JP5089681B2 - c−fmsキナーゼの阻害剤としての複素環式化合物 - Google Patents
c−fmsキナーゼの阻害剤としての複素環式化合物 Download PDFInfo
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- JP5089681B2 JP5089681B2 JP2009506739A JP2009506739A JP5089681B2 JP 5089681 B2 JP5089681 B2 JP 5089681B2 JP 2009506739 A JP2009506739 A JP 2009506739A JP 2009506739 A JP2009506739 A JP 2009506739A JP 5089681 B2 JP5089681 B2 JP 5089681B2
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- Prior art keywords
- phenyl
- mmol
- alkyl
- enyl
- imidazole
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- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
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- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- YDXJVXWWCWMZQA-UHFFFAOYSA-N spiro[2.5]oct-6-ene Chemical compound C1CC11CC=CCC1 YDXJVXWWCWMZQA-UHFFFAOYSA-N 0.000 description 1
- QVAIACDIALQIMN-UHFFFAOYSA-N spiro[3.5]non-7-ene Chemical compound C1CCC21CC=CCC2 QVAIACDIALQIMN-UHFFFAOYSA-N 0.000 description 1
- TVLQWRPGMSMZBU-UHFFFAOYSA-N spiro[5.5]undec-3-ene Chemical compound C1CCCCC21CC=CCC2 TVLQWRPGMSMZBU-UHFFFAOYSA-N 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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Classifications
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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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60/793,697および2007年1月5日付けで出願した米国仮出願連続番号60/883,539(これらの両方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、
R4はH、F、Cl、Br、I、OH、OCH3、OCH2CH3、−C(1−3)アルキル、−CO2R5、CONR6R7、C≡CR8またはCNであり;かつ
R5はHまたは−C(1−3)アルキルであり;
R6はHまたは−C(1−3)アルキルであり;
R7はHまたは−C(1−3)アルキルであり;そして
R8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);
Xは、下記:
R1およびR10は、独立して、H、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1または2個で置換されていてもよい−C2からC5アルキルであり、かつ前記C2からC5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在する如くであり、そして
R3は、−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9はHまたはC(1−3)アルキルであり;
Zは、H、F、Cl、Br、C1−C3アルキルまたは−CH2OHであり;そして
Jは、CHまたはN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、
R4はH、F、Cl、Br、I、OH、OCH3、OCH2CH3、−C(1−3)アルキル、−CO2R5、CONR6R7、C≡CR8またはCNであり;かつ
R5はHまたは−C(1−3)アルキルであり;
R6はHまたは−C(1−3)アルキルであり;
R7はHまたは−C(1−3)アルキルであり;そして
R8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−エン、スピロ[3.5]ノノ−6−エン、スピロ[4.5]デコ−7−エンおよびスピロ[5.5]ウンデコ−2−エンを包含)、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]ウンデカンおよび8−アザ−スピロ[4.5]デカンを包含)、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);
Xは、
R1およびR10は、独立して、H、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1または2個で置換されていてもよい−C2からC5アルキルであり、かつ前記C2からC5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在する如くであり、そして
R3は、−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9はHまたはC(1−3)アルキルであり;
Zは、H、F、Cl、Br、C1−C3アルキルまたは−CH2OHであり;そして
Jは、CHまたはN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
Xが
R1およびR10が独立してH、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1または2個で置換されていてもよい−C2からC5アルキルであり、かつ前記C2からC5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在する如くであり、そして
R3が−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9がHまたはC(1−3)アルキルであり;
ZがH、F、Cl、Br、C1−C3アルキルまたは−CH2OHであり;そして
JがCHまたはN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
Xが
R1がH、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1または2個で置換されていてもよい−C2からC5アルキルであり、かつ前記C2からC5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在する如くであり、そして
R3が−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9がHまたはC(1−3)アルキルであり;
ZがH、C1−C3アルキルまたは−CH2OHであり;そして
JがCHまたはN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
R2が
ZがHまたは−CH2OHであり;
JがCHであり;
Xが
R1がH、−CH2CH3、−CH2CH2OHまたは−CH3であり;そして
R3が−SO2CH3、−CO2CH3、−NO2または−CN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
R2が
ZがHまたは−CH2OHであり;
JがCHであり;
Xが
R1がHまたは−CH3であり;そして
R3が−SO2CH3または−CN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。
である式1で表される化合物の合成を記述する。
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−(2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド
70.0mg(0.131ミリモル)の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−シクロヘキソ−1−エニル−4−(2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド(この上に示した段階で調製したまま)をCH2Cl2(10mL)に入れることで生じさせた室温の溶液をEtOH(2滴)およびTFA(3mL)で1.5時間処理した。溶媒を真空下で除去した。その残留物を逆相高性能液体クロマトグラフィー(RP−HPLC)(C18)にかけて0.1% TFA/H2O中10から80%のCH3CNに30分かけて至らせて精製することで5.3mg(8%)の表題の化合物を白色の固体として得た:1H−NMR(CD3OD;400MHz):δ 8.18(d、1H、J=8.4Hz)、8.01(s、1H)、7.24(dd、1H、J=8.4、2.4Hz)、7.15(d、1H、J=2.4Hz)、5.85−5.78(m、1H)、3.48−3.38(m、1H)、2.90−2.71(m、4H)、2.32−2.22(m、4H)、1.90−1.73(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C22H21N5O3、404.2(M+H)、測定値:404.0。
表題の化合物の調製を4−(4−ニトロ−フェニル)−ピペリジン−2,6−ジオン(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(i)−(m)に示した手順と同じ手順を用いることで実施した。スペクトルは実施例1の段階(m)に示したスペクトルと同じである。
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−(2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド
190mg(0.338ミリモル)の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−(2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド(この上に示した段階で調製したまま)をCH2Cl2(10mL)に入れることで生じさせた室温の溶液をMeOH(200μL)およびTFA(3mL)で1.5時間処理した。MeOH(30mL)を加えた後の混合物に濃縮を体積が半分になるまで受けさせ、MeOH(15mL)を加えた後、溶媒を真空下<35℃で完全に除去した。その残留物をシリカゲルクロマトグラフィーにかけて25−75% EtOAc−ヘキサンを用いることで92.9mg(64%)の表題の化合物を白色の固体として得た:1H−NMR(CD3OD;400MHz):δ 8.22(d、1H、J=8.4Hz)、8.02(s、1H)、7.26(dd、1H、J=8.4、2.4Hz)、7.18(d、1H、J=2.4Hz)、5.79−5.75(m、1H)、3.52−3.42(m、1H)、2.93−2.76(m、4H)、2.37−2.30(m、2H)、2.12−2.07(m、2H)、1.62(t、2H、J=5.6Hz)、1.10(s、6H).質量スペクトル(ESI、m/z):下記として計算した値:C24H25N5O3、432.2(M+H)、測定値:432.1。
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−シクロヘキソ−1−エニル−4−(2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミド(この上に示した段階で調製したまま、14mg、0.026ミリモル)をDCM(1mL)とEtOH(30μL)とTFA(0.3mL)に溶解させた。その結果として得た混合物を一晩撹拌した後、濃縮した。その得た残留物をC18カラム使用RP−HPLCにかけて0.1% TFA/H2O中20%から100% CH3CNに20分かけて至らせて溶離させることで表題の化合物(1.1mg、8%)を得た:1H−NMR(CD3OD/CDCl3;400MHz):δ 8.23(d、1H、J=8.0Hz)、7.90(s、1H)、7.20(dd、1H、J=8.0、2.2Hz)、7.09(d、1H、J=2.2Hz)、5.75(br s、1H)、3.47(4H、m)、3.17(m、1H)、2.22−2.33(m、4H)、1.72−1.83(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C21H22N6O2、391.3(M+H)、測定値:391.2。
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−シクロヘキソ−1−エニル−4−(1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−フェニル]−アミド(この上に示した段階で調製したまま、17.8mg、0.0320ミリモル)をDMF(35μL)とエチレンジアミン(13μL、0.18ミリモル)に入れることで生じさせた溶液に固体状フッ化テトラブチルアンモニウム(TBAF)(25mg、0.090ミリモル)を加えた。その結果として生じた溶液を60℃で12時間撹拌した。その反応混合物に濃縮を真空下で受けさせた後、その結果として得た残留物をシリカ(20−100% EtOAc−ヘキサン)で精製することで表題の化合物を得た(9.3mg、68%):1H−NMR(CD3OD;400MHz):δ 8.19(d、1H、J=8.7Hz)、8.05(s、1H)、7.18(dd、1H、J=8.7、2.2Hz)、7.08(d、1H、J=2.2Hz)、5.81(br s、1H)、3.62(m、2H)、3.35(m、2H)、2.93(m、1H)、2.24−2.34(m、4H)、1.82−1.90(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C20H22N6O3S、427.1(M+H)、測定値:427.2。
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−(1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−5−ヒドロキシメチル−フェニル]−アミド
4−シアノ−1H−イミダゾール−2−カルボン酸[2−シクロヘキソ−1−エニル−4−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミドのトリフルオロ酢酸塩
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[2−シクロヘキソ−1−エニル−4−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−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[2−シクロヘキソ−1−エニル−4−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミド(この上に示した段階で調製したまま、66mg、0.12ミリモル)をDMF(2mL)に入れることで生じさせた溶液に固体状TBAF(109mg、0.410ミリモル)を加えた。その結果として得た混合物を60℃で6時間撹拌した。DMFを真空下で除去した後、その結果として得た残留物をC18カラム使用RP−HPLCにかけて0.1% TFA/H2O中20%から100%のCH3CNに20分かけて至らせることで溶離させて精製することで表題の化合物を得た(26mg、52%):1H−NMR(CDCl3;400MHz):δ 9.50(s、1H)、8.45(d、1H、J=8.4Hz)、7.75(s、1H)、7.24(dd、1H、J=8.4、2.0Hz)、7.08(d、1H、J=2.0Hz)、5.87(br s、1H)、3.62(m、2H)、3.35(m、3H)、2.94(s、6H)、2.22−2.34(m、4H)、1.72−1.90(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C23H26N6O2、419.2(M+H)、測定値:419.3。
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−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミド
表題の化合物の合成を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−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−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7の段階(e)に記述したようにして実施した。 1H−NMR(CDCl3;400MHz):δ 9.55(s、1H)、8.43(d、1H、J=8.4Hz)、7.73(s、1H)、7.24(dd、1H、J=8.4、2.1Hz)、7.06(s、1H)、5.82(br s、1H)、3.60(m、2H)、3.33(m、3H)、3.13(s、6H)、2.28−2.35(m、2H)、2.08−2.17(m、2H)、1.62(m、2H)、1.16(s、6H);質量スペクトル(ESI、m/z):下記として計算した値:C25H30N6O2、447.2(M+H)、測定値:447.3。
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−シクロヘプト−1−エニル−4−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミド(この上に示した段階で調製したまま、86mg、0.15ミリモル)をDMF(2mL)に入れることで生じさせた溶液に固体状TBAF(213mg、0.816ミリモル)を加えた。その結果として得た混合物を60℃で6時間撹拌した。DMFを真空下で除去した後、その結果として得た残留物をC18カラム使用RP−HPLCにかけて0.1% TFA/H2O中20から100%のCH3CNに20分かけて至らせることで溶離させて精製することで表題の化合物を得た(39mg、47%):1H−NMR(CD3OD;400MHz):δ 8.15(d、1H、J=8.4Hz)、8.02(s、1H)、7.22(dd、1H、J=8.4、2.1Hz)、7.13(d、1H、J=2.1Hz)、5.98(t、1H、J=6.4Hz)、3.53−3.38(m、5H)、2.96(m、6H)、2.54(m、2H)、2.42(m、2H)、1.92(m、2H)、1.65−1.83(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C24H28N6O2、433.2(M+H)、測定値:433.2。
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−(2,6−ジメチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−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−シクロヘキソ−1−エニル−4−(2,6−ジメチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−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9の段階(b)に記述したSEM保護基除去手順に従うことで実施した:1H−NMR(CDCl3;400MHz):δ 11.85(br s、1H)、9.54(s、1H,)、8.37(d、1H、J=8.4Hz)、7.73(d、1H、J=2.1Hz)、7.38(dd、1H、J=8.4、2.1Hz)、7.04(s、1H)、5.98(m、1H)、3.85(m、2H)、3.46(m、2H)、3.33(m、2H)、2.35−2.20(m、4H)、1.65−1.92(m、4H):質量スペクトル(ESI、m/z):下記として計算した値:C22H26N6O2S、455.1(M+H)、測定値:455.2。
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−(2−シアノイミノ−ヘキサヒドロ−ピリミジン−5−イル)−2−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)に実施例9の段階(c)に記述した如きSEM保護基除去を受けさせることで表題の化合物を得た:1H−NMR(CD3OD/CDCl3;400MHz):δ 8.25(d、1H、J=8.4Hz)、7.73(s、1H)、7.24(dd、1H、J=8.4、2.1Hz)、7.08(d、1H、J=2.1Hz)、5.85(br s、1H)、3.4−3.6(m、4H)、3.1−3.2(m、1H)、2.22−2.34(m、4H)、1.77−1.90(m、4H):質量スペクトル、(ESI、m/z):下記として計算した値:C22H27N8O2、415.2(M+H)、測定値:415.2。
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−シクロヘキソ−1−エニル−4−(2−メタンスルホニルイミノ−ヘキサヒドロ−ピリミジン−5−イル)−フェニル]−アミド(この上に示した段階で調製したまま)に実施例9の段階(c)に記述した如きSEM保護基除去を受けさせることで表題の化合物を得た:1H−NMR(DMSO−d6;400MHz):δ 14.2(br s,1H),9.69(s,1H),8.25(s,1H),7.82(d,1H、J=8.4Hz)、7.44(s、1H)、7.17(dd、1H、J=8.4、2.2Hz)、7.08(d、1H、J=2.2Hz)、5.65(br s、1H)、3.32−3.36(m、4H)、2.98−3.05(m、1H)、2.68(s、3H)、2.02−2.18(m、4H)、1.45−1.68(m、4H):質量スペクトル(ESI、m/z):下記として計算した値:C22H25N7O3S、468.2(M+H)、測定値:468.3。
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−(1−メチル−2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド
130mg(0.237ミリモル)の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−シクロヘキソ−1−エニル−4−(1−メチル−2,6−ジオキソ−ピペリジン−4−イル)−フェニル]−アミド(この上に示した段階で調製したまま)をCH2Cl2(10mL)に入れることで生じさせた室温の溶液をMeOH(200μL)およびTFA(3mL)で1.25時間処理した。MeOH(30mL)を加えた後の混合物を濃縮して体積を半分にし、MeOH(20mL)を加えた後、溶媒を真空下<35℃で完全に除去した。その残留物を50−g Varian MegaBond Elut 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−ヘキサンを用いそしてRP−HPLC(C18)にかけて0.1% TFA/H2O中10から80%のCH3CNに30分かけて至らせることで8.0mg(8%)の表題の化合物を白色の固体として得た:1H−NMR(CD3OD;400MHz):δ 8.19(d、1H、J=8.4Hz)、8.03(s、1H)、7.24(dd、1H、J=8.4、2.4Hz)、7.16(d、1H、J=2.4Hz)、5.87−5.82(m、1H)、3.47−3.37(m、1H)、3.16(s、3H)、2.96−2.91(m、4H)、2.33−2.25(m、4H)、1.92−1.77(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C23H23N5O3、418.2(M+H)、測定値:418.1。
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−(2−ヒドロキシ−1−ヒドロキシメチル−エチル)−フェニル]−アミド(この上に示した段階で調製したまま、5.4mg、0.015ミリモル)およびピリジン(3.0μL、0.037ミリモル)を0.5mLのTHFに入れることで生じさせた−78℃の溶液にトリホスゲン(1.8mg、0.0061ミリモル)を0.5mLのDCMに入れることで生じさせた溶液を加えた。その結果として得た混合物を室温に温めて撹拌をAr下で1時間継続した。溶媒を減圧下で除去した後、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(1−2% MeOH−DCM)にかけることで2.8mg(48%)の表題の化合物を白色の固体として得た:1H−NMR(CD3OD;400MHz):δ 8.01(s、1H)、7.66(dd、1H、J=8.6、2.3Hz)、7.59(d、1H、J=2.3Hz)、7.29(d、1H、J=8.6Hz)、5.66(m、1H)、4.65(dd、2H、J=10.9、10.9Hz)、4.45(dd、2H、J=10.9、4.9Hz)、3.72(m、1H)、2.24(m、4H)、1.70−1.88(m、4H).質量スペクトル(ESI、m/z):下記として計算した値:C21H20N4O4、393.2(M+H)、測定値:393.1。
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−(2−メチル−1,1,3,3−テトラオキソ−1λ6,3λ6−[1,3,2]ジチアジナン−5−イル)−フェニル]−アミド
表題の化合物の調製を5−(4−ニトロ−フェニル)−[1,3,2]ジチアジナン1,1,3,3−テトラオキサイド(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(i)−(m)に示した手順と同様な手順を用いることで実施する。
4−メチル−1H−イミダゾール−2−カルボン酸[4−(2,6−ジエチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−2−(4−メチル−ピペリジン−1−イル)−フェニル]−アミド
表題の化合物の調製を4−(2,6−ジエチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−2−(4−メチル−ピペリジン−1−イル)−フェニルアミン(この上に示した段階で調製したまま)および5−メチル−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(この上に示した実施例の段階(c)で調製したまま)を用いて実施例11の段階(d)−(e)の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[6’−(1,3−ジメチル−2−オキソ−ヘキサヒドロ−ピリミジン−5−イル)−4,4−ジメチル−3,4,5,6−テトラヒドロ−2H−[1,2’]ビピリジニル−3’−イル]−アミド
表題の化合物の調製を5−(3’−アミノ−4,4−ジメチル−3,4,5,6−テトラヒドロ−2H−[1,2’]ビピリジニル−6’−イル)−1,3−ジメチル−テトラヒドロ−ピリミジン−2−オン(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(l)および(m)に示した手順に従うことで実施する。
4−クロロ−1H−イミダゾール−2−カルボン酸[6’−(2,6−ジエチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−4−メチル−3,4,5,6−テトラヒドロ−2H−[1,2’]ビピリジニル−3’−イル]−アミド
表題の化合物の調製を6’−(2,6−ジエチル−1,1−ジオキソ−1λ6−[1,2,6]チアジアジナン−4−イル)−4−メチル−3,4,5,6−テトラヒドロ−2H−[1,2’]ビピリジニル−3’−イルアミン(この上に示した段階で調製したまま)および4−クロロ−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−カルボン酸のカリウム塩(この実施例の段階(b)で調製したまま)を用いて実施例1の段階(l)の手順に続いて実施例1の段階(m)の手順に従うことで実施する。
{5−[4−[(4−ブロモ−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−ピリミジン−2−イリデン}−カルバミン酸メチルエステル
表題の化合物の調製を4−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−2−カルボン酸のカリウム塩(この実施例の段階(c)で調製したまま)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−カルボン酸のカリウム塩の代わりに用いかつ4,4−ジメチル−シクロヘキソ−1−エニルホウ素酸をシクロヘキソ−1−エニルホウ素酸の代わりに用いて実施例12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[4−(2−シアノイミノ−1,3−ジメチル−ヘキサヒドロ−ピリミジン−5−イル)−2−(4,4−ジメチル−シクロヘキソ−1−エニル)−フェニル]−アミドのトリフルオロ酢酸塩
表題の化合物の合成を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−(2−シアノイミノ−1,3−ジメチル−ヘキサヒドロ−ピリミジン−5−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)を用いて実施例7の段階(e)に記述したようにして実施した:1H−NMR(CD3OD;400MHz):δ 8.22(d、1H、J=8.4Hz)、8.01(s、1H)、7.25(dd、1H、J=8.4、2.1Hz)、7.08(d、1H、J=2.1Hz)、5.82(br s、1H)、3.4−3.6(m、4H)、3.25(s、6H)、3.1−3.2(m、1H)、2.38(m、2H)、2.15(m、2H)、1.62(m、2H)、1.15(s、6H);質量スペクトル(ESI、m/z):下記として計算した値:C26H30N8O、471.2(M+H)、測定値:471.3。
蛍光偏光競合免疫測定法
合成CSF−1R555−568ペプチド(SYEGNSYTFIDPTQ)を用いて化合物がチロシンのCSF−1R燐酸化を阻害する度合を測定する目的で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(カタログ番号42−000−0117、Molecular Devices、Sunnyvale、CA)を用いて実施した。各穴に5μLの化合物(4%のDMSOに入れた)を入れて、これを検定用緩衝液(100mM HEPES、pH7.5、1mM DTT、0.01% Tween−20)中3.5nMのCSF−1Rと25mMのMgCl2(2μL)および検定用緩衝液中1540μMのペプチド(2μL)と一緒にして混合した。検定用緩衝液中10mMのATPを1μL添加することでキナーゼ反応を開始させた。10uLの反応混合物中の最終濃度は100mMのHEPES(pH7.5)、1mMのDTT、0.01%のTween−20、2%のDMSO、308μMのSYEGNSYTFIDPTQ、1mMのATP、5mMのMgCl2および0.7nMのCSF−1Rであった。正および負対照の穴を各プレートに含め、その場合には、検定用緩衝液中4%のDMSOを当該化合物の代わりに用い、加うるに、正対照の穴には反応開始前に50mMのEDTAを1.2μL入れた。
FCS(ウシ胎仔血清)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0.1百万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℃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培地を除去して200の定着用溶液を代わりに入れて室温に30’間置く。次に、その定着液を前記プレートから除去した後、そのプレートを空気乾燥させる。その定着させて乾燥させた細胞の中に取り込まれているBrDUをExalpha Corporation(Watertown MA)の特異的ELISA(Cat X1327K)を用いて量化する。穴にBrDU反応体を入れないことで背景値を測定する。IC50値の計算を化合物を存在させないでCSF−1で刺激した細胞からのシグナルを基にして行う。
Claims (10)
- 式I:
Wは、
R4はH、F、Cl、Br、I、OH、OCH3、OCH2CH3、−C(1-3)アルキル、−CO2R5、CONR6R7、C≡CR8またはCNであり;かつ
R5はHまたは−C(1-3)アルキルであり;
R6はHまたは−C(1-3)アルキルであり;
R7はHまたは−C(1-3)アルキルであり;そして
R8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;
Xは、下記:
R1およびR10は、独立して、H、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1または2個で置換されていてもよい−C2−C5アルキルであり、かつ前記C2−C5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在し、そして
R3は、−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9は、HまたはC(1-3)アルキルであり;
Zは、H、F、Cl、Br、C1−C3アルキルまたは−CH2OHであり;そして
Jは、CHまたはNである]
で表される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がシクロヘキセニル、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、4−t−ブチルシクロヘキセニル、シクロヘプテニル、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、スピロ[5.5]ウンデコ−2−エニル、3−アザ−スピロ[5.5]ウンデカニル、8−アザ−スピロ[4.5]デカニル、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、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およびジヒドロピラニルから成る群より選択される請求項1記載の化合物。
- R2が
Xが
R1がH、−CH3、または場合によりMe、Et、OH、NH2、NHMe、NMe2、NHEt、NEt2、ピロリジニル、ピリジル、モルホリノ、CONH2またはCOOHの中の1個または2個で置換されていてもよい−C2からC5アルキルであり、かつ前記C2からC5アルキル基にいずれかのヘテロ原子が2個結合している時にはそれらの間に少なくとも2個の炭素原子が存在する如くであり;
R3が−SO2Me、SO2Et、−CO2R9、−NO2または−CNであり;かつ
R9=HまたはC(1-3)アルキル;そして
ZがH、C1−C3アルキルまたは−CH2OHである;
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。
- 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哺乳動物におけ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、多発性硬化症および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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KR101367645B1 (ko) | 2006-04-20 | 2014-02-27 | 얀센 파마슈티카 엔.브이. | C-fms 키나제의 저해제로서의 복소환식 화합물 |
JO3240B1 (ar) | 2007-10-17 | 2018-03-08 | Janssen Pharmaceutica Nv | c-fms مثبطات كيناز |
JP2011502266A (ja) | 2007-10-31 | 2011-01-20 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Fms治療に対する応答を評価するバイオマーカー |
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2009534418A (ja) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | C−kitキナーゼ阻害法 |
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CA2649736A1 (en) | 2007-11-01 |
EP2021335A1 (en) | 2009-02-11 |
EP2021335B1 (en) | 2011-05-25 |
US7414050B2 (en) | 2008-08-19 |
AU2007240437A1 (en) | 2007-11-01 |
PL2021335T3 (pl) | 2011-10-31 |
AR060608A1 (es) | 2008-07-02 |
JP2009534403A (ja) | 2009-09-24 |
SI2021335T1 (sl) | 2011-09-30 |
US7973035B2 (en) | 2011-07-05 |
US20110195960A1 (en) | 2011-08-11 |
PT2021335E (pt) | 2011-07-25 |
CA2649736C (en) | 2013-11-26 |
CY1111749T1 (el) | 2015-10-07 |
DK2021335T3 (da) | 2011-09-05 |
US20080275031A1 (en) | 2008-11-06 |
US20070249593A1 (en) | 2007-10-25 |
US20140243382A1 (en) | 2014-08-28 |
US8481564B2 (en) | 2013-07-09 |
AU2007240437B2 (en) | 2012-12-06 |
NZ572073A (en) | 2011-09-30 |
WO2007124316A1 (en) | 2007-11-01 |
US8759347B2 (en) | 2014-06-24 |
MX2008013533A (es) | 2009-01-15 |
US20150051196A1 (en) | 2015-02-19 |
US9296726B2 (en) | 2016-03-29 |
TW200811162A (en) | 2008-03-01 |
KR101367645B1 (ko) | 2014-02-27 |
US8895584B2 (en) | 2014-11-25 |
US20130281475A1 (en) | 2013-10-24 |
ATE510832T1 (de) | 2011-06-15 |
KR20090008371A (ko) | 2009-01-21 |
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