、−OC(1-4)アルキルNA1A2、−OCH2CO2Hまたはテトラゾリルであり;
A1がHまたは−CH3であり;
A2がH、−CH2CH2OCH3、−COCH3または−CH3であるか;あるいは
A1とA2がこれらの結合している窒素と一緒になって下記:
RbbがH、-C(1-4)アルキル、−CH2CO2Hまたは−COCH3であり;
RyがHまたは-CH3であり;
RzがH、−CH3であるか、または-CH2CH2−として一緒になっていてもよく;
R3がH、−CH2CF3、−COCH3、−CH3、−CO2CH3、−CONH2または−CO2Hである;
請求項2記載の化合物ばかりでなくこれの溶媒和物、水化物、互変異性体および製薬学的に許容される塩。 - 請求項1記載の化合物および製薬学的に許容される担体を含有して成る製薬学的組成物。
- 請求項1記載の少なくとも1種の化合物を有効成分として含んでなる哺乳動物における炎症を治療するための製薬学的製剤。
- 請求項1記載の少なくとも1種の化合物を有効成分として含んでなる全身性エリテマトーデス、関節リウマチおよび他の形態の炎症性関節炎、乾癬、シェーグレン症候群、多発性硬化症並びにブドウ膜炎から成る群より選択される自己免疫病を治療するための製薬学的製剤。
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