JP2012509262A - Mmp−13阻害剤として有用なヘテロアリールジアミド化合物 - Google Patents
Mmp−13阻害剤として有用なヘテロアリールジアミド化合物 Download PDFInfo
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- JP2012509262A JP2012509262A JP2011536394A JP2011536394A JP2012509262A JP 2012509262 A JP2012509262 A JP 2012509262A JP 2011536394 A JP2011536394 A JP 2011536394A JP 2011536394 A JP2011536394 A JP 2011536394A JP 2012509262 A JP2012509262 A JP 2012509262A
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- Prior art keywords
- alkyl
- hydroxyl
- amino
- optionally substituted
- alkoxy
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- -1 Heteroaryl diamide compounds Chemical class 0.000 title claims description 27
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- 108050005238 Collagenase 3 Proteins 0.000 title abstract description 18
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
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- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 8
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- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
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- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
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- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 4
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- 150000001412 amines Chemical class 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000013543 active substance Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
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- 239000000047 product Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- 150000001408 amides Chemical class 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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Abstract
Description
本出願は、2008年11月17日に出願された米国仮出願第61/115,216号の利益を主張する。
1.技術分野
本発明は、MMP−13メタロプロテアーゼ阻害化合物に関する。
マトリックスメタロプロテイナーゼ(MMP)は、亜鉛依存性エンドペプチダーゼである。MMPは、細胞外マトリックスタンパク質の分解に機能し、細胞表面レセプター、成長因子、細胞−接着分子、サイトカイン及びケモカイン、並びに他のMMP及び無関係なプロテアーゼの切断に関与する。MMPはまた、増殖、移動(接着/分散)、分化、血管形成、アポトーシス及び宿主防御のような細胞過程に主要な役割を果たすと考えられている。(Hu J. et al. Nat. Rev. Drug Discov. 2007 6:480-498; Ramnath N. and Creaven P.J. Curr. Oncol. Rep. 2004 6:96-102)。したがって、MMPは、リウマチ性関節炎、骨関節炎、骨粗鬆症、歯周炎、アテローム性動脈硬化症、うっ血性心不全、多発性硬化症及び腫瘍転移を含む治療疾患に関する標的である。
本発明の化合物は、MMP−13の阻害剤であることが見出された。
最も広範で包括的である実施態様1において、式(I):
[式中、
R1は、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ、C3〜C6カルボシクリル、ヘテロシクリル、アミノ、アルキルアミノ、ジアルキルアミノ、アリール及びヘテロアリールから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2は、C1〜C5アルキル、炭素環、ヘテロ環、アリール又はヘテロアリールであり、各々、アミノ、ヒドロキシル、C1〜C5アルコキシ、オキソ、アリール、C3〜C6カルボシクリル及びカルボキシルから選択される1〜2個の置換基で場合により独立して置換されており;
R3は、結合、水素、CH2、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、S(O)0−2−、SO2−NH−又は−NH−SO2−であり;ここでRaは、C1〜C5アルキルであり;
R4は、C1〜C5アルキル、C2〜C4アルケニル、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、シアノ、ヒドロキシル、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル、O−CH2−アリール、アリールオキシ、O−CH2−ヘテロアリール,−NH−SO2−、カルボシクリル、ヘテロシクリル、アリール又はヘテロアリールであり、各々、C1〜C5アルキル、アシル、アミノ、アリール、ハロゲン、ヒドロキシル、オキソ、トリハロアルキル、カルボキサミド及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
Xは、N又はCHであり、
そして、
Arは、フラニル、チアゾリル、ピラゾリル、イミダゾリル、ピロリル、チエニル、ピリジニル、ピリミジニル、ピリダジニル、オキサゾリル及びキノリニルから選択されるヘテロアリール環であり、ここで各環は、C1〜C5アルキル、ハロゲン、アミノ及びオキソから選択される1〜2個の置換基で場合により置換されていてもよい]の化合物又はその薬学的に許容される塩が提供される。
R1が、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ、C3〜C6カルボシクリル、アミノ、アルキルアミノ及びジアルキルアミノから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C5アルキル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、テトラヒドロフラニル、テトラヒドロピラニル、ピペリジニル、フェニル、ナフチル、ベンゾチエニル、ベンゾフラニル、インドリル、チエニル、フラニル又はピロリルであり、各々、ヒドロキシル、C1〜C5アルコキシ、C3〜C6カルボシクリル、フェニル及びカルボキシルから選択される1〜2個の置換基で場合により独立して置換されており;
R3が、結合、水素、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、SO2−NH−又は−NH−SO2−であり;
R4が、C1〜C5アルキル、C2〜C4アルケニル、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、シアノ、ヒドロキシル、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル、O−CH2−アリール、O−CH2−ヘテロアリール、アリールオキシ、−NH−SO2−、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、フェニル、フラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、ピラジニル、イミダゾピリジニル、ベンゾフラニル、ベンゾチエニル、又はインドリルであり、各々、C1〜C5アルキル、C1〜C5アシル、アミノ、フェニル、ハロゲン、ヒドロキシル、オキソ、トリフルオロメチル、カルボキサミド及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニル、チアゾリル、ピラゾリル、イミダゾリル、ピロリル、チエニル、ピリジニル、ピリミジニル、ピリダジニル、オキサゾリル及びキノリニルから選択されるヘテロアリール環であり、ここで各環は、C1〜C5アルキル、ハロゲン、アミノ及びオキソから選択される1〜2個の置換基で場合により置換されていてもよい化合物が提供される。
R1が、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ及びC3〜C6シクロアルキルから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C5アルキル、シクロプロピル、シクロペンチル、シクロヘキシル、テトラヒドロピラニル又はピペリジニルであり、各々ヒドロキシル、C1〜C5アルコキシ及びフェニルから選択される1〜2個の置換基で場合により独立して置換されており;
R3が、結合、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、SO2−NH−又は−NH−SO2−であり;
R4が、C1〜C5アルキル、C1〜C5アルキルアミノ、アミノ、C1〜C5ジアルキルアミノ、フェニルアミノ、シアノ、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル,−NH−SO2−、−OCH2−フェニル、シクロプロピル、フェニル、フラニル、チエニル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、イミダゾピリジニル又はベンゾフラニルであり、各々、C1〜C5アルキル、アミノ、ハロゲン、トリフルオロメチル及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニル又はチアゾリルである、化合物が提供される。
R1が、ヒドロキシル及びメトキシから選択される1〜2個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C3アルキル、シクロヘキシル又はテトラヒドロピラニルであり、ここでアルキル基は、場合によりヒドロキシルで置換されており;
R3が、結合、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、又は−CH2−NH−C(O)であり;
R4が、C1〜C5アルキル、フェニル、フラニル、チエニル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、イミダゾピリジニル又はベンゾフラニルであり、各々、C1〜C3アルキル及びトリフルオロメチルから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニルである化合物が提供される。
R1が、メチルであり;
R3が、−O−CH2−である化合物が提供される。
R1が、メチルであり;
R3が、−NH−C(O)−である、化合物が提供される。
R1が、メチルであり;
R3が、−CH2−NH−C(O)−である化合物が提供される。
本発明は、式(I)の化合物の製造方法をも提供する。全てのスキームにおいて、別段の指定がない限り、下記式中のR1、R2、R3、R4、Ar及びXは、上記本発明の式(I)におけるR1、R2、R3、R4、Ar及びXの意味を有するものとする。
アセトン(100mL)中の2−ブロモ−5−ヒドロキシピリジン(5g、29mmol)の溶液に、K2CO3(7.9g、58mmoL)続いてベンジルブロミド(5.1mL、43mmol)を加えた。得られた懸濁液を、70℃で2時間加熱した。溶液を、次に水で希釈し、アセトンを減圧下で除去した。水相を酢酸エチルで抽出し、合わせた有機抽出物をブラインで洗浄し、Na2SO4で乾燥させ、減圧下で濃縮した。得られた残留物を、ヘキサン/酢酸エチルを溶離剤として用いてシリカで精製した。6.4g、85%、LC/MS ESI m/z(M+H)+=266.3。
フルアルデヒド4−ボロン酸(10.2g、73mmol)、パラジウムテトラキストリフェニルホスフィン(2.9g、2.4mmol)及び5−ベンジルオキシ−2−ブロモ−ピリジン(6.4g、24mmol)を、炭酸ナトリウム水溶液(30mL、61mmol)、1,2−ジメトキシエタン(120mL)で希釈し、次にアルゴンで5分間かけて脱気した。溶液を、アルゴン下で、一晩加熱還流した(94℃)。冷却後、反応混合物を、酢酸エチル及び水で希釈し、水相を大量の酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、減圧下で濃縮した。得られた残留物は、ヘキサン/酢酸エチルを溶離剤として用いてシリカで精製して、黄色の固体を得た。3.1g、46%、LC/MS ESI m/z(M+H)+=280.4。
1,4−ジオキサン(160mL)中の5−(5−ベンジルオキシ−ピリジン−2−イル)−フラン−2−カルボアルデヒド(4.4g、14mmol)の溶液に、水(30mL)中のリン酸ナトリウム(一塩基性、7.7g、56mmol)、続いてスルファミン酸(2.1g、22mmol)を加えた。反応混合物を、0℃に冷却し、水(30mL)中の亜塩素酸ナトリウム(3.27g、80%、29mmol)を0℃で10分間かけて加えた。氷浴を除去し、溶液を30分間撹拌した。過剰な亜硫酸ナトリウムを加え、得られた懸濁液を、30分間撹拌した。反応混合物を、2N HCl(pH=4)で酸性化し、酢酸エチル(2x100mL)で抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、溶媒を減圧下で蒸発させた。生成物を、暗黄色〜褐色の固体として得て、更に精製しないで用いた。4.0g、94%、LC/MS ESI m/z(M+H)+=296.6。
5−(5−ベンジルオキシ−ピリジン−2−イル)−フラン−2−カルボキシラート(4.4g、15mmol)をDMF(150mL)に溶解し、そしてTBTU(9.7g、30mmol)、ジイソプロピルエチルアミン(16mL、91mmol)、及び(S)−2−アミノ−2−シクロヘキシル−N−メチル−アセトアミド(6.4g、22mmol)を加えた。反応物に蓋をし、室温で5時間撹拌した。反応物を、過剰量の水でクエンチし、生成物を酢酸エチル中に抽出した。合わせた有機層を水で洗浄し、乾燥させ(硫酸ナトリウム)、濾過し、減圧下で蒸発させて、油状物を得た。粗物質を、メタノール/ジクロロメタンを溶離剤として用いてシリカゲルで精製して、褐色の固体を得た。4.3g、64%、LC/MS ESI m/z(M+H)+=448.7.
酢酸エチル(26mL)及びメタノール(26mL)中の5−(5−ベンジルオキシ−ピリジン−2−イル)−フラン−2−カルボン酸((S)−シクロヘキシル−メチルカルバモイル−メチル)−アミド(1.43g、2.8mmol)の溶液に、10%Pd/C(277mg、0.26mmol)を加えた。反応物を、アルゴンでパージし、1,4−シクロヘキサジエン(2.4mL、26mmol)をシリンジを介して加えた。反応混合物を、2時間加熱還流し、室温に冷まし、セライトパッドを通して濾過し、パッドを酢酸エチルですすいだ。得られた濾液を、減圧下で蒸発させて、明黄色の固体を得て、これを更に精製しないで用いた。1.06g、95%、LC/MS ESI m/z(M+H)+=358.4。
THF(2mL)中の5−(5−ヒドロキシ−ピリジン−2−イル)−フラン−2−カルボン酸((S)−シクロヘキシル−メチルカルバモイル−メチル)−アミド(170mg、0.47mmoL)、2−ピリジンメタノール(103mg、0.95mmol)及びPPh3(ポリスチレン樹脂に支持されたもの、320mg 0.95mmol)の溶液に、DIAD(0.18mL、0.95mmol)をアルゴン下、0℃で滴下した。混合物を、室温に温まるにまかせ、19時間撹拌し、THFで希釈し、セライトを通して濾過した。濾液を、減圧下で蒸発させ、粗物質を、逆相HPLCで精製して、白色の固体を得た。72mg、34%、LC/MS ESI m/z(M+H)+=449.7。
(S)−2−アミノ−2−シクロヘキシル−N−メチル−アセトアミド塩酸塩(0.75g、3.6mmol)を、ジクロロメタン(5mL)に取り、DIEA(1.87mL、10.7mmol)を溶液に加えた。5−(4−ニトロ−フェニル)−フラン−2−カルボン酸(0.92g、3.9mmol)、EDC(1.37g、7.2mmol)及びHOBT(0.97g、7.2mmol)を加え、反応物を、室温で一晩撹拌した。反応物を、DCMで希釈し、10%クエン酸で洗浄した。合わせた有機層を、飽和重炭酸ナトリウム、ブラインで洗浄し、無水硫酸マグネシウムで乾燥させた。溶液を濾過し、減圧下で濃縮して、固体を得て、これをシリカゲル(ヘキサン/酢酸エチル)で精製して、標記化合物0.96gを得た。63% LC/MS ESI m/z(M+H)+=383.3。
5−(4−ニトロ−フェニル)−フラン−2−カルボン酸((S)−シクロヘキシル−メチルカルバモイル−メチル)−アミド(760mg、1.96mmol)、酢酸15mL及び亜鉛(1.2g、19mmol)を合わせて、室温で30分間撹拌した。粗反応混合物を、セライトを通して濾過し、アセトニトリルで洗浄し、合わせた洗浄物を減圧下で濃縮した。粗物質を、DCM中の10%メタノールに取り、飽和重炭酸ナトリウム水溶液で洗浄した。有機層を乾燥させ、濾過し減圧下で蒸発させて、標記化合物を得て、これを更に精製しないで用いた。660mg、94%、LC/MS ESI m/z(M+H)+=356.2。
5−(4−アミノ−フェニル)−フラン−2−カルボン酸((S)−1−シクロヘキシル−2−メチルアミノ−アリル)−アミド(35mg、0.1mmol)を、DMF(1mL)に溶解し、4−メチルモルホリン(43uL、0.4mmol)を加えた。DMF 1mL中のHATU(57mg、0.15mmol)を、5−メチルフランカルボキシラート(14mg、0.11mmol)に加え、この混合物をアミン混合物に加え、得られた溶液を一晩撹拌した。16時間後、溶媒を減圧下で蒸発させ、残留物を逆相LCで精製して、標記化合物を得た。20mg、43%、LC/MS ESI m/z(M+H)+464.2。
5−ブロモ−フラン−2−カルボン酸(2.0g、10.4mmol)を、DMF(25mL)に溶解し、HATU(4.3g、11.5mmol)、DIEA(5.8mL、31mmol)及び(S)−2−アミノ−2−シクロヘキシル−N−メチル−アセトアミド塩酸塩(2.97g、10.4mmol)を加えた。反応物を、室温で一晩撹拌した。16時間後、反応物を、水でクエンチし、生成物を酢酸エチルで抽出した。有機層を乾燥させ(硫酸ナトリウム)、濾過し、減圧下で蒸発させて、灰色の固体を得た。2.8g、78% LC/MS ESI m/z(M+H)+=343.3。
5−ブロモ−フラン−2−カルボン酸((S)−シクロヘキシル−メチルカルバモイル−メチル)−アミド(500mg、1.45mmol)、2−NBoc−アミノメチルフェニルボロン酸(365mg、1.45mmol)及びビス(ジ−tert−ブチル(4−ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)塩(206mg、0.29mmol)を、DMF(7mL)中に懸濁し、2M Na2CO3水溶液(2mL)を加えた。反応物をボルテックスし、次にマイクロ波反応器中で100℃で60分間加熱した。反応混合物を、DMF6mL及び水4mLに希釈し、激しく1時間撹拌して懸濁液を形成し、これを濾過して、明黄色の固体を得て、これを更に精製しないで用いた。0.69g、95%、LC/MS ESI m/z(M+H)+470.5。
MeOH(74mL)中の(3−{5−[((S)−シクロヘキシル−メチルカルバモイル−メチル)−カルバモイル]−フラン−2−イル}−ベンジル)−カルバミン酸tert−ブチルエステル(4.3g、7.32mmol)の懸濁液に、ジオキサン中の4N HCl(18mL)を加え、得られた懸濁液を、室温で16時間撹拌した。反応混合物を、酢酸エチルで希釈し、飽和NaHCO3水溶液でpH10に塩基性化した。水層を大量の酢酸エチルで抽出した。合わせた有機物を水、ブラインで洗浄し、MgSO4で乾燥させ、減圧下で濃縮して、鮮黄色の固体を得て、これをシリカで精製して、標記化合物をオフホワイトの固体として得た。1.37g、50%、LC/MS ESI m/z(M+H)+370.5。
DMF(1mL)中の2−フルオロ−イソニコチン酸(22mg、0.16mmol)の溶液に、HATU(61mg、0.16mmol)及びEt3N(0.044mL、0.3mmol)を加えた。室温で30分間撹拌した後、DMF(1mL)中の5−(3−アミノメチル−フェニル)−フラン−2−カルボン酸((S)−シクロヘキシル−メチルカルバモイル−メチル)−アミドトリフルオロ酢酸塩(50mg、0.12mmol)の溶液を加えた。反応物を、2時間撹拌し、酢酸エチルで希釈し、有機層を水及びブラインで洗浄した。有機層を、減圧下で蒸発させ、得られた油状物を逆相HPLCで精製して、標記化合物を固体として得た。21mg、41%、LC/MS ESI m/z(M+H)+493.5。
無水ジクロロメタン(10mL)及び無水ピリジン(2mL)中の5−(5−ヒドロキシ−ピリジン−2−イル)−フラン−2−カルボン酸((S)−2−メチル−1−メチルカルバモイル−プロピル)−アミド(0.7g、2.20mmol)の溶液に、室温で、トリフルオロメタンスルホン酸無水物(0.41mL、2.42mmol)を加えた。1時間後、水(10mL)を加え、混合物を酢酸エチル(20mL)で抽出した。有機層をブラインで洗浄し、MgSO4で乾燥させ、減圧下で蒸発させた。トリフルオロメタンスルホン酸6−[5−((S)−2−メチル−1−メチルカルバモイル−プロピルカルバモイル)−フラン−2−イル]−ピリジン−3−イルエステルを褐色の固体として得て、更に精製しないで用いた。0.78g、79%、LC/MS ESI m/z(M+H)+=450.32。
トリフルオロメタンスルホン酸6−[5−((S)−2−メチル−1−メチルカルバモイル−プロピルカルバモイル)−フラン−2−イル]−ピリジン−3−イルエステル(50mg、0.11mmol)、フェニルボロン酸(27mg、0.22mmol)、パラジウムテトラキストリフェニルホスフィン(13mg、0.01mmol)、及び炭酸カリウム(61mg、0.44mmol)を入れたフラスコを、アルゴンでフラッシュした。トルエン(2mL)、エタノール(0.5mL)、及び水(1mL)を加え、反応物を100℃で2時間撹拌した。反応物を室温に冷まし、酢酸エチル(10mL)を加え、混合物を水(10mL)、ブライン(10mL)で洗浄し、MgSO4で乾燥させた。溶液を濾過し、減圧下で蒸発させて、油状物を得て、これを、分取HPLCで精製した。5−(5−フェニル−ピリジン−2−イル)−フラン−2−カルボン酸((S)−2−メチル−1−メチルカルバモイル−プロピル)−アミドを白色の固体として得た。16mg、38%、LC/MS ESI m/z(M+H)+=377.43。
式Iの化合物の生物学的特性は、当該技術で認められている他のアッセイの他に、下記のアッセイを用いて評価することができる。
上記のアッセイに示されるように、本発明の化合物は、MMP−13を阻害する上で有用である。したがって、式1の化合物は、リウマチ性関節炎、骨関節炎、骨粗鬆症、歯周炎、アテローム性動脈硬化症、うっ血性心不全、多発性硬化症及び腫瘍転移を含む疾患の処置に有用である。これらは、患者に薬剤として、特に本明細書に記載の医薬組成物の形態で使用することができる。前述のように、MMP−13は、細胞外マトリックス分解及び増殖、移動(接着/分散)、分化、血管形成、アポトーシス及び宿主防御のような細胞過程で主要な役割を果たすと考えられるので、式1の化合物は、以下の疾患の処置においても有用である:
接触性皮膚炎、骨吸収疾患、再灌流障傷害、喘息、ギラン−バレー症候群、クローン病、潰瘍性大腸炎、乾癬、移植片対宿主病、全身性エリテマトーデス及びインスリン依存性糖尿病、中毒性ショック症候群、アルツハイマー病、糖尿病、炎症性腸疾患、急性及び慢性疼痛並びに炎症性の症状及び循環器疾患、脳卒中、心筋梗塞(単独で又は血栓溶解治療後に)、熱傷、成人呼吸窮迫症候群(ARDS)、外傷に続発する多臓器損傷、急性糸球体腎炎、急性炎症性要素を有する皮膚病、急性化膿性髄膜炎又は他の中枢神経系障害、血液透析、白血球除去療法に関連する症侯群、顆粒球輸注関連症候群、及び壊死性腸炎、経皮経壁冠動脈拡張後の再狭窄を含む合併症、外傷性関節炎、敗血症、慢性閉塞性肺疾患及びうっ血性心不全。
医薬品として使用されるとき、本発明の化合物は、通常、医薬組成物の形態で投与される。このような組成物は、医薬品分野で周知の手順を利用して調製することができ、そして本発明の化合物を少なくとも1種含む。本発明の化合物はまた、単独で、または、本発明の化合物の安定性を向上させ、ある実施態様ではこれらを含有する医薬組成物の投与を促進し、溶解若しくは分散の上昇、阻害活性の上昇を与え、補助療法などを与える補助剤と組合せて投与することができる。本発明の化合物を、それ自体で、または本発明の他の活性物質と共に、または場合により他の薬理活性物質と共に使用することができる。一般に、本発明の化合物は、治療有効量又は薬学的有効量で投与されるが、診断目的又は他の目的にはそれより少量で投与してもよい。
Claims (10)
- 式(I):
[式中、
R1は、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ、C3〜C6カルボシクリル、ヘテロシクリル、アミノ、アルキルアミノ、ジアルキルアミノ、アリール及びヘテロアリールから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2は、C1〜C5アルキル、炭素環、ヘテロ環、アリール又はヘテロアリールであり、各々、アミノ、ヒドロキシル、C1〜C5アルコキシ、オキソ、アリール、C3〜C6カルボシクリル及びカルボキシルから選択される1〜2個の置換基で場合により独立して置換されており;
R3は、結合、水素、CH2、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、S(O)0−2−、SO2−NH−又は−NH−SO2−であり;ここでRaは、C1〜C5アルキルであり;
R4は、C1〜C5アルキル、C2〜C4アルケニル、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、シアノ、ヒドロキシル、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル、O−CH2−アリール、アリールオキシ、O−CH2−ヘテロアリール,−NH−SO2−、カルボシクリル、ヘテロシクリル、アリール又はヘテロアリールであり、各々、C1〜C5アルキル、アシル、アミノ、アリール、ハロゲン、ヒドロキシル、オキソ、トリハロアルキル、カルボキサミド及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
Xは、N又はCHであり、
そして、
Arは、フラニル、チアゾリル、ピラゾリル、イミダゾリル、ピロリル、チエニル、ピリジニル、ピリミジニル、ピリダジニル、オキサゾリル及びキノリニルから選択されるヘテロアリール環であり、ここで各環は、C1〜C5アルキル、ハロゲン、アミノ及びオキソから選択される1〜2個の置換基で場合により置換されていてもよい]の化合物又はその薬学的に許容される塩。 - 請求項1記載の化合物であって、
R1が、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ、C3〜C6カルボシクリル、アミノ、アルキルアミノ及びジアルキルアミノから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C5アルキル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、テトラヒドロフラニル、テトラヒドロピラニル、ピペリジニル、フェニル、ナフチル、ベンゾチエニル、ベンゾフラニル、インドリル、チエニル、フラニル又はピロリルであり、各々、ヒドロキシル、C1〜C5アルコキシ、C3〜C6カルボシクリル、フェニル及びカルボキシルから選択される1〜2個の置換基で場合により独立して置換されており;
R3が、結合、水素、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、SO2−NH−又は−NH−SO2−であり;
R4が、C1〜C5アルキル、C2〜C4アルケニル、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、シアノ、ヒドロキシル、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル、O−CH2−アリール、O−CH2−ヘテロアリール、アリールオキシ,−NH−SO2−、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、フェニル、フラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、ピラジニル、イミダゾピリジニル、ベンゾフラニル、ベンゾチエニル、又はインドリルであり、各々、C1〜C5アルキル、C1〜C5アシル、アミノ、フェニル、ハロゲン、ヒドロキシル、オキソ、トリフルオロメチル、カルボキサミド及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニル、チアゾリル、ピラゾリル、イミダゾリル、ピロリル、チエニル、ピリジニル、ピリミジニル、ピリダジニル、オキサゾリル及びキノリニルから選択されるヘテロアリール環であり、ここで各環は、C1〜C5アルキル、ハロゲン、アミノ及びオキソから選択される1〜2個の置換基で場合により置換されていてもよい化合物。 - 請求項2記載の化合物であって、
R1が、ヒドロキシル、カルボキサミド基で場合により置換されているC1〜C5アルコキシ及びC3〜C6シクロアルキルから選択される1〜3個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C5アルキル、シクロプロピル、シクロペンチル、シクロヘキシル、テトラヒドロピラニル又はピペリジニルであり、各々ヒドロキシル、C1〜C5アルコキシ及びフェニルから選択される1〜2個の置換基で場合により独立して置換されており;
R3が、結合、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、−CH2−NH−C(O)、SO2−NH−又は−NH−SO2−であり;
R4が、C1〜C5アルキル、C1〜C5アルキルアミノ、アミノ、C1〜C5ジアルキルアミノ、フェニルアミノ、シアノ、ハロゲン、ニトロ、C1〜C5チオアルキル(ここで硫黄原子は、酸化されていてよい)、C1〜C5アルコキシル、−O−アルコキシル,−NH−SO2−、−OCH2−フェニル、シクロプロピル、フェニル、フラニル、チエニル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、イミダゾピリジニル又はベンゾフラニルであり、各々、C1〜C5アルキル、アミノ、ハロゲン、トリフルオロメチル及びC1〜C5アルコキシから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニル又はチアゾリルである化合物。 - 請求項3記載の化合物であって、
R1が、ヒドロキシル及びメトキシから選択される1〜2個の置換基で場合により置換されているC1〜C5アルキルであり;
R2が、C1〜C3アルキル、シクロヘキシル又はテトラヒドロピラニルであり、ここでアルキル基は、場合によりヒドロキシルで置換されており;
R3が、結合、−C(O)−NH−、−NH−C(O)−、−CHRa−O−、−O−CH2−、−C(O)−NH−CH2−、又は−CH2−NH−C(O)であり;
R4が、C1〜C5アルキル、フェニル、フラニル、チエニル、ピラゾリル、イミダゾリル、ピリジニル、ピリミジニル、イミダゾピリジニル又はベンゾフラニルであり、各々、C1〜C3アルキル及びトリフルオロメチルから選択される1〜3個の置換基で場合により独立して置換されており;
そして、
Arが、フラニルである化合物。 - R1が、メチルであり;
R3が、−O−CH2−である、請求項4記載の化合物。 - R1が、メチルであり;
R3が、−NH−C(O)−である、請求項4記載の化合物。 - R1が、メチルであり;
R3が、−CH2−NH−C(O)−である、請求項4記載の化合物。 - 治療有効量の請求項1〜8のいずれか一項記載の化合物並びに1つ以上の薬学的に許容される担体及び/又は補助剤を含む医薬組成物。
- 治療有効量の請求項1〜8のいずれか一項記載の化合物を投与することを含む、リウマチ性関節炎、骨関節炎、骨粗鬆症、歯周炎、アテローム性動脈硬化、うっ血性心不全、多発性硬化症及び腫瘍転移から選択される疾患の処置方法。
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WO2003097617A1 (en) | 2002-05-14 | 2003-11-27 | Axys Pharmaceuticals, Inc. | Cysteine protease inhibitors |
WO2004052921A1 (en) | 2002-12-05 | 2004-06-24 | Axys Pharmaceuticals, Inc. | Cyanomethyl derivatives as cysteine protease inhibitors |
EP2344480A1 (en) | 2008-10-15 | 2011-07-20 | Boehringer Ingelheim International GmbH | Fused heteroaryl diamide compounds useful as mmp-13 inhibitors |
EP2340243B1 (en) | 2008-10-17 | 2014-10-08 | Boehringer Ingelheim International GmbH | Heteroaryl substituted indole compounds useful as mmp-13 inhibitors |
JP5584696B2 (ja) | 2008-11-17 | 2014-09-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Mmp−13阻害剤として有用なヘテロアリールジアミド化合物 |
-
2009
- 2009-11-05 JP JP2011536394A patent/JP5584696B2/ja active Active
- 2009-11-05 WO PCT/US2009/063343 patent/WO2010056585A2/en active Application Filing
- 2009-11-05 EP EP09752604.0A patent/EP2346831B1/en active Active
- 2009-11-05 US US13/127,256 patent/US8637550B2/en active Active
- 2009-11-05 CA CA2743146A patent/CA2743146A1/en not_active Abandoned
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WO2001010798A1 (en) * | 1999-08-04 | 2001-02-15 | Chemrx Advanced Technologies, Inc. | Solid phase synthesis of oxa- and thiazoles |
WO2004084843A2 (en) * | 2003-03-24 | 2004-10-07 | Irm Llc | Inhibitors of cathepsin s |
WO2004084842A2 (en) * | 2003-03-24 | 2004-10-07 | Irm Llc | Inhibitors of cathepsin s |
US20050014816A1 (en) * | 2003-07-03 | 2005-01-20 | Pfizer Inc | Thiophene amino acid derivatives, process for preparing them and pharmaceutical compositions containing them |
WO2007008994A2 (en) * | 2005-07-11 | 2007-01-18 | Wyeth | Glutamate aggrecanase inhibitors |
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Also Published As
Publication number | Publication date |
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WO2010056585A3 (en) | 2010-11-25 |
US20110275625A1 (en) | 2011-11-10 |
EP2346831B1 (en) | 2015-01-07 |
WO2010056585A2 (en) | 2010-05-20 |
JP5584696B2 (ja) | 2014-09-03 |
US8637550B2 (en) | 2014-01-28 |
EP2346831A2 (en) | 2011-07-27 |
CA2743146A1 (en) | 2010-05-20 |
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