JP2016199497A - Medicine containing hydroxamic acid derivative - Google Patents
Medicine containing hydroxamic acid derivative Download PDFInfo
- Publication number
- JP2016199497A JP2016199497A JP2015080513A JP2015080513A JP2016199497A JP 2016199497 A JP2016199497 A JP 2016199497A JP 2015080513 A JP2015080513 A JP 2015080513A JP 2015080513 A JP2015080513 A JP 2015080513A JP 2016199497 A JP2016199497 A JP 2016199497A
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- Prior art keywords
- compound
- acid
- added
- solution
- methyl
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 29
- 229940079593 drug Drugs 0.000 title claims abstract description 20
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title description 6
- 239000002253 acid Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 208000015181 infectious disease Diseases 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- -1 1-Aminocyclopropyl Chemical group 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 208000035473 Communicable disease Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 abstract description 27
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 18
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- 230000000069 prophylactic effect Effects 0.000 abstract 2
- 229940124597 therapeutic agent Drugs 0.000 abstract 2
- LMGDGOHVSAAQKR-UHFFFAOYSA-N 2-[[4-[4-(1-aminocyclopropyl)buta-1,3-diynyl]benzoyl]-methylamino]-N-hydroxy-N',2-dimethylpropanediamide Chemical compound CNC(=O)C(C)(N(C)C(=O)C1=CC=C(C=C1)C#CC#CC1(N)CC1)C(=O)NO LMGDGOHVSAAQKR-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
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- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 5
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- XBHDGYBZTODLSE-UHFFFAOYSA-N 1-ethynylcyclopropan-1-amine hydrochloride Chemical compound Cl.C#CC1(N)CC1 XBHDGYBZTODLSE-UHFFFAOYSA-N 0.000 description 4
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- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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- NIYGLRKUBPNXQS-FYYLOGMGSA-N n-[(4r)-1'-[(2r)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]-4-hydroxyspiro[3,4-dihydrochromene-2,4'-piperidine]-6-yl]methanesulfonamide Chemical compound C1CC2=CC(C#N)=CC=C2C[C@@H]1N(CC1)CCC11OC2=CC=C(NS(=O)(=O)C)C=C2[C@H](O)C1 NIYGLRKUBPNXQS-FYYLOGMGSA-N 0.000 description 4
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、グラム陰性細菌及びその薬剤耐性菌に対して抗菌活性を有する新規なヒドロキサム酸誘導体に関する。本発明は、ヒドロキサム酸誘導体を含有する感染症の予防及び/又は治療のために用いる医薬に関するものである。 The present invention relates to a novel hydroxamic acid derivative having antibacterial activity against gram-negative bacteria and their drug-resistant bacteria. The present invention relates to a medicament used for the prevention and / or treatment of an infectious disease containing a hydroxamic acid derivative.
グラム陰性細菌には、グラム陽性細菌には存在しない脂質二重層からなる外膜が存在する。したがって、薬剤透過性の問題からグラム陽性細菌と比較して、グラム陰性細菌は強い薬剤抵抗性を有する傾向にある。また、グラム陰性細菌は複数の薬剤排出蛋白を持つことが知られている。非特許文献1には、薬剤排出蛋白も薬剤抵抗性に関与していることが開示されている。さらに、外膜の主要な構成成分の一つであるリポポリサッカライド(LPS)は、エンドトキシンとして毒性に大きく関与している。 Gram-negative bacteria have an outer membrane consisting of a lipid bilayer that is not present in Gram-positive bacteria. Therefore, Gram-negative bacteria tend to have stronger drug resistance compared to Gram-positive bacteria due to drug permeability issues. In addition, gram-negative bacteria are known to have multiple drug efflux proteins. Non-Patent Document 1 discloses that drug efflux proteins are also involved in drug resistance. Furthermore, lipopolysaccharide (LPS), one of the main components of the outer membrane, is greatly involved in toxicity as an endotoxin.
グラム陰性細菌の中でも、特に緑膿菌(Pseudomonas aeruginosa)は各種の抗菌薬に自然耐性を示す傾向が強いことが知られている。緑膿菌は自然環境や生活環境中に広く常在するが、健常者には通常病原性を示さない弱毒細菌である。しかし、重篤な基礎疾患を持つ患者や、移植等により免疫抑制剤を使用するいわゆるコンプロマイズドホストといわれる患者、医療用カテーテルや気管挿管、外科手術等の医療行為を行っている患者に対しては、緑膿菌は敗血症等の重篤な急性感染症を引き起こす病原菌となる。それゆえに、緑膿菌は日和見感染症や院内感染症の重要な起因細菌の一つである。 Among gram-negative bacteria, Pseudomonas aeruginosa is known to have a strong tendency to exhibit natural resistance to various antibacterial drugs. Pseudomonas aeruginosa is an attenuated bacterium that is ubiquitous in the natural environment and living environment, but usually does not show pathogenicity in healthy individuals. However, for patients with serious underlying diseases, patients who are said to be so-called "complied hosts" that use immunosuppressants by transplantation, etc., patients who are performing medical procedures such as medical catheters, tracheal intubation, and surgery In the past, Pseudomonas aeruginosa is a pathogen that causes serious acute infections such as sepsis. Therefore, Pseudomonas aeruginosa is one of the important causative bacteria of opportunistic and nosocomial infections.
近年、医療現場において、本来緑膿菌に効果が期待される第3世代セフェム系薬、カルバペネム系薬、又はアミノ配糖体系薬等に耐性を獲得した緑膿菌がしばしば臨床分離されている(非特許文献2)。また、前記3系統薬全てに耐性を獲得した多剤耐性緑膿菌も分離されている(非特許文献3)。 In recent years, Pseudomonas aeruginosa that has acquired resistance to third-generation cephem drugs, carbapenem drugs, aminoglycosides, and the like that are originally expected to have an effect on Pseudomonas aeruginosa has been clinically isolated ( Non-patent document 2). In addition, multidrug-resistant Pseudomonas aeruginosa that has acquired resistance to all the three drugs has been isolated (Non-patent Document 3).
多剤耐性緑膿菌に感染すると有用な薬剤がほとんどないことから、多剤耐性緑膿菌は、難治性の感染症疾患の起因菌として世界的に大きな問題となっている。そこで、新規作用機序を有する薬剤の開発が切望されている。 Since there are few useful drugs when infected with multidrug-resistant Pseudomonas aeruginosa, multidrug-resistant Pseudomonas aeruginosa has become a major problem worldwide as a causative bacterium for intractable infectious diseases. Therefore, development of a drug having a novel mechanism of action is eagerly desired.
UDP−3−O−アシル−N−アセチルグルコサミンデアセチラーゼ(LpxC)は、外膜の構成成分であるLPSの疎水性アンカーであるリピドAの合成を担う酵素である。リピドA生合成は10段階の反応からなる。LpxCはその生合成反応の第2段階を触媒し、UDP−3−O−アシル−N−アセチルグルコサミンのアセチル基を離脱させる(非特許文献4)。リピドAは外膜形成に必須な成分であり、結果的にグラム陰性細菌の生存に必須である(非特許文献5)。 UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme responsible for the synthesis of lipid A, which is a hydrophobic anchor of LPS, which is a component of the outer membrane. Lipid A biosynthesis consists of 10 reactions. LpxC catalyzes the second stage of its biosynthetic reaction and releases the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (Non-Patent Document 4). Lipid A is an essential component for outer membrane formation, and as a result is essential for the survival of Gram-negative bacteria (Non-patent Document 5).
すなわち、LpxCは、リピドA生合成過程において律速となる重要な酵素の一つであり、リピドA生合成に必須な酵素である。したがって、LpxCの活性を阻害する薬剤は、緑膿菌を含むグラム陰性細菌に対して、特に従来薬剤と異なる作用機序を有することから薬剤耐性緑膿菌に対して有効な抗菌剤になり得ることが強く期待される。 That is, LpxC is one of the important enzymes that are rate-limiting in the lipid A biosynthesis process, and is an essential enzyme for lipid A biosynthesis. Therefore, an agent that inhibits the activity of LpxC can be an effective antibacterial agent against Gram-negative bacteria including Pseudomonas aeruginosa, particularly against drug-resistant Pseudomonas aeruginosa, because it has a different mechanism of action from conventional agents. It is highly expected.
LpxC阻害剤として、アミド構造を有する阻害剤が特許文献1〜11及び非特許文献6〜13に開示されている。 As LpxC inhibitors, inhibitors having an amide structure are disclosed in Patent Documents 1 to 11 and Non-Patent Documents 6 to 13.
これらの中で、マロン酸アミド骨格を有する化合物として、特許文献5及び9には、マロン酸アミド骨格及びジエチニル構造を有する化合物が開示されている。 Among these, as compounds having a malonic amide skeleton, Patent Documents 5 and 9 disclose compounds having a malonic amide skeleton and a diethynyl structure.
特許文献5には、具体的に、シクロプロピル環をジエチニル末端部分に有する化合物507が開示されている。 Patent Document 5 specifically discloses a compound 507 having a cyclopropyl ring at the end of the diethynyl terminal.
また、特許文献9には、具体的に、シクロプロピル環を有する化合物として化合物233が開示されている。特許文献9には、化合物197、化合物209及び化合物221が開示され、化合物8は合成法及び抗菌活性が開示されている。 Patent Document 9 specifically discloses Compound 233 as a compound having a cyclopropyl ring. Patent Document 9 discloses Compound 197, Compound 209, and Compound 221, and Compound 8 discloses a synthesis method and antibacterial activity.
しかしながら、特許文献5に開示される化合物507は骨格部分のヒドロキサム酸に隣接する炭素原子にメチル基を有していない。また、置換基として無置換アミノ基をジエチニル末端部分に有する化合物も特許文献5には開示されていない。 However, the compound 507 disclosed in Patent Document 5 does not have a methyl group at the carbon atom adjacent to the hydroxamic acid of the skeleton portion. Further, Patent Document 5 does not disclose a compound having an unsubstituted amino group as a substituent at the diethynyl terminal portion.
また、特許文献9に開示される化合物は全てヒドロキシメチル基をシクロプロピル環上に置換基として有する化合物であり、またキラルな末端構造を有している。また、特許文献9には、置換基としてアミノ基をジエチニル末端部分に有する化合物は開示されていない。 In addition, all the compounds disclosed in Patent Document 9 are compounds having a hydroxymethyl group as a substituent on the cyclopropyl ring, and have a chiral terminal structure. Patent Document 9 does not disclose a compound having an amino group as a substituent at the end of the diethylinyl terminal.
本発明の課題は、緑膿菌をはじめとするグラム陰性細菌及びその薬剤耐性菌に対して強い抗菌活性を有し、医薬品として有用な新規化合物を有効成分として含有する感染症の予防及び/又は治療のために用いる医薬を提供することにある。 An object of the present invention is to prevent and / or prevent infectious diseases having a novel antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and their drug-resistant bacteria and containing a novel compound useful as a pharmaceutical agent. It is to provide a medicament used for treatment.
本発明者らは鋭意研究を進めた結果、ジエチニル末端部分にアキラルな置換基である1−アミノシクロプロピル基を有する、下記式[1] As a result of diligent research, the inventors of the present invention have the following formula [1] having a 1-aminocyclopropyl group which is an achiral substituent at the end of the diethylinyl moiety.
で表される2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミドを含有する感染症の予防及び/又は治療のために用いる医薬が上記課題を解決し得ることを見出し、本発明を完成した。 2-[{4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′, 2-dimethyl It has been found that a medicament used for the prophylaxis and / or treatment of an infectious disease containing propanediamide can solve the above problems, and has completed the present invention.
本発明は、以下のとおりである。
(1)
式[1]
The present invention is as follows.
(1)
Formula [1]
で表される2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミドである化合物又はその薬学的に許容される塩を有効成分として含有する感染症の予防及び/又は治療のために用いる医薬。
(2)
式[2]
2-[{4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′, 2-dimethyl A medicament used for the prophylaxis and / or treatment of an infectious disease comprising a compound which is propanediamide or a pharmaceutically acceptable salt thereof as an active ingredient.
(2)
Formula [2]
で表される(2S)−2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミドである化合物又はその薬学的に許容される塩を有効成分として含有する感染症の予防及び/又は治療のために用いる医薬。 (2S) -2-[{4- [4- (1-aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′ , A drug used for the prevention and / or treatment of an infectious disease containing a compound that is 2-dimethylpropanediamide or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明により、緑膿菌をはじめとするグラム陰性細菌及びその薬剤耐性菌に強い抗菌活性を有する新規なヒドロキサム酸誘導体を有効成分として含有する感染症の予防及び/又は治療のために用いる医薬を提供することができる。 According to the present invention, a medicament used for the prevention and / or treatment of infectious diseases containing a novel hydroxamic acid derivative having strong antibacterial activity against gram-negative bacteria such as Pseudomonas aeruginosa and its drug-resistant bacteria as an active ingredient. Can be provided.
以下、本発明を実施するための形態について以下詳細に説明する。なお、本発明は、以下の実施形態に限定されるものではなく、その要旨の範囲内で種々変形して実施することができる。 Hereinafter, embodiments for carrying out the present invention will be described in detail. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.
本発明において、「薬学的に許容される塩」とは、細菌感染症の化学療法及び予防において使用される塩を意味する。 In the present invention, “pharmaceutically acceptable salt” means a salt used in chemotherapy and prevention of bacterial infections.
「薬学的に許容される塩」としては、例えば、酢酸、プロピオン酸、酪酸、ギ酸、トリフルオロ酢酸、マレイン酸、酒石酸、クエン酸、ステアリン酸、コハク酸、エチルコハク酸、マロン酸、ラクトビオン酸、グルコン酸、グルコヘプトン酸、安息香酸、メタンスルホン酸、エタンスルホン酸、2−ヒドロキシエタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸(トシル酸)、ラウリル硫酸、リンゴ酸、アスパラギン酸、グルタミン酸、アジピン酸、システイン、N−アセチルシステイン、塩酸、臭化水素酸、リン酸、硫酸、ヨウ化水素酸、ニコチン酸、シュウ酸、ピクリン酸、チオシアン酸、ウンデカン酸、アクリル酸ポリマー及びカルボキシビニルポリマー等の酸との塩、モルホリン及びピペリジン等の有機アミンとの塩、並びにアミノ酸との塩などが挙げられる。 Examples of the “pharmaceutically acceptable salt” include acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, malonic acid, lactobionic acid, Gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid (tosylic acid), lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid Acids such as cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymer and carboxyvinyl polymer With organic amines such as morpholine and piperidine As well, such as salts with amino acids, and the like.
「薬学的に許容される塩」としては、無機塩基との塩であってもよい。無機塩基との塩としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩及びカルシウム塩などが挙げられる。 The “pharmaceutically acceptable salt” may be a salt with an inorganic base. Examples of the salt with an inorganic base include lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt.
本発明の化合物(以下、「本発明の化合物」とは、式[1]で表される化合物、式[2]で表される化合物又はそれらの薬学的に許容される塩である場合を含む意味で用いる。)は、水和物を形成していてもよく、溶媒和物を形成していてもよい。本発明の化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。 The compound of the present invention (hereinafter referred to as “the compound of the present invention” includes a compound represented by the formula [1], a compound represented by the formula [2], or a pharmaceutically acceptable salt thereof. Used in the meaning) may form a hydrate or a solvate. Where the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention.
本発明の化合物が「溶媒和物」を形成する場合の「溶媒」とは特に示さない限り、例えば極性溶媒(例えば、メタノール、エタノール、1−プロパノール、2−プロパノール及びブタノール等のアルコール系溶媒並びに酢酸エチル等)、不活性溶媒(例えば、クロロホルム及び塩化メチレン等のハロゲン化炭化水素系溶媒、ジエチルエーテル、イソプロピルエーテル、テトラヒドロフラン及びジオキサン等のエーテル系溶媒、ジメチルホルムアミド及びジメチルアセトアミド等のアミド系溶媒、ジメチルスルホキシド及びアセトニトリル等の非プロトン性溶媒、トルエン等の芳香族炭化水素類並びにヘキサン及びシクロヘキサン等の炭化水素類など)、2−ブタノン及びアセトンなどを意味する。 Unless otherwise indicated, the “solvent” when the compound of the present invention forms a “solvate” includes, for example, polar solvents (eg, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and butanol, and Ethyl acetate, etc.), inert solvents (for example, halogenated hydrocarbon solvents such as chloroform and methylene chloride, ether solvents such as diethyl ether, isopropyl ether, tetrahydrofuran and dioxane, amide solvents such as dimethylformamide and dimethylacetamide, An aprotic solvent such as dimethyl sulfoxide and acetonitrile, aromatic hydrocarbons such as toluene and hydrocarbons such as hexane and cyclohexane), 2-butanone and acetone.
「溶媒」としては、ここに例示した溶媒の混合溶媒であってもよい。 The “solvent” may be a mixed solvent of the solvents exemplified herein.
本発明において、「抗菌剤」とは、グラム陽性細菌やグラム陰性細菌といった細菌に作用してその生育を抑制又は殺菌する能力を持つ物質を意味する。菌の繁殖を抑えたり、一部の菌を殺してその数を減少させたりするようなものでもよい。 In the present invention, the term “antibacterial agent” means a substance having the ability to act on bacteria such as Gram positive bacteria and Gram negative bacteria to suppress or sterilize their growth. It may be something that suppresses the growth of bacteria or kills some bacteria to reduce their number.
グラム陽性細菌としては、例えば、ブドウ球菌属(黄色ブドウ球菌及び表皮ブドウ球菌等)、連鎖球菌属(化膿連鎖球菌、B群連鎖球菌及び肺炎球菌等)、腸球菌属(エンテロコッカス・フェカーリス及びエンテロコッカス・フェシウム等)などが挙げられる。 Gram-positive bacteria include, for example, Staphylococcus (S. aureus and Staphylococcus epidermidis, etc.), Streptococcus (S. pyogenes, Group B Streptococcus, pneumococci, etc.), Enterococcus (Enterococcus faecalis and Enterococcus Fesium, etc.).
グラム陰性細菌としては、例えば、シュードモナス属(緑膿菌等)、大腸菌属(大腸菌等)、クレブシエラ属(肺炎桿菌及びクレブシエラ・オキシトカ等)、ヘモフィルス属(インフルエンザ菌及びパラインフルエンザ菌等)、ボルデテラ属(百日咳菌及び気管支敗血症菌等)、セラチア属(セラチア・マルセッセンス等)、プロテウス属(プロテウス・ブルガリス及びプロテウス・ミラビリス等)、エンテロバクター属(エンテロバクター・エアロジェネシス及びエンテロバクター・クロアカ等)、カンピロバクター属(カンピロバクター・ジェジュニ等)、シトロバクター属(シトロバクター・フレウンディ等)、プロビデンシア属(プロビデンシア・スチュアーティ等)、ステノトロフォモナス属(ステノトロフォモナス・マルトフィリア等)、ビブリオ属(腸炎ビブリオ及びコレラ菌等)、モルガネラ属(モルガネラ・モルガニ等)、サルモネラ属(チフス菌及びパラチフス菌等)、シゲラ属(赤痢菌等)、アシネトバクター属(アシネトバクター・バウマニー及びアシネトバクター・カルコアセチカス等)、レジオネラ属(レジオネラ・ニューモフィラ等)、バクテロイデス属(バクテロイデス・フラジリス等)、ナイセリア属(淋菌及び髄膜炎菌等)、モラキセラ属(モラキセラ・カタラーリス等)、クラミジア属(クラミジア・トラコマティス及びクラミジア・シッタシー等)及びヘリコバクター属(ヘリコバクター・ピロリ等)などが挙げられる。本発明の化合物はグラム陰性細菌への抗菌剤として好ましく使用することができる。 Gram-negative bacteria include, for example, Pseudomonas genus (Pseudomonas aeruginosa, etc.), Escherichia genus (E. coli etc.), Klebsiella genus (Klebsiella pneumoniae and Klebsiella oxytoca, etc.), Haemophilus genus (H. influenzae and Parainfluenza etc.) (Pertussis and bronchial septic bacteria, etc.), Serratia (Serratia marcescens, etc.), Proteus (Proteus vulgaris, Proteus Mirabilis, etc.), Enterobacter (Enterobacter aerogenesis and Enterobacter cloaca, etc.), Campylobacter genus (Campylobacter jejuni etc.), Citrobacter genus (Citrobacter Freundi etc.), Providencia genus (Providencia Stuati etc.), Stenotrophomonas genus (Stenotrophomonas maltofi) A), Vibrio genus (Vibrio parahaemolyticus, Vibrio cholerae, etc.), Morganella genus (Morganella morgani, etc.), Salmonella genus (S. typhi and Paratyphi), Shigella genus (Shigella, etc.), Acinetobacter genus (Acinetobacter baumannii) Acinetobacter calcoaceticus), Legionella genus (Legionella pneumophila etc.), Bacteroides genus (Bacteroides fragilis etc.), Neisseria genus (gonococci and meningococcus etc.), Moraxella genus (Moraxella catarrhalis etc.), Chlamydia genus (Chlamydia) -Trachomatis and Chlamydia cyttashi etc.) and Helicobacter genus (Helicobacter pylori etc.). The compound of the present invention can be preferably used as an antibacterial agent against gram-negative bacteria.
本発明の化合物である下記式[1] The following formula [1] which is a compound of the present invention
で表される2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミドには光学異性体が存在しうるが、式[1]で表される化合物には、それら光学異性体及び光学異性体の混合物が含まれる。医薬組成物や抗菌剤は、特定の光学異性体を含有してもよいし、光学異性体の混合物、とりわけラセミ体を含有してもよい。 2-[{4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′, 2-dimethyl Although propanediamide may have optical isomers, the compound represented by the formula [1] includes optical isomers and a mixture of optical isomers. The pharmaceutical composition or antibacterial agent may contain a specific optical isomer, or may contain a mixture of optical isomers, particularly a racemate.
本発明の化合物は、式[1]で表される化合物及びその薬学的に許容される塩が含まれ、式[1]で表される化合物及びその薬学的に許容される塩の結晶多形も含まれる。 The compound of the present invention includes a compound represented by the formula [1] and a pharmaceutically acceptable salt thereof, and a crystal polymorph of the compound represented by the formula [1] and a pharmaceutically acceptable salt thereof. Is also included.
本発明の化合物の好ましい光学異性体は、下記式[2] A preferred optical isomer of the compound of the present invention is represented by the following formula [2].
本発明には、式[2]で表される化合物及びその薬学的に許容される塩が含まれ、式[2]で表される化合物及びその薬学的に許容される塩の結晶多形も本発明に含まれる。 The present invention includes a compound represented by the formula [2] and a pharmaceutically acceptable salt thereof, and also includes a crystal polymorph of the compound represented by the formula [2] and a pharmaceutically acceptable salt thereof. It is included in the present invention.
本発明の化合物は、一つ又は二つ以上の医薬的に許容される担体、賦形剤又は希釈剤と組み合せて医薬的組成物とすることができる。 The compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
上記担体、賦形剤及び希釈剤として、例えば、水、乳糖、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、デンプン、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、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、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾソルベート、タルク、ステアリン酸マグネシウム、ステアリン酸、グリセリン及び各種油(ゴマ油、オリーブ油及び大豆油等)などが挙げられる。 Examples of the carrier, excipient and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, Examples include water syrup, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, alkylparahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, and various oils (eg, sesame oil, olive oil, and soybean oil).
医薬組成物には、上記担体、賦形剤又は希釈剤に必要に応じて一般に使用される増量剤、結合剤、崩壊剤、pH調整剤、溶解剤及び着香剤等の添加剤を混合してもよい。 In the pharmaceutical composition, additives such as a bulking agent, a binder, a disintegrant, a pH adjuster, a solubilizer and a flavoring agent that are generally used are mixed as necessary with the carrier, excipient or diluent. May be.
医薬組成物は、常用の製剤技術によって錠剤、丸剤、カプセル剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、軟膏剤、注射剤(筋肉内注射剤及び静脈内注射剤を含む)、点滴静注剤及び皮膚貼付剤などの経口又は非経口用医薬として調製することができる。 The pharmaceutical composition is prepared by a conventional formulation technique using tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections (including intramuscular injections and intravenous injections), It can be prepared as an oral or parenteral pharmaceutical such as an intravenous drip infusion or a skin patch.
本発明の化合物は、成人患者に対して30〜3000mg、好ましくは100〜1500mgを1日1回又は数回に分けて非経口又は経口で投与することが可能である。好ましい投与形態は、点滴静脈内注射又は静脈内注射であり、より好ましい投与形態は点滴静脈内注射である。投与量は治療対象となる疾病の種類、患者の年齢、体重及び症状などに応じて、適宜増減することが可能である。また、本発明の化合物は、他の薬剤との組み合わせで使用することも可能である。 The compound of the present invention can be administered parenterally or orally in an amount of 30 to 3000 mg, preferably 100 to 1500 mg, once a day or several times a day for an adult patient. A preferred dosage form is intravenous infusion or intravenous injection, and a more preferred dosage form is intravenous infusion. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight and symptoms of the patient. The compounds of the present invention can also be used in combination with other drugs.
とくに、液体組成物とする際には、pH調節剤としては、とくに制限されないが、例えば塩酸、硫酸、クエン酸、酢酸、リン酸、コハク酸、乳酸、酒石酸、安息香酸等の酸性物質、また必要に応じて水酸化ナトリウム、クエン酸三ナトリウム等の塩基性物質を用いることができる。pH調節剤は、好ましくは、塩酸、クエン酸である。 In particular, when preparing a liquid composition, the pH regulator is not particularly limited, but for example, acidic substances such as hydrochloric acid, sulfuric acid, citric acid, acetic acid, phosphoric acid, succinic acid, lactic acid, tartaric acid, benzoic acid, Basic substances such as sodium hydroxide and trisodium citrate can be used as necessary. The pH adjuster is preferably hydrochloric acid or citric acid.
注射剤に用いられる容器としては、ガラス製やプラスチック製が好ましく、プラスチック製の具体例としては、環状ポリオレフィン、ポリプロピレン、ポリエチレン、ポリカーボネート、ポリスチレン、ポリエチレンテレフタレート等が挙げられる。 The container used for the injection is preferably made of glass or plastic, and specific examples of plastic include cyclic polyolefin, polypropylene, polyethylene, polycarbonate, polystyrene, polyethylene terephthalate and the like.
とくに、注射剤とする際には、無菌充填にて容器に注射液を充填する他、加熱滅菌、高圧蒸気滅菌等、注射液に対する種々の公知の滅菌方法を採用することができる。 In particular, when an injection is prepared, various known sterilization methods for an injection solution such as heat sterilization and high-pressure steam sterilization can be employed in addition to filling the container with aseptic filling.
注射剤として液体組成物等の溶液を調製する際には、例えば滅菌蒸留水を用い滅菌状態の溶液を得たり、メンブランフィルターろ過等の滅菌処理を行う等の操作を行うこともできる。 When preparing a solution such as a liquid composition as an injection, a sterilized solution can be obtained using, for example, sterilized distilled water, or a sterilization treatment such as membrane filter filtration can be performed.
一度、液体組成物とした溶液を各種の乾燥手段により、乾燥物とする方法等が挙げられる。乾燥手段としては、凍結乾燥法、スプレードライ法、減圧乾燥法等があるが、特に凍結乾燥法が好ましい。このようにして得られた水性組成物又は乾燥組成物は、注射剤、経口剤、坐剤、経粘膜投与剤及び外用剤等の製剤として使用できる。 Examples include a method in which a solution once formed into a liquid composition is dried by various drying means. As the drying means, there are a freeze-drying method, a spray-drying method, a reduced-pressure drying method and the like, and the freeze-drying method is particularly preferable. The aqueous composition or dry composition thus obtained can be used as preparations such as injections, oral preparations, suppositories, transmucosal administration agents, and external preparations.
以下に、実施例及び試験例により本発明をさらに詳細に説明する。本発明はこれらの実施例によって何ら限定されるものではない。特に、本発明における化合物の合成法は以下の方法に限定されず、各工程の順序を入れ替える、官能基の保護・脱保護を経るなど、当業者に周知の方法を用いて合成することもできる。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples. The present invention is not limited by these examples. In particular, the method for synthesizing the compound in the present invention is not limited to the following method, and it can also be synthesized using methods well known to those skilled in the art, such as changing the order of each step, and undergoing functional group protection / deprotection. .
MS(マススペクトル)はLCMS−IT−TOF (Shimadzu)の装置にて測定した。イオン化法としては、ESI(Electrospray Ionization、エレクトロスプレーイオン化)法又は、ESIとAPCI(Atmospheric Pressure Chemical Ionization、大気圧化学イオン化)法とのデュアルイオン化法を用いた。データは実測値(found)を記載した。通常、分子イオンピークが観測されるが、水酸基(−OH)を有する化合物の場合、フラグメントピークとしてH2Oが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピーク若しくはフラグメントイオンピークが観測される。 MS (mass spectrum) was measured with an apparatus of LCMS-IT-TOF (Shimadzu). As the ionization method, an ESI (Electrospray Ionization) method or a dual ionization method of ESI and APCI (Atmospheric Pressure Chemical Ionization) method was used. The data described the actual value (found). Usually, a molecular ion peak is observed, but in the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
高速液体クロマトグラフィーマススペクトル(LCMS)は、以下の条件を用いた。
測定機械:Agilent社 Agilent1290及びAgilent社 Agilent6130
カラム:Waters社 Acquity UPLC(登録商標) CSH(登録商標) C18 1.7μm 2.1x50mm
イオン化法:電子衝撃イオン化法Electron Spray Ionization: ESI)
溶媒:A液;0.1%ぎ酸含有水、B液;0.1%ぎ酸含有アセトニトリル
(条件1)
流速:0.8mL/min
グラジエント:0分(A液/B液=80/20)、1.2分(A液/B液=80/20)、1.4分(A液/B液=1/99)
(条件2)
流速:0.8mL/min(0分−1.2分)、1.0mL/min(1.2分−1.38分)
グラジエント:0分(A液/B液=95/5)、1.2分(A液/B液=50/50)、1.38分(A液/B液=3/97)
The following conditions were used for the high performance liquid chromatography mass spectrum (LCMS).
Measuring machine: Agilent Agilent 1290 and Agilent Agilent 6130
Column: Waters Acquity UPLC (registered trademark) CSH (registered trademark) C18 1.7 μm 2.1 × 50 mm
Ionization method: Electron impact ionization (Electron Spray Ionization: ESI)
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile (Condition 1)
Flow rate: 0.8mL / min
Gradient: 0 minutes (A liquid / B liquid = 80/20), 1.2 minutes (A liquid / B liquid = 80/20), 1.4 minutes (A liquid / B liquid = 1/99)
(Condition 2)
Flow rate: 0.8 mL / min (0 min-1.2 min), 1.0 mL / min (1.2 min-1.38 min)
Gradient: 0 minutes (A liquid / B liquid = 95/5), 1.2 minutes (A liquid / B liquid = 50/50), 1.38 minutes (A liquid / B liquid = 3/97)
NMRスペクトルはプロトンNMRを示し、内部基準としてテトラメチルシランを用いて、δ値をppmで示した。 The NMR spectrum showed proton NMR, and δ value was expressed in ppm using tetramethylsilane as an internal standard.
元素分析はvario MICRO cube(elementar)の装置にて測定した。 Elemental analysis was carried out using an apparatus of a vario MICRO cube (elemental).
OH型シリカゲルクロマトグラフィー及びNH型シリカゲルクロマトグラフィーにおける担体は、グレースジャパン株式会社製REVELERIS(登録商標)などのパックドカラムを用いた。フェーズセパレーターは、バイオタージ株式会社製のものを用いた。 As a carrier in OH type silica gel chromatography and NH type silica gel chromatography, a packed column such as REVERLIS (registered trademark) manufactured by Grace Japan Co., Ltd. was used. A phase separator manufactured by Biotage Corporation was used.
実施例中の略号を以下に示す。
AcOEt:酢酸エチル
BSA:Bovine Serum Albumin(ウシ血清アルブミン)
CuI:ヨウ化銅
DMAPO:4−(ジメチルアミノ)ピリジン 1−オキシド
HEPES:2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonic acid
(2−[4−(2−ヒドロキシエチル)−1−ピペラジニル]エタンスルホン酸)
IPE:ジイソプロピルエーテル
MeOH:メタノール
MNBA:2−メチル−6−ニトロ安息香酸無水物
NBS:N−ブロモコハク酸イミド
PdCl2(PPh3)2:ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド
スーパースティブルパラジウム:トリス{トリス[3,5−ビス(トリフルオロメチル)フェニル]ホスフィン}パラジウム
p−TsOH・H2O:p−トルエンスルホン酸一水和物
TEA:トリエチルアミン
THF:テトラヒドロフラン
s:シングレット
br.s.:ブロードシングレット(幅広いシングレット)
d:ダブレット
dd:ダブルダブレット
m:マルチプレット
t:トリプレット
q:カルテット
本発明において、「p−」は、パラを意味する。「n−」はノルマルを、「t−」はターシャリーを意味する。また、室温とは10〜30度を意味し、場合によっては1〜30度を意味する。
Abbreviations in the examples are shown below.
AcOEt: Ethyl acetate BSA: Bovine Serum Albumin (bovine serum albumin)
CuI: Copper iodide DMAPO: 4- (Dimethylamino) pyridine 1-oxide HEPES: 2- [4- (2-Hydroxyethyl) -1-piperazinyl] ethanesulfonic acid
(2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid)
IPE: diisopropyl ether MeOH: methanol MNBA: 2-methyl-6-nitrobenzoic anhydride NBS: N-bromosuccinimide PdCl 2 (PPh 3) 2: Bis (triphenylphosphine) palladium (II) dichloride super side stable palladium : Tris {Tris [3,5-bis (trifluoromethyl) phenyl] phosphine} palladium p-TsOH.H 2 O: p-toluenesulfonic acid monohydrate TEA: triethylamine THF: tetrahydrofuran s: singlet br. s. : Broad singlet (wide singlet)
d: doublet dd: double doublet m: multiplet t: triplet q: quartet In the present invention, “p−” means para. “N-” means normal, and “t-” means tertiary. Moreover, room temperature means 10-30 degree | times, and means 1-30 degree | times depending on the case.
実施例1
(2S)−2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミド(化合物1)
Example 1
(2S) -2-[{4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′, 2-dimethyl Propane diamide (compound 1)
(1)窒素雰囲気下、特許文献5(国際公開第2011/132712号)に記載の方法で得られた(2S)−2−[(4−ヨードベンゾイル)(メチル)アミノ]−N,2−ジメチル−N’−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパンジアミド(19.2g)のTHF(200mL)懸濁液に室温でCuI(0.299g)、PdCl2(PPh3)2(0.551g)及びTEA(10.9mL)を加えた。その後、トリメチルシリルアセチレン(5.01g)を5分間かけて加え、室温で2時間撹拌した。反応混合物をNH型シリカゲル(クロロホルム/MeOH=95/5)でろ過、濃縮して得られた残渣をOH型シリカゲルカラムクロマトグラフィー(ヘキサン/AcOEt=100/0→0/100)で精製して得られた淡橙色固体をIPEで洗浄、乾燥して(2S)−N,2−ジメチル−2−(メチル{4−[(トリメチルシリル)エチニル]ベンゾイル}アミノ)−N’−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパンジアミド(17.6g、無色固体、97%)を得た。
MS(ESI/APCI dual):m/z=482(M+Na)+,458(M−H)−
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.26 (9H, s), 1.48 - 1.90 (6H m), [1.80], 1.81 (3H , s), 2.82 - 2.87 (3H, m), [3.13], 3.15 (3H, s), 3.50 - 3.69 (1H, m), 3.82 - 4.05 (1H, m), 4.92 - 5.01 (1H, m), 7.41 - 7.48 (2H, m), 7.48 - 7.54 (2H, m), [6.99], 7.62 (1H, br. s.), [10.06], 10.47 (1H, s)
(1) (2S) -2-[(4-iodobenzoyl) (methyl) amino] -N, 2-obtained by the method described in Patent Document 5 (International Publication No. 2011-132712) under a nitrogen atmosphere. To a suspension of dimethyl-N ′-(tetrahydro-2H-pyran-2-yloxy) propanediamide (19.2 g) in THF (200 mL) at room temperature was added CuI (0.299 g), PdCl 2 (PPh 3 ) 2 (0 .551 g) and TEA (10.9 mL) were added. Thereafter, trimethylsilylacetylene (5.01 g) was added over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through NH silica gel (chloroform / MeOH = 95/5) and concentrated, and the resulting residue was purified by OH silica gel column chromatography (hexane / AcOEt = 100/0 → 0/100). The resulting pale orange solid was washed with IPE and dried to give (2S) -N, 2-dimethyl-2- (methyl {4-[(trimethylsilyl) ethynyl] benzoyl} amino) -N ′-(tetrahydro-2H-pyran -2-yloxy) propanediamide (17.6 g, colorless solid, 97%) was obtained.
MS (ESI / APCI dual): m / z = 482 (M + Na) + , 458 (M−H) −
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.26 (9H, s), 1.48-1.90 (6H m), [1.80], 1.81 (3H, s), 2.82-2.87 (3H, m), [3.13 ], 3.15 (3H, s), 3.50-3.69 (1H, m), 3.82-4.05 (1H, m), 4.92-5.01 (1H, m), 7.41-7.48 (2H, m), 7.48-7.54 (2H , m), [6.99], 7.62 (1H, br. s.), [10.06], 10.47 (1H, s)
(2)実施例1−(1)で得られた化合物(17.1g)のMeOH(250mL)溶液に氷冷下で炭酸カリウム(5.14g)を加え、同温で50分間撹拌後、室温に昇温して1時間撹拌した。反応混合物を、飽和塩化アンモニウム水溶液(1.0L)とクロロホルム(1.0L)の混合物に加えて有機層を分離し、水層をクロロホルム(0.5L)で抽出した。合わせた有機層を、乾燥(硫酸マグネシウム)、ろ過、濃縮した。得られた粗精製物をOH型シリカゲルカラムクロマトグラフィー(ヘキサン/AcOEt=80/20→0/100)で精製して得られた淡橙色固体をIPEで洗浄、乾燥して(2S)−2−[(4−エチニルベンゾイル)(メチル)アミノ]−N,2−ジメチル−N’−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパンジアミド(12.4g、無色固体、86%)を得た。
MS(ESI/APCI dual):m/z=410(M+Na)+,386(M−H)−
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49 - 1.91 (6H, m), [1.80], 1.81 (3H, s), 2.83 - 2.87 (3H, m), 3.12 - 3.19 (1H, m), [3.14], 3.16 (3H, s), 3.53 - 3.69 (1H, m), 3.83 - 4.05 (1H, m), 4.93 - 5.01 (1H, m), 7.44 - 7.51 (2H, m), 7.52 - 7.57 (2H, m), [6.98], 7.62 (1H, br. s.), [10.06], 10.47 (1H, s)
(2) Potassium carbonate (5.14 g) was added to a solution of the compound (17.1 g) obtained in Example 1- (1) in MeOH (250 mL) under ice-cooling, and the mixture was stirred at the same temperature for 50 minutes. The mixture was warmed to 1 hour and stirred for 1 hour. The reaction mixture was added to a mixture of saturated aqueous ammonium chloride (1.0 L) and chloroform (1.0 L), the organic layer was separated, and the aqueous layer was extracted with chloroform (0.5 L). The combined organic layers were dried (magnesium sulfate), filtered and concentrated. The obtained crude product was purified by OH type silica gel column chromatography (hexane / AcOEt = 80/20 → 0/100), and the pale orange solid obtained was washed with IPE and dried (2S) -2- [(4-Ethynylbenzoyl) (methyl) amino] -N, 2-dimethyl-N ′-(tetrahydro-2H-pyran-2-yloxy) propanediamide (12.4 g, colorless solid, 86%) was obtained.
MS (ESI / APCI dual): m / z = 410 (M + Na) + , 386 (M−H) −
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49-1.91 (6H, m), [1.80], 1.81 (3H, s), 2.83-2.87 (3H, m), 3.12-3.19 (1H, m) , [3.14], 3.16 (3H, s), 3.53-3.69 (1H, m), 3.83-4.05 (1H, m), 4.93-5.01 (1H, m), 7.44-7.51 (2H, m), 7.52- 7.57 (2H, m), [6.98], 7.62 (1H, br. S.), [10.06], 10.47 (1H, s)
(3)NBS(6.62g)とトリフルオロ酢酸銀(342mg)のアセトン(50mL)混合物に氷冷下で、実施例1−(2)で得られた化合物(12.0g)のアセトン(150mL)混合物を滴下し、同温で1.5時間撹拌した。反応混合物を飽和重曹水(600mL)に加えて0.5時間撹拌後、クロロホルム(600mL)を加えて不溶物をろ過し、有機層を分離した。水層をクロロホルム(100mL)で抽出した。合わせた有機層を、乾燥(無水硫酸マグネシウム)、ろ過、濃縮した。得られた残渣に水(500mL)を加えた懸濁液を1.5時間撹拌後、ろ過、洗浄(水、500mL)した。得られた淡橙色固体をクロロホルム(500mL)に溶解した。得られたクロロホルム溶液を水(200mL)で洗浄し、乾燥(無水硫酸マグネシウム)、ろ過、濃縮した。得られた淡橙色固体をOH型シリカゲルカラムクロマトグラフィー(クロロホルム/MeOH=100/0→90/10)で精製後、再結晶(AcOEt/IPE)して(2S)−2−{[4−(ブロモエチニル)ベンゾイル](メチル)アミノ}−N,2−ジメチル−N’−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパンジアミド(8.02g、56%)を得た。
MS(ESI/APCI dual):m/z=488(M+Na)+,464(M−H)−
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.46 - 1.90 (6H, m), [1.80], 1.81 (3H, s), 2.82 - 2.87 (3H, m), [3.14], 3.16 (3H, s), 3.52 - 3.68 (1H, m), 3.82 - 4.04 (1H, m), 4.92 - 5.01 (1H, m), 7.42 - 7.53 (4H, m), [6.97], 7.61 (1H, br. s.), [10.05], 10.47 (1H, s)
(3) A mixture of NBS (6.62 g) and silver trifluoroacetate (342 mg) in acetone (50 mL) under ice-cooling, the compound obtained in Example 1- (2) (12.0 g) in acetone (150 mL) ) The mixture was added dropwise and stirred at the same temperature for 1.5 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate (600 mL) and stirred for 0.5 hr, chloroform (600 mL) was added, insoluble material was filtered, and the organic layer was separated. The aqueous layer was extracted with chloroform (100 mL). The combined organic layers were dried (anhydrous magnesium sulfate), filtered and concentrated. The suspension obtained by adding water (500 mL) to the obtained residue was stirred for 1.5 hours, and then filtered and washed (water, 500 mL). The resulting pale orange solid was dissolved in chloroform (500 mL). The obtained chloroform solution was washed with water (200 mL), dried (anhydrous magnesium sulfate), filtered and concentrated. The obtained pale orange solid was purified by OH-type silica gel column chromatography (chloroform / MeOH = 100/0 → 90/10) and then recrystallized (AcOEt / IPE) to (2S) -2-{[4- ( Bromoethynyl) benzoyl] (methyl) amino} -N, 2-dimethyl-N ′-(tetrahydro-2H-pyran-2-yloxy) propanediamide (8.02 g, 56%) was obtained.
MS (ESI / APCI dual): m / z = 488 (M + Na) + , 464 (M−H) −
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.46-1.90 (6H, m), [1.80], 1.81 (3H, s), 2.82-2.87 (3H, m), [3.14], 3.16 (3H, s), 3.52-3.68 (1H, m), 3.82-4.04 (1H, m), 4.92-5.01 (1H, m), 7.42-7.53 (4H, m), [6.97], 7.61 (1H, br. s .), [10.05], 10.47 (1H, s)
(4)文献(Synthesis、2010年、23巻、3967―3973頁)に記載の方法により合成した1−エチニルシクロプロピルアミン塩酸塩(1.59g)のアセトニトリル(50mL)溶液にTEA(4.35g)、スーパースティブルパラジウム(547mg)及びCuI(49mg)を加え、実施例1−(3)で得られた化合物のアセトニトリル(10mL)溶液を10分かけて滴下し、窒素雰囲気下、室温で1時間した。反応液をろ過後、ろ液を減圧下濃縮し、得られた残留物をOH型シリカゲルクロマトグラフィー(ヘキサン/AcOEt=50/50→0/100)にて精製して、(2S)−2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N,2−ジメチル−N’−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパンジアミドを得た(2.42g、淡黄色泡状物、60%)。
LCMS保持時間:0.81分(条件2)
MS(ESI):m/z=465(M−H)−
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.00 - 1.02 (2H, m), 1.06 - 1.08 (2H, m), 1.39 - 2.13 (6H, m), [1.79], 1.80 (3H, s), 2.83 - 2.85 (3H, m), [3.13], 3.16 (3H, s), 3.55 - 3.66 (1H, m), 3.84 - 4.02 (1H, m), 4.89 - 5.00 (1H, m), 7.41 - 7.55 (4H, m), [6.97], 7.61 (1H, br. s.), [10.07], 10.48 (1H, br. s.)
(4) TEA (4.35 g) was added to an acetonitrile (50 mL) solution of 1-ethynylcyclopropylamine hydrochloride (1.59 g) synthesized by the method described in the literature (Synthesis, 2010, 23, 3967-3773). ), Superstable palladium (547 mg) and CuI (49 mg) were added, and a solution of the compound obtained in Example 1- (3) in acetonitrile (10 mL) was added dropwise over 10 minutes. Time. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel chromatography (hexane / AcOEt = 50/50 → 0/100) to obtain (2S) -2- [{4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N, 2-dimethyl-N ′-(tetrahydro-2H-pyran- 2-yloxy) propanediamide was obtained (2.42 g, pale yellow foam, 60%).
LCMS retention time: 0.81 minutes (condition 2)
MS (ESI): m / z = 465 (M−H) −
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.00-1.02 (2H, m), 1.06-1.08 (2H, m), 1.39-2.13 (6H, m), [1.79], 1.80 (3H, s) , 2.83-2.85 (3H, m), [3.13], 3.16 (3H, s), 3.55-3.66 (1H, m), 3.84-4.02 (1H, m), 4.89-5.00 (1H, m), 7.41- 7.55 (4H, m), [6.97], 7.61 (1H, br.s.), [10.07], 10.48 (1H, br.s.)
(5)実施例1−(4)で得られた化合物(2.39g)のMeOH溶液(50mL)にp−TsOH・H2O(1.46g)を加え、室温で1時間攪拌した。反応液に飽和炭酸水素ナトリウム溶液を加え、クロロホルムで抽出後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後に乾燥剤を濾別し、溶媒を減圧下留去した。得られた残留物をOH型シリカゲルクロマトグラフィー(クロロホルム/MeOH=100/0→85/15)にて精製して、(2S)−2−[{4−[4−(1−アミノシクロプロピル)ブタ−1,3−ジイン−1−イル]ベンゾイル}(メチル)アミノ]−N−ヒドロキシ−N’,2−ジメチルプロパンジアミド(化合物1、1.69g、淡黄色固体、86%)を得た。
LCMS保持時間:0.53分(条件2)
MS(ESI):m/z=381(M−H)−
1H NMR (600 MHz, CD3OD) δ ppm 0.95 - 1.00 (2H, m), 1.02 - 1.06 (2H, m), 1.76 (3H, s), 2.78 (3H, s), 3.13 (3H, s), 7.47 - 7.60 (4H, m)
(5) p-TsOH · H 2 O (1.46 g) was added to a MeOH solution (50 mL) of the compound (2.39 g) obtained in Example 1- (4), and the mixture was stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by OH type silica gel chromatography (chloroform / MeOH = 100/0 → 85/15) to obtain (2S) -2-[{4- [4- (1-aminocyclopropyl)]. Buta-1,3-diin-1-yl] benzoyl} (methyl) amino] -N-hydroxy-N ′, 2-dimethylpropanediamide (Compound 1, 1.69 g, pale yellow solid, 86%) was obtained. .
LCMS retention time: 0.53 minutes (condition 2)
MS (ESI): m / z = 381 (M−H) −
1 H NMR (600 MHz, CD3OD) δ ppm 0.95-1.00 (2H, m), 1.02-1.06 (2H, m), 1.76 (3H, s), 2.78 (3H, s), 3.13 (3H, s), 7.47-7.60 (4H, m)
化合物1は、以下に示す方法によっても合成することができる。 Compound 1 can also be synthesized by the method shown below.
(6)2−((tert−ブトキシカルボニル)アミノ)マロン酸ジエチル(25・7g)のジメチルホルムアミド(250mL)溶液に、炭酸セシウム122gを加えた後、水浴下でヨウ化メチル(23.2mL)を滴下した。滴下終了後、反応系を密閉系にして室温で5日間攪拌した。反応液に水を加え、n−ヘキサン/AcOEt=4/1溶液(700mL)を加えて抽出後、有機層を飽和塩化アンモニウム水溶液及び飽和食塩水で順次洗浄した。有機層に無水硫酸マグネシウム及び活性炭(2g)を加えて1時間攪拌し、セライト(登録商標)濾過した。濾液を減圧下濃縮して、2−((tert−ブトキシカルボニル)(メチル)アミノ)−2−メチルマロン酸ジエチルを得た(25.0g、淡黄色油状物、88%)。
MS(ESI/APCI dual):m/z=326(M+Na)+
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 (6H, t, J=7.0 Hz), 1.38 - 1.47 (9H, m), 1.68 (3H, s), 2.87 (3H, s) 4.22 (4H, q, J=7.0 Hz)
(6) To a solution of diethyl 2-((tert-butoxycarbonyl) amino) malonate (25.7 g) in dimethylformamide (250 mL) was added 122 g of cesium carbonate, and then methyl iodide (23.2 mL) in a water bath. Was dripped. After completion of dropping, the reaction system was closed and stirred at room temperature for 5 days. Water was added to the reaction solution, n-hexane / AcOEt = 4/1 solution (700 mL) was added for extraction, and the organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine. Anhydrous magnesium sulfate and activated carbon (2 g) were added to the organic layer, stirred for 1 hour, and filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give diethyl 2-((tert-butoxycarbonyl) (methyl) amino) -2-methylmalonate (25.0 g, pale yellow oil, 88%).
MS (ESI / APCI dual): m / z = 326 (M + Na) +
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 (6H, t, J = 7.0 Hz), 1.38-1.47 (9H, m), 1.68 (3H, s), 2.87 (3H, s) 4.22 (4H , q, J = 7.0 Hz)
(7)実施例1−(6)で得られた化合物(22.8g)に、リン酸バッファー水溶液(680mL)を加え、これにPLE(Pig Liver Esterase、豚肝臓エステラーゼ)(342mg)を加えて室温で26時間攪拌した。リン酸バッファー水溶液は、0.2Mのリン酸二水素ナトリウム水溶液(65mL)及び0.2Mのリン酸水素二ナトリウム水溶液(435mL)の混合物を水で希釈して1000mLにしたものを用いた。反応液に1mol/Lの水酸化ナトリウム水溶液(75mL)を加えてpH8〜9に調整した後、トルエン(0.5L)を用いて抽出した。この際に混合液が泡状になったため、セライト(登録商標)濾過を2度実施した。抽出後得られた水層にリン酸(20mL)を加えてpH2〜3に調整し、AcOEt(1L)を用いて抽出した。この際にも混合液が泡状になったため、セライト(登録商標)濾過を実施した。得られた有機層に無水硫酸マグネシウムを加えて乾燥した後に乾燥剤を濾別し、溶媒を減圧下留去した。残留物をAcOEt(0.2L)に溶かして活性炭(1.8g)を加えて1時間攪拌した。活性炭を濾別し溶媒を減圧下留去して、(R)−2−((tert−ブトキシカルボニル)(メチル)アミノ)−3−エトキシ−2−メチル−3−オキソプロパン酸を得た(18.0g、淡黄色シロップ状物、87%、ee>99%)。
MS(ESI/APCI dual):m/z=298(M+Na)+
1H NMR (600 MHz, DMSO-d6) δ ppm 1.11 - 1.19 (3H, m), 1.32 (9H, br. s.), 1.54 (3H, s), 2.73 (3H, s), 4.02 - 4.13 (2H, m)
(7) A phosphate buffer aqueous solution (680 mL) is added to the compound (22.8 g) obtained in Example 1- (6), and PLE (Pig Liver Esterase, porcine liver esterase) (342 mg) is added thereto. Stir at room temperature for 26 hours. The phosphate buffer aqueous solution used was a mixture of a 0.2 M aqueous sodium dihydrogen phosphate solution (65 mL) and a 0.2 M aqueous solution of disodium hydrogen phosphate (435 mL) diluted to 1000 mL with water. A 1 mol / L sodium hydroxide aqueous solution (75 mL) was added to the reaction solution to adjust the pH to 8 to 9, followed by extraction with toluene (0.5 L). Since the liquid mixture became foamy at this time, Celite (registered trademark) filtration was performed twice. Phosphoric acid (20 mL) was added to the aqueous layer obtained after extraction to adjust to pH 2 to 3, and extraction was performed using AcOEt (1 L). Also at this time, since the mixed liquid became foamy, Celite (registered trademark) filtration was performed. The obtained organic layer was dried by adding anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in AcOEt (0.2 L), activated carbon (1.8 g) was added, and the mixture was stirred for 1 hr. The activated carbon was filtered off and the solvent was distilled off under reduced pressure to obtain (R) -2-((tert-butoxycarbonyl) (methyl) amino) -3-ethoxy-2-methyl-3-oxopropanoic acid ( 18.0 g, pale yellow syrup, 87%, ee> 99%).
MS (ESI / APCI dual): m / z = 298 (M + Na) +
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 1.11-1.19 (3H, m), 1.32 (9H, br. S.), 1.54 (3H, s), 2.73 (3H, s), 4.02-4.13 (2H, m)
実施例1−(7)で得られた化合物のキラル分析は、以下の要領で実施した。 Chiral analysis of the compound obtained in Example 1- (7) was performed as follows.
測定機器は、島津製作所製高速液体クロマトグラフィーを用いた。各機器の型番は以下の通りである。
ポンプ:LC−30AD、オートサンプラー:SIL−30AC、カラムオーブン:CTO−20AC、光ダイオードアレイ検出器:SPD−M20A、デガッサー:DGO−20A5R。
The measuring instrument used was Shimadzu high performance liquid chromatography. The model number of each device is as follows.
Pump: LC-30AD, autosampler: SIL-30AC, column oven: CTO-20AC, photodiode array detector: SPD-M20A, degasser: DGO-20A5R.
キラルカラムは、株式会社ダイセル製AD3を、4.6×150mmと4.6×250mmを直列連結して用いた。展開溶媒はn−ヘキサン/エタノール=98/2、流速は1.0mL/毎分であった。 As the chiral column, AD3 manufactured by Daicel Corporation was used by connecting 4.6 × 150 mm and 4.6 × 250 mm in series. The developing solvent was n-hexane / ethanol = 98/2, and the flow rate was 1.0 mL / min.
210nmにおける吸収波長で検出し、2−((tert−ブトキシカルボニル)(メチル)アミノ)−3−エトキシ−2−メチル−3−オキソプロパン酸のラセミ体のピークの保持時間は、(S)体が26.5分、(R)体が37.9分であった。 Retention time of the racemic peak of 2-((tert-butoxycarbonyl) (methyl) amino) -3-ethoxy-2-methyl-3-oxopropanoic acid was detected at an absorption wavelength at 210 nm. Was 26.5 minutes, and the (R) isomer was 37.9 minutes.
上記条件のもとで実施例1−(7)で得られた化合物の分析を実施した結果、(R)体のみが検出され、(S)体は検出限界以下であった。鏡像体過剰率(ee)は>99%であった。 As a result of analyzing the compound obtained in Example 1- (7) under the above conditions, only the (R) isomer was detected, and the (S) isomer was below the detection limit. The enantiomeric excess (ee) was> 99%.
(8)実施例1−(7)で得られた化合物(13.3g)のトルエン(121mL)溶液に氷冷下で塩化チオニル(10.5mL)を滴下し、室温に昇温して16時間撹拌した。反応混合物を減圧濃縮して(S)−3−クロロ−2−メチル−2−(メチルアミノ)−3−オキソプロパン酸エチルを粗精製物として得た(9.37g、褐色固体)。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.30 (3H, t, J=7.8 Hz), 1.72 (3H, s), 2.93 (3H, s), 4.23 - 4.33 (2H, m)
Anal.cald for C7H12ClNO3 : C, 43.42; H, 6.25; N, 7.23;
Found : C, 45.49; H, 6.09; N, 6.75;
(8) Thionyl chloride (10.5 mL) was added dropwise to a toluene (121 mL) solution of the compound (13.3 g) obtained in Example 1- (7) under ice cooling, and the temperature was raised to room temperature for 16 hours. Stir. The reaction mixture was concentrated under reduced pressure to obtain ethyl (S) -3-chloro-2-methyl-2- (methylamino) -3-oxopropanoate as a crude product (9.37 g, brown solid).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.30 (3H, t, J = 7.8 Hz), 1.72 (3H, s), 2.93 (3H, s), 4.23-4.33 (2H, m)
Anal.cald for C 7 H 12 ClNO 3 : C, 43.42; H, 6.25; N, 7.23;
Found: C, 45.49; H, 6.09; N, 6.75;
(9)O−(テトラヒドロ−2H−ピラン−2−イル)ヒドロキシルアミン(1.00g)をトルエンで2回共沸乾燥後、トルエン(5.0mL)を加えた溶液にTEA(3.57mL)を加え、氷冷下で実施例1−(8)で得られた化合物(1.95g)のトルエン(25mL)/THF(5.0mL)混合物を5分間かけて滴下し、室温に昇温して16時間撹拌した。反応混合物にAcOEt(10mL)を加えた懸濁液をろ過し、ろ液を濃縮して得られた粗精製物をOH型シリカゲルクロマトグラフィー(ヘキサン/AcOEt=50/50→0/100)にて精製して、(2R)−2−メチル−2−(メチルアミノ)−3−オキソ−3−(((テトラヒドロ−2H−ピラン−2−イル)オキシ)アミノ)プロパン酸エチルを得た(1.78g、淡褐色油状物、76%)。
MS(ESI/APCI dual):m/z=275(M+H)+,273(M−H)−
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 - 1.30 (3H, m), 1.43 - 1.90 (6H, m), [1.529] 1.532 (3H, s), 2.30 (3H, s), 3.58 - 3.67 (1H, m), 3.88 - 4.00 (1H, m), 4.13 - 4.34 (2H, m), 4.82 - 5.02 (1H, m), 9.68 (1H, br. s.)
(9) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1.00 g) was azeotropically dried twice with toluene, and then a solution containing toluene (5.0 mL) was added to TEA (3.57 mL). Under ice cooling, a toluene (25 mL) / THF (5.0 mL) mixture of the compound (1.95 g) obtained in Example 1- (8) was added dropwise over 5 minutes, and the temperature was raised to room temperature. And stirred for 16 hours. The suspension obtained by adding AcOEt (10 mL) to the reaction mixture was filtered, and the filtrate was concentrated. The crude product obtained by concentrating the filtrate was subjected to OH type silica gel chromatography (hexane / AcOEt = 50/50 → 0/100). Purification gave ethyl (2R) -2-methyl-2- (methylamino) -3-oxo-3-(((tetrahydro-2H-pyran-2-yl) oxy) amino) propanoate (1 .78 g, light brown oil, 76%).
MS (ESI / APCI dual): m / z = 275 (M + H) + , 273 (M−H) −
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25-1.30 (3H, m), 1.43-1.90 (6H, m), [1.529] 1.532 (3H, s), 2.30 (3H, s), 3.58- 3.67 (1H, m), 3.88-4.00 (1H, m), 4.13-4.34 (2H, m), 4.82-5.02 (1H, m), 9.68 (1H, br.s.)
(10)実施例1−(9)で得られた化合物(540mg)に、40%のメチルアミンメタノール溶液(6.0mL)を室温で加え、49時間攪拌した。反応液を減圧下濃縮し、得られた残渣をOH型シリカゲルクロマトグラフィー(ヘキサン/AcOEt=50/50→0/100→クロロホルム/MeOH=19/1)にて精製して、(2S)−N,2−ジメチル−2−(メチルアミノ)−N’−((テトラヒドロ−2H−ピラン−2−イル)オキシ)マロンアミドを得た(433mg、淡黄色油状物、85%)。
LCMS保持時間:0.28分(条件2)
MS(ESI):m/z=260(M+H)+
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.48 - 1.94 (6H, m), [1.529] 1.532 (3H, s), 2.29 (3H, d, J=4.5 Hz), 2.84 (3H, dd, J=5.0, 1.2 Hz), 3.62 - 3.70 (1H, m), 3.93 - 4.06 (1H, m), 4.93 - 5.03 (1H, m), 7.60 - 7.91 (1H, m), 10.72 (1H, br. s.)
(10) A 40% methylamine methanol solution (6.0 mL) was added to the compound (540 mg) obtained in Example 1- (9) at room temperature, and the mixture was stirred for 49 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel chromatography (hexane / AcOEt = 50/50 → 0/100 → chloroform / MeOH = 19/1) to obtain (2S) -N , 2-Dimethyl-2- (methylamino) -N ′-((tetrahydro-2H-pyran-2-yl) oxy) malonamide was obtained (433 mg, pale yellow oil, 85%).
LCMS retention time: 0.28 minutes (condition 2)
MS (ESI): m / z = 260 (M + H) +
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.48-1.94 (6H, m), [1.529] 1.532 (3H, s), 2.29 (3H, d, J = 4.5 Hz), 2.84 (3H, dd, J = 5.0, 1.2 Hz), 3.62-3.70 (1H, m), 3.93-4.06 (1H, m), 4.93-5.03 (1H, m), 7.60-7.91 (1H, m), 10.72 (1H, br. s.)
(11)1−エチニルシクロプロピルアミン塩酸塩(10.0g)のMeOH(100mL)溶液に、TEA(14.2mL)を室温で加え、5分撹拌した。反応液にエチルトリフルオロアセテート(11.2mL)を室温で加えて終夜撹拌した。反応液を減圧下濃縮し、水を加えてAcOEtにて2回抽出した。得られた有機層を合わせて、飽和塩化アンモニウム水溶液で洗浄した後、得られた有機層に無水硫酸マグネシウムを加えて乾燥した後に乾燥剤を濾別し、溶媒を減圧下留去した。残渣よりN−(1−エチニルシクロプロピル)−2,2,2−トリフルオロアセトアミドを得た(14.9g、淡黄色固体、99%)。
MS(ESI/APCI dual):m/z=200(M+Na)+
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.19 - 1.23 (2H, m), 1.35 - 1.43 (2H, m), 2.23 (1H, s), 6.74 (1H, br. s.)
(11) To a solution of 1-ethynylcyclopropylamine hydrochloride (10.0 g) in MeOH (100 mL) was added TEA (14.2 mL) at room temperature and stirred for 5 minutes. Ethyl trifluoroacetate (11.2 mL) was added to the reaction solution at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted twice with AcOEt. The obtained organic layers were combined, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate added to the obtained organic layer, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. N- (1-ethynylcyclopropyl) -2,2,2-trifluoroacetamide was obtained from the residue (14.9 g, pale yellow solid, 99%).
MS (ESI / APCI dual): m / z = 200 (M + Na) +
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.19-1.23 (2H, m), 1.35-1.43 (2H, m), 2.23 (1H, s), 6.74 (1H, br.s.)
(12)塩化銅(I)(44mg)を30%ブチルアミン水溶液(74.1mL)に溶解し、ヒドロキシルアミン塩酸塩(36.7mg)を加えた。反応液に、N−(1−エチニルシクロプロピル)−2,2,2−トリフルオロアセトアミド(4.3g)を加えた後、直ちに反応液を氷冷し、5分撹拌した。反応液に4−ブロモエチニル安息香酸(5.0g)を加えて室温に昇温したのち、ヒドロキシルアミン塩酸塩(22.0mg)を加えて30分撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて、AcOEtで2回抽出した。得られた有機層に無水硫酸マグネシウムを加えて乾燥した後に乾燥剤を濾別し、溶媒を減圧下留去した。得られた淡黄色固体をIPEで洗浄、乾燥して4−((1−(2,2,2−トリフルオロアセトアミド)シクロプロピル)ブタ−1,3−ジイン−1−イル)安息香酸を得た(1.8g、淡紫色固体、25%)。
MS(ESI/APCI dual):m/z=344(M+Na)+
1H NMR (600 MHz, DMSO-d6) δ ppm 1.18 - 1.29 (2H, m), 1.32 - 1.43 (2H, m), 7.62 (2H, d, J=8.3 Hz), 7.83 - 7.97 (2H, m), 10.23 (1H, s)
(12) Copper (I) chloride (44 mg) was dissolved in 30% aqueous butylamine solution (74.1 mL), and hydroxylamine hydrochloride (36.7 mg) was added. After adding N- (1-ethynylcyclopropyl) -2,2,2-trifluoroacetamide (4.3 g) to the reaction solution, the reaction solution was immediately ice-cooled and stirred for 5 minutes. 4-Bromoethynylbenzoic acid (5.0 g) was added to the reaction mixture, and the mixture was warmed to room temperature. Hydroxylamine hydrochloride (22.0 mg) was added, and the mixture was stirred for 30 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with AcOEt. The obtained organic layer was dried by adding anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained pale yellow solid was washed with IPE and dried to obtain 4-((1- (2,2,2-trifluoroacetamido) cyclopropyl) buta-1,3-diin-1-yl) benzoic acid. (1.8 g, pale purple solid, 25%).
MS (ESI / APCI dual): m / z = 344 (M + Na) +
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 1.18-1.29 (2H, m), 1.32-1.43 (2H, m), 7.62 (2H, d, J = 8.3 Hz), 7.83-7.97 (2H, m), 10.23 (1H, s)
(13)実施例1−(10)で得られた(2S)−N,2−ジメチル−2−(メチルアミノ)−N’−((テトラヒドロ−2H−ピラン−2−イル)オキシ)マロンアミド(45.0mg)のクロロホルム(3.5mL)溶液に、実施例1−(12)で得られた4−((1−(2,2,2−トリフルオロアセトアミド)シクロプロピル)ブタ−1,3−ジイン−1−イル)安息香酸(50.2mg)、TEA(72.6μL)、DMAPO(4.8mg)、MNBA(77.7mg)を加えて、室温で4日間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて3回抽出した。得られた有機層を合わせてフェーズセパレーターにて乾燥後、減圧留去した。得られた残渣をOH型シリカゲルクロマトグラフィー(クロロホルム/MeOH=98/2→80/20)にて精製して、(2S)−N,2−ジメチル−2−(N−メチル−4−((1−(2,2,2−トリフルオロアセトアミド)シクロプロピル)ブタ−1,3−ジイン−1−イル)ベンズアミド)−N’−((テトラヒドロ−2H−ピラン−2−イル)オキシ)マロンアミド(淡黄色固体)を得た(33.0mg,34%)。
MS(ESI/APCI dual):m/z=585(M+Na)+
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 - 1.34 (2H, m), 1.41 - 1.51 (2H, m), 1.49 - 1.90 (9H, m), 2.84 (3H, m), 3.15 (3H, m), 3.50 - 3.74 (1H, m), 3.83 - 4.09 (1H, m), 4.86 - 5.06 (1H, m), 6.94 - 7.62 (6H, m), 9.98 - 10.57 (1H, m)
(13) (2S) -N, 2-dimethyl-2- (methylamino) -N ′-((tetrahydro-2H-pyran-2-yl) oxy) malonamide obtained in Example 1- (10) 4-((1- (2,2,2-trifluoroacetamido) cyclopropyl) buta-1,3 obtained in Example 1- (12) was added to a chloroform (3.5 mL) solution of 45.0 mg). -Diin-1-yl) benzoic acid (50.2 mg), TEA (72.6 μL), DMAPO (4.8 mg), MNBA (77.7 mg) were added, and the mixture was stirred at room temperature for 4 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The obtained organic layers were combined, dried with a phase separator, and then distilled off under reduced pressure. The obtained residue was purified by OH type silica gel chromatography (chloroform / MeOH = 98/2 → 80/20), and (2S) -N, 2-dimethyl-2- (N-methyl-4-(( 1- (2,2,2-trifluoroacetamido) cyclopropyl) buta-1,3-diin-1-yl) benzamido) -N ′-((tetrahydro-2H-pyran-2-yl) oxy) malonamide ( A pale yellow solid) was obtained (33.0 mg, 34%).
MS (ESI / APCI dual): m / z = 585 (M + Na) +
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27-1.34 (2H, m), 1.41-1.51 (2H, m), 1.49-1.90 (9H, m), 2.84 (3H, m), 3.15 (3H , m), 3.50-3.74 (1H, m), 3.83-4.09 (1H, m), 4.86-5.06 (1H, m), 6.94-7.62 (6H, m), 9.98-10.57 (1H, m)
実施例1−(13)で得られた(2S)−N,2−ジメチル−2−(N−メチル−4−((1−(2,2,2−トリフルオロアセトアミド)シクロプロピル)ブタ−1,3−ジイン−1−イル)ベンズアミド)−N’−((テトラヒドロ−2H−ピラン−2−イル)オキシ)マロンアミドのトリフルオロアセチル基を脱保護することによって、実施例1−(4)で得られた化合物と同一の化合物を得ることができる。さらに実施例1−(5)の方法でテトラヒドロピラニル基を脱保護することによって、化合物1を得ることができる。トリフルオロアセチル基の脱保護方法としては例えば、P.G.M.ワッツら、プロテクティブ・グループス・イン・オーガニック・シンセシス(Protective Groups in Organic Synthesis)第4版、2006年、ジョン・ウィリイ・アンド・サンズ社(John Wiley & Sons,INC.)に記載されている方法が挙げられる。 (2S) -N, 2-Dimethyl-2- (N-methyl-4-((1- (2,2,2-trifluoroacetamido) cyclopropyl) buta-) obtained in Example 1- (13) Example 1- (4) by deprotecting the trifluoroacetyl group of 1,3-diin-1-yl) benzamido) -N ′-((tetrahydro-2H-pyran-2-yl) oxy) malonamide The same compound as the compound obtained in (1) can be obtained. Furthermore, the compound 1 can be obtained by deprotecting the tetrahydropyranyl group by the method of Example 1- (5). Examples of the method for deprotecting the trifluoroacetyl group include P.I. G. M.M. Watts et al., Protective Groups in Organic Synthesis, 4th edition, 2006, John Wiley & Sons, Inc. Is mentioned.
1−エチニルシクロプロピルアミン塩酸塩のアミノ基に対する保護基は、実施例1−(11)に記載したトリフルオロアセチル基に限るものではなく、上記の「プロテクティブ・グループス・イン・オーガニック・シンセシス」に記載されているような通常よく知られたアミノ基の保護基で保護することも可能である。アミノ基の保護基としては、tert−ブトキシカルボニル基やエトキシカルボニル基のようなカーバメート系の保護基又はトリチル基などが挙げられる。例えば、1−エチニルシクロプロピルアミン塩酸塩のアミノ基をトリチル基で保護する事で1−エチニル−N−トリチルシクロプロピルアミンを得た後、実施例1−(12)及び1−(13)と同様の方法を実施し、さらに上記「プロテクティブ・グループス・イン・オーガニック・シンセシス」に記載されているような適切な脱保護方法を用いて、トリチル基及びテトラヒドロピラニル基を順次、あるいは同時に脱保護することによって、化合物1を得ることができる。 The protecting group for the amino group of 1-ethynylcyclopropylamine hydrochloride is not limited to the trifluoroacetyl group described in Example 1- (11), but the above-mentioned “Protective Groups in Organic Synthesis” It is also possible to protect with a well-known protecting group of an amino group as described in the above. Examples of the amino-protecting group include carbamate-based protecting groups such as tert-butoxycarbonyl group and ethoxycarbonyl group, and trityl groups. For example, after obtaining 1-ethynyl-N-tritylcyclopropylamine by protecting the amino group of 1-ethynylcyclopropylamine hydrochloride with a trityl group, Examples 1- (12) and 1- (13) The same method is performed, and the trityl group and the tetrahydropyranyl group are sequentially or simultaneously removed using an appropriate deprotection method as described in “Protective Groups in Organic Synthesis” above. By protecting, compound 1 can be obtained.
本発明において化合物1は注射用蒸留水に加えて撹拌溶解し、また必要に応じてpH調節剤を加えた後に用量調整し、このものをプラスチック製シリンジに充填した後、加熱滅菌等し注射剤とすることができる。 In the present invention, Compound 1 is dissolved by stirring in addition to distilled water for injection, and the dosage is adjusted after adding a pH adjuster as necessary, and after filling this into a plastic syringe, it is sterilized by heating and the like. It can be.
また、本発明において化合物1は、適宜、賦形剤や結合剤を加えて混合後、流動層造粒機等によって造粒、乾燥し、篩過し化合物1を含む顆粒として、これをカプセルに充填しカプセル剤としたり、打錠し錠剤とすることができる。 In the present invention, compound 1 is appropriately mixed with excipients and binders, then granulated and dried by a fluidized bed granulator or the like, and sieved as granules containing compound 1 into capsules. It can be filled into capsules or compressed into tablets.
本発明化合物の作用は以下の試験により確認された。 The action of the compound of the present invention was confirmed by the following test.
試験例1 抗菌活性評価試験
最小発育阻止濃度(MIC)測定はCLSI(クリニカル アンド ラボラトリー スタンダーズ インスティテュート)標準法に準じ、下記に示す微量液体希釈法を用いた。
Test Example 1 Antibacterial Activity Evaluation Test The minimum growth inhibitory concentration (MIC) was measured according to the CLSI (Clinical and Laboratory Standards Institute) standard method using the following micro liquid dilution method.
Legionella pneumophilia ATCC33152については、BCYE寒天培地で72時間培養した被検菌体を掻き取り、マクファーランド0.5相当に懸濁し、得られた懸濁液を10倍に希釈して接種菌液とした。接種菌液0.005mLを、被検化合物を含む、BYEα培地に接種し、35℃にて72時間培養した。 For Legionella pneumophilia ATCC 33152, scrape the test cells cultured for 72 hours on BCYE agar medium, suspend them in McFarland 0.5 equivalent, and dilute the resulting suspension 10 times to obtain the inoculum and did. 0.005 mL of the inoculated bacterial solution was inoculated into BYEα medium containing the test compound and cultured at 35 ° C. for 72 hours.
Haemophilus influenza ATCC43095については、チョコレートII寒天培地で24時間培養した被検菌体を掻き取り、マクファーランド0.5相当に懸濁し、得られた懸濁液を10倍に希釈して接種菌液とした。接種菌液0.005mLを、被検化合物を含む、HTM培地に接種し、35℃にて22時間培養した。 For Haemophilus influenza ATCC 43095, the test cells cultured for 24 hours in chocolate II agar medium are scraped off and suspended in McFarland 0.5 equivalent, and the resulting suspension is diluted 10 times to inoculate bacterial solution It was. 0.005 mL of the inoculum solution was inoculated into an HTM medium containing a test compound and cultured at 35 ° C. for 22 hours.
上述の菌株以外の菌株については、ハートインフュージョン寒天培地で1晩培養した被検菌体を掻き取り,マクファーランド0.5相当に懸濁し、得られた懸濁液を10倍に希釈して接種菌液とした。接種菌液0.005mLを、被検化合物を含む、カチオン調整ミューラーヒントン培地、または終濃度が5%となるようにヒト血清アルブミン(HSA)を添加したカチオン調整ミューラーヒントン培地に接種し、35℃にて18時間培養した。菌の発育が肉眼的に認められない最小の薬剤濃度をもってMICとした。 For strains other than the above strains, scrape the test cells cultured overnight on the heart infusion agar medium, suspend them in the equivalent of McFarland 0.5, and dilute the resulting suspension 10 times. The inoculum was used. Inoculate 0.005 mL of the inoculum into a cation-adjusted Mueller Hinton medium containing a test compound or a cation-adjusted Mueller Hinton medium supplemented with human serum albumin (HSA) to a final concentration of 5%. For 18 hours. The MIC was defined as the minimum drug concentration at which no bacterial growth was observed.
化合物1の試験結果を表1に示した。 The test results of Compound 1 are shown in Table 1.
試験例2 感受性分布試験
緑膿菌30株及び肺炎桿菌27株の臨床分離株の最小発育阻止濃度(MIC)を測定し、90%の菌株の発育を阻止したMICをMIC90として算出した。各臨床分離株のMIC測定は試験例1で示したものと同様に行った。
Minimum inhibitory concentration of clinical isolates of Test Example 2 Sensitivity Distribution Test Pseudomonas aeruginosa 30 strains and Klebsiella pneumoniae 27 strain (MIC) was determined, the MIC was prevented growth of 90% of the strains was calculated as MIC 90. The MIC measurement of each clinical isolate was performed in the same manner as shown in Test Example 1.
化合物1のMIC90は、緑膿菌では2μg/mLであり、肺炎桿菌では2μg/mLであった。 The MIC 90 for Compound 1 was 2 μg / mL for P. aeruginosa and 2 μg / mL for K. pneumoniae.
試験例3 感染動物における薬理効果試験
細菌として、緑膿菌TS88株(臨床分離株)を用いた。ハートインフュージョン寒天培地で1晩培養した菌体を掻き取り、生理食塩液に懸濁してマクファーランド3.5相当となるように調製した。得られた懸濁液を3w/v%ムチン含有生理食塩液にて約6x105CFU/mLとなるよう希釈し、接種菌液とした。マウス(ICR系、雄性、4.5週齢)に接種菌液0.5mLを腹腔内接種して感染させ、接種1時間後に化合物1(6.25mg/kg)又は媒体(11w/v%β−シクロデキストリンスルホブチルエーテルナトリウム塩(カプチゾル:登録商標、Ligand社))を静脈内投与した。
Test Example 3 Pharmacological effect test in infected animals Pseudomonas aeruginosa TS88 strain (clinical isolate) was used as a bacterium. The cells cultured overnight on the heart infusion agar medium were scraped off and suspended in a physiological saline solution so as to be equivalent to McFarland 3.5. The obtained suspension was diluted to 3 × 10 5 CFU / mL with 3 w / v% mucin-containing physiological saline to prepare an inoculum solution. Mice (ICR system, male, 4.5 weeks old) were infected by inoculating intraperitoneally with 0.5 mL of the inoculum, and compound 1 (6.25 mg / kg) or vehicle (11 w / v% β) 1 hour after inoculation -Cyclodextrin sulfobutyl ether sodium salt (Captisol: registered trademark, Ligand) was administered intravenously.
化合物1投与群での接種3日後における生存率は100%(8例中8例生存)、媒体投与群での生存率は0%(8例全例死亡)であった。 The survival rate 3 days after inoculation in the compound 1 administration group was 100% (8 of 8 cases survived), and the survival rate in the vehicle administration group was 0% (all of 8 cases died).
試験例4 溶解度測定試験
化合物1の過剰量に生理食塩水0.5mLを加え、塩酸を加えてpH4に調整した後、24時間振とうした。振とう後の溶解量をHPLC(高速液体クロマトグラフィー)により測定し、溶解度を測定した。本試験は25℃で実施した。
Test Example 4 Solubility Measurement Test 0.5 mL of physiological saline was added to an excess amount of Compound 1, adjusted to pH 4 by adding hydrochloric acid, and then shaken for 24 hours. The amount of dissolution after shaking was measured by HPLC (high performance liquid chromatography), and the solubility was measured. This test was conducted at 25 ° C.
化合物1の溶解度は、15.6mg/mLであった。 The solubility of Compound 1 was 15.6 mg / mL.
試験例5 血清タンパク結合試験
血清タンパク結合率は平衡透析法を用いて評価した。
Test Example 5 Serum Protein Binding Test Serum protein binding rate was evaluated using an equilibrium dialysis method.
ヒト血清及びマウス血清に化合物1のジメチルスルホキシド溶液を添加し、1μg/mL血清試料を調製した。平衡透析装置の膜の一方に各種血清試料、反対側にリン酸バッファー(pH7.4)を添加し、37℃で4時間インキュベートした。インキュベーション終了後、血清試料及びリン酸バッファーをサンプリングし、アセトニトリル/MeOH(9:1)を加え、遠心分離した。LC−MS/MSにて上清中化合物1の濃度を測定し、血清タンパク結合率を算出した。 A dimethyl sulfoxide solution of Compound 1 was added to human serum and mouse serum to prepare a 1 μg / mL serum sample. Various serum samples were added to one of the membranes of the equilibrium dialysis apparatus, and phosphate buffer (pH 7.4) was added to the other side, and incubated at 37 ° C. for 4 hours. At the end of the incubation, serum samples and phosphate buffer were sampled, acetonitrile / MeOH (9: 1) was added and centrifuged. The concentration of Compound 1 in the supernatant was measured by LC-MS / MS, and the serum protein binding rate was calculated.
化合物1のヒト及びマウスにおける血清タンパク結合率は、それぞれ59.3%、61.8%であった。 The serum protein binding rates of Compound 1 in humans and mice were 59.3% and 61.8%, respectively.
試験例6 ラット最大耐用量(MTD)試験
化合物1の0(対照)、400、600及び800mg/kgを雄1〜3例/群のSDラットに単回静脈内投与(10mL/kg、3mL/min)して、その最大耐用量(MTD)について検討した。対照群には、11%カプチゾル(登録商標、Ligand社)(pH4)を同様に投与した。
Test Example 6 Rat Maximum Tolerated Dose (MTD) Test Compound 1 0 (control), 400, 600 and 800 mg / kg were administered intravenously (10 mL / kg, 3 mL / kg) to 1 to 3 male / group SD rats. min) and the maximum tolerated dose (MTD) was examined. The control group was similarly administered with 11% Captisol (registered trademark, Ligand) (pH 4).
800mg/kg群の1/1例で死亡が認められた。死亡例では、投与中に紅涙、体をよじる及び鳴く行動が認められ、投与終了直後に死亡した。死因は明らかではなかった。 Death was observed in 1/1 cases in the 800 mg / kg group. In the case of death, red tears, kinking and squeaking were observed during administration, and the patient died immediately after the end of administration. The cause of death was not clear.
生存例では、400及び600mg/kg群で紅涙、体をよじる及び鳴く行動、尾の変色(青紫色)、600mg/kg群で腹臥位が認められた。 In the surviving cases, red tears, kinking and crying behavior, discoloration of the tail (blue purple), and prone position in the 600 mg / kg group were observed in the 400 and 600 mg / kg groups.
剖検では特筆すべき変化は認められなかった。 There were no notable changes at autopsy.
対照群では著変は認められなかった。 There was no marked change in the control group.
以上より、化合物1を雄性ラットに単回静脈内投与した時、800mg/kgで死亡が認められ、MTDは600mg/kgと推定された。 From the above, when Compound 1 was administered to male rats once intravenously, death was observed at 800 mg / kg, and the MTD was estimated to be 600 mg / kg.
試験例7 hERGチャネル結合試験
ヒト型hERGチャネル安定発現細胞より調製した膜画分を、結合試験用緩衝液[終濃度;10mM HEPES(pH7.4)、71.5mM NaCl、60mM KCl、2mM MgCl2、1mM CaCl2、0.1% BSA]にて希釈した。予め試験化合物が分注された96穴プレートに、膜画分(終濃度30μg/mL)、[35S]MK−499(終濃度0.5nM)を添加して、室温で75分間反応させた。反応液をGF/Cフィルタ−プレート上に吸引濾過し、洗浄用緩衝液[終濃度;10mM HEPES(pH7.4)、131.5mM NaCl、2mM MgCl2、1mM CaCl2]で5回洗浄し、45℃で乾燥させた。乾燥したフィルタープレートにMicroScint−Oを添加し、トップカウントNXTを用いて放射活性を測定した。
Test Example 7 hERG Channel Binding Test A membrane fraction prepared from cells that stably express human hERG channel was subjected to binding test buffer [final concentration: 10 mM HEPES (pH 7.4), 71.5 mM NaCl, 60 mM KCl, 2 mM MgCl 2]. 1 mM CaCl 2 , 0.1% BSA]. The membrane fraction (final concentration 30 μg / mL) and [ 35 S] MK-499 (final concentration 0.5 nM) were added to a 96-well plate into which the test compound had been dispensed in advance, and allowed to react at room temperature for 75 minutes. . The reaction solution was suction filtered onto a GF / C filter plate, and washed 5 times with a washing buffer [final concentration: 10 mM HEPES (pH 7.4), 131.5 mM NaCl, 2 mM MgCl 2 , 1 mM CaCl 2 ]. Dry at 45 ° C. MicroScint-O was added to the dried filter plate, and the radioactivity was measured using TopCount NXT.
上記反応において、試験化合物存在下で得られた[35S]MK−499結合量との差を特異的結合量とし、MK−499存在下で得られた[35S]MK−499結合量を非特異的結合量とした。試験化合物非存在下での特異的結合量に対する試験化合物存在下での特異的結合量から、濃度反応曲線のシグモイド解析を行ない、IC50値を算出した。 In the above reaction, the difference from the [ 35 S] MK-499 binding amount obtained in the presence of the test compound was defined as the specific binding amount, and the [ 35 S] MK-499 binding amount obtained in the presence of MK-499 was determined as the specific binding amount. Non-specific binding amount. From the specific binding amount in the presence of the test compound relative to the specific binding amount in the absence of the test compound, a sigmoid analysis of the concentration response curve was performed to calculate an IC 50 value.
化合物1のIC50値は、30μM以上であった。 The IC 50 value of Compound 1 was 30 μM or more.
試験例8 麻酔下モルモット心血管系に対する安全性薬理試験
化合物1の0(対照)及び70mg/kgを30分間で麻酔下モルモットに静脈内持続投与(5mL/kg/30min)し、心電図に対する影響を検討した。対照群には、11%カプチゾル(登録商標、Ligand社)(pH4)を同様に投与した。人工呼吸及びペントバルビタール麻酔下において、心電計を用いて四肢標準誘導(第II誘導)心電図を測定し、試験物質投与開始15分前から投与終了30分後まで5分間隔で解析を実施した。Bazett式(QTcB=QT/√RR)を用いて補正QTcBを求め、ベースライン値[試験物質の投与前3ポイント(−15、−10及び−5分)の平均値]からの変化率(ΔQTcB)を算出した。
Test Example 8 Safety pharmacological test for anesthetized guinea pig cardiovascular system Compound 0 (control) and 70 mg / kg were administered intravenously to anesthetized guinea pigs for 30 minutes (5 mL / kg / 30 min), and the effect on the electrocardiogram was observed. investigated. The control group was similarly administered with 11% Captisol (registered trademark, Ligand) (pH 4). Under artificial respiration and pentobarbital anesthesia, limb standard lead (lead II) electrocardiogram was measured using an electrocardiograph, and analysis was performed at 5-minute intervals from 15 minutes before the start of test substance administration to 30 minutes after the end of administration. . The corrected QTcB was determined using the Bazett equation (QTcB = QT / √RR), and the rate of change (ΔQTcB from the baseline value [average value of 3 points (−15, −10 and −5 minutes) before administration of test substance)] ) Was calculated.
化合物1の投与終了時のΔQTcBは−0.1%、最大で+0.2%(投与開始後20分及び45分)であり(対照群:−4.6〜−1.0%)、QTcBについて被験物質投与による明らかな影響は認められなかった。化合物1は安全性にも優れることが確認できた。 ΔQTcB at the end of administration of Compound 1 was −0.1%, and maximum was + 0.2% (20 minutes and 45 minutes after the start of administration) (control group: −4.6 to −1.0%), QTcB There was no apparent effect of test substance administration. It was confirmed that Compound 1 was excellent in safety.
本発明の新規なヒドロキサム酸誘導体は、緑膿菌をはじめとするグラム陰性細菌及びその薬剤耐性菌に強い抗菌活性を有し、感染症の予防及び/又は治療のための医薬として利用可能である。 The novel hydroxamic acid derivative of the present invention has strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant bacteria, and can be used as a medicament for the prevention and / or treatment of infectious diseases. .
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