JP2005508962A - 2’−メチル−5−(1,3,4−オキサジアゾール−2−イル)−1,1’−ビフェニル−4−カルボキサミド誘導体およびp38キナーゼ阻害剤としてのそれらの使用 - Google Patents
2’−メチル−5−(1,3,4−オキサジアゾール−2−イル)−1,1’−ビフェニル−4−カルボキサミド誘導体およびp38キナーゼ阻害剤としてのそれらの使用 Download PDFInfo
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- JP2005508962A JP2005508962A JP2003535790A JP2003535790A JP2005508962A JP 2005508962 A JP2005508962 A JP 2005508962A JP 2003535790 A JP2003535790 A JP 2003535790A JP 2003535790 A JP2003535790 A JP 2003535790A JP 2005508962 A JP2005508962 A JP 2005508962A
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- methyl
- alkyl
- mmol
- compound
- biphenyl
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- QPMDWIOUHQWKHV-ODZAUARKSA-M potassium;(z)-4-hydroxy-4-oxobut-2-enoate Chemical compound [K+].OC(=O)\C=C/C([O-])=O QPMDWIOUHQWKHV-ODZAUARKSA-M 0.000 description 1
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- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 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
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- 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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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-N sodium;2-hydroxybenzoic acid Chemical class [Na+].OC(=O)C1=CC=CC=C1O ABBQHOQBGMUPJH-UHFFFAOYSA-N 0.000 description 1
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 1
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- 230000000087 stabilizing effect Effects 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- PQCKZKIMUVIUNF-UHFFFAOYSA-N tert-butyl n-[[3-[4-(cyclopropylmethylcarbamoyl)phenyl]-4-methylbenzoyl]amino]carbamate Chemical compound CC1=CC=C(C(=O)NNC(=O)OC(C)(C)C)C=C1C1=CC=C(C(=O)NCC2CC2)C=C1 PQCKZKIMUVIUNF-UHFFFAOYSA-N 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000005490 tosylate group Chemical class 0.000 description 1
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
【化1】
Description
mが0〜4である場合、R1はC1-6アルキル、C3-7シクロアルキル、C2-6アルケニル、-SO2NR4R5、-CONR4R5および-COOR4から選択され;
mが2〜4である場合、R1はさらにC1-6アルコキシ、ヒドロキシ、NR4R5、-NR4SO2R5、-NR4SOR5、-NR4COR5および-NR4CONR4R5から選択され;
R2は、水素、C1-6アルキルおよび-(CH2)n-C3-7シクロアルキルから選択され;
R3は基:
R4およびR5は、独立して、水素、C1-6アルキル、場合によりC1-4アルキルで置換されているヘテロ環およびフェニルから選択され、ここで該フェニルは場合により、独立してC1-6アルコキシ、C1-6アルキルおよびハロゲンから選択される2個以下の基で置換されているか;あるいは、R4およびR5は、それが結合している窒素原子と一緒になって、場合により酸素、硫黄および窒素から選択される1個のさらなるヘテロ原子を含む5員〜6員のヘテロ環もしくはヘテロアリール環を形成し、ここで該環は、2個以下のC1-6アルキル基で置換されていてもよく;
R6は、水素およびC1-4アルキルから選択され;
Uは、メチルおよびハロゲンから選択され;
XおよびYは、それぞれ独立して、水素、メチルおよびハロゲンから選択され;
mは、0、1、2、3および4から選択され、ここで、得られる炭素鎖の各炭素原子は場合により、独立してC1-6アルキルから選択される1個または2個の基で置換されていてもよく;
nは、0、1、2および3から選択され;
rは、0、1および2から選択される]
の化合物、またはその薬学的に許容される塩もしくは溶媒和物が提供される。
の化合物、またはその薬学的に許容される塩もしくは溶媒和物が提供される。
N-(3,3-ジメチルブチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミド;および
N-(2,3-ジメチルシクロヘキシル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミド。
(ii) TFA
(iii) R4C(OEt)3
(iv) (4-メトキシカルボニルフェニル)ボロン酸、(Ph3P)4Pd、CsCO3、DME
(v) LiOH、THF、H2O
(vi) R1(CH2)mNR2H、HOBT、HBTU、DIPEA、DMF
例えば、式(I)の化合物を製造するための一般的方法(B)は、下記のスキーム2に示す反応を含む。
(ii) TFA
(iii) R4C(OEt)3
(iV) ビス(ピナコレート)ジボロン、KOAc、PdCl2dppf、DMF
(v) SOCl2
(vi) R1(CH2)mNR2H Na2CO3、アセトン
(vii) (Ph3P)4P、Na2CO3、DMF
例えば、式(I)の化合物を製造するための一般的方法(C)は、下記のスキーム3に示す反応を含む。
(ii) R1(CH2)mNH2、HOBT、HBTU、DIPEA、DMF
(iii) R2-hal、NaH、DMF
したがって、本発明によれば、式(I)の化合物の製造方法であって、
(a) 式(XII):
の化合物を、式(XIII):
R1(CH2)mNR2H (XIII)
[式中、R1、R2およびmは上記で定義したとおりである]
の化合物と、アミド形成条件下で反応させるか;
b) 式(XIV):
の化合物と、触媒、例えばテトラキス(トリフェニルホスフィン)パラジウムの存在下で反応させるか;または
c) 式(XVI):
の化合物を、式(XVII):
R1(CH2)mNH2 (XVII)
[式中、R1およびmは上記で定義したとおりである]
の化合物と、アミド形成条件下で反応させ、
続いて、式(XVIII):
R2-hal (XVIII)
[式中、R2およびhalは上記で定義したとおりである]
の化合物と、水素化ナトリウムなどの塩基の存在下で反応させること
を含む、上記方法が提供される。
以下の実施例は、本発明を説明するための実施形態であるが、本発明の範囲を如何ようにも限定するものではない。試薬は、市販されているか、または文献の手順に従って調製する。
トリエチルオルトアセテート(20ml)中のヒドラジド(4.36mmol)の懸濁液を、100℃で2時間、次に130℃で1.5時間温めた。過剰のトリエチルオルトアセテートを減圧下で除去し、残渣を酢酸エチル(50ml)と水(50ml)とに分配した。有機物質を水(50ml)、食塩水(50ml)で洗浄し、硫酸マグネシウムで乾燥した。この溶液を減圧下で濃縮乾固し、残渣をシクロヘキサンで粉砕してオキサジアゾールを得た。
t-ブトキシカルボニルヒドラジド(7.57mmol)を、0℃にて、トリフルオロ酢酸溶液に何回かに分けて添加した。添加が完了したら、溶液を0℃で15分間撹拌し、次に室温にて30分間撹拌した。溶液を減圧下で濃縮乾固し、残渣を酢酸エチル(100ml)と炭酸ナトリウム溶液(2N、100ml)とに分配した。水性画分を酢酸エチル(2回×75ml)で抽出した。1つに合わせた有機画分を食塩水(100ml)で洗浄し、乾燥(硫酸マグネシウム)し、減圧下で蒸発乾固して、ヒドラジドを得た。
N,N-ジイソプロピルエチルアミン(69.75mmol)を0℃で、DMF(15ml)中の安息香酸(23.25mmol)、HOBT(23.25mmol)、t-ブチルカルバゼート(23.25mmol)、HBTU(27.9mmol)の溶液に滴下した。反応物を0℃で15分間撹拌し、次に室温にて6時間撹拌した。DMFを減圧下で蒸発させ、残渣をDCM(150ml)と水(150ml)とに分配した。水性画分をDCM(2回×100ml)で抽出した。1つに合わせた有機画分を食塩水(100ml)で洗浄し、乾燥(硫酸マグネシウム)し、減圧下で蒸発乾固した。固体の残渣を炭酸ナトリウム水溶液(2N)で洗浄し、乾燥した。
一般的方法D:
DME(30ml)中の芳香族臭化物またはヨウ化物(4.0mmol)、フェニルボロン酸(4.8mmol)、テトラキス(トリフェニルホスフィン)パラジウム(100mg)および炭酸セシウム(2.4g)を、窒素下で90℃にて20時間加熱した。冷却した反応物をシリカに前吸着させ、シリカSPE(10g)のクロマトグラフィーにかけ、酢酸エチル/シクロヘキサン勾配(0〜100%の酢酸エチル)で溶出させた。1つに合わせた生成物画分を減圧下で蒸発乾固した。
安息香酸メチル(1.0mmol)をTHF(10ml)に溶解し、水(10ml)中の水酸化リチウム一水和物(2.1mmol)の溶液を添加した。反応混合液を、75℃で4時間加熱した。THFを減圧下で蒸発させ、この溶液を塩酸(2N)で酸性化した。生成した沈殿を濾過し、水で洗浄し、減圧下で乾燥した。
安息香酸(0.1mmol)、HOBT(0.1mmol)、PyBOP(0.1mmol)およびアミン(1.2mmol)を1.75mlのDMF中で混合し、DIPEA(52μl)を添加し、反応物を室温にて72時間撹拌した。DMFを減圧下で蒸発させ、残渣をDCMと炭酸水素ナトリウム水溶液とに分配した。有機画分を分け取り、溶液を減圧下で蒸発乾固した。残渣を、シリカSPEのクロマトグラフィーにかけ、DCM/エタノール/アンモニア勾配(500:8:1から40:8:1)で溶出させた。生成物画分を1つに合わせ、蒸発乾固した。残渣を、再度シリカSPEのクロマトグラフィーにかけ、酢酸エチル /シクロヘキサン勾配(1:8から1:1)で溶出させた。生成物画分を減圧下で蒸発乾固した。
安息香酸(3.1mmol)、HATU(3.7mmol)、DIPEA(6.8mmol)およびアミン(3.1mmol)をDMF(30ml)中で混合し、80℃で18時間加熱した。冷却した反応物から溶媒を減圧下で蒸発させ、残渣をDCMに溶解させた。このDCM溶液を水酸化ナトリウム水溶液(2M)、塩酸(2M)および食塩水で洗浄した。硫酸マグネシウムで乾燥し、溶媒を減圧下で蒸発させた。残渣を、シリカのクロマトグラフィーにかけ、DCM/エタノール/アンモニア(500:8:1)で溶出させ、生成物画分から溶媒を減圧下で蒸発させた。
二級アミド(0.06mmol)、ヨードアルカンまたはブロモアルカン(3滴)および水素化ナトリウム(鉱油中60%、0.5mmol)をDMF(5ml)中で18時間撹拌した。反応物を塩酸(2N)で酸性化し、DCM(2回×10ml)で抽出した。1つに合わせた抽出物からDCMを減圧下で蒸発させ、残渣を、SPE(シリカ、1g)により酢酸エチルで溶出させて精製した。酢酸エチルを減圧下で蒸発させて、三級アミドを得た。
安息香酸(0.1mmol)、HATU(0.1mmol)、DIPEA(0.3mmol)およびアミン(0.12mmol)をTHF(5ml)中で混合し、室温にて16時間加熱した。溶媒を減圧下で蒸発させ、残渣をDCMに溶解した。このDCM溶液を炭酸ナトリウム水溶液(2M)で洗浄し、シリカSPE(5g)に吸着させ、DCM/エタノール/アンモニア勾配(500:8:1〜15:8:1)で溶出させた。溶媒を生成物画分から減圧下で蒸発させて、アミドを得た。
a) 2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(59mg、0.2mmol)、3-アミノ-1-プロパノール(15mg、0.2mmol)および1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(0.2mmol)を、無水DCM(7ml)中で懸濁し、窒素下で室温にて20時間撹拌した。3-アミノ-1-プロパノール(45mg、0.6mmol)を添加し、反応物を室温にて21時間撹拌した。1-ヒドロキシベンゾトリアゾール(27mg、0.2mmol)を添加し、反応物を35℃で70時間加熱した。水(10ml)を冷却した反応物に添加し、有機画分を分離した。有機相をシリカフラッシュカラムに吸着させ、DCM/エタノール/アンモニア勾配(300:8:1から150:8:1)で溶出させた。生成物画分から溶媒を減圧下で留去して、N-(3-ヒドロキシプロピル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た(21mg、30%)。NMR; δH[2H6]-DMSO 8.52,(1H, t), 7.94-7. 88, (3H,m), 7.75, (1H, m), 7.55-7.49, (3H, m), 3.47, (2H, t), 3.33, (2H, m), 2.56, (3H, s), 2.30, (3H, s), 1.69, (2H, m). LCMS; 保持時間2.68分、MH+ 352。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸は、メチル2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキレートから方法Eを用いて調製した。NMR;δH [2H6] - DMSO 8.03,(2H,d), 7.90,(1H,dd), 7.75,(1H,d), 7.57-7.52,(3H,m), 2.56,(3H,s), 2.30,(3H,s)。LCMS;保持時間3.14分、MH+ 295。
メチル2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキレートは、2-(3-ブロモ-4-メチルフェニル)-5-メチル-1,3,4-オキサジアゾールおよび[4-(メトキシカルボニル)フェニル]ボロン酸から方法Dを用いて調製した。NMR;δH CDCl3 8.12,(2H,d), 7.94,(1H,dd), 7.90,(1H,d), 7.43,(3H,m), 3.96,(3H,s), 2.61,(3H,s), 2.33,(3H,s)。LCMS;保持時間3.37分、MH+ 309。
2-(3-ブロモ-4-メチルフェニル)-5-メチル-1,3,4-オキサジアゾールは、(3-ブロモ-4-メチルベンゾイル)ヒドラジンから方法Aを用いて調製した。NMR;δH [2H6] - DMSO 8.08,(1H,d), 7.86,(1H,dd), 7.56,(1H,d), 2.56,(3H,s), 2.41,(3H,s)。LCMS;保持時間3.19分、MH+ 254。
(3-ブロモ-4-メチルベンゾイル)ヒドラジンは、t-ブチル2-(3-ブロモ-4-メチルベンゾイル)ヒドラジン-1-カルボキシレートから方法Bを用いて調製した。NMR;δH [2H6] - DMSO 9.82,(1H,b), 8.00,(1H,d), 7.73,(1H,dd), 7.42,(1H,d), 4.49,(2H,b), 2.36,(3H,s)。LCMS;保持時間2.47分。
t-ブチル2-(3-ブロモ-4-メチルベンゾイル)ヒドラジン-1-カルボキシレートは、3-ブロモ-4-メチル安息香酸から方法Cを用いて調製した。NMR;δH [2H6] - DMSO 10.25,(1H,b), 8.94,(1H,b), 8.04,(1H,s), 7.76,(1H,d), 7.47,(1H,d), 2.39,(3H,s), 1.41,(9H,s)。LCMS;保持時間3.24分、MH+ 330。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(59mg、0.2mmol)、シクロプロピルアミン(11mg、0.2mmol)および1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(0.2mmol)を、無水DCM(7ml)中で懸濁し、窒素下で室温にて20時間撹拌した。シクロプロピルアミン(33mg、0.6mmol)を添加し、反応物を室温で21時間撹拌した。1-ヒドロキシベンゾトリアゾール(27mg、0.2mmol)を添加し、反応物を35℃で70時間加熱した。水(10ml)を冷却した反応物に添加し、有機画分を分離した。有機相をシリカフラッシュカラムに吸着させ、DCM/エタノール/アンモニア(300:8:1)で溶出させた。溶媒を生成物画分から減圧下で留去して、N-(シクロプロピル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た(26mg、39%)。
DIPEA(76μl、0.6mmol)を、DMF(0.5ml)中の2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(59mg、0.2mmol)、3-ジメチルアミノプロピルアミン(20mg、0.2mmol)、HBTU(91mg、0.24mmol)およびHOBT(27mg、0.2mmol)の溶液に添加した。反応物を室温にて16時間撹拌した。DMFを減圧下で留去し、残渣をDCM(5ml)と水(5ml)とに分配した。有機相をシリカフラッシュカラムに吸着させ、DCM/エタノール/アンモニア(80:8:1)で溶出させた。生成物画分を減圧下で濃縮して、N-[(ジメチルアミノ)プロピル]-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサアミドを得た(37mg、49%)。
a) シクロプロピルメチルアミン(78mg、1.10mmol)および2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボニルクロリド(115mg、0.368mmol)をDCM(15ml)中で混合し、室温にて17時間撹拌した。反応物をシリカフラッシュカラムに吸着させ、DCM/エタノール/アンモニア(150:8:1)で溶出させた。生成物画分を減圧下で濃縮して、N-(シクロプロピルメチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを白色泡状物質として得た(75mg、59%)。NMR;δH [2H6] - DMSO 8.65,(1H, t), 7.95,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.55-7.49,(3H, m), 3.17,(2H, t), 2.56,(3H, s), 2.31,(3H, s), 1.05,(1H, m), 0.43,(2H, m), 0.24,(2H, m)。LCMS;保持時間 3.15分、MH+ 348。
塩化オキサリル(0.073ml, 0.82mmol)を、DCM(10ml)中の2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(200mg、0.68mmol)およびDMF(2滴)の懸濁液に0℃で添加した。反応物を室温にて1.5時間撹拌し、溶媒を減圧下で留去して、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボニルクロリドを白色固体として得た(0.212g, 100%)。NMR;δH [2H6] - DMSO 8.03,(2H, d), 7.90,(1H, dd), 7.76,(1H, d), 7.56-7.53,(3H, m), 2.56,(3H, s), 2.30,(3H, s)。
DIPEA(130μl, 1.0mmol)を、DMF(1.0ml)中の2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(100mg、0.34mmol)、3-ジエチルアミノプロピルアミン(49mg、0.37mmol)、HBTU(155mg、0.41mmol)およびHOBT(46mg、0.34mmol)の溶液に添加した。反応物を室温にて66時間撹拌した。DMFを減圧下で留去し、残渣をDCM(5ml)と水(5ml)とに分配した。有機相をシリカフラッシュカラムに吸着させ、DCM/エタノール/アンモニア(100:8:1)で溶出させた。生成物画分を減圧下で濃縮して、N-[3-(ジエチルアミノ)プロピル]-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た(88mg、64%)。NMR;δH [2H6] - DMSO 8.60,(1H, t), 7.92,(2H, d), 7.89,(1H, dd), 7.75,(1H, d), 7.54,(1H, d), 7.50,(2H, d), 3.30,(2H, m), 2.56,(3H, s), 2.46-2.41,(6H, m), 2.30,(3H, s), 1.65,(2H, m), 0.94,(6H, t)。LCMS;保持時間 2.44分、MH+ 407。
N-(シクロプロピルメチル)-N-メチル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドは、N-(シクロプロピルメチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミド およびヨードメタンから方法Hを用いて調製した。NMR;δH [2H6] - DMSO 7.89,(1H, dd), 7.76,(1H, d), 7.54,(1H, d), 7.47,(4H, s), 3.14-3.01,(5H, m), 2.56,(3H, s), 2.32,(3H, s), 1.08-0.95,(1H, b), 0.47,(2H, b), 0.29,(1H, b), 0.06,(1H, b)。LCMS;保持時間 3.20分、MH+ 362。
N-(3-ヒドロキシプロピル)-N-メチル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドは、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸およびN-(3-ヒドロキシプロピル)-N-メチルアミンから方法Iを用いて調製した。NMR;δH [2H6] - DMSO 7.89,(1H, d), 7.76,(1H, s), 7.54,(1H, d), 7.46,(4H, s), 4.51-4.42,(1H, m), 3.49,(2H, s), 3.32,(3H, s), 2.95,(2H, s), 2.56,(3H, s), 2.32,(3h, s), 1.75,(2H, m)。LCMS;保持時間 2.74分、MH+ 366。
N-シクロヘキシル-N-エチル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドは、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸およびN-シクロヘキシル-N-エチルアミンから方法Iを用いて調製した。NMR;δH [2H6] - DMSO 7.89,(1H, dd), 7.77,(1H, s), 7.54,(1H, d), 7.46,(2H, d), 7.41,(2H, d), 3.37,(2H, b), 3.22,(1H, b), 2.56,(3H, s), 2.31,(3H, s), 1.81-0.89,(13H, b)。LCMS;保持時間 3.57分、MH+ 404。
N-ジシクロプロピルメチル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドは、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸およびジシクロプロピルメチルアミンから方法Iを用いて調製した。NMR;δH [2H6] - DMSO 7.89,(1H, d), 7.77,(1H, d), 7.54,(1H, d), 7.46,(4H, m), 3.46,(2H, b), 3.22,(2H, b), 2.56,(3H, s), 2.32,(3H, s), 1.16,(1H, b), 0.98,(1H, b), 0.47,(4H, b), 0.33,(2H, b), 0.04,(2H, b)。LCMS;保持時間 3.59分、MH+ 402。
2'-メチル-N-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-N-ペンチル-1,1'-ビフェニル-4-カルボキサミドは、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸およびメチルペンチルアミンから方法Iを用いて調製した。NMR;δH [2H6] - DMSO 7.89,(1H, dd), 7.76,(1H, d), 7.54,(1H, d), 7.47,(4H, s), 3.45,(1H, m), 3.23,(1H, m), 2.96-2.93,(3H, m), 2.56,(3H, s), 2.31,(3H, s), 1.59-1.51,(2H, m), 1.32,(2H, b), 1.08,(2H, b), 0.90-0.77,(3H, m)。LCMS;保持時間 3.47分、MH+ 378。
a) N-(シクロプロピルメチル)-5'-(ヒドラジノカルボニル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミド(20mg、0.06mmol)およびトリエチルオルトプロピオネート(211mg、1.2mmol)を130℃で18時間加熱した。過剰のトリエチルオルトプロピオネートを減圧下で留去し、残渣をシリカSPEにかけ、酢酸エチル/シクロヘキサン勾配(1:8から1:0)で溶出させた。溶媒を留去して、N-(シクロプロピルメチル)-5'-(5-エチル-1,3,4-オキサジアゾール-2-イル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミドを得た(16.9mg、78%)。LCMS;保持時間 3.36分、MH+ 362。
5'-[2-t-ブトキシカルボニル(ヒドラジノカルボニル)]-N-(シクロプロピルメチル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミド(450mg、1.06mmol)をトリフルオロ酢酸(4ml)に溶解し、室温にて3.5時間撹拌した。トリフルオロ酢酸を減圧下で留去し、残渣をDCMと炭酸水素ナトリウム水溶液とに分配した。有機相と生成した析出物を分離し、食塩水で洗浄し、減圧下で濃縮して、N-(シクロプロピルメチル)-5'-(ヒドラジノカルボニル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミド(210mg、61%)を白色固体として得た。LCMS;保持時間 2.79分、MH+ 324。
4-[N-(シクロプロピルメチル)アミノカルボニル]フェニルボロン酸(356mg、1.63mmol)、t-ブチル2-(3-ブロモ-4-メチルベンゾイル)ヒドラジン-1-カルボキシレート(537mg、1.63mmol)、テトラキス(トリフェニルホスフィン)パラジウム(190mg、0.16mmol)および炭酸水素ナトリウム水溶液(1M、2.5ml)をDME(5ml)中で80℃にて9時間加熱した。溶媒を減圧下で留去し、残渣をシリカフラッシュカラムでDCM/エタノール/アンモニア(300:8:1)により溶出させて精製し、溶媒を留去した後で、5'-[2-t-ブトキシカルボニル(ヒドラジノカルボニル)]-N-(シクロプロピルメチル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミド(460mg、67%)を黄色泡状物質として得た。LCMS;保持時間 3.28分、MH+ 424。
(シクロプロピルメチル)アミン(470mg、6.0mmol)、 4-カルボキシフェニルボロン酸(1.0g、6.0mmol)、HOBT(810mg、6.0mmol)、HBTU(2.73g、7.2mmol)およびDIPEA(1.71g、7.2mmol)をDMF(10ml)中で混合し、室温にて18時間撹拌した。DMFを減圧下で留去し、残渣をDCMおよび炭酸水素ナトリウム水溶液とに分配した。有機相を分離し、水および食塩水で洗浄し、乾燥させた(硫酸マグネシウム)。溶媒を減圧下で留去し、残渣をシリカフラッシュカラムでDCM/エタノール/アンモニア(15:8:1、次に10:10:1)により溶出させて精製し、溶媒を留去した後で、4-[N-(シクロプロピルメチル)アミノカルボニル]フェニルボロン酸を得た(300mg、23%)。NMR;δH [2H6] - DMSO 8.54,(1H, t), 8.18,(2H, s), 7.83,(2H, d), 7.78,(2H, d), 3.15,(2H, m), 1.02,(1H, m), 0.42,(2H, m), 0.21,(2H, m)。
N-(シクロプロピルメチル)-5'-(ヒドラジノカルボニル)-2'-メチル-1,1'-ビフェニル-4-カルボキサミド(20mg、0.06mmol)およびトリエチルオルトブタレート(229mg、1.2mmol)を130℃で18時間加熱した。過剰のトリエチルオルトブタレートを減圧下で留去し、残渣をシリカSPEにかけ、酢酸エチル/シクロヘキサン勾配(1:8から1:0)で溶出させた。溶媒を留去して、N-(シクロプロピルメチル)-2'-メチル-5'-(5-n-プロピル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。NMR;δH [2H6] - DMSO 8.64,(1H, t), 7.95,(2H, d), 7.90,(1H, dd), 7.76,(1H, d), 7.55,(1H, d), 7.50,(2H, d), 3.17,(2H, t), 2.89,(2H, t), 2.31,(3H, s), 1.77,(2H, m), 1.08,(1H, m), 0.96,(3H, t), 0.43,(2H, m), 0.24,(2H, m)。LCMS;保持時間 3.47分、MH+ 376。
N-[2-(3,4-ジメトキシフェニルアミノ)-2-オキソエチル]-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドは、2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸および2-アミノ-N-(3,4-ジメトキシフェニル)アセトアミドから方法Iを用いて調製した。NMR;δH [2H6] - DMSO 9.93,(1H, s), 8.92,(1H, t), 8.01,(2H, d), 7.90,(1H, dd), 7.78,(1H, d), 7.56-7.53,(3H, m), 7.33,(1H, d), 7.10,(1H, dd), 6.89,(1H, d), 4.06,(2H, d), 3.71,(6H, m), 2.57,(3H, s), 2.32,(3H, s)。LCMS;保持時間 2.96分、MH+ 487。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および3,3-ジメチルブチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M, 0.2ml)で洗浄し、DCMを減圧下で留去した。残渣を、マスディレクテッドHPLC(mass directed HPLC)により精製して、N-(3,3-ジメチルブチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.46分、MH+ 378。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2,3-ジメチルシクロヘキシルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCにより精製して、N-(2,3-ジメチルシクロヘキシル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.57分、MH+ 404。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)およびイソブチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(イソブチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.21分、MH+ 350。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2-アミノ-N,3,3-トリメチルブタナミド(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-[2,2-ジメチル-1-(メチルアミノカルボニル)プロピル]-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.03分、MH+ 421。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および3-メチルシクロヘキシルアミン(0.34mmol)をDMF(0.7ml) 中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、2'-メチル-N-(3-メチルシクロヘキシル)-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.50分、MH+ 390。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)およびシクロヘキシルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-シクロヘキシル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.38分、MH+ 376。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)およびシクロプロピルアミン(0.34mmol)をDMF(0.7ml) 中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-シクロプロピル-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.25分、MH+ 362。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および1,2-ジメチルプロピルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(1,2-ジメチルプロピル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.31分、MH+ 364。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および1,3-ジメチルペンチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(1,3-ジメチルペンチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.58分、MH+ 392。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2-シクロヘキシルエチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(2-シクロヘキシルエチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.69分、MH+ 404。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2-メチルブチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、2'-メチル-N-(2-メチルブチル)-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.33分、MH+ 364。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)およびシクロブチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(シクロブチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.15分、MH+ 348。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および1-シクロプロピルエチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(1-シクロプロピルエチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.13分、MH+ 362。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2,4-ジメチル-3-ペンチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、N-(2,4-ジメチル-3-ペンチル)-2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.48分、MH+ 392。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および1-メチルブチルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、2'-メチル -N-(1-メチルブチル)-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.33分、MH+ 364。
2'-メチル-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボン酸(11.3mg、0.034mmol)、HOBT(6.0mg、0.044mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(8.0mg、0.042mmol)および2-メチルアリルアミン(0.34mmol)をDMF(0.7ml)中で混合し、反応物を室温にて18時間静置した。DMFを減圧下で留去し、残渣をDCM(0.4ml)と水(0.4ml)とに分配した。有機相を水酸化ナトリウム水溶液(0.5M、0.2ml)で洗浄し、DCMを減圧下で留去した。残渣をマスディレクテッドHPLCで精製して、2'-メチル-N-(2-メチルアリル)-5'-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1,1'-ビフェニル-4-カルボキサミドを得た。LCMS;保持時間 3.13分、MH+ 348。
DCM ジクロロメタン
DIPEA N,N-ジイソプロピルエチルアミン
DME ジメトキシエタン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
HATU O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
HBTU O-ベンゾトリアゾール-1-イル-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
HOBT 1-ヒドロキシベンゾトリアゾール水和物
PyBOP ベンゾトリアゾール-1-イル-オキシ-トリピロリジノホスホニウムヘキサフルオロホスフェート
SPE 固相抽出
THF テトラヒドロフラン
本発明の化合物のp38阻害剤としての活性は、以下のアッセイにおいて実証することができる。
p38アッセイに用いたペプチド基質はビオチン-IPTSPITTTYFFFRRR-アミドであった。p38およびMEK6タンパク質を大腸菌(E.coli)発現系から均一に精製した。融合タンパク質をグルタチオン−S−トランスフェラーゼ(GST)でN末端にタグ付けした。100mM HEPES、pH 7.5中、1.5uMペプチドおよび10mM Mg(CH3CO2)2の存在下での30nM MEK6タンパク質と120nM p38タンパク質との反応混合物20uLを、6%DMSO中に阻害剤15uLを含むまたは含まず、0.08uCi [g-33P]ATPを含有する1.5uM ATP混合物15uLに加えてインキュベートすることで、最大の活性化がなし遂げられた。このときの対照は50 mM EDTAの存在(負の対照)または不在(正の対照)下での反応であった。反応を室温で60分間進行させ、50uLの250mM EDTAの添加によりクエンチして150uLのストレプトアビジンSPAビーズ(Amersham)を0.5mg/反応で混合した。Dynatechマイクロフルオロ白色U底プレートを密閉し、ビーズを一晩放置した。このプレートをPackard TopCountで60秒間計数した。生データを%I = 100*(1-(I-C2)/(C1-C2))(式中、IはバックグラウンドのCPMであり、C1は正の対照であり、かつC2は負の対照である)に当てはめてIC50値を得た。
αP38は、社内で調製した。SB4777790-Rリガンドは、MgCl2、CHAPS、DTTおよびDMSOを含有するHEPESで希釈した。これを、Black NUNC 384ウェルプレートのブランクウェルに加えた。このリガンド混合物にαP38を加え、次に、対照および化合物を含むその384ウェルプレートの残りの部分に加えた。プレートをLJL Analystで読み取り、Fluorescence Anisotropyを用いて化合物の阻害を算出した。
Claims (14)
- 式(I):
mが0〜4である場合、R1はC1-6アルキル、C3-7シクロアルキル、C2-6アルケニル、-SO2NR4R5、-CONR4R5および-COOR4から選択され;
mが2〜4である場合、R1はさらにC1-6アルコキシ、ヒドロキシ、NR4R5、-NR4SO2R5、-NR4SOR5、-NR4COR5および-NR4CONR4R5から選択され;
R2は、水素、C1-6アルキルおよび-(CH2)n-C3-7シクロアルキルから選択され;
R3は基:
R4およびR5は、独立して、水素、C1-6アルキル、場合によりC1-4アルキルで置換されているヘテロ環およびフェニルから選択され、ここで該フェニルは場合により、独立してC1-6アルコキシ、C1-6アルキルおよびハロゲンから選択される2個以下の基で置換されているか;あるいは、R4およびR5は、それが結合している窒素原子と一緒になって、場合により酸素、硫黄および窒素から選択される1個のさらなるヘテロ原子を含む5員〜6員のヘテロ環もしくはヘテロアリール環を形成し、ここで該環は、2個以下のC1-6アルキル基で置換されていてもよく;
R6は、水素およびC1-4アルキルから選択され;
Uは、メチルおよびハロゲンから選択され;
XおよびYは、それぞれ独立して、水素、メチルおよびハロゲンから選択され;
mは、0、1、2、3および4から選択され、ここで、得られる炭素鎖の各炭素原子は場合により、独立してC1-6アルキルから選択される1個または2個の基で置換されていてもよく;
nは、0、1、2および3から選択され;
rは、0、1および2から選択される]
の化合物、またはその薬学的に許容される塩もしくは溶媒和物。 - R1が、C1-4アルキル、C3-6シクロアルキル、-CONHCH3、-SO2NH2、-SO2N(CH3)2、メトキシ、-NHSO2CH3および-NHCOCH3から選択される、請求項1に記載の化合物。
- R1が、C1-6アルキル、C3-7シクロアルキル、C2-6アルケニル、-CONR4R5、ヒドロキシおよびNR4R5から選択される、請求項1に記載の化合物。
- R2が、水素、C1-4アルキルおよび-CH2-シクロプロピルから選択され、さらに好ましくは水素である、請求項1〜3のいずれか1項に記載の化合物。
- R2が水素である、請求項4に記載の化合物。
- R6がC1-4アルキルである、請求項1〜5のいずれか1項に記載の化合物。
- mが0、1および2から選択される、請求項1〜6のいずれか1項に記載の化合物。
- pが0および1から選択される、請求項1〜7のいずれか1項に記載の化合物。
- 実施例1〜29のいずれか1つで規定される請求項1に記載の化合物、またはその薬学的に許容される塩もしくは溶媒和物。
- (a) 式(XII):
の化合物を、式(XIII):
R1(CH2)mNR2H (XIII)
[式中、R1、R2およびmは請求項1で定義されているとおりである]
の化合物と、アミド形成条件下で反応させるか;
b) 式(XIV):
の化合物を、式(XV):
の化合物と、触媒存在下で反応させるか;または
c) 式(XVI):
の化合物を、式(XVII):
R1(CH2)mNH2 (XVII)
[式中、R1およびmは請求項1で定義されているとおりである]
の化合物と、アミド形成条件下で反応させ、
続いて、式(XVIII):
R2-hal (XVIII)
[式中、R2は請求項1で定義されているとおりであり、halはハロゲンである]
の化合物と、塩基の存在下で反応させること
を含む、請求項1〜9のいずれか1項に記載の化合物の製造方法。 - 請求項1〜9のいずれか1項に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物を、1種以上の薬学的に許容される担体、希釈剤もしくは賦形剤と混合させて含む医薬組成物。
- p38キナーゼ活性により媒介されるか、またはp38キナーゼの活性により産生されるサイトカインにより媒介される症状または疾患状態の治療方法であって、その治療が必要な患者に、請求項1〜9のいずれか1項に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物を投与することを含む上記方法。
- 治療に使用するための、請求項1〜9のいずれか1項に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物。
- p38キナーゼ活性により媒介されるか、またはp38キナーゼの活性により産生されるサイトカインにより媒介される症状または疾患状態の治療に使用するための医薬の製造における、請求項1〜9のいずれか1項に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物の使用。
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PCT/EP2002/011575 WO2003032987A1 (en) | 2001-10-17 | 2002-10-16 | 2'-methyl-5'-(1,3,4-oxadiazol-2-yl)-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors |
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EP (1) | EP1435950A1 (ja) |
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AR037233A1 (es) * | 2001-09-07 | 2004-11-03 | Euro Celtique Sa | Piridinas aril sustituidas, composiciones farmaceuticas y el uso de dichos compuestos para la elaboracion de un medicamento |
GB0124848D0 (en) * | 2001-10-16 | 2001-12-05 | Celltech R&D Ltd | Chemical compounds |
GB0124939D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124941D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124932D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124934D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124931D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124936D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124938D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124933D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
KR101058292B1 (ko) * | 2002-02-12 | 2011-08-22 | 글락소스미스클라인 엘엘씨 | P38 억제제로 유용한 니코틴아미드 유도체 |
US20030225089A1 (en) * | 2002-04-10 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors |
US20040116479A1 (en) * | 2002-10-04 | 2004-06-17 | Fortuna Haviv | Method of inhibiting angiogenesis |
US7136850B2 (en) * | 2002-12-20 | 2006-11-14 | International Business Machines Corporation | Self tuning database retrieval optimization using regression functions |
AU2004261589B2 (en) * | 2003-07-25 | 2008-05-22 | Novartis Ag | p-38 kinase inhibitors |
-
2001
- 2001-10-17 GB GBGB0124938.2A patent/GB0124938D0/en not_active Ceased
-
2002
- 2002-10-16 US US10/492,497 patent/US7166623B2/en not_active Expired - Fee Related
- 2002-10-16 EP EP02782930A patent/EP1435950A1/en not_active Withdrawn
- 2002-10-16 WO PCT/EP2002/011575 patent/WO2003032987A1/en active Application Filing
- 2002-10-16 JP JP2003535790A patent/JP2005508962A/ja active Pending
-
2006
- 2006-11-08 US US11/557,607 patent/US20070112046A1/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009508835A (ja) * | 2005-09-16 | 2009-03-05 | アロー セラピューティクス リミテッド | ビフェニル誘導体及びc型肝炎の治療におけるその使用 |
JP2009528273A (ja) * | 2006-01-25 | 2009-08-06 | シンタ ファーマシューティカルズ コーポレーション | 炎症および免疫関連使用用の置換ビアリール化合物 |
US8623871B2 (en) | 2006-01-25 | 2014-01-07 | Synta Pharmaceuticals Corp. | Substituted biaryl compounds for inflammation and immune-related uses |
Also Published As
Publication number | Publication date |
---|---|
WO2003032987A1 (en) | 2003-04-24 |
US20070112046A1 (en) | 2007-05-17 |
GB0124938D0 (en) | 2001-12-05 |
US20050090491A1 (en) | 2005-04-28 |
EP1435950A1 (en) | 2004-07-14 |
US7166623B2 (en) | 2007-01-23 |
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