JP2009534407A - 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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- JP2009534407A JP2009534407A JP2009506744A JP2009506744A JP2009534407A JP 2009534407 A JP2009534407 A JP 2009534407A JP 2009506744 A JP2009506744 A JP 2009506744A JP 2009506744 A JP2009506744 A JP 2009506744A JP 2009534407 A JP2009534407 A JP 2009534407A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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Abstract
【化1】
[式中、Z、X、J、R2およびWは本明細書に示す通りである]
で表され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に向けたものであり、これらは蛋白質チロシンキナーゼ、特にc−fmsキナーゼを阻害する。また、式Iで表される化合物を用いて自己免疫病および炎症性要素を伴う病気を治療、卵巣癌、子宮癌、乳癌、前立腺癌、肺癌、結腸癌、胃癌、ヘアリー細胞白血病からの転移を治療、および腫瘍転移または変形性関節症が原因の骨格痛または内蔵、炎症および神経原性疼痛を包含する痛みばかりでなく骨粗しょう症、パジェット病および病的状態に骨吸収が介在する他の病気(関節リウマチおよび他の形態の炎症性関節炎、変形性関節症、人工器官不全、溶骨性肉腫、骨髄腫および骨への腫瘍転移を包含)を治療する方法も提供する。
Description
Flt−1)、VEGFR−2(KDR)、VEGFR−3(Flt−4)と表示される。関連した群の受容体であるtie−1およびtie−2キナーゼが血管内皮および造血細胞内で同定された。VEGF受容体は脈管形成および血管新生に関係している。
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:
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、
Rzは、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、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
R9は、H、C(1−4)アルキル、ORa、−NA1A2、NA1SO2C(1−4)アルキル、NA1COC(1−4)アルキル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR3とR9が一緒になってオキソ、−OCH2CH2O−または−OCH2C(Ra)2CH2O−を形成してい
てもよく;
R10は、H、−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]トリアジニルおよび[1,3,4]チアジアゾリルであり;
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:
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、
Rzは、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、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
R9は、H、C(1−4)アルキル、ORa、−NA1A2、NA1SO2C(1−4)アルキル、NA1COC(1−4)アルキル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR3とR9が一緒になってオキソ、−OCH2CH2O−または−OCH2C(Ra)2CH2O−を形成していてもよく;
R10は、H、−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]トリアジニルおよび[1,3,4]チアジアゾリルであり;
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
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または
−NRaCH2CH2NA1A2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;
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
あり;
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
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
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または−NRaCH2CH2NA1A2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:
から選択される複素環式環を形成していてもよく;
RbbがH、−C(1−4)アルキル、−CH2CO2Hまたは−COCH3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であり;
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
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
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または−NRaCH2CH2NA1A2l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;
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であり;
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
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
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。
性要素を伴う病気の例には、糸球体腎炎、炎症性腸疾患、人工器官不全、サルコイドーシス、うっ血性閉塞性肺疾患、突発性肺線維症、喘息、膵炎、HIV感染、乾癬、糖尿病、腫瘍関連血管新生、加齢性黄斑変性症、糖尿病性網膜症、再狭窄、統合失調症またはアルツハイマー型認知症が含まれる。それらを本発明の化合物で有効に治療することができる。有効に治療可能な他の病気には、これらに限定するものでないが、アテローム性動脈硬化症および心臓肥大が含まれる。
による投与が含まれる。投与を経口経路で交互または同時に実施することも可能である。非経口投与に適した製剤には、本活性化合物の水溶性形態物、例えば水溶性塩などが入っている水溶液、酸性溶液、アルカリ性溶液、デキストロース−水溶液、等張性炭水化物溶液およびシクロデキストリン包接錯体が含まれる。
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。
調製方法
Chemistry、M.Hudlicky、Wiley、New York、1984を参照)を用いて受けさせることで得ることができる。好適な条件は、パラジウム触媒を用いた接触水添を適切な溶媒、例えばメタノールまたはエタノールなど中で実施する条件である。Rbがハロゲンでありかつ式1−1で表されるアミンとして入手することができない場合には、ニトロの還元を鉄または亜鉛を用いて適切な溶媒、例えば酢酸など中で実施するか、または鉄と塩化アンモニウムを用いてエタノールと水中で実施してもよい。
に対する修飾をほとんど行わないか、または若干行うことでその化学を記述するXおよびRzの全部に適用することができることを認識するであろう。加うるに、この上のスキーム1に記述したように、JがCHである基質に関して反応体および条件を定義するが、また、JがNの場合にも同様な合成方法を若干の修飾を伴わせて利用することができるとも理解する。
4などを反応(例えばTetrahedron、62(4)、647−651;(2006)を参照)させることで得ることができる。
zの全部に適用することができることを認識するであろう。加うるに、この上のスキーム1に記述したように、JがCHである基質に関して反応体および条件を定義したが、また、JがNの場合にも同様な合成方法を若干の修飾を伴わせて利用することができるとも理解する。
カルボン酸P1−WCOOHとのカップリングを実施した後に任意の保護基の除去を1−2から1−6を生じさせる変換に関してスキーム1に記述したようにして実施することで得ることができる。
および条件を定義する。当技術分野の技術者は、反応体および条件を若干修飾することでその化学をこの上に示したX、Rz、R3、R9およびJの全部に適用して用いることができることを認識するであろう。
たは活性エステルと反応させることでアミド化合物を生じさせることができる。それをまた適切なカルボニル化剤、例えばホスゲン、カルボニルジイミダゾールまたは好適にはトリホスゲンと塩基、例えばピリジンまたはDIEAなどの存在下で反応させることも可能である。そのようにして生じさせた中間体を第一級もしくは第二級アミンで捕捉することで相当する尿素化合物を得ることができる。同様に、化合物4−2中のアミノ基を適切なオクザリル化剤、例えば塩化オクザリルなどと塩基、例えばピリジンまたはDIEAなどの存在下で反応させた後にそのようにして生じた中間体の捕捉を第一級もしくは第二級アミンを用いて行うことでオクザルアミド化合物を得ることができる。その上、前記アミノ基を適切なアルデヒドまたはケトンと適切な還元剤、例えばNaBH4またはNaBH3CNまたは好適にはNaBH(OAc)3などの存在下でスキーム1に記述した如き標準的還元アミノ化手順に従って反応させることでR10がNA1A2である式Iで表される化合物を生じさせることも可能である。
c Synthesis、John Wiley and Sons、Inc.、NY(1991)を参照)。
して用いる。
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−(1−ヒドロキシ−シクロヘキシル)−フェニル]−アミド
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)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−(1−ヒドロキシ−シクロヘキシル)−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(159mg、0.397ミリモル、実施例1の段階(g)で調製したまま)をTHF(15mL)に入れることで生じさせた溶液をAr下に置いて−78℃に冷却した後、i−PrMgCl(199μL、0.397ミリモル)で処理した。その混合物を室温に温めて室温で10分間撹拌し、−78℃に冷却し、t−BuLi(701μL、1.19ミリモル)で処理し、その温度で10分間撹拌した後、シクロヘキサノン(411μL、3.97ミリモル)で処理した。その混合物を室温に温め、1.5時間撹拌し、飽和NH4Cl水溶液(20mL)で反応を消滅させた後、EtOAc(2 x 50mL)を用いた抽出を実施した。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75.0mg(45%)の表題の化合物を白色固体として得た。1H−NMR(CD3OD;400MHz):δ 12.11−11.91(br s、1H)、9.63(s、1H)、8.31(d、1H、J=8.4Hz)、7.71(s、1H)、7.43(dd、1H、J=8.4、2.0Hz)、7.36(d、1H、J=2.0Hz)、5.82−5.75(m、1H)、3.77−3.67(m、1H)、2.62−2.53(m、1H)、2.42−2.24(m、4H)、2.17−2.07(m、2H)、1.96−1.55(m、10H)、1.10(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C25H30NO2、419.2(M+H)、測定値:419.1.
4−[4−[(5−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]−シス−4−ヒドロキシ−シクロヘキサンカルボン酸
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]−シス−4−ヒドロキシ−シクロヘキサンカルボン酸エチルエステル(50mg、0.10ミリモル)(この上に示した段階で調製)を1mLのEtOHに入れることで生じさせた溶液に2N KOH(0.16mL、0.32ミリモル)を加えた後、その反応物を室温で2時間撹拌した。その混合物を5mLのH2Oで希釈し、pHを2M TFA/H2Oで2に調整した後、表題の化合物をC18カラム使用RP−HPLCにかけて0.1% TFA/H2O中30%から50%のCH3CNに10分かけて至らせる線形勾配で溶離させて精製することで14mg(19%、段階(a)および(b))の白色固体を得た。1H−NMR(400MHz、CD3OD):δ 8.13(d、J=8.6Hz、1H)、7.98(s、1H)、7.39(dd、J=8.6、2.2Hz、1H)、7.34(d、J=2.2Hz、1H)、5.72(m、1H)、2.39(m、1H)、2.34−2.27(m、2H)、2.09−1.77(m、10H)、1.58(t、J=6.2Hz、1H)、1.07(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C26H30N4O4、461.2(M−H)、測定値:461.3.
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−(1−ヒドロキシ−シクロペンチル)−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−(1−シアノ−シクロプロピル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
b)1−[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]−シクロプロパンカルボニトリル
H NMR(CD3OD;400MHz):δ 6.95(dd、1H、J=8.2、2.3Hz)、6.88(d、1H、J=2.3Hz,)、6.71(d、1H、J=8.2Hz)、5.62(m、1H)、2.52−2.23(m、2H)、1.98−1.97(m、2H)、1.55−1.51(m、4H)、1.31−1.28(m、2H)、1.01(s、6H).
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[4−(1−シアノ−シクロプロピル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
表題の化合物の調製を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−(1−シアノ−シクロプロピル)−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)を用いて実施例1の段階(g)に記述した条件を用いることで実施した。1H NMR(CD3OD;400MHz):δ 8.24(d、1H、J=8.4Hz)、7.99(s、1H)、7.24−7.22(m、1H)、7.17(s、1H)、5.76(s、1H)、2.30(br s、2H)、2.08(br s、2H)、1.69(br s、2H)、1.60(t、2H、J=6.01Hz)、1.47(br s、2H)、1.00(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C23H23N5O、386.1(M+H)、測定値:386.1.
以下の実施例の製造を以下の表に示す如き相当する反応体を用いて前記実施例の手順に従うことで実施した。
4−シアノ−1H−イミダゾール−2−カルボン酸[4−(1−シアノ−シクロヘキシル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル}−アミド
b)1−(4−アミノ−フェニル)−シクロヘキサンカルボニトリル
c)1−(4−アミノ−3−ブロモ−フェニル)−シクロヘキサンカルボニトリル
d)1−[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]−シクロヘキサンカルボニトリル
、m/z):下記として計算した値:C32H43N5O2Si、558.3(M+H)、測定値:557.8.
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−(1−シアノ−シクロヘキシル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド(66.0mg、0.118ミリモル、この上に示した段階で調製したまま)をCH2Cl2(6mL)に入れることで生じさせた室温の溶液にEtOH(3滴)およびTFA(0.8mL)を用いた処理を2時間受けさせた。溶媒を真空下で蒸発させた。その残留物をRP−HPLC(C18)にかけて0.1%のTFA/H2O中20%から80%のCH3CNに25分かけて至らせることによって精製することで表題の化合物(25.7mg、43%)を白色固体として得た。1H−NMR(CD3OD;400MHz):δ 8.20(d、1H、J=8.8Hz)、7.93(s、1H)、7.37(dd、1H、J=8.8、2.0Hz)、7.26(d、1H、J=2.0Hz)、5.73−5.67(m、1H)、2.29−2.21(m、2H)、2.08−1.98(m、4H)、1.88−1.68(m、6H)、1.58−1.50(m、2H)、1.02(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C26H29N5O、428.2(M+H)、測定値:428.2.
1−[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]−シクロペンタンカルボン酸
b)1−(4−ニトロ−フェニル)−シクロペンタンカルボン酸
c)1−(4−ニトロ−フェニル)−シクロペンタンカルボン酸t−ブチルエステル
表題の化合物の調製を1−(4−ニトロ−フェニル)−シクロペンタンカルボン酸t−ブチルエステル(この上に示した段階で調製したまま)を用いて実施例4の段階(a)そして実施例1の段階(e)−(g)に示した手順に従うことで実施する。
4−[4−[(5−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]−シクロヘキサンカルボン酸
表題の化合物の調製を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]−シクロヘキサンカルボン酸メチルエステル(この上に示した段階で調製したまま)を用いて実施例2の段階(b)に示した手順に従うことで実施する。
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−(1−ヒドロキシ−4,4−ジメトキシ−シクロヘキシル)−フェニル]−アミド
Lett.、1107−8(1975)および同書、31、3237−40(1990))を用いて実施例1の段階(h)の手順に従うことで実施する。
5−シアノ−1H−イミダゾール−2−カルボン酸[4−(4,4−ジメトキシ−シクロ
ヘキシル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
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−(1−ヒドロキシ−4−オキソ−シクロヘキシル)−フェニル]−アミド
5−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−ジメチルアミノ−1−ヒドロキシ−シクロヘキシル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミド
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−オキソ−シクロヘキシル)−フェニル]−アミド
b)4−(4−アミノ−フェニル)−シクロヘキサノン
c)4−(4−アミノ−3−ブロモ−フェニル)−シクロヘキサノン
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]−シクロヘキサノン
うことで実施した。質量スペクトル(ESI、m/z):下記として計算した値:C20H27NO、298.2(M+H)、測定値:298.2.
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[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(4−オキソ−シクロヘキシル)−フェニル]−アミド
表題の化合物の調製を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−オキソ−シクロヘキシル)−フェニル]−アミド(この上に示した段階で調製したまま)を用いて実施例1の段階(g)に示した手順に従うことで実施した。1H−NMR(CDCl3;400MHz):δ 9.59(s、1H)、8.31(d、1H、J=8.4Hz)、7.72(s、1H)、7.20(dd、1H、J=8.4、2.0Hz)、7.08(d、1H、J=2.0Hz)、5.81−5.75(m、1H)、3.04(tt、1H、J=11.6Hz、4.0Hz)、2.56−2.48(m、4H)、2.33−2.19(m、4H)、2.14−2.08(m、2H)、2.04−1.91(2H)、1.62−1.55(m、2H)、1.11(s、6H).質量スペクトル(APCI、m/z):下記として計算した値:C31H42N4O3、417.2(M+H)、測定値:417.2.
4−シアノ−1H−イミダゾール−2−カルボン酸[4−(4−ジエチルアミノ−シクロヘキシル)−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−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−[1−(4−エチル−ピペラジン−1−イル)−シクロペンチル]−ピリジン−3−イル}−アミド
表題の化合物の調製を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−(1−ヒドロキシ−シクロペンチル)−ピリジン−3−イル]−アミド(この上に示した段階で調製したまま)、N−エチルピペラジンおよびチオニルクロライドを用いてDCM溶媒中で実施例43に示した手順に従うことで実施する。
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−[1−(2−ピロリジン−1−イル−エトキシ)−シクロペンチル]−ピリジン−3−イル}−アミド
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−[1−(2−メトキシ−エチルアミノ)−シクロヘキシル]−フェニル}−アミド
4−シアノ−1H−イミダゾール−2−カルボン酸[2−(4,4−ジメチル−シクロヘキソ−1−エニル)−4−(シス−1−ヒドロキシ−シス−4−モルホリン−4−イル−シクロヘキシル)−フェニル]−アミド(44)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−(シス−1−ヒドロキシ−トランス−4−モルホリン−4−イル−シクロヘキシル)−フェニル]−アミド(45)
b)4−モルホリン−4−イル−シクロヘキサノン
表題の化合物の調製を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(実施例1の段階(g)で調製したまま)および4−モルホリン−4−イル−シクロヘキサノン(この上に示した段階で調製したまま)を用いて実施例22に記述した如き手順に従うことで実施した。
44:1H−NMR(CD3OD;400MHz):δ 8.12(d、1H、J=8.6Hz)、7.93(s、1H)、7.39(dd、1H、J=8.6、2.3Hz)、7.34(d、1H、J=2.3Hz)、5.73(m、1H)、3.72−3.74(m、4H)、2.69(m、4H)、2.43(t、1H、J=6.4Hz)、2.26−2.34(m、2H)、2.07(m、2H)、1.77−1.92(m、8H)、1.59(t、2H、J=6.3Hz)、1.07(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C29H37N5O3、504.3(M+H)、測定値:504.2.
45:1H−NMR(CD3OD;400MHz):δ 8.20(d、1H、J=8.6Hz)、7.97(s、1H)、7.45(dd、1H、J=8.6、2.3Hz)、7.36(d、1H、J=2.3Hz)、5.74(m、1H)、3.69(m、4H)、2.54(m、4H)、2.36−2.45(m、2H)、2.28−2.36(m、3H)、2.08(m、2H)、1.92−2.02(m、2H)、1.48−1.69(m、6H)、1.09(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C29H37N5O3、504.3(M+H)、測定値:504.3.
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1000RPM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 (21)
- 式I
Wは、
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、
Rzは、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、CH2CH2NH2、CH2CH2ORa、−COCH3、CONH2またはCO2Raであり;
R9は、H、C(1−4)アルキル、ORa、−NA1A2、NA1SO2C(1−4)アルキル、NA1COC(1−4)アルキル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、、またはR3とR9が一緒になってオキソ、−OCH2CH2O−または−OCH2C(Ra)2CH2O−を形成していてもよく;
R10は、H、−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]トリアジニルおよび[1,3,4]チアジアゾリルであり;
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;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。 - Wが
R2が
ZがHであり;
Xが
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または
−NRaCH2CH2NA1A2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;
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であり;そして
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH
2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
請求項1記載の化合物。 - Wが
R2が
Xが
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または−NRaCH2CH2NA1A2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;
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であり;そして
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
請求項2記載の化合物。 - Wが
R2が
Xが
R10がH、−CO2H、−CN、−OH、−CH2NH2、−NA1A2、−OCH2CH2NA1A2または−NRaCH2CH2NA1A2l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;
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であり;そして
R9がH、−OH、−N(CH3)2、−N(CH2CH3)2、モルホリニル、N−メチル−ピペラジニル、N−エチル−ピペラジニル、−NHCH2CH2OCH2CH3、−N(CH2CH2OH)2、−N(CH3)CH2CH2OCH3、−NHCH2CH2SO2CH3、−NHCH2CON(CH3)2であるか、またはR9がR3と一緒になってオキソまたは−OCH2CH2O−を形成していてもよい;
請求項3記載の化合物。 - 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。
- 製薬学的に許容される担体および請求項1記載の少なくとも1種の化合物を約0.5mgから約10g含有して成る製薬学的投薬形態物。
- 非経口または経口投与に適した請求項9記載の投薬形態物。
- 蛋白質チロシンキナーゼの活性を阻害する方法であって、前記キナーゼを有効阻害量の請求項1記載の少なくとも1種の化合物と接触させることを含んで成る方法。
- 前記蛋白質チロシンキナーゼがc−fmsである請求項11記載の方法。
- 哺乳動物における炎症を治療する方法であって、前記哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 哺乳動物における癌を治療する方法であって、前記哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 哺乳動物における心臓血管疾患を治療する方法であって、前記哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 哺乳動物における糸球体腎炎、炎症性腸疾患、人工器官不全、サルコイドーシス、うっ血性閉塞性肺疾患、突発性肺線維症、喘息、膵炎、HIV感染、乾癬、糖尿病、腫瘍関連血管新生、加齢性黄斑変性症、糖尿病性網膜症、再狭窄、統合失調症またはアルツハイマー型認知症を包含する炎症性要素を伴う病気を治療する方法であって、前記哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 哺乳動物における腫瘍転移または変形性関節症によって引き起こされる骨格痛または内臓、炎症および神経原性疼痛を包含する痛みを治療する方法であって、前記治療を必要としている哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 骨粗しょう症、パジェット病および病的状態に骨吸収が介在する他の病気[関節リウマチおよび他の形態の炎症性関節炎、変形性関節症、人工器官不全、溶骨性肉腫、骨髄腫および骨への腫瘍転移を包含]を治療する方法であって、前記治療を必要としている哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 卵巣癌、子宮癌、乳癌、前立腺癌、肺癌、結腸癌、胃癌およびヘアリー細胞白血病を治療しかつそれらからの転移を防止する方法であって、前記治療を必要としている哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
- 自己免疫病、例えば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、多発性硬化症またはブドウ膜炎を治療する方法であって、前記治療を必要としている哺乳動物に請求項1記載の少なくとも1種の化合物を治療的に有効な量で投与することを含んで成る方法。
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