JP4246991B2 - 新規なピリジン置換ピラゾロピリジン誘導体 - Google Patents
新規なピリジン置換ピラゾロピリジン誘導体 Download PDFInfo
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- JP4246991B2 JP4246991B2 JP2002544435A JP2002544435A JP4246991B2 JP 4246991 B2 JP4246991 B2 JP 4246991B2 JP 2002544435 A JP2002544435 A JP 2002544435A JP 2002544435 A JP2002544435 A JP 2002544435A JP 4246991 B2 JP4246991 B2 JP 4246991B2
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- WVTADHLQTPDLPZ-NTMALXAHSA-N CN(C)/C=C(\c1ccncc1)/C#N Chemical compound CN(C)/C=C(\c1ccncc1)/C#N WVTADHLQTPDLPZ-NTMALXAHSA-N 0.000 description 1
- ABOJKLHOYVSECN-NTMALXAHSA-N CN(C)/C=C(\c1cnccc1)/C#N Chemical compound CN(C)/C=C(\c1cnccc1)/C#N ABOJKLHOYVSECN-NTMALXAHSA-N 0.000 description 1
- 0 CN(C)C=C(*)C#N Chemical compound CN(C)C=C(*)C#N 0.000 description 1
- BMWWTENKQLYLGH-UHFFFAOYSA-N Nc1c(-c2ccncc2)c(Cl)nc(-c2n[n](Cc(cccc3)c3F)c3ncccc23)n1 Chemical compound Nc1c(-c2ccncc2)c(Cl)nc(-c2n[n](Cc(cccc3)c3F)c3ncccc23)n1 BMWWTENKQLYLGH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Description
R1が、4-ピリジニルまたは3-ピリジニルであり、
R2が、H、NH2またはClである、
化合物ならびにその塩、異性体および水和物に関する。
R1が、4-ピリジニルまたは3-ピリジニルであり、
R2が、Hである、
化合物ならびにその塩、異性体および水和物に関する。
また、本発明の化合物は、それらの可能な水和物の形態で存在することもできる。
以下の式(II):
(A)以下の式(III):
で示される化合物と、適切であれば有機溶媒中で加熱しながら反応させて、式(I)で示される化合物を得るか、または
(B)以下の式(IV):
で示される化合物と、有機溶媒中で加熱しながら反応させて、以下の式(V):
で示される化合物を得、次に、ハロゲン化剤と反応させて、以下の式(VI):
で示される化合物を得、最後に、アンモニア水溶液と加熱下および高圧下に反応させる。
式(I)で示される化合物は、血管弛緩および血小板凝集の阻害を導き、血圧の低下および冠状動脈血流の増加を導く。これらの作用は、可溶性グアニル酸シクラーゼの直接刺激および細胞内cGMPの増加によって媒介される。さらに、本発明の式(I)で示される化合物は、cGMPレベルを増加させる物質、例えばEDRF(内皮由来の弛緩因子)、NO供与体、プロトポルフィリンIX、アラキドン酸またはフェニルヒドラジン誘導体の作用を増強する。
該化合物は、脳卒中、脳虚血および頭蓋脳外傷のような脳梗塞の後遺症の予防および抑制にも好適である。本発明の式(I)で示される化合物は、疼痛状態の抑制にも使用することができる。
さらに、本発明の化合物は、抗炎症作用を有し、従って、抗炎症物質としても使用することができる。
本発明において有機硝酸塩およびNO供与体とは、一般に、NOまたはNO種の放出によってそれらの治療作用を示す物質である。ニトロプルシドナトリウム、ニトログリセリン、イソソルビドジニトレート、イソソルビドモノニトレート、モルシドミンおよびSIN-1が好ましい。
インビトロにおける血管弛緩作用
首の後に一撃を加えてウサギを気絶させ、放血させる。大動脈を取り出し、付着組織を除去し、1.5mm幅の輪に分割し、これを、以下の組成(mM):NaCl(119)、KCl(4.8)、CaCl2x2H2O(1)、MgSO4x7H2O(1.4)、KH2PO4(1.2)、NaHCO3(25)、グルコース(10)を有する、37℃のカルボゲン(carbogen)ガス処理したKrebs-Henseleit溶液を含有する器官浴5mL中で、1つずつ緊張状態におく。収縮力をStatham UC2セルで検出し、A/D変換器(DAS-1802 HC、Keithley Instruments Munich)で増幅し、数値化し、並行してチャートレコーダーに記録する。収縮を発生させるために、フェニレフリンを、増加する濃度で漸増的に浴に添加する。数回の対照サイクル後に、被験物質を、それぞれの後続パッセージにおいて、各場合に増加する用量で試験し、収縮の高さを、直前のパッセージで到達した収縮の高さと比較する。これから、対照値の高さを50%減少させるのに必要な濃度(IC50)を算出する。標準適用容量は5μlであり、浴溶液中のDMSOの割合は0.1%に相当する。結果を下記の表1に示す。
ラットを麻酔し、ヘパリン投与し、門脈を介して肝臓を原位置で灌流する。次に、一次ラット肝細胞を、コラゲナーゼ溶液を使用して肝臓からインビトロで得る。2・106肝細胞/mLを、それぞれの場合に同濃度の被験化合物を使用して、37℃でインキュベートした。経時的な被験物質の減少を、生物学的分析(HPLC/UV、HPLC/蛍光またはLC/MSMS)によって、インキュベートの開始から0〜15分の時間内に、各場合に5つの時点で測定した。これから、細胞数および肝臓重量によってクリアランスを算出した。
被験物質を、ラットの尾静脈に、溶液として静脈内投与する。所定の時点にラットから採血し、ヘパリン処理し、これから常法により血漿を得る。被験物質を、生物学的分析によって、血漿において定量する。この目的に使用される通常の非分画法(non-compartmental method)を使用してこのように求めた血漿濃度/時間の推移から、薬物速度論パラメーターを算出した。
活性化合物は、所望により、1つまたはそれ以上の前記担体中にマイクロカプセル封入形態で存在することもできる。
本発明の式(I)で示される化合物の他に、前記の医薬調製物は、他の医薬活性化合物をも含有することができる。
略語
RT:室温
EA:酢酸エチル
MCPBA:m-クロロペルオキシ安息香酸
BABA:酢酸n-ブチル/n-ブタノール/氷酢酸/燐酸塩緩衝液pH6(50:9:25.15;有機相)
DMF:N,N-ジメチルホルムアミド
T1E1:トルエン/酢酸エチル(1:1)
T1EtOH1:トルエン/メタノール(1:1)
C1E1:シクロヘキサン/酢酸エチル(1:1)
C1E2:シクロヘキサン/酢酸エチル(1:2)
方法A(LC-MS):
溶離剤:A=アセトニトリル+0.1%蟻酸、B=水+0.1%蟻酸
流量:25mL/分
温度:40℃
装填物質:Symmetry C18、50x2.1mm、3.5μm
溶離剤:A=Milli-Q-水+0.6g濃塩酸(1L H2O)、B=アセトニトリル
流量:50mL/分
温度:室温
充填物質:YMC-Gel ODS-AQS、11μm、250x30mm
I.4-[(ジメチルアミノ)メチレン]-ピリジンアセトニトリル(E/Z混合物)の合成
収量:10.2g(93%)。
Rf:0.29(CH2Cl2/EA 20/1)。
1H-NMR:(300MHz、D6-DMSO)、δ=3.25(s、6H、2xCH3)、7.25(d、2H、Ar-H)、7.80(s、1H、Ar-H)、8.33(d、2H、Ar-H)。
MS:(ESI pos.)、m/z=174([M+H]+)。
収量:4.23g(96%)。
Rf:0.27(CH2Cl2/MeOH 40/1)。
1H-NMR:(300MHz、D6-DMSO)、δ=3.08(s、3H、CH3)、3.25(s、3H、CH3)、7.29(dd、1H、Ar-H)、7.57(s、1H、=C-H)、7.66(dt、1H、Ar-H)、8.26(d、1H、Ar-H)、8.54(d、1H、Ar-H)。
LCMS:保持時間:0.33分[カラム:Symmetry、C-18、3.5μm、50x2.1mm、流量0.5mL/分、40℃、勾配:水(+0.1%蟻酸):アセトニトリル(+0.1%蟻酸) 0分において90:10、7.5分において10:90];MS:(ESI pos.)、m/z=174([M+H]+)。
3A:5-アミノ-1-(2-フルオロベンジル)ピラゾール-3-カルボン酸エチル
収量:91.6g(2段階で理論量の49.9%)。
融点:85℃
Rf(SiO2、T1E1):0.83
Rf(SiO2、T1E1):0.33
収量:33.7g(理論量の100%)
融点:81℃
Rf(SiO2、T1E1):0.74
1H-NMR(d6-DMSO、200MHz):δ=5.93(s、2H)、7.1-7.5(m、4H)、7.55(dd、1H)、8.12(dd、1H)、8.30(dd、1H)、9.5(bs、4H-交換可能)ppm。
MS(EI):m/z=270.2(M-HCl)。
収量:2.43g(43%)。
LC-MS:Rf:2.69分(方法A);MS(ESI pos.)、m/z=415([M+H]+)。
収量:0.67g(24%)。
LC-MS:Rf:4.34分(方法A);MS(ESI pos.)、m/z=451([M+H]+、Cl1)。
収量:0.24g(33%)。
Rf:0.17(EA/MeOH 20:1)。
沸点:254℃
保持時間:2.7分[カラム:Symmetry、C-18、3.5μm、50x2.1mm、流量0.5mL/分、40℃、勾配:水(+0.1%蟻酸):アセトニトリル(+0.1%蟻酸) 0分において90:10、7.5分において10:90]
1H-NMR:(300MHz、d6-DMSO):δ=5.81(s、2H、CH2)、7.0-7.6(m、9H、Ar-H、NH2)、8.64(m、3H、Ar-H)、9.05(d、1H、Ar-H)。
MS:(ESI pos.)、m/z=398([M+H]+)、(ESI neg.)、m/z=396([M−H]+)。
収量:0.024g(0.4%)。
Rf:0.17(EA/MeOH 20:1)。
1H-NMR:(200MHz、d6-DMSO)、δ=5.81(s、2H、OCH2)、6.95-7.6(m、8H、Ar-H、NH2)、7.92(dt、1H、Ar-H)、8.21(s、1H、Ar-H)、8.6-8.75(m、2H、Ar-H)、9.03(dd、1H、Ar-H)。
LCMS:保持時間:2.66分[カラム:Symmetry、C-18、3.5μm、50x2.1mm、流量0.5mL/分、40℃、勾配:水(+0.1%蟻酸):アセトニトリル(+0.1%蟻酸) 0分において90:10、7.5分において10:90];MS:(ESI pos.)、m/z=398([M+H]+)、(ESI neg.)、m/z=396([M−H]+)。
収量:34mg(15%)。
Rf:0.45(CH2Cl2/MeOH 20:1)。
1H-NMR:(300MHz、d6-DMSO)、δ=5.85(s、2H、CH2)、7.10-7.48(m、9H、7Ar-HおよびNH2)、8.61-8.75(m、3H、Ar-H)、8.99(dd、1H、Ar-H)。
LC-MS:Rf=3.55分(方法A);MS(ESI pos.)、m/z=432.3([M+H]+)、885.2([2M+Na]+)。
収量:45mg(20%)。
Rf:0.30(CH2Cl2/MeOH 20:1)。
1H-NMR:(300MHz、d6-DMSO)、δ=5.82(s、2H、CH2)、6.02(br.s、4H、NH2)、7.08-7.48(m、7H、Ar-H)、8.57-8.68(m、3H、Ar-H)、9.13(dd、1H、Ar-H)。
LC-MS:Rf=2.55分(方法A);MS(ESI pos.)、m/z=413.3([M+H]+)、847.8([2M+Na]+)。
Claims (15)
- 式(I)において、
R1が、4-ピリジニルまたは3-ピリジニルであり、
R2が、H、NH2またはClである、
請求項1に記載の化合物ならびにその塩、異性体および水和物。 - 式(I)において、
R1が、4-ピリジニルまたは3-ピリジニルであり、
R2が、Hである、
請求項1に記載の化合物ならびにその塩、異性体および水和物。 - 式(I)で示される化合物の製造方法であって、下記の工程を含んでなる方法:
以下の式(II):
(A)以下の式(III):
で示される化合物と、有機溶媒中で加熱しながら反応させて、式(I)で示される化合物を得るか、または
(B)以下の式(IV):
で示される化合物と、有機溶媒中で加熱しながら反応させて、以下の式(V):
で示される化合物を得、次に、ハロゲン化剤と反応させて、以下の式(VI):
で示される化合物を得、最後に、アンモニア水溶液と加熱下および高圧下に反応させる。 - 疾患治療用の請求項1に記載の式(I)で示される化合物。
- 少なくとも1つの請求項1に記載の式(I)の化合物を含んでなる薬剤。
- 請求項1に記載の式(I)の化合物を、一般的な賦形剤および添加剤と組み合わせることを含んでなる薬剤の製造方法。
- 請求項1に記載の式(I)の化合物を、有機硝酸塩、または、ニトロプルシドナトリウム、ニトログリセリン、イソソルビドジニトレート、イソソルビドモノニトレート、モルシドミンもしくはSIN-1と組合せて含んでなる薬剤。
- 請求項1に記載の式(I)の化合物を、ホスホジエステラーゼ1、2もしくは5の阻害物質と組合せて含んでなる薬剤。
- 心血管疾患の治療のための薬剤の製造における、請求項1に記載の式(I)で示される化合物の使用。
- 高血圧症の治療のための薬剤の製造における、請求項1に記載の式(I)で示される化合物の使用。
- 血栓塞栓性疾患および虚血の治療のための薬剤の製造における、請求項1に記載の式(I)で示される化合物の使用。
- 性機能障害の治療のための薬剤の製造における、請求項1に記載の式(I)で示される化合物の使用。
- 抗炎症特性を有する薬剤の製造における、請求項1に記載の式(I)で示される化合物の使用。
- 請求項1に記載の式(I)で示される化合物を、有機硝酸塩、ニトロプルシドナトリウム、ニトログリセリン、イソソルビドジニトレート、イソソルビドモノニトレート、モルシドミンもしくはSIN-1と組合せるか、またはホスホジエステラーゼ1、2もしくは5の阻害物質と組合せて使用する請求項10〜14のいずれかに記載の使用。
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PCT/EP2001/012969 WO2002042301A1 (de) | 2000-11-22 | 2001-11-09 | Neue pyridin-substituierte pyrazolopyridinderivate |
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CN115140558B (zh) * | 2022-08-25 | 2024-05-03 | 湖南核三力技术工程有限公司 | 基于管道内风力流层交换的低造碎气力输送方法与装置 |
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AU736303B2 (en) | 1996-10-14 | 2001-07-26 | Bayer Aktiengesellschaft | New heterocyclylmethyl-substituted pyrazol derivates |
DE19642255A1 (de) | 1996-10-14 | 1998-04-16 | Bayer Ag | Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten |
DE19649460A1 (de) | 1996-11-26 | 1998-05-28 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19834047A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
DE19834045A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin |
DE19846514A1 (de) | 1998-10-09 | 2000-04-20 | Bayer Ag | Neue Heterocyclyl-methyl-substituierte Pyrazole |
DE19920352A1 (de) | 1999-05-04 | 2000-11-09 | Bayer Ag | Substituiertes Pyrazolderivat |
DE10021069A1 (de) | 2000-04-28 | 2001-10-31 | Bayer Ag | Substituiertes Pyrazolderivat |
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EP1343786B1 (de) | 2005-06-29 |
US20020173514A1 (en) | 2002-11-21 |
US6693102B2 (en) | 2004-02-17 |
WO2002042301A1 (de) | 2002-05-30 |
NO20032299L (no) | 2003-07-02 |
AU2002220692A1 (en) | 2002-06-03 |
SI1343786T1 (sl) | 2005-12-31 |
CZ294648B6 (cs) | 2005-02-16 |
ES2243598T3 (es) | 2005-12-01 |
HUP0303283A2 (hu) | 2004-01-28 |
TW582998B (en) | 2004-04-11 |
UY27029A1 (es) | 2002-07-31 |
EP1343786A1 (de) | 2003-09-17 |
BG107804A (bg) | 2004-02-27 |
AR031176A1 (es) | 2003-09-10 |
SK5912003A3 (en) | 2003-10-07 |
BR0115477A (pt) | 2003-08-19 |
MXPA03004500A (es) | 2004-05-14 |
CA2429312A1 (en) | 2002-05-30 |
ATE298752T1 (de) | 2005-07-15 |
HRP20030489A2 (en) | 2005-06-30 |
JP2004521872A (ja) | 2004-07-22 |
NO20032299D0 (no) | 2003-05-21 |
CA2429312C (en) | 2011-01-04 |
IL155974A0 (en) | 2003-12-23 |
NZ525963A (en) | 2006-09-29 |
EE200300243A (et) | 2003-10-15 |
PL366090A1 (en) | 2005-01-24 |
DK1343786T3 (da) | 2005-09-12 |
PT1343786E (pt) | 2005-11-30 |
CZ20031435A3 (cs) | 2003-10-15 |
CN1555374A (zh) | 2004-12-15 |
MA26060A1 (fr) | 2004-04-01 |
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