JP2007277096A - Medicine containing phenethyl-nicotinamide derivative - Google Patents
Medicine containing phenethyl-nicotinamide derivative Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Abstract
Description
本発明は、血管内皮細胞由来の一酸化窒素(NO)産生促進剤及び／又は内皮性一酸化窒素合成酵素(eNOS)活性化剤として有用な医薬に関する。また、本発明は、フェネチルニコチンアミド誘導体を有効成分とする医薬に関する。更に、血管内皮性NO産生促進作用及び／又はeNOS活性化作用を有し、医薬として有用な新規なフェネチルニコチンアミド誘導体及びその塩に関する。 The present invention relates to a medicament useful as a vascular endothelial cell-derived nitric oxide (NO) production promoter and / or an endothelial nitric oxide synthase (eNOS) activator. The present invention also relates to a medicament comprising a phenethylnicotinamide derivative as an active ingredient. Furthermore, the present invention relates to a novel phenethylnicotinamide derivative and a salt thereof having a vascular endothelial NO production promoting action and / or an eNOS activating action and useful as a medicament.
NO（一酸化窒素）はＬ−アルギニンが酸化されＬ−シトルリンになる際に産生され、その反応はNO合成酵素（NO Synthase：NOS）によって触媒される。NO産生は生体内の様々な組織、細胞種で観察されるが、恒常的にNOを産生、放出する代表的な細胞種が血管内皮細胞である。血管内皮細胞で産生されるNO（血管内皮性NO）が内皮由来血管弛緩因子（EDRF）であることが報告されている〔Nature, 1987,327,524-526 ; Proc.Natl.Acad.Sci.USA, 1987, 84, 9265-9269〕。
高脂血症・動脈硬化などの動脈硬化性疾患にみられる血管内皮の機能障害は、eNOSから産生されるNOの低下による内皮依存性血管弛緩・拡張反応（EDR）の減弱がその大きな原因であると言われている。
またeNOSにより産生される血管内皮性NOは、血管弛緩作用だけでなく、血小板凝集抑制・抗血栓作用、抗増殖作用、抗炎症作用などを有する（医学のあゆみ 204(4), 621-625, 2003）。
NOがEDRFの本体であることが判明し、更にNOが全身の循環調節において重要な役割を果たすことが明らかになったことから、循環不全治療薬としてニトログリセリン製剤をはじめとするNO供与製剤（硝酸剤）が臨床的に頻用されるようになった。しかし、NO供与製剤は作用持続時間が短く、長期服用した際に耐性が生じやすい。また対象臓器特異性に乏しいことから副作用として全身血圧低下、血圧下降による頻脈、頭痛、めまいが出現する。また、過度のNO産生は細胞毒性を生じることが知られている。
また、NOSの基質であるＬ−アルギニンの効果がNOに関連する疾患で検討されてきたが、Ｌ−アルギニン長期投与の効果は微弱で部分的であると報告されている〔Hypertension, 1994, 23, 752-756 ; Hypertension, 1996, 25, 898-902〕。
NO (nitrogen monoxide) is produced when L-arginine is oxidized to L-citrulline, and the reaction is catalyzed by NO synthase (NOS). Although NO production is observed in various tissues and cell types in the living body, typical cell types that constantly produce and release NO are vascular endothelial cells. It has been reported that NO produced in vascular endothelial cells (vascular endothelial NO) is endothelium-derived vasorelaxation factor (EDRF) [Nature, 1987, 327, 524-526; Proc. Natl. Acad. Sci. USA, 1987, 84, 9265-9269].
Vascular endothelium dysfunction seen in arteriosclerotic diseases such as hyperlipidemia and arteriosclerosis is mainly due to attenuation of endothelium-dependent vasorelaxation and dilatation (EDR) caused by a decrease in NO produced from eNOS. It is said that there is.
In addition, vascular endothelial NO produced by eNOS has not only a vasorelaxant action, but also platelet aggregation inhibition, antithrombotic action, antiproliferative action, anti-inflammatory action, etc. (Ayumi of Medicine 204 (4), 621-625, 2003).
Since NO was found to be the main body of EDRF, and NO was also found to play an important role in systemic circulation control, NO-donating preparations such as nitroglycerin preparations (as circulatory failure drugs) (Nitric acid) has been frequently used clinically. However, the NO-donating preparation has a short duration of action and tends to be resistant to long-term use. In addition, due to poor target organ specificity, systemic blood pressure drop, tachycardia due to blood pressure drop, headache, and dizziness appear as side effects. Excessive NO production is also known to cause cytotoxicity.
Moreover, although the effect of L-arginine, which is a NOS substrate, has been studied in diseases related to NO, it has been reported that the effect of long-term administration of L-arginine is weak and partial [Hypertension, 1994, 23 752-756; Hypertension, 1996, 25, 898-902].
これら知見より、血管内皮細胞での自発的かつ十分量のNO産生を促進する化合物、及び／又はeNOS活性化作用を有する化合物が、血管内皮機能を改善し、血流障害、動脈硬化、高脂血症、虚血性心疾患や各種臓器での循環不全等の血管内皮機能低下に起因する疾患等の疾患に対して優れた治療剤になると考えられる。
これまで知られている血管内皮性NO産生促進又はeNOSに関する作用を有する化合物としては、HMG-CoA還元酵素阻害剤（コレステロール合成阻害剤）が、血管内皮細胞においてeNOSのmRNA量を増加させることにより、NO産生を促進することが報告されている。また、4-フルオロ-N-インダン-2-イルベンズアミド（特許文献１）、ヘテロ環基又はアリールでアシル化されたインダニルアミノ誘導体(特許文献２)、ヘテロ環基又はアリールでアシル化された6,7,8,9-テトラヒドロ-5H-ベンゾシクロヘプチルアミノ誘導体(特許文献３)、及びヘテロ環基等でアシル化された1,2,3,4-テトラヒドロナフチルアミン(特許文献４)がeNOS発現亢進作用を有することが開示されている。また、ソイステロール、ピリドキシン類、リボフラビン類、タウリン、イノシトールヘキサニコチネート及びパンテチンも血管内皮性一酸化窒素の合成促進及び／又は内皮性酸化窒素血中濃度の維持・向上作用を有することが知られている（特許文献５）
しかしながら、本発明化合物はこれらの化合物とは構造的に異なる。
一方、フェネチルニコチンアミド誘導体としては、以下の化合物が知られている。
フェネチルニコチンアミド誘導体のうち、フェネチルニコチンアミド及びベンゼン環の２位が塩素で置換された化合物は製造中間体として知られているが(特許文献６)、これらの化合物は弱いカリウムチャンネル開口作用及び弱い血管拡張作用を有することも知られている（非特許文献１）。
ベンゼン環の３又は４位が塩素でジ置換された化合物(それぞれ、非特許文献２、CASレジストリー番号489416-65-1)、及び３位がフッ素で１置換された化合物(特許文献７)は、合成中間体または試薬として知られている。
また、ベンゼン環の２及び４位が塩素でジ置換され、かつピリジン環上の５位が臭素で置換された化合物は、合成中間体(特許文献８)として、またベンゼン環の２及び４位が塩素でジ置換され、かつピリジン環上の６位が塩素で置換された化合物は、試薬(CASレジストリー番号380470-94-0)として知られている。
しかしながら、本発明のベンゼン環が少なくとも１つのハロゲンで置換されたフェネチルニコチンアミド誘導体が血管内皮性NO産生促進作用及び／又はeNOS活性化作用を有することは、上記文献には開示も示唆もない。
Based on these findings, a compound that promotes spontaneous and sufficient NO production in vascular endothelial cells and / or a compound having an eNOS activation action improves vascular endothelial function, blood flow disorder, arteriosclerosis, high fat It is considered to be an excellent therapeutic agent for diseases such as illness, ischemic heart disease and diseases caused by reduced vascular endothelial function such as circulatory failure in various organs.
HMG-CoA reductase inhibitor (cholesterol synthesis inhibitor) increases the amount of mRNA of eNOS in vascular endothelial cells as a compound having an effect on vascular endothelial NO production or eNOS known so far. Have been reported to promote NO production. In addition, 4-fluoro-N-indan-2-ylbenzamide (Patent Document 1), an indanylamino derivative acylated with a heterocyclic group or aryl (Patent Document 2), acylated with a heterocyclic group or aryl 6,7,8,9-tetrahydro-5H-benzocycloheptylamino derivative (Patent Document 3) and 1,2,3,4-tetrahydronaphthylamine acylated with a heterocyclic group or the like (Patent Document 4) It is disclosed to have an expression enhancing action. In addition, soysterol, pyridoxine, riboflavin, taurine, inositol hexanicotinate and pantethine are also known to promote the synthesis of vascular endothelial nitric oxide and / or maintain and improve endothelial nitric oxide blood levels. (Patent Document 5)
However, the compounds of the present invention are structurally different from these compounds.
On the other hand, the following compounds are known as phenethyl nicotinamide derivatives.
Among the phenethyl nicotinamide derivatives, phenethyl nicotinamide and compounds in which the 2-position of the benzene ring is substituted with chlorine are known as production intermediates (Patent Document 6). However, these compounds have weak potassium channel opening action and weakness. It is also known to have a vasodilatory effect (Non-patent Document 1).
A compound in which the 3 or 4 position of the benzene ring is di-substituted with chlorine (Non-Patent Document 2, CAS Registry Number 489416-65-1) and a compound in which the 3 position is 1-substituted with fluorine (Patent Document 7) , Known as synthetic intermediates or reagents.
A compound in which the 2 and 4 positions of the benzene ring are disubstituted with chlorine and the 5 position on the pyridine ring is substituted with bromine is used as a synthetic intermediate (Patent Document 8) and also in the 2 and 4 positions of the benzene ring. Is a compound (CAS Registry Number 380470-94-0) that is disubstituted with chlorine and substituted at the 6-position on the pyridine ring with chlorine.
However, the above document does not disclose or suggest that the phenethylnicotinamide derivative in which the benzene ring of the present invention is substituted with at least one halogen has a vascular endothelial NO production promoting action and / or an eNOS activating action.
本発明の課題は、新規な血管内皮性NO産生促進剤及び／又はeNOS活性化剤を提供することである。また、フェネチルニコチンアミド誘導体を有効成分とする医薬、更に、血管内皮性NO産生促進作用及び／又はeNOS活性化作用を有する新規なフェネチルニコチンアミド誘導体およびその塩を提供することである。 An object of the present invention is to provide a novel vascular endothelial NO production promoter and / or eNOS activator. Another object of the present invention is to provide a pharmaceutical comprising a phenethyl nicotinamide derivative as an active ingredient, a novel phenethyl nicotinamide derivative having a vascular endothelial NO production promoting action and / or an eNOS activating action, and a salt thereof.
本発明者等は、血管内皮性NO産生促進作用及び／又はeNOS活性化作用を有する化合物について鋭意検討した結果、ベンゼン環が少なくとも１以上のハロゲンで置換された化合物が、優れた血管内皮性NO産生促進作用を有することを知見し、本発明を完成した。
即ち、本発明は、下記一般式(I)で示されるフェネチルニコチンアミド誘導体又はその製薬学的に許容される塩を有効成分とする血管内皮性NO産生促進及び／又はeNOS活性化剤に関する。
Hal：ハロゲン、
R：NO2、CN、低級アルキル、OH、ハロゲノ低級アルキル、COOH、-O-低級アルキル、-COO-低級アルキル、-CONH2、-CO-(モノ又はジ低級アルキルアミノ)、又は-低級アルキレン-O-低級アルキル、
R1：H、ハロゲン、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
R2：H、低級アルキル、-低級アルキレン-COOH、-低級アルキレン-CONH2、又は-低級アルキレン-CO-(モノ又はジ低級アルキルアミノ)、
m：１乃至５の整数、
n:0、又は1 但し、m+n≦5、
X：N、又はN-オキシド。）
また、本発明は、これまで医薬としての用途が知られていなかった下記一般式（I)で示されるフェネチルニコチンアミド誘導体又はその製薬学的に許容される塩を有効成分とする医薬に関する。
但し、２−クロロフェネチル−３−ニコチンアミドを除く。）
更に、本発明は、医薬、殊に血管内皮性NO産生促進剤として有用な新規なフェネチルニコチンアミド誘導体又はその塩に関する。
R1a：H、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
Hal,R, R2及びXは前記の意味を示す。
但し、HalがCl又はFでありかつmが1のときは、nは1を示す。）
As a result of intensive studies on a compound having a vascular endothelial NO production promoting action and / or an eNOS activating action, the present inventors have found that a compound in which the benzene ring is substituted with at least one halogen is an excellent vascular endothelial NO. The present invention was completed by finding that it has a production promoting effect.
That is, the present invention relates to a vascular endothelial NO production promotion and / or eNOS activator comprising a phenethylnicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
Hal: halogen,
R: NO 2 , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH 2 , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R 1 : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R 2 : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH 2 , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide. )
The present invention also relates to a medicament comprising as an active ingredient a phenethyl nicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which has not been known to be used as a medicament so far.
However, 2-chlorophenethyl-3-nicotinamide is excluded. )
Furthermore, the present invention relates to a novel phenethylnicotinamide derivative or a salt thereof useful as a pharmaceutical, particularly a vascular endothelial NO production promoter.
R 1a : H, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
Hal, R, R2 and X have the above meanings.
However, when Hal is Cl or F and m is 1, n represents 1. )
本発明医薬の有効成分であるフェネチルニコチンアミド誘導体又はその塩は，優れた血管内皮性NO産生促進及び／又はeNOS活性化作用による血流循環改善作用を有し、更に、血小板凝集抑制・抗血栓作用、抗増殖作用、抗炎症作用などの作用も有する。本発明医薬は、血管内皮性NO産生低下及び／又はeNOS機能低下を起因とする血管内皮機能不全が病因である疾患又は病理学的状態の改善、殊に、末梢動脈閉塞症（PAOD）、動脈硬化、虚血性心疾患などの循環不全等の疾患の治療剤として有用である。また、本発明医薬は血圧や心拍に対する影響が少ないことも期待できる。 The phenethylnicotinamide derivative or a salt thereof, which is an active ingredient of the medicament of the present invention, has an excellent blood vessel circulation improvement action by promoting vascular endothelial NO production and / or eNOS activation action, and further suppressing platelet aggregation and antithrombosis It also has effects such as action, antiproliferative action, and anti-inflammatory action. The medicament of the present invention is used to improve diseases or pathological conditions caused by vascular endothelial dysfunction caused by reduced vascular endothelial NO production and / or reduced eNOS function, particularly peripheral arterial occlusion (PAOD), arteries It is useful as a therapeutic agent for diseases such as circulatory failure such as sclerosis and ischemic heart disease. In addition, the pharmaceutical of the present invention can be expected to have little influence on blood pressure and heart rate.
本発明の好ましい態様を以下に示す。
（１）一般式（Ia)において、mが2乃至5の整数であり、nが0であるフェネチルニコチンアミド誘導体又はその塩、及びこれらを有効成分として含有する医薬、殊に血管内皮性NO産生促進及び／又はeNOS活性化剤。
（２）一般式（Ia)において、mが2であり、nが0、R1aがH、かつXがNであるフェネチルニコチンアミド誘導体又はその塩、及びこれらを有効成分として含有する医薬、殊に血管内皮性NO産生促進及び／又はeNOS活性化剤。
（３）一般式（Ｉ）で示されるフェネチルニコチンアミド誘導体又はその製薬学的に許容される塩を有効成分として含有する医薬が、末梢動脈閉塞症、動脈硬化、又は虚血性心疾患の予防・治療剤である剤。
Preferred embodiments of the present invention are shown below.
(1) A phenethylnicotinamide derivative or a salt thereof in which m is an integer of 2 to 5 and n is 0 in the general formula (Ia), and a medicine containing these as an active ingredient, particularly vascular endothelial NO production Facilitating and / or eNOS activator.
(2) A phenethylnicotinamide derivative or a salt thereof, in which m is 2, n is 0, R 1a is H, and X is N in the general formula (Ia), and a medicament containing these as an active ingredient, And vascular endothelial NO production promoter and / or eNOS activator.
(3) A medicine containing a phenethylnicotinamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient prevents peripheral arterial occlusion, arteriosclerosis, or ischemic heart disease An agent that is a therapeutic agent.
更に本発明を詳述する。
「ハロゲン」としては、フッ素、塩素、臭素又はヨウ素原子が挙げられる。
なお、mが２以上を示す場合には、それぞれのハロゲンは、同一であってもよく、異なっていてもよい。
「低級アルキル」とは、直鎖又は分岐状飽和のC1-6アルキルであり、好ましくはメチル、エチル、イソプロピル、ヘキシルである。
「ハロゲノ低級アルキル」とは、前記低級アルキルの任意の１以上の水素原子が前記ハロゲンに置換された基を意味する。好ましくはハロゲノC1-3アルキルであり、更に好ましくは、トリフルオロメチル、トリフルオロエチルである。
「モノ又はジ低級アルキルアミノ」とは、アミノ基の水素が１または２の低級アルキルで置換された対称又は非対称のアミノ基であり、好ましくは、メチルアミノ、ジメチルアミノである。
本発明の化合物には、プロドラッグを形成する基に置換された化合物も含まれる。
ここに、本発明のプロドラッグを形成する基としては、Prog. Med.、5、2157-2161 (1985)や「医薬品の開発」第7巻(廣川書店、1990年)分子設計163-198頁に記載の基等が挙げられる。
Further, the present invention will be described in detail.
“Halogen” includes fluorine, chlorine, bromine or iodine atoms.
In addition, when m shows 2 or more, each halogen may be the same and may differ.
The “lower alkyl” is linear or branched saturated C 1-6 alkyl, preferably methyl, ethyl, isopropyl or hexyl.
The “halogeno lower alkyl” means a group in which any one or more hydrogen atoms of the lower alkyl are substituted with the halogen. Halogeno C 1-3 alkyl is preferable, and trifluoromethyl and trifluoroethyl are more preferable.
The “mono or di-lower alkylamino” is a symmetric or asymmetric amino group in which the hydrogen of the amino group is substituted with 1 or 2 lower alkyl, preferably methylamino or dimethylamino.
The compounds of the present invention also include compounds substituted with a group that forms a prodrug.
Here, examples of the group that forms the prodrug of the present invention include Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs”, Volume 7 (Yodogawa Shoten, 1990), Molecular Design pages 163-198. And the like.
本発明化合物（I）及び(Ia)は、酸付加塩又は置換基の種類によっては塩基との塩を形成する場合もあり、かかる塩が製薬学的に許容され得る塩である限りにおいて本発明に包含される。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、又はグルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩やアンモニウム塩等が挙げられる。本発明は、本発明化合物及びその製薬学的に許容され得る塩の各種の水和物や溶媒和物、及び結晶多形も包含する。
本発明化合物は基の種類によっては、光学異性体（光学活性体、ジアステレオマー等）が存在する。また、本発明化合物はアミド結合を有する化合物であり、互変異性体が存在する。本発明には、これらの異性体の分離されたもの、あるいは混合物を包含する。
また、本発明には、本発明化合物を放射性同位元素でラベル化した化合物も包含する。
The compounds (I) and (Ia) of the present invention may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the present invention Is included. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc. Inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like. The present invention also includes various hydrates and solvates and crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof.
The compounds of the present invention may have optical isomers (optically active substances, diastereomers, etc.) depending on the type of group. Moreover, this invention compound is a compound which has an amide bond, and a tautomer exists. The present invention includes a separated or a mixture of these isomers.
The present invention also includes compounds obtained by labeling the compounds of the present invention with radioisotopes.
(製造法)
本発明化合物及びその製薬学的に許容され得る塩は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。
その際、官能基の種類によっては、当該官能基を原料乃至中間体の段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては例えばアミノ基、水酸基、カルボキシ基等であり、それらの保護基としては例えばグリーン(Greene)及びウッツ(Wuts)著、「Protective Groups in Organic Synthesis(第3版)」に記載の保護基等を挙げることができ、これらを反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行った後、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
以下、本発明化合物の代表的な製造法を説明する。なお、本発明の製造法は以下図示した例に限られるわけではない。
以下の文章中の記号は、次の通りである。
(Production method)
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent.
In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. Examples of such functional groups include amino groups, hydroxyl groups, carboxy groups, and the like. For example, Greene and Wuts, Protective Groups in Organic Synthesis (Third Edition). The protecting groups described can be used, and these may be appropriately selected according to the reaction conditions. In such a method, a desired compound can be obtained by carrying out the reaction by introducing the protecting group and then removing the protecting group as necessary.
Hereafter, the typical manufacturing method of this invention compound is demonstrated. The production method of the present invention is not limited to the examples illustrated below.
The symbols in the following sentences are as follows.
第１製法（アミド化）
本発明化合物（Ｉ）は、対応するカルボン酸化合物（ＩＩ）と式（ＩＩＩ）で示されるフェネチルアミンとを公知の方法（例えばM. Bodanszky、Peptide Chemistry、ｐ５５−７３（１９８８）、泉屋信夫ら，ペプチド合成の基礎と実験，ｐ８９−１４２，（１９８５）などが参照される）によりアミド化することにより製造できる。なお、XがＮ−オキシドである本発明化合物（Ｉ）は、対応するカルボン酸誘導体（ＩＩ）のＮ−オキシドを用いて製造することができる。
好ましくは、カルボン酸化合物（ＩＩ）を反応性誘導体（例えば酸クロリド、酸ブロミド等の酸ハライド；酸アジド；メタノール、エタノール、ベンジルアルコール、置換していてもよいフェノール、Ｎ−ヒドロキシスクシンイミド等を用いて調整できる活性エステル；対称酸無水物；アルキル炭酸；ｐ−トルエンスルホン酸等との混合酸無水物等）に変換した後、化合物（ＩＩＩ）と反応させることにより行うことができる。カルボン酸の反応性誘導体を用いる場合、塩基（水酸化ナトリウム等の無機塩基、又はトリエチルアミン（TEA）、ジイソプロピルエチルアミン、ピリジン等の有機塩基）を添加することが好ましい。更にアミド化はカルボン酸を縮合剤（１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（WSC）、１，１’−カルボニルビス−１−１Ｈ−イミダゾール（CDI）等）の存在下に反応させることによって行うこともできる。その際1-ヒドロキシベンゾトリアゾール（HOBt）等の添加剤を加えてもよい。
反応温度は、原料化合物に応じて適宜選択できる。溶媒は不活性溶媒、例えばベンゼン、トルエン等の芳香族炭化水素系溶媒、１、４−ジオキサン、テトラヒドロフラン（ＴＨＦ）などのエーテル系の溶媒、Ｎ、Ｎ−ジメチルホルムアミド（ＤＭＦ）等が挙げられ、原料化合物の種類等に従い適宜選択され、単独、或いは２種以上混合して用いられる。
First production method (amidation)
The compound (I) of the present invention is obtained by reacting the corresponding carboxylic acid compound (II) and phenethylamine represented by the formula (III) by a known method (for example, M. Bodanszky, Peptide Chemistry, p55-73 (1988), Nobuo Izumiya et al., Peptide synthesis basis and experiment, p89-142, (1985) and the like). In addition, this invention compound (I) whose X is N-oxide can be manufactured using N-oxide of a corresponding carboxylic acid derivative (II).
Preferably, carboxylic acid compound (II) is used as a reactive derivative (for example, acid halide such as acid chloride or acid bromide; acid azide; methanol, ethanol, benzyl alcohol, optionally substituted phenol, N-hydroxysuccinimide or the like). Active ester, symmetric acid anhydride, alkyl carbonate, mixed acid anhydride with p-toluenesulfonic acid, etc.), and then reacted with compound (III). When a reactive derivative of carboxylic acid is used, it is preferable to add a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, or pyridine). Further, amidation is carried out in the presence of a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1′-carbonylbis-l-1H-imidazole (CDI), etc.). It can also be performed by reacting. At that time, an additive such as 1-hydroxybenzotriazole (HOBt) may be added.
The reaction temperature can be appropriately selected depending on the raw material compound. Examples of the solvent include inert solvents such as aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as 1,4-dioxane and tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and the like. It is appropriately selected according to the type of raw material compound and the like, and is used alone or in combination of two or more.
第２製法（アルキル化）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ2が低級アルキル又は−Ｚ−ＣＯＯＲbで置換されたアミド化合物（Ｉｂ）は、対応するＲ2がＨのアミド化合物（ＩＶ）及び式（Ｖ）で示されるアルキル化剤と反応させる常法のＮ−アルキル化反応によって製造できる。
反応は適当な不活性溶媒（好ましくは、ＴＨＦなどのエーテル系溶媒あるいはＤＭＦ）中、反応対応量の化合物（ＩＶ）と化合物（Ｖ）あるいはいずれか一方の過剰量を用い、必要ならば酸補足剤として、例えば水素化ナトリウム、カリウム ｔｅｒｔ−ブトキシド、炭酸カリウム、ＴＥＡ等の無機または有機塩基を加え、冷却下、室温下又は加熱下に実施するのが有利である。
Second production method (alkylation)
In the present invention compounds, among the compounds of formula (I), amide compound R 2 is substituted by a lower alkyl or -Z-COOR b (Ib) is the corresponding R 2 is an amide compound of the H (IV) And a conventional N-alkylation reaction in which the compound is reacted with an alkylating agent represented by the formula (V).
In the reaction, an appropriate inert solvent (preferably an ether solvent such as THF or DMF) is used in an amount corresponding to compound (IV) and / or compound (V) in an amount corresponding to the reaction, and if necessary, supplemented with an acid. As an agent, for example, an inorganic or organic base such as sodium hydride, potassium tert-butoxide, potassium carbonate, TEA or the like is added, and the reaction is advantageously carried out under cooling, at room temperature or under heating.
第３製法（ケン化）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ2が低級アルキレン-COOHで置換されたアミド化合物（ＶＩＩ）は、対応するエステル化合物（ＶＩ）のケン化によって製造できる。
反応は常法を適用して行うことができ、適当な不活性溶媒（好ましくは、メタノール、エタノールなどのアルコール溶媒）中、適当な無機塩基、例えば水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を添加し、冷却下、室温下又は加熱下に実施するのが有利である。
Third production method (saponification)
Among the compounds of the present invention, among the compounds represented by the formula (I), the amide compound (VII) in which R 2 is substituted with lower alkylene-COOH can be produced by saponification of the corresponding ester compound (VI).
The reaction can be carried out by applying a conventional method, and in a suitable inert solvent (preferably an alcohol solvent such as methanol or ethanol), a suitable inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. It is advantageous to carry out under cooling, at room temperature or under heating.
第４製法（アミド化）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ2が低級アルキレン−ＣＯＮＨ2、低級アルキレン−ＣＯ−モノ又はジ低級アルキルアミノで置換されたアミド化合物（Ｘ）は、対応するカルボン酸化合物（ＶＩＩＩ）又はその活性化体と式（ＩＸ）で示されるアンモニア又はモノ−若しくはジ−低級アルキルアミンとを、第１製法と同様にアミド化（アンモニアの時はアンモノリシス）することにより製造できる。
Fourth production method (amidation)
Among the compounds of the present invention, among the compounds represented by the formula (I), the amide compound (X) in which R 2 is substituted with lower alkylene-CONH 2 , lower alkylene-CO-mono or di-lower alkylamino is a corresponding carboxylic acid. Produced by amidating acid compound (VIII) or an activated form thereof with ammonia or mono- or di-lower alkylamine represented by formula (IX) (ammonolysis in the case of ammonia) in the same manner as in the first production method. it can.
本発明化合物は、遊離化合物、その製薬学的に許容される塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。本発明化合物(I)の製薬学的に許容される塩は、常法の造塩反応に付すことにより製造することもできる。
単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等通常の化学操作を適用して行われる。
各種の異性体は、適当な原料化合物を選択することにより、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は適当な原料を選択することにより、あるいはラセミ化合物の光学分割法(例えば、一般的な光学活性な塩基又は酸とのジアステレオマー塩に導き、光学分割する方法、キラルカラム等を用い分取する方法等)により、立体化学的に純粋な異性体に導くことができる。
以上、本製造法と同様にして後述の実施例化合物の他に下表の化合物が得られる。また当該下表中一部の化合物を得た。
本発明有効成分並びに本発明化合物又はその製薬学的に許容され得る塩は単独でも医薬として供しうるが通常1種又は2種以上の有効成分を、当分野において通常用いられている薬剤用担体、賦形剤等を用いて通常使用されている方法によって調製することができる。投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種又は2種以上の有効成分を、少なくとも1種の不活性な希釈剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び/又はメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な希釈剤以外の添加剤、例えばステアリン酸マグネシウムのような潤滑剤や繊維素グリコール酸カルシウムのような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要によりショ糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレートなどの糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
The compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate, or crystalline polymorphic substance. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be separated by selecting an appropriate raw material compound or utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be selected by selecting appropriate raw materials or by optical resolution of racemates (for example, diastereomeric salts with general optically active bases or acids, optical resolution, chiral columns, etc. Can be led to a stereochemically pure isomer.
As described above, the compounds shown in the following table can be obtained in the same manner as in the present production method in addition to the example compounds described later. In addition, some compounds in the table below were obtained.
The active ingredient of the present invention as well as the compound of the present invention or a pharmaceutically acceptable salt thereof can be used alone or as a medicament, but usually one or two or more active ingredients are used as a pharmaceutical carrier usually used in the art, It can be prepared by a commonly used method using an excipient or the like. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active ingredients are combined with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, And / or mixed with magnesium aluminate metasilicate. The composition contains additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers, and solubilizing agents according to a conventional method. May be. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, or a film of a gastric or enteric substance.
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶液剤又は懸濁剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水溶性の溶液剤又は懸濁剤としては、例えばプロピレングリコール、ポリエチレングリコール又はオリーブ油のような植物油、エタノールのようなアルコール類、又はポリソルベート８０（局方名）等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。
経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知のpH調整剤、防腐剤、増粘剤や賦形剤が適宜添加され、固体、液体若しくは半固体状に成形される。経鼻剤は通常のスプレー器具、点鼻容器、チューブ、又は鼻腔内挿入具等を用いて投与される。
通常経口投与の場合、1日の投与量は、約0.001〜1000mg、好ましくは0.1〜300mg、更に好ましくは0.1〜100mgが適当であり、これを1回であるいは2乃至4回に分けて投与する。静脈内投与される場合は、1日の投与量は、約0.0001〜500mgが適当で、1日1回乃至複数回に分けて投与する。また、経粘膜剤としては、約0.001〜500mgを1日1回乃至複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solution or suspension include distilled water for injection or physiological saline. Examples of the water-insoluble solution or suspension include vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
A transmucosal agent such as a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method. For example, known pH adjusters, preservatives, thickeners and excipients are appropriately added to form a solid, liquid or semi-solid. The nasal agent is administered using a normal spray device, a nasal container, a tube, or an intranasal insertion device.
Usually, in the case of oral administration, the daily dose is about 0.001 to 1000 mg, preferably 0.1 to 300 mg, more preferably 0.1 to 100 mg, which is administered once or divided into 2 to 4 times. . When administered intravenously, the daily dose is suitably about 0.0001 to 500 mg, and is administered once a day or divided into multiple times. As a transmucosal agent, about 0.001 to 500 mg is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
［実施例］
以下、実施例に基づき本発明を更に詳細に説明する。本発明化合物は下記実施例に記載の化合物に限定されるものではない。また原料化合物の製法を参考例に示す。
なお、明細書中の略号は、以下の通りである。
FAB-MS：高速原子衝撃イオン化質量分析法による測定値； EI-MS;電子衝撃イオン化質量分析法による測定値； NMR(DMSO):NMR(DMSO-d6、TMS内部標準)の特徴的ピークδppm; Me:メチル;null:存在しない；Salt:塩
参考例１ ２−（４−ブロモ−２−クロロフェニル）エチルアミン
（４−ブロモ−２−クロロフェニル）メタノール2.6gのクロロホルム30ml溶液に、室温下塩化チオニル1.7mlを加え１時間撹拌した。溶媒を減圧下留去し、残留物2.4gを得た。得られた残留物はそのまま次反応に用いた。
残留物のアセトニトリル30ml溶液に、室温下シアン化カリウム2.4gおよび１８−クラウン−６−エーテル3.4gを順次加え８０℃で一晩撹拌した。室温まで冷却後、反応液に水を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル：ヘキサン）に付し、淡黄色油状物を得た。得られた淡黄色油状物はこれ以上の精製を行うことなくそのまま次反応に用いた。
淡黄色油状物のＴＨＦ20ml溶液に、ボラン−ＴＨＦ錯体（１ＭＴＨＦ溶液）20mlを加え４時間加熱還流した。室温まで冷却後、１Ｍ塩酸水溶液を加えさらに１時間加熱還流した。再び室温まで冷却後、１Ｍ水酸化ナトリウム水溶液を加え反応系を塩基性とした後、酢酸エチルで抽出した。有機層より１Ｍ塩酸水溶液で抽出し、１Ｍ水酸化ナトリウム水溶液を加え塩基性とした後、再度酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し溶媒を減圧留去し、２−（４−ブロモ−２−クロロフェニル）エチルアミン772mgを淡黄色油状物として得た。
FAB-MS:234、236(M+1)
[Example]
Hereinafter, the present invention will be described in more detail based on examples. The compounds of the present invention are not limited to the compounds described in the following examples. Moreover, the manufacturing method of a raw material compound is shown in a reference example.
Abbreviations in the specification are as follows.
FAB-MS: Measured by fast atom bombardment ionization mass spectrometry; EI-MS; Measured by electron impact ionization mass spectrometry; NMR (DMSO): NMR (DMSO-d 6 , TMS internal standard) characteristic peak δppm ; Me: methyl; null: not present; Salt: salt
Reference Example 1 2- (4-Bromo-2-chlorophenyl) ethylamine 1.7 ml of thionyl chloride was added to a solution of 2.6 g of (4-bromo-2-chlorophenyl) methanol in 30 ml of chloroform at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain 2.4 g of a residue. The obtained residue was used for the next reaction as it was.
To a 30 ml solution of the residue in acetonitrile, 2.4 g of potassium cyanide and 3.4 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 80 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate: hexane) to give a pale yellow oil. The obtained pale yellow oil was used in the next reaction as it was without further purification.
To a 20 ml THF solution of a pale yellow oil was added 20 ml borane-THF complex (1M THF solution), and the mixture was heated to reflux for 4 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to make the reaction system basic, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic with a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 772 mg of 2- (4-bromo-2-chlorophenyl) ethylamine as a pale yellow oil.
FAB-MS: 234, 236 (M + 1)
参考例２ ２−［２−クロロ−５−（トリフルオロメチル）フェニル］エチルアミン
［２−クロロ−５−（トリフルオロメチル）フェニル］アセトニトリル787mgのＴＨＦ7ml溶液に、ボラン−ジメチルスルフィド錯体1.66mlを加え６時間加熱還流した。室温まで冷却後、４Ｍ塩酸水溶液を加えさらに１時間加熱還流した。再び室温まで冷却後、水層をジエチルエーテルで洗浄し、１Ｍ水酸化ナトリウム水溶液を加え水層を塩基性とした後、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し溶媒を減圧留去し、２−［２−クロロ−５−（トリフルオロメチル）フェニル］エチルアミン(参考例2-1)682mgを無色油状物として得た。
同様にして、（表１）に示される化合物を製造した。
Reference Example 2 2- [2-Chloro-5- (trifluoromethyl) phenyl] ethylamine [2-Chloro-5- (trifluoromethyl) phenyl] acetonitrile 1.66 ml of borane-dimethyl sulfide complex was added to 787 mg of THF 7 ml solution. Heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, the aqueous layer was washed with diethyl ether, 1M aqueous sodium hydroxide solution was added to make the aqueous layer basic, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 682 mg of 2- [2-chloro-5- (trifluoromethyl) phenyl] ethylamine (Reference Example 2-1) as colorless. Obtained as an oil.
In the same manner, the compounds shown in (Table 1) were produced.
参考例３ ２−（４−ブロモ−２−フルオロフェニル）エチルアミン
４−ブロモ−２−フルオロベンジルクロリド1.0gのアセトニトリル30ml溶液に、室温下シアン化カリウム874mgおよび１８−クラウン−６−エーテル1.4gを順次加え６０℃で二晩撹拌した。室温まで冷却後、反応液に水を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し溶媒を減圧留去した。得られた残留物864mgはそのまま次反応に用いた。
残留物864mgのＴＨＦ10ml溶液に、ボラン−ＴＨＦ錯体（１ＭＴＨＦ溶液）20mlを加え２時間加熱還流した。室温まで冷却後、１Ｍ塩酸水溶液を加えさらに１時間加熱還流した。再び室温まで冷却後、１Ｍ水酸化ナトリウム水溶液を加え反応系を塩基性とした後、酢酸エチルで抽出した。有機層より１Ｍ塩酸水溶液で抽出し、１Ｍ水酸化ナトリウム水溶液を加え塩基性とした後、再度酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し溶媒を減圧留去し、２−（４−ブロモ−２−フルオロフェニル）エチルアミン388mgを淡黄色油状物として得た。
FAB-MS:218, 220(M+1)
参考例４ （４−クロロ−２−メトキシフェニル）アセトニトリル
（４−クロロ−２−メトキシフェニル）メタノール5.3gのＴＨＦ100ml溶液に、氷冷下塩化チオニル2.7mlを加え３０分間撹拌した。室温まで昇温後、溶媒を減圧留去し、残留物を無色油状物として得た。得られた残留物はそのまま次反応に用いた。
残留物のアセトニトリル100ml溶液に、室温下シアン化カリウム3.0gおよび１８−クラウン−６−エーテル12.3gを順次加え６０℃で一晩撹拌した。室温まで冷却後、反応液をある程度まで減圧留去した。残留物に水を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル−ヘキサン＝１：２）で精製し、（４−クロロ−２−メトキシフェニル）アセトニトリル3.6gを淡黄色固体として得た。
FAB-MS:180(M-1)
参考例５ ２−（４−クロロ−４−メトキシフェニル）エチルアミン
（４−クロロ−２−メトキシフェニル）アセトニトリル3.6g、ラネーニッケル約10g、３０％アンモニア水溶液およびエタノールの混液を水素気流下６時間撹拌した。セライトを用いてろ過後、溶媒を減圧下留去し、２−（４−クロロ−４−メトキシフェニル）エチルアミン3.5gを無色油状物として得た。
ES-MS:186, 188(M+1)
Reference Example 3 2- (4-Bromo-2-fluorophenyl) ethylamine To a solution of 1.0 g of 4-bromo-2-fluorobenzyl chloride in 30 ml of acetonitrile was added sequentially 874 mg of potassium cyanide and 1.4 g of 18-crown-6-ether at room temperature. Stir at 60 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue 864 mg was directly used in the next reaction.
To a solution of 864 mg of the residue in 10 ml of THF, 20 ml of borane-THF complex (1M THF solution) was added and heated under reflux for 2 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to make the reaction system basic, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic with a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 388 mg of 2- (4-bromo-2-fluorophenyl) ethylamine as a pale yellow oil.
FAB-MS: 218, 220 (M + 1)
Reference Example 4 (4-Chloro-2-methoxyphenyl) acetonitrile (4-Chloro-2-methoxyphenyl) Methanol (5.3 g) in 100 ml of THF was added with 2.7 ml of thionyl chloride under ice-cooling and stirred for 30 minutes. After raising the temperature to room temperature, the solvent was distilled off under reduced pressure to obtain the residue as a colorless oil. The obtained residue was used for the next reaction as it was.
To a solution of the residue in 100 ml of acetonitrile, 3.0 g of potassium cyanide and 12.3 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. After cooling to room temperature, the reaction solution was distilled off under reduced pressure to some extent. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane = 1: 2) to obtain 3.6 g of (4-chloro-2-methoxyphenyl) acetonitrile as a pale yellow solid.
FAB-MS: 180 (M-1)
Reference Example 5 2- (4-Chloro-4-methoxyphenyl) ethylamine (4-chloro-2-methoxyphenyl) acetonitrile (3.6 g), Raney nickel (about 10 g), a 30% aqueous ammonia solution and ethanol were mixed in a hydrogen stream for 6 hours. . After filtration using Celite, the solvent was evaporated under reduced pressure to obtain 3.5 g of 2- (4-chloro-4-methoxyphenyl) ethylamine as a colorless oil.
ES-MS: 186, 188 (M + 1)
製造例１ Ｎ−［２−（２−クロロフェニル）エチル］ニコチンアミド塩酸塩
２−（２−クロロフェニル）エチルアミン778mgのピリジン4mlおよび１、４−ジオキサン4mlの混液に、ニコチン酸クロリド塩酸塩890mgを徐々に加え８０℃で２時間撹拌した。室温まで冷却後、反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物を４Ｍ塩酸酢酸エチル溶液を用いて塩酸塩とした後、メタノール-酢酸エチルにて析出した結晶をろ取し、Ｎ−［２−（２−クロロフェニル）エチル］ニコチンアミド塩酸塩1.36gを白色固体として得た。
製造例２乃至４ 製造例１と同様にして、後記（表２）に示す製造例２乃至４の化合物を製造した。
製造例５及び６ 後記実施例５１と同様にして、後記（表２）に示す製造例５及び６の化合物を製造した。
Production Example 1 N- [2- (2-Chlorophenyl) ethyl] nicotinamide hydrochloride 890 mg of nicotinic acid chloride hydrochloride was gradually added to a mixture of 778 mg of 2- (2-chlorophenyl) ethylamine in 4 ml of pyridine and 4 ml of 1,4-dioxane. And stirred at 80 ° C. for 2 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was made into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with methanol-ethyl acetate were collected by filtration to give N- [2- (2-chlorophenyl) ethyl] nicotinamide hydrochloride. 1.36 g was obtained as a white solid.
Production Examples 2 to 4 In the same manner as in Production Example 1, the compounds of Production Examples 2 to 4 shown in the following (Table 2) were produced.
Production Examples 5 and 6 In the same manner as in Example 51 described below, the compounds of Production Examples 5 and 6 shown in the following (Table 2) were produced.
実施例１ 製造例１と同様に後記（表３）に示す実施例１の化合物を製造した。
実施例２ Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］ニコチンアミド塩酸塩
（１）（２−クロロ−４−フルオロフェニル）アセトニトリル10.2gのＴＨＦ100ml溶液に、ボラン−ジメチルスルフィド錯体17mlを加え一晩加熱還流した。室温まで冷却後、４Ｍ塩酸酢酸エチル溶液を加え２時間攪拌した。溶媒を減圧留去した後、１Ｍ塩酸水溶液を加え酢酸エチルで洗浄し、１Ｍ水酸化ナトリウム水溶液を加え水層を塩基性とした後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し溶媒を減圧留去し、２−（２−クロロ−４−フルオロフェニル）エチルアミン(参考例2-9)7.35gを得た。
（２）２−（２−クロロ−４−フルオロフェニル）エチルアミン1.05gのピリジン3mlおよび１、４−ジオキサン4mlの混液に、ニコチン酸クロリド塩酸塩1.2gを徐々に加え８０℃で１時間撹拌した。室温まで冷却後、反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物を４Ｍ塩酸酢酸エチル溶液を用いて塩酸塩とした後、エタノール-酢酸エチルにて析出した結晶をろ取した。得られた結晶をエタノールより再結晶し、Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］ニコチンアミド塩酸塩1.18gを白色固体として得た。
実施例３乃至３９ 実施例２（２）と同様にして、後記（表３）乃至（表６）に示す実施例３乃至３９の化合物を製造した。
Example 1 In the same manner as in Production Example 1, the compound of Example 1 shown in the following (Table 3) was produced.
Example 2 N- [2- (2-Chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride (1) (2-chloro-4-fluorophenyl) acetonitrile 10.2 g of borane-dimethylsulfide complex was added to 100 ml of THF solution. 17 ml was added and heated to reflux overnight. After cooling to room temperature, 4M hydrochloric acid ethyl acetate solution was added and stirred for 2 hours. After distilling off the solvent under reduced pressure, 1M aqueous hydrochloric acid solution was added and washed with ethyl acetate. The aqueous layer was made basic by adding 1M aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 7.35 g of 2- (2-chloro-4-fluorophenyl) ethylamine (Reference Example 2-9).
(2) To a mixed solution of 2- (2-chloro-4-fluorophenyl) ethylamine 1.05 g of pyridine 3 ml and 1,4-dioxane 4 ml, nicotinic acid chloride hydrochloride 1.2 g was gradually added and stirred at 80 ° C. for 1 hour. . After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was converted into a hydrochloride using 4M hydrochloric acid ethyl acetate solution, and crystals precipitated with ethanol-ethyl acetate were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain 1.18 g of N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride as a white solid.
Examples 3 to 39 The compounds of Examples 3 to 39 shown in the following (Table 3) to (Table 6) were produced in the same manner as in Example 2 (2).
実施例４０ Ｎ−［２−（２、３、４−トリフルオロフェニル）エチル］ニコチンアミド塩酸塩
（２、３、４−トリフルロフェニル）アセトニトリル428mgのＴＨＦ5ml溶液に、ボラン−ジメチルスルフィド錯体1.19mlを加え、6時間加熱還流した。室温まで冷却後、４Ｍ塩酸水溶液を加え、さらに１時間加熱還流した。再び室温まで冷却後、水層をジエチルエーテルで洗浄した。１Ｍ水酸化ナトリウム水溶液を加え水層を塩基性とした後、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物270mgはそのまま次反応に用いた。
残留物270mgのピリジン3.1mlおよび１、４−ジオキサン6.2mlの混液に、ニコチン酸クロリド塩酸塩329mgを加え８０℃で３０分間撹拌した。室温まで冷却後、反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物を４Ｍ塩酸酢酸エチル溶液を用いて塩酸塩とした後、エタノールにて析出した結晶をろ取し、Ｎ−［２−（２、３、４−トリフルオロフェニル）エチル］ニコチンアミド塩酸塩235mgを白色固体として得た。
実施例４１ 実施例４０と同様にして後記（表６）に示す実施例４１の化合物を製造した。
Example 40 N- [2- (2,3,4-trifluorophenyl) ethyl] nicotinamide hydrochloride (2,3,4-trifluorophenyl) acetonitrile (428 mg) in THF (5 ml) and borane-dimethyl sulfide complex (1.19 ml) And heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added, and the mixture was further heated to reflux for 1 hr. After cooling to room temperature again, the aqueous layer was washed with diethyl ether. A 1 M aqueous sodium hydroxide solution was added to make the aqueous layer basic, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue 270 mg was used as it was in the next reaction.
329 mg of nicotinic acid chloride hydrochloride was added to a mixture of 270 mg of 270 mg of pyridine and 6.2 ml of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 30 minutes. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was made into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with ethanol were collected by filtration, and N- [2- (2,3,4-trifluorophenyl) ethyl] nicotine was collected. 235 mg of amide hydrochloride was obtained as a white solid.
Example 41 In the same manner as in Example 40, the compound of Example 41 shown below (Table 6) was produced.
実施例４２ Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］−２−メチルニコチンアミド塩酸塩
２−メチルニコチン酸206mgのＤＭＦ4ml溶液に、室温下ＨＯＢｔ243mgおよびＷＳＣ塩酸塩575mgを順次加えた。３０分後、２−（２−クロロ−４−フルオロフェニル）エチルアミン347mgを加え、さらに３時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル）で精製し、４Ｍ塩酸酢酸エチル溶液を用いて塩酸塩とした後、エタノール−ジエチルエーテルにて析出した結晶をろ取し、Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］−２−メチルニコチンアミド塩酸塩371mgを白色固体として得た。
実施例４３乃至５０ 実施例４２と同様にして、後記（表７）に示す実施例４３乃至５０の化合物を合成した。
Example 42 N- [2- (2-Chloro-4-fluorophenyl) ethyl] -2-methylnicotinamide hydrochloride To a solution of 206 mg of 2-methylnicotinic acid in 4 ml of DMF, 243 mg of HOBt and 575 mg of WSC hydrochloride were successively added at room temperature. It was. After 30 minutes, 347 mg of 2- (2-chloro-4-fluorophenyl) ethylamine was added, and the mixture was further stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate), converted into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with ethanol-diethyl ether were collected by filtration and filtered with N- [2 371 mg of-(2-chloro-4-fluorophenyl) ethyl] -2-methylnicotinamide hydrochloride was obtained as a white solid.
Examples 43 to 50 In the same manner as in Example 42, compounds of Examples 43 to 50 shown in the following (Table 7) were synthesized.
実施例５１ Ｎ−［２−（２、４−ジクロロフェニル）エチル］−２−メトキシニコチンアミド
２−メトキシニコチン酸1.0gのＴＨＦ20ml溶液に、室温下ＴＥＡ2.73ml、クロロギ酸エチル1.87mlおよび２−（２、４−ジクロロフェニル）エチルアミン0.98mlを順次加え５時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物より酢酸エチル−ヘキサンにて析出した結晶をろ取し、Ｎ−［２−（２、４−ジクロロフェニル）エチル］−２−メトキシニコチンアミド1.25gを白色固体として得た。
実施例５２乃至５５ 実施例５１と同様にして、後記（表８）に示す実施例５２乃至５５の化合物を合成した。
Example 51 N- [2- (2,4-dichlorophenyl) ethyl] -2-methoxynicotinamide To a solution of 1.0 g of 2-methoxynicotinic acid in 20 ml of THF, 2.73 ml of TEA, 1.87 ml of ethyl chloroformate and 2- ( 2,4-Dichlorophenyl) ethylamine (0.98 ml) was sequentially added and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration to obtain 1.25 g of N- [2- (2,4-dichlorophenyl) ethyl] -2-methoxynicotinamide as a white solid.
Examples 52 to 55 In the same manner as in Example 51, the compounds of Examples 52 to 55 shown in the following (Table 8) were synthesized.
実施例５６ N-[2-(2,4-ジクロロフェニル)エチル]ニコチンアミド １−オキシド
NMR (DMSO) : 2.96 (2H, t, J=6.8Hz), 3.51 (2H, dt, J=6.8, 6.8Hz), 7.35-7.39 (2H), 7.51 (1H, dd, J=8.4, 6.4Hz), 7.59 (1H, s), 7.66 (1H, d, J=8.4Hz), 8.34 (1H, d, J=6.4Hz), 8.51 (1H), 8.84 (1H).
ES-MS:311, 313, 315(M+1)
実施例５７ 実施例５１と同様にして、後記（表８）に示す実施例５７の化合物を合成した。
実施例５８ ［［２−（２、４−ジクロロフェニル）エチル］（ピリジン−３−イルカルボニル）アミノ］酢酸
Ｎ−［２−（２、４−ジクロロフェニル）エチル］ニコチンアミド2.9gのＴＨＦ50ml溶液に、氷冷撹拌下６０％油性水素化ナトリウム520mgを徐々に加えた。３０分後、室温まで昇温しブロモ酢酸エチル1.6mlを加えさらに２時間撹拌した。反応液に塩化アンモニウム、１Ｍ塩酸水溶液を順次加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル：ヘキサン）に付し、淡黄色油状物873mgを得た。得られた淡黄色油状物はこれ以上の精製を行うことなくそのまま次反応に用いた。
淡黄色油状物673mgのメタノール15ml溶液に、室温下１Ｍ水酸化ナトリウム水溶液3.4mlを加え１時間撹拌した。反応液に１Ｍ塩酸水溶液3.4mlを加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物より酢酸エチル−ヘキサンにて析出した結晶をろ取し、［［２−（２、４−ジクロロフェニル）エチル］（ピリジン−３−イルカルボニル）アミノ］酢酸562mgを白色固体として得た。
Example 56 N- [2- (2,4-Dichlorophenyl) ethyl] nicotinamide 1-oxide
NMR (DMSO): 2.96 (2H, t, J = 6.8Hz), 3.51 (2H, dt, J = 6.8, 6.8Hz), 7.35-7.39 (2H), 7.51 (1H, dd, J = 8.4, 6.4Hz) ), 7.59 (1H, s), 7.66 (1H, d, J = 8.4Hz), 8.34 (1H, d, J = 6.4Hz), 8.51 (1H), 8.84 (1H).
ES-MS: 311, 313, 315 (M + 1)
Example 57 In the same manner as in Example 51, the compound of Example 57 shown in the following (Table 8) was synthesized.
Example 58 [[2- (2,4-Dichlorophenyl) ethyl] (pyridin-3-ylcarbonyl) amino] acetic acid N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide 2.9 g in a 50 ml THF solution 520 mg of 60% oily sodium hydride was gradually added with stirring on ice. After 30 minutes, the temperature was raised to room temperature, and 1.6 ml of ethyl bromoacetate was added, followed by further stirring for 2 hours. Ammonium chloride and 1M aqueous hydrochloric acid solution were sequentially added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate: hexane) to obtain 873 mg of a pale yellow oil. The obtained pale yellow oil was used in the next reaction as it was without further purification.
To a solution of 673 mg of pale yellow oil in 15 ml of methanol was added 3.4 ml of 1M aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 1 hour. To the reaction solution was added 3.4 ml of 1M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration to obtain 562 mg of [[2- (2,4-dichlorophenyl) ethyl] (pyridin-3-ylcarbonyl) amino] acetic acid as a white solid. It was.
実施例５９ Ｎ−（２−アミノ−２−オキソエチル）−Ｎ−［２−（２、４−ジクロロフェニル）エチル］ニコチンアミド
［［２−（２、４−ジクロロフェニル）エチル］（ピリジン−３−イルカルボニル）アミノ］酢酸331mgのＤＭＦ6ml溶液に、室温下ＨＯＢｔ153mgおよびＷＳＣ塩酸塩360mgを順次加えた。３０分後、炭酸アンモニウム約500mgを加え、さらに３時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物より酢酸エチル−ヘキサンにて析出した結晶をろ取し、Ｎ−（２−アミノ−２−オキソエチル）−Ｎ−［２−（２、４−ジクロロフェニル）エチル］ニコチンアミド310mgを白色固体として得た。
実施例６０及び６１ 実施例５９と同様にして、後記（表８）に示す実施例６０及び６１の化合物を合成した。
Example 59 N- (2-amino-2-oxoethyl) -N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide [[2- (2,4-dichlorophenyl) ethyl] (pyridin-3-yl To a solution of carbonyl) amino] acetic acid (331 mg) in DMF (6 ml), HOBt (153 mg) and WSC hydrochloride (360 mg) were sequentially added at room temperature. After 30 minutes, about 500 mg of ammonium carbonate was added, and the mixture was further stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration, and 310 mg of N- (2-amino-2-oxoethyl) -N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide was added. Obtained as a white solid.
Examples 60 and 61 In the same manner as in Example 59, the compounds of Examples 60 and 61 shown below (Table 8) were synthesized.
実施例６２ Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］−Ｎ−メチルニコチンアミド臭化水素酸塩
Ｎ−［２−（２、４−ジクロロフェニル）エチル］ニコチンアミド1.0gのＴＨＦ15ml溶液に、氷冷撹拌下６０％油性水素化ナトリウム203mgを徐々に加えた。１時間後、ヨウ化メチル0.57mlを加え、直ちに室温まで昇温しさらに１時間撹拌した。反応液に塩化アンモニウム、１Ｍ塩酸水溶液を順次加え酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル：ヘキサン＝２：１）で精製し、臭化水素酸エターノール溶液を用いて臭化水素酸塩とした後、エタノール−ジエチルエーテルにて析出した結晶をろ取し、Ｎ−［２−（２−クロロ−４−フルオロフェニル）エチル］−Ｎ−メチルニコチンアミド臭化水素酸塩1.23gを白色固体として得た。
実施例６３ Ｎ−［２−（３−ブロモ−４−メトキシフェニル）エチル］ニコチンアミド
ニコチン酸クロリド塩酸塩 5.3 mgのＴＨＦ1 mL溶液に２−（３−ブロモ−４−メトキシフェニル）エチルアミン6.9 mgのＮ−メチル−２−ピロリジノン溶液 0.06 mLを加え、さらにＰＳ−ジイソプロピルエチルアミン (Argonaut Technologies社製、3.57 mmol/g) 21 mgを加えた後、室温下1日攪拌した。反応液にＰＳ−トリスアミン (Argonaut Technologies社製、3.38mmol/g) 27 mgとＰＳ−イソシアネート (Argonaut Technologies社製、1.47mmol/g) 34 mg を加えた後、室温下2時間攪拌した。反応液を濾過して得られた溶液を、HPLC（カラム：CAPCELLPAK C18 AQ 5μM 30 x 50mm （資生堂製）； 溶媒：MeOH / 0.1% HCOOH-H2O = 10/90 (0 min)- 10/90 (1 min)- 100/0 (9 min)-100/0 (12 min)； 流速30 mL/min）にて分取精製を行い、Ｎ−［２−（３−ブロモ−４−メトキシフェニル）エチル］ニコチンアミドを定量的に得た。
実施例６４ 実施例２（２）と同様にして後記（表８）に示す実施例６４の化合物を製造した。
Example 62 N- [2- (2-Chloro-4-fluorophenyl) ethyl] -N-methylnicotinamide hydrobromide 1.0 g of N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide To 15 ml of THF, 203 mg of 60% oily sodium hydride was gradually added with stirring under ice cooling. After 1 hour, 0.57 ml of methyl iodide was added, and the mixture was immediately warmed to room temperature and further stirred for 1 hour. Ammonium chloride and 1M aqueous hydrochloric acid solution were sequentially added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 2: 1), converted into a hydrobromide salt using a hydrobromic acid ethanol solution, and then precipitated with ethanol-diethyl ether. The crystals were collected by filtration to obtain 1.23 g of N- [2- (2-chloro-4-fluorophenyl) ethyl] -N-methylnicotinamide hydrobromide as a white solid.
Example 63 N- [2- (3-Bromo-4-methoxyphenyl) ethyl] nicotinamide Nicotinic acid chloride hydrochloride In a solution of 5.3 mg of THF in 1 mL of THF, 6.9 mg of 2- (3-bromo-4-methoxyphenyl) ethylamine was added. After adding 0.06 mL of N-methyl-2-pyrrolidinone solution and further adding 21 mg of PS-diisopropylethylamine (Argonaut Technologies, 3.57 mmol / g), the mixture was stirred at room temperature for 1 day. After adding 27 mg of PS-trisamine (Argonaut Technologies, 3.38 mmol / g) and 34 mg of PS-isocyanate (Argonaut Technologies, 1.47 mmol / g) to the reaction solution, the mixture was stirred at room temperature for 2 hours. The solution obtained by filtering the reaction solution was subjected to HPLC (column: CAPCELLPAK C18 AQ 5 μM 30 x 50 mm (manufactured by Shiseido); solvent: MeOH / 0.1% HCOOH-H 2 O = 10/90 (0 min) -10 / 90 (1 min)-100/0 (9 min) -100/0 (12 min); flow rate 30 mL / min), and purification was performed, and N- [2- (3-bromo-4-methoxyphenyl) was obtained. ) Ethyl] nicotinamide was obtained quantitatively.
Example 64 The compound of Example 64 shown in the postscript (Table 8) was manufactured like Example 2 (2).
上記製造例及び実施例により得られた化合物及び物性値を下記表２乃至８に示す。 The compounds and physical property values obtained by the above production examples and examples are shown in Tables 2 to 8 below.
また、上記実施例に準じ、下記表９の化合物を合成することができる。
本発明化合物のNO産生促進活性、eNOS活性化活性及び血流増加作用は以下の試験法により確認した。
実験例１：培養上清NOx量測定
ヒト大動脈由来血管内皮細胞（HAEC、Clonetics社製）をコラーゲンタイプIV処理24wellプレート（イワキ（株）社製）にコンフルエントまで培養した後、培地を無血清培地に変え、16時間培養を続けた。培地の除去後、供試化合物を含む無血清培地にて細胞を30分間処理した。細胞から放出されたNO量は培養上清中のNOx（NO2 -、NO3 -）量を測定することで算出した。NO2 -、NO3 -量は酸化窒素分析システム（Eicom社）を用い、添付の方法に従って測定した。
結果：培養上清中NOx増加率を溶媒添加(0.1％ DMSO)群に対する相対比で下記表に示す。
この結果、本発明に用いられる化合物はNO産生促進活性を有することが確認された。
The NO production promoting activity, eNOS activation activity and blood flow increasing action of the compound of the present invention were confirmed by the following test methods.
Experimental example 1: Measurement of culture supernatant NOx amount Human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) were cultured to collagen type IV-treated 24-well plate (manufactured by Iwaki Co., Ltd.) until confluent, and then the medium was serum-free medium The culture was continued for 16 hours. After removing the medium, the cells were treated with a serum-free medium containing the test compound for 30 minutes. The amount of NO released from the cells was calculated by measuring the amount of NOx (NO 2 − , NO 3 − ) in the culture supernatant. The amounts of NO 2 − and NO 3 − were measured using a nitric oxide analysis system (Eicom) according to the attached method.
Results: The NOx increase rate in the culture supernatant is shown in the table below as a relative ratio to the solvent addition (0.1% DMSO) group.
As a result, it was confirmed that the compound used in the present invention has NO production promoting activity.
実験例２：3H-アルギニンによる細胞内eNOS活性測定
3H-アルギニンによる細胞内eNOS活性測定はRajesh K.D.らの報告に従った(Rajesh K.D. et al., Hypertension,1993,21,939-94)。ヒト大動脈由来血管内皮細胞（HAEC、Clonetics社製）をコラーゲンタイプIV処理24wellプレート（イワキ（株）社製）にコンフルエントまで培養後、培地をL-Arg無添加、無血清培地に変え、16時間培養を続けた。培地の除去後、3H-Arg（最終濃度1.5μCi/mL）、供試化合物を含むmodified HEPES溶液(25mM Hepes(pH7.4), 140mM NaCl, 5.4mM KCl, 1.8mM CaCl2, 1.0mM MgCl2, 5.0mM glucose)にて細胞を処理した。ice-cold 1.3N TCAを400ul/well加え、反応を停止させた後、凍結融解で細胞を破砕した。細胞破砕液をエーテル処理後、Stop buffer（200mM Hepes (pH5.5), 20mM EDTA）、Dowex樹脂（Bio-Rad）を加え混合した後に、ろ過によりDowex樹脂を除き、3H-Citrullin量を液体シンチレーションカウンターにより測定した。
Experimental example 2: Measurement of intracellular eNOS activity with 3 H-arginine
The measurement of intracellular eNOS activity by 3 H-arginine followed the report of Rajesh KD et al. (Rajesh KD et al., Hypertension, 1993, 21, 939-94). Human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) were cultured until they became confluent in collagen type IV-treated 24-well plates (manufactured by Iwaki Co., Ltd.), then the medium was changed to serum-free medium without L-Arg, and 16 hours The culture was continued. After removing the medium, 3 H-Arg (final concentration 1.5 μCi / mL), modified HEPES solution containing the test compound (25 mM Hepes (pH 7.4), 140 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, The cells were treated with 5.0 mM glucose). Ice-cold 1.3N TCA was added at 400 ul / well to stop the reaction, and the cells were disrupted by freeze-thawing. The cell lysate is treated with ether, Stop buffer (200 mM Hepes (pH 5.5), 20 mM EDTA) and Dowex resin (Bio-Rad) are added and mixed, then Dowex resin is removed by filtration, and 3H-Citrullin is liquid scintillated. Measured with a counter.
実験例３ 麻酔ラット後肢血流増加作用
本発明の製造例及び実施例について、Pentobarbital麻酔ラットにおける後肢血流増加作用を以下の試験方法により確認した。
Wistar系雄性ラット（日本SLC）を用いた。供試化合物は経口投与し、その2時間後、Pentobarbital Na 60 mg/kgを腹腔内投与し麻酔を施した。後肢血流はレーザー血流画像化装置（PIM II; インテグラル）を用いて測定した。
上記試験の結果、本発明化合物の血流改善効果が確認された。
Experimental Example 3 Increased hindlimb blood flow in anesthetized rats For the production examples and examples of the present invention, the increased hindlimb blood flow in Pentobarbital anesthetized rats was confirmed by the following test method.
Wistar male rats (Japan SLC) were used. The test compound was orally administered, and 2 hours later, Pentobarbital Na 60 mg / kg was intraperitoneally administered and anesthetized. The hindlimb blood flow was measured using a laser blood flow imaging device (PIM II; Integral).
As a result of the above test, the blood flow improving effect of the compound of the present invention was confirmed.
Claims (3)
Hal：ハロゲン、
R：NO2、CN、低級アルキル、OH、ハロゲノ低級アルキル、COOH、-O-低級アルキル、-COO-低級アルキル、-CONH2、-CO-(モノ又はジ低級アルキルアミノ)、又は-低級アルキレン-O-低級アルキル、
R1：H、ハロゲン、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
R2：H、低級アルキル、-低級アルキレン-COOH、-低級アルキレン-CONH2、又は-低級アルキレン-CO-(モノ又はジ低級アルキルアミノ)、
m：１乃至５の整数、
n:0、又は1 但し、m+n≦5、
X：N、又はN-オキシド。） Vascular endothelial nitric oxide production promotion and / or endothelial nitric oxide synthase activator comprising a phenethylnicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient .
Hal: halogen,
R: NO 2 , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH 2 , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R 1 : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R 2 : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH 2 , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide. )
Hal：ハロゲン、
R：NO2、CN、低級アルキル、OH、ハロゲノ低級アルキル、COOH、-O-低級アルキル、-COO-低級アルキル、-CONH2、-CO-(モノ又はジ低級アルキルアミノ)、又は-低級アルキレン-O-低級アルキル、
R1：H、ハロゲン、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
R2：H、低級アルキル、-低級アルキレン-COOH、-低級アルキレン-CONH2、又は-低級アルキレン-CO-(モノ又はジ低級アルキルアミノ)、
m：１乃至５の整数、
n:0、又は1 但し、m+n≦5、
X：N、又はN-オキシド。
但し、２−クロロフェネチル−３−ニコチンアミドを除く。） The pharmaceutical which contains the phenethyl nicotinamide derivative or its pharmaceutically acceptable salt shown by the following general formula (I) as an active ingredient.
Hal: halogen,
R: NO 2 , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH 2 , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R 1 : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R 2 : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH 2 , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide.
However, 2-chlorophenethyl-3-nicotinamide is excluded. )
Hal：ハロゲン、
R：NO2、CN、低級アルキル、OH、ハロゲノ低級アルキル、COOH、-O-低級アルキル、-COO-低級アルキル、-CONH2、-CO-(モノ又はジ低級アルキルアミノ)、又は-低級アルキレン-O-低級アルキル、
R1a：H、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
R2：H、低級アルキル、-低級アルキレン-COOH、-低級アルキレン-CONH2、又は-低級アルキレン-CO-(モノ又はジ低級アルキルアミノ)、
m：１乃至５の整数、
n:0、又は1 但し、m+n≦5、
X：N、又はN-オキシド。
但し、HalがCl又はFでありかつmが1のときは、nは1を示す。）
A phenethylnicotinamide derivative represented by the following general formula (Ia) or a salt thereof.
Hal: halogen,
R: NO 2 , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH 2 , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R 1a : H, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R 2 : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH 2 , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide.
However, when Hal is Cl or F and m is 1, n represents 1. )
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004208547A JP2007277096A (en) | 2004-07-15 | 2004-07-15 | Medicine containing phenethyl-nicotinamide derivative |
| PCT/JP2005/012991 WO2006009054A1 (en) | 2004-07-15 | 2005-07-14 | Phenethylnicotinamide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004208547A JP2007277096A (en) | 2004-07-15 | 2004-07-15 | Medicine containing phenethyl-nicotinamide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2007277096A true JP2007277096A (en) | 2007-10-25 |
Family
ID=35785167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004208547A Withdrawn JP2007277096A (en) | 2004-07-15 | 2004-07-15 | Medicine containing phenethyl-nicotinamide derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP2007277096A (en) |
| WO (1) | WO2006009054A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009516722A (en) * | 2005-11-22 | 2009-04-23 | バイエル・クロツプサイエンス・エス・アー | Novel N-phenethylcarboxamide derivatives |
| US8324208B2 (en) | 2006-06-23 | 2012-12-04 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2674237C (en) | 2006-12-28 | 2015-11-24 | Rigel Pharmaceuticals, Inc. | N-substituted-heterocycloalkyloxybenzamide compounds and methods of use |
| DK2891492T3 (en) * | 2012-08-30 | 2022-11-21 | Univ Tokyo | ENDOPARASITE CONTROL AGENT |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI243164B (en) * | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
| PE20020856A1 (en) * | 2001-02-13 | 2002-11-11 | Aventis Pharma Gmbh | 1,2,3,4-TETRAHYDRONAFTIL ACILATED AMINES |
| MY136316A (en) * | 2001-02-13 | 2008-09-30 | Sanofi Aventis Deutschland | Acylated 6,7,8,9-tetrahydro-5h-benzocycloheptenyl amines and their use as pharmaceutical. |
| JP5065570B2 (en) * | 2002-09-06 | 2012-11-07 | 第一三共ヘルスケア株式会社 | Vascular endothelial nitric oxide synthesis promoter |
-
2004
- 2004-07-15 JP JP2004208547A patent/JP2007277096A/en not_active Withdrawn
-
2005
- 2005-07-14 WO PCT/JP2005/012991 patent/WO2006009054A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009516722A (en) * | 2005-11-22 | 2009-04-23 | バイエル・クロツプサイエンス・エス・アー | Novel N-phenethylcarboxamide derivatives |
| US9440946B2 (en) | 2005-11-22 | 2016-09-13 | Bayer Intellectual Property Gmbh | N-phenethylcarboxamide derivatives |
| US8324208B2 (en) | 2006-06-23 | 2012-12-04 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
| US8557834B2 (en) | 2006-06-23 | 2013-10-15 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
| US8815884B2 (en) | 2006-06-23 | 2014-08-26 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
| US10035779B2 (en) | 2006-06-23 | 2018-07-31 | GlaxoSmithKline, LLC | Prolyl hydroxylase inhibitors |
| US10336711B2 (en) | 2006-06-23 | 2019-07-02 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
| US11643397B2 (en) | 2006-06-23 | 2023-05-09 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006009054A1 (en) | 2006-01-26 |
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