JP4405732B2 - β−カルボリン誘導体ならびにうつ病および不安に対する医薬的使用 - Google Patents
β−カルボリン誘導体ならびにうつ病および不安に対する医薬的使用 Download PDFInfo
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- JP4405732B2 JP4405732B2 JP2002579459A JP2002579459A JP4405732B2 JP 4405732 B2 JP4405732 B2 JP 4405732B2 JP 2002579459 A JP2002579459 A JP 2002579459A JP 2002579459 A JP2002579459 A JP 2002579459A JP 4405732 B2 JP4405732 B2 JP 4405732B2
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- 210000000496 pancreas Anatomy 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 230000004037 social stress Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- NHXLMOGPVYXJNR-UHFFFAOYSA-N srif Chemical compound N1C(=O)C(C(C)O)NC(=O)C(CCCCN)NC(=O)C(CC=2C3=CC=CC=C3NC=2)NC(=O)C(CC=2C=CC=CC=2)NC(=O)C(CC=2C=CC=CC=2)NC(=O)C(CC(N)=O)NC(=O)C(CCCCN)NC(=O)C(NC(=O)CNC(=O)C(C)N)CSSCC(C(O)=O)NC(=O)C(CO)NC(=O)C(C(O)C)NC(=O)C1CC1=CC=CC=C1 NHXLMOGPVYXJNR-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- YCWUQOPEBRCJOR-DCVZUYTOSA-N tert-butyl n-[(1r)-2-(1h-indol-3-yl)-1-(5-pyridin-4-yl-1h-imidazol-2-yl)ethyl]carbamate;(1r)-2-(1h-indol-3-yl)-1-(5-pyridin-4-yl-1h-imidazol-2-yl)ethanamine;dihydrochloride Chemical compound Cl.Cl.N1C([C@@H](CC=2C3=CC=CC=C3NC=2)N)=NC=C1C1=CC=NC=C1.N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)OC(C)(C)C)=NC=C1C1=CC=NC=C1 YCWUQOPEBRCJOR-DCVZUYTOSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
であり、
R2およびR3は、独立して、(C1〜4)アルコキシ(C1〜4)アルキルまたは(C3〜7)シクロアルキル(C1〜4)アルキルであるか、あるいは
R1が所望により置換されていてもよいフェニル基でないならば、(C1〜12)アルキルであり、
R4は、水素、(C1〜4)アルキル、(C1〜4)アルコキシ、ハロゲンまたはトリフルオロメチルであり、そして
R5は、水素または(C1〜4)アルキルである。〕
の化合物を提供する。
ハロゲンは、フッ素、塩素、臭素またはヨウ素、好ましくはフッ素または塩素である。上で定義したアルキルおよびアルコキシ基は、好ましくはメチルおよびメトキシを表す。
の化合物を、式III
の化合物と反応させ、そしてかくして得られた式Iの化合物を遊離塩基または酸付加塩の形態で回収することによる、式Iの化合物およびそれらの塩の製造方法を提供する。
上記の方法にしたがう反応混合液の後処理およびそのようにして得られた化合物の精製は、既知の手順にしたがって実施され得る。
式IIおよび式IIIの化合物は既知であるか、または既知の手順にしたがって、例えば式IIの化合物のためのWO 99/64420にしたがって、製造され得る。
(R)−1,1−ジブチル−3−(4−ピリジン−4−イル−1H−イミダゾール−2−イル)−2,3,4,9−テトラヒドロ−1H−β−カルボリン
2−ブロモ−1−ピリジン−4−イル−エタノン 臭化水素酸塩を、1−ピリジン−4−イル−エタノンから、既知の手順(A. Taurins, A. Blaga, J. Heterocycl. Chem. 7, 1139 (1970))にしたがって83%収率で製造する。
DMF(85ml)中の、Boc−D−トリプトファン(7.00g、23.0mmol)およびCs2CO3(7.49g、23.0mmol)の溶液を、室温で30分間攪拌する。2−ブロモ−1−ピリジン−4−イル−エタノン 臭化水素酸塩(6.49g、23.0mmol)を加え、そして攪拌を室温で1時間継続する。溶媒を真空中で除去し、残渣をAcOEt中に再懸濁させ、hyfloで濾過し、そして蒸発させる。得られた油状物質をキシレン(290ml)中に溶かし、酢酸アンモニウム(35.46g、460mmol)を加え、そして混合物をDean−Starkトラップを用いて160℃で2時間加熱する。室温まで冷却後、AcOEt(100ml)を加え、そして溶液を飽和水性K2CO3溶液および食塩水(それぞれ100ml)で洗浄する。水層を、AcOEt(2×100ml)で再抽出し;合わせた有機層をNa2SO4で乾燥し、そして蒸発させる。MPLC(400gシリカゲル、AcOEt:MeOH 95:5から90:10)により、3.36g(36%)の[(R)−2−(1H−インドール−3−イル)−1−(4−ピリジン−4−イル−1H−イミダゾール−2−イル)−エチル]−カルバミン酸 tert−ブチルエステルを得る(TLC:シリカゲル、トルエン:エタノール 5:1、Rf=0.31)。
[(R)−2−(1H−インドール−3−イル)−1−(4−ピリジン−4−イル−1H−イミダゾール−2−イル)−エチル]−カルバミン酸 tert−ブチルエステル(3.46g、8.58mmol)を、氷酢酸(99.5%、25ml)および濃水性HCl(37%、2.5ml)の混合液中に溶解させ、そして溶液をアルゴン下で室温にて1時間攪拌する。得られた沈澱を濾過し、アセトンで洗浄し、そして乾燥すると、3.04g(94%)の(R)−2−(1H−インドール−3−イル)−1−(4−ピリジン−4−イル−1H−イミダゾール−2−イル)−エチルアミン 二塩酸塩を得る(TLC:シリカゲル、トルエン:エタノール:AcOH 4:4:1、Rf=0.18)。
n−ブタノール(20ml)中の、上記のアミン二塩酸塩(1.200g、3.19mmol)および5−ノナノン(0.544g、0.663ml、3.83mmol)の混合液を、135℃で4.5時間加熱還流する。Dean−Starkトラップを用いて、2mlの溶媒を留去し、次いで、攪拌を135℃で2時間および100℃で15時間継続する。室温まで冷却しそして溶媒を蒸発させた後に、AcOEt(50ml)を加え、そして溶液を飽和水性NaHCO3溶液(20ml)で洗浄し、水層をAcOEt(2×50ml)で再抽出し、合わせた有機層をNa2SO4で乾燥し、濾過し、そして蒸発させる。MPLC(80gシリカゲル、AcOEt:トリエチルアミン 95:5)およびメタノール:水(80:20)からの再結晶後、(R)−1,1−ジブチル−3−(4−ピリジン−4−イル−1H−イミダゾール−2−イル)−2,3,4,9−テトラヒドロ−1H−β−カルボリン(0.806g、59%)を、無色の結晶性固体として得る(融点200〜205℃、TLC:シリカゲル、トルエン:エタノール 5:1、Rf=0.42、ESI−MS:[M+H]+=428.2)。
Claims (11)
- 遊離塩基または酸付加塩の形態の、式I
であり、
R2およびR3は、独立して、(C1〜4)アルコキシ(C1〜4)アルキルまたは(C3〜7)シクロアルキル(C1〜4)アルキルであるか、あるいは
R1が所望により置換されていてもよいフェニル基でないならば、(C1〜12)アルキルであり、
R4は、水素、(C1〜4)アルキル、(C1〜4)アルコキシ、ハロゲンまたはトリフルオロメチルであり、そして
R5は、水素または(C1〜4)アルキルである。〕
の化合物。 - 遊離塩基または酸付加塩の形態の、(R)−1,1−ビス−エトキシメチル−3−(4−フェニル−1H−イミダゾール−2−イル)−2,3,4,9−テトラヒドロ−1H−β−カルボリンである、請求項1に記載の化合物。
- 医薬として使用するための、遊離塩基または薬学的に許容される酸付加塩の形態の、請求項1に記載の化合物。
- うつ病、不安および双極性障害の処置において使用するための、遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物。
- 医薬担体または希釈剤とともに、遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物を含んでなる医薬組成物。
- 同時的または逐次的投与のための、治療上有効量の遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物、および第2の医薬物質を含み、ここで、第2の医薬物質が三環化合物、MAOインヒビター、SSRI(Selective serotonin reuptake inhibitor)、SNRI(Serotonin−norepinephrine reuptake inhibitor)、NK受容体アンタゴニスト、CRF受容体アンタゴニスト、5HT7受容体アンタゴニスト、mGlu受容体アゴニスト/アンタゴニスト/モジュレーター、GABA A またはGABA A /B受容体アゴニスト/アンタゴニストまたはモジュレーター、バゾプレッシン受容体アンタゴニストまたは生薬から選択される、組合せ剤。
- 同時的または逐次的投与のための、治療上有効量の遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物、および第2の医薬物質を含み、ここで、第2の医薬物質がミトコンドリア性ベンゾジアゼピンリガンドを含むベンゾジアゼピン化合物、5−HT1A受容体アゴニスト、SSRI、SNRI、NK受容体アンタゴニスト、CRF受容体アンタゴニスト、バゾプレッシン受容体アンタゴニスト、mGlu受容体アゴニスト/アンタゴニスト/モジュレーター、GABA A またはGABA A /B受容体アゴニスト/アンタゴニストまたはモジュレーターから選択される、組合せ剤。
- 同時的または逐次的投与のための、治療上有効量の遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物、および第2の医薬物質を含み、ここで、第2の医薬物質がアセチルコリンエステラーゼインヒビター、混合アセチルコリン/ブチリルコリンエステラーゼインヒビターおよびニコチン性α受容体アゴニストから選択される、組合せ剤。
- 同時的または逐次的投与のための、治療上有効量の遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物、および第2の医薬物質を含み、ここで、第2の医薬物質が任意の典型的または非典型的抗精神病薬、およびニコチン性α受容体アゴニストから選択される、組合せ剤。
- うつ病、不安および双極性障害の処置用医薬の製造のための、遊離塩基または薬学的に許容される酸付加塩の形態の請求項1に記載の化合物の使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0108337.7A GB0108337D0 (en) | 2001-04-03 | 2001-04-03 | Organic compounds |
PCT/EP2002/003624 WO2002081471A1 (en) | 2001-04-03 | 2002-04-02 | Beta-carboline derivatives and its pharmaceutical use against depression and anxiety |
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Publication Number | Publication Date |
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JP2004525178A JP2004525178A (ja) | 2004-08-19 |
JP2004525178A5 JP2004525178A5 (ja) | 2005-12-22 |
JP4405732B2 true JP4405732B2 (ja) | 2010-01-27 |
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JP2002579459A Expired - Fee Related JP4405732B2 (ja) | 2001-04-03 | 2002-04-02 | β−カルボリン誘導体ならびにうつ病および不安に対する医薬的使用 |
Country Status (27)
Country | Link |
---|---|
US (1) | US6861430B2 (ja) |
EP (1) | EP1377578B1 (ja) |
JP (1) | JP4405732B2 (ja) |
KR (1) | KR100564840B1 (ja) |
CN (1) | CN1309721C (ja) |
AR (1) | AR035451A1 (ja) |
AT (1) | ATE517104T1 (ja) |
AU (1) | AU2002316828B2 (ja) |
BR (1) | BR0208566B1 (ja) |
CA (1) | CA2440014C (ja) |
CZ (1) | CZ295992B6 (ja) |
EC (1) | ECSP034754A (ja) |
ES (1) | ES2368389T3 (ja) |
GB (1) | GB0108337D0 (ja) |
HU (1) | HUP0400317A3 (ja) |
IL (1) | IL157545A0 (ja) |
MX (1) | MXPA03009057A (ja) |
MY (1) | MY134026A (ja) |
NO (1) | NO20034413D0 (ja) |
NZ (1) | NZ528370A (ja) |
PE (1) | PE20021018A1 (ja) |
PL (1) | PL210861B1 (ja) |
PT (1) | PT1377578E (ja) |
RU (1) | RU2003130644A (ja) |
SK (1) | SK12222003A3 (ja) |
WO (1) | WO2002081471A1 (ja) |
ZA (1) | ZA200306108B (ja) |
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DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
ES2427166T3 (es) * | 2003-06-23 | 2013-10-29 | Ono Pharmaceutical Co., Ltd. | Compuesto heterocíclico tricíclico novedoso |
AR051780A1 (es) * | 2004-11-29 | 2007-02-07 | Japan Tobacco Inc | Compuestos en anillo fusionados que contienen nitrogeno y utilizacion de los mismos |
PL1829874T3 (pl) | 2004-12-22 | 2014-07-31 | Ono Pharmaceutical Co | Tricykliczny związek i jego zastosowanie |
US20070149557A1 (en) * | 2005-11-21 | 2007-06-28 | Amgen Inc. | CXCR3 antagonists |
US7879859B2 (en) * | 2005-11-21 | 2011-02-01 | Merck Sharp & Dohme Corp. | Diagnosis and treatment of type 2 diabetes and other disorders |
WO2009011836A1 (en) * | 2007-07-19 | 2009-01-22 | Merck & Co., Inc. | Beta carboline derivatives as antidiabetic compounds |
WO2009016329A1 (en) * | 2007-07-31 | 2009-02-05 | Cambridge Enterprise Limited | Use of gabaa receptor antagonists to treat cognitive impairment in patients with psychiatric conditions |
CN102131805A (zh) | 2008-06-20 | 2011-07-20 | 百时美施贵宝公司 | 用作激酶抑制剂的咪唑并吡啶和咪唑并吡嗪化合物 |
ES2541528T3 (es) | 2008-11-19 | 2015-07-21 | Forum Pharmaceuticals Inc. | Tratamiento de trastornos cognitivos con (R)-7-cloro-N-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida y sales farmacéuticamente aceptables de la misma |
TW201028414A (en) * | 2009-01-16 | 2010-08-01 | Merck Sharp & Dohme | Oxadiazole beta carboline derivatives as antidiabetic compounds |
JP2013517272A (ja) | 2010-01-15 | 2013-05-16 | メルク・シャープ・エンド・ドーム・コーポレイション | 抗糖尿病化合物としてのオキサジアゾール・ベータ・カルボリン誘導体 |
MX357676B (es) | 2010-05-17 | 2018-07-18 | Forum Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin- 3-il)benzo[b]tiofeno-2-carboxamida monohidratado. |
RU2635522C2 (ru) | 2012-05-08 | 2017-11-13 | Форум Фармасьютикалз, Инк. | Способы поддержания, лечения или улучшения когнитивной функции |
CN111349096B (zh) * | 2020-04-14 | 2021-03-09 | 石河子大学 | 一种吲哚类化合物及其制备方法、应用 |
KR102467844B1 (ko) | 2021-04-21 | 2022-11-16 | 삼성전자주식회사 | 솔리드 스테이트 드라이브 장치 및 이를 포함하는 데이터 저장 장치 |
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DE4118741A1 (de) | 1991-06-05 | 1992-12-10 | Schering Ag | Neue hetaryloxy-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
US6057340A (en) | 1998-02-03 | 2000-05-02 | American Home Products Corporation | Oxazole derivatives as serotonin-1A receptor agonists |
AU761020B2 (en) * | 1998-06-12 | 2003-05-29 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Beta-carboline compounds |
-
2001
- 2001-04-03 GB GBGB0108337.7A patent/GB0108337D0/en not_active Ceased
-
2002
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