JPH075606B2 - New cephalosporin compounds - Google Patents
New cephalosporin compoundsInfo
- Publication number
- JPH075606B2 JPH075606B2 JP15407190A JP15407190A JPH075606B2 JP H075606 B2 JPH075606 B2 JP H075606B2 JP 15407190 A JP15407190 A JP 15407190A JP 15407190 A JP15407190 A JP 15407190A JP H075606 B2 JPH075606 B2 JP H075606B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- pyridone
- nch
- diphenylmethyloxy
- methoxybenzyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は新規なβ−ラクタム系抗菌剤及びその医薬とし
て許容される塩、及びエステル類に関する。さらに詳細
には本発明は抗菌活性を有する新規なセファロスポリン
系化合物及びその医薬として許容される塩、及びエステ
ル並びにその用途に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to a novel β-lactam antibacterial agent and pharmaceutically acceptable salts and esters thereof. More specifically, the present invention relates to a novel cephalosporin compound having antibacterial activity, a pharmaceutically acceptable salt and ester thereof, and uses thereof.
［従来の技術及び発明が解決しようとする課題］ セファロスポリン系抗生物質はグラム陽性菌、グラム陰
性菌に対し幅広い抗菌活性を示し、すでに種々の半合成
セファロスポリン系化合物が市販され、各種感染性疾病
の治療剤として臨床的に用いられている。しかしなが
ら、これらの化合物の中で緑膿菌や変形菌に対して抗菌
活性を示す治療剤は数少ない、またこれらの化合物の多
くは耐性菌により産生されるβ−ラクタマーゼに対して
不安定であり、現在臨床上問題とされている緑膿菌に対
する抗菌活性が低い等の欠点がある。[Prior Art and Problems to be Solved by the Invention] Cephalosporin antibiotics show a wide range of antibacterial activities against Gram-positive and Gram-negative bacteria, and various semi-synthetic cephalosporin-based compounds have already been marketed. It is clinically used as a therapeutic agent for infectious diseases. However, among these compounds, few therapeutic agents exhibiting antibacterial activity against Pseudomonas aeruginosa and Pseudomonas aeruginosa, and many of these compounds are unstable to β-lactamase produced by resistant bacteria, There are drawbacks such as low antibacterial activity against Pseudomonas aeruginosa, which is currently a clinical problem.
［課題を解決するための手段］ 本発明者らは既に特願昭63-164165号において、セファ
ロスポリンの３位にビニル基を介して１−置換−５−ヒ
ドロキシ−４−ピリドン−２−イル基を有する新規セフ
ァロスポリン誘導体が広範囲の病原菌に対し強い活性を
有することを見出した。今回更に、前者の５−ヒドロキ
シ−４−ピリドン構造に着目し研究を発展させた結果式
（Ｉ）で示される新規セフェム化合物が、グラム陽性
菌、及びグラム陰性菌に対し幅広く強力な抗菌活性を有
しており、特に緑膿菌に対し極めて強い抗菌活性を示す
こと、さらに種々のβ−ラクタマーゼ産生菌に対しても
強い抗菌活性を示すこと、しかも低毒性でよく吸収され
ること、等を見いだして本発明を完成した。[Means for Solving the Problems] In the Japanese Patent Application No. 63-164165, the present inventors have already described 1-substituted-5-hydroxy-4-pyridone-2- via a vinyl group at the 3-position of cephalosporins. It was found that the novel cephalosporin derivative having an yl group has strong activity against a wide range of pathogenic bacteria. Furthermore, as a result of further research focusing on the former 5-hydroxy-4-pyridone structure, the novel cephem compound represented by the formula (I) has a broad and powerful antibacterial activity against Gram-positive and Gram-negative bacteria. In particular, it exhibits extremely strong antibacterial activity against Pseudomonas aeruginosa, and further exhibits strong antibacterial activity against various β-lactamase-producing bacteria, and is well absorbed with low toxicity. Found and completed the present invention.
したがって本発明は、抗菌剤として有用な一般式（Ｉ） ［式中、R1は水素原子、低級アルキル基、低級アルケニ
ル基、又はカルボキシ基又は保護されたカルボキシ基で
置換されている低級アルキル基、低級アルケニル基、R2
は水素原子又は置換基を有しても良い低級アルキル基、
低級アルケニル基を表す。］で表される新規セファロス
ポリン系化合物及びその薬理上許容される塩、又はエス
テル及びそれらを有効成分として含有する抗菌剤に関す
る。本発明の式（Ｉ）で示される化合物の薬理学上許容
される塩としては、医学上許容される塩類、とくに慣用
の非毒性塩、例えばナトリウム塩、カリウム塩等のアル
カリ金属塩、カルシウム塩、マグネシウム塩等のアルカ
リ土類金属塩、アンモニウム塩、有機塩基との塩類、例
えばトリエチルアミン塩、ピリジン塩、エタノールアミ
ン塩、トリエタノールアミン塩、ジシクロヘキシルアミ
ン塩等の有機アミン塩及びリジン、アルギニンのような
塩基性アミノ酸塩が挙げられる。一般式（Ｉ）の化合物
のR4で示される、１もしくは複数の置換基を有してもよ
い炭素数１−４のアルキル基の置換基の例としては、水
酸基及び、メトキシ基、エトキシ基等の低級アルコキシ
基及び、アミノ基及び、メチルアミノ基、ジメチルアミ
ノ基等のモノ及びジ低級アルキル置換アミノ基及び、ホ
ルミル基、アセチル基等のアシル基、低級アルコキシカ
ルボニル基、カルボキシル基、カルバモイル基、シアノ
基、フッ素原子、塩素原子、ニトロ基、スルホン酸基、
スルホン酸アミド基、メルカプト基、アルキルチオ基、
アルキルスルホニル基、アルキルスルフィニル基等が挙
げられる。本発明の化合物（Ｉ）は次に示す方法によっ
て製造することができる。Therefore, the present invention provides a compound of general formula (I) useful as an antibacterial agent. [Wherein R 1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkyl group, a lower alkenyl group, or a R 2 which is substituted with a carboxy group or a protected carboxy group.
Is a hydrogen atom or a lower alkyl group which may have a substituent,
Represents a lower alkenyl group. ] The novel cephalosporin type compound represented by these, its pharmacologically acceptable salt, or ester, and the antibacterial agent containing them as an active ingredient. The pharmacologically acceptable salt of the compound represented by the formula (I) of the present invention includes medically acceptable salts, particularly conventional non-toxic salts such as alkali metal salts such as sodium salt and potassium salt, calcium salt. Alkaline earth metal salts such as magnesium salts, ammonium salts, salts with organic bases such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, organic amine salts such as dicyclohexylamine salts and lysine, arginine, etc. Basic amino acid salts. Examples of the substituent of the alkyl group having 1 to 4 carbon atoms which may have one or more substituents represented by R 4 of the compound of the general formula (I) include a hydroxyl group, a methoxy group and an ethoxy group. Lower alkoxy groups such as, and amino groups, mono- and di-lower alkyl-substituted amino groups such as methylamino group and dimethylamino group, and acyl groups such as formyl group and acetyl group, lower alkoxycarbonyl groups, carboxyl groups, carbamoyl groups , Cyano group, fluorine atom, chlorine atom, nitro group, sulfonic acid group,
Sulfonic acid amide group, mercapto group, alkylthio group,
Examples thereof include an alkylsulfonyl group and an alkylsulfinyl group. The compound (I) of the present invention can be produced by the following method.
すなわち次式（II） ［式中、R1は前記と同意義、Ｚは水素原子、又はアミノ
保護基、Ｙは水素原子又はカルボキシル保護基、Ｘはハ
ロゲン原子を表す。］で示される化合物に、次式（II
I） ［式中、R2は前記と同意義R3は水素原子又は水酸基の保
護基を表す。］で示される化合物を反応せしめることに
よって製造できる。一般式（Ｉ）のアミノ保護基Ｚとし
ては第３級ブトキシカルボニル基のごときアルコキシカ
ルボニル基、又はホルミル基、クロロアセチル基のごと
きアシル基もしくはトリチル基など酸加水分解等で容易
に脱離できる通常のアミノ保護基である。カルボキシル
基保護基Ｙとしてはｐ−メトキシベンジル基、ジフェニ
ルメチル基、ｐ−ニトロベンジル基、アリル基、低級ア
ルキル基、低級アルコキシ基等通常セファロスポリンに
用いられる保護基が挙げられる。一般式（II）のエノー
ル性水酸基の保護基Ｗとしては通常セファロスポリンに
おいてカルボキシル基の保護基として用いられるものが
使用でき、例えばｐ−メトキシベンジル基、ジフェニル
メチル基、ｐ−ニトロベンジル基、アリル基、低級アル
キル基、低級アルコキシ基が挙げられる。That is, the following equation (II) [Wherein R 1 has the same meaning as described above, Z represents a hydrogen atom or an amino protecting group, Y represents a hydrogen atom or a carboxyl protecting group, and X represents a halogen atom. ] To the compound represented by the following formula (II
I) [In the formula, R 2 has the same meaning as described above, and R 3 represents a hydrogen atom or a hydroxyl-protecting group. ] It can manufacture by making the compound shown by these react. As the amino-protecting group Z in the general formula (I), an alkoxycarbonyl group such as a tertiary butoxycarbonyl group, or an acyl group such as a formyl group or a chloroacetyl group, or a trityl group, which can be easily eliminated by acid hydrolysis or the like, is usually used. Is an amino-protecting group of. Examples of the carboxyl group protecting group Y include p-methoxybenzyl group, diphenylmethyl group, p-nitrobenzyl group, allyl group, lower alkyl group, lower alkoxy group and other protecting groups usually used in cephalosporins. As the protective group W for the enolic hydroxyl group of the general formula (II), those usually used as a protective group for a carboxyl group in cephalosporin can be used, and examples thereof include p-methoxybenzyl group, diphenylmethyl group, p-nitrobenzyl group, Examples thereof include an allyl group, a lower alkyl group and a lower alkoxy group.
この化合物（II）と（III）との反応は、通常、アセト
ン、ジオキサン、アセトニトリル、クロロホルム、塩化
メチレン、テトラヒドロフラン、酢酸エチル、N,N−ジ
メチルホルムアミド、ピリジンのような慣用溶媒又はこ
の反応に悪影響を与えない他の有機溶媒中で行なわれ
る。これらの溶媒は水と混合して使用してもよい。The reaction between the compounds (II) and (III) usually adversely affects the conventional solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or the reaction. In other organic solvents that do not give These solvents may be used as a mixture with water.
反応温度は特に限定されず、反応は通常、冷却下ないし
加温下に行なわれる。The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.
これらの方法により得られる生成物は、本発明の目的化
合物（Ｉ）であるか、又は目的化合物（Ｉ）のアミノ
基、カルボキシル基、並びにピリドン環上の水酸基の保
護体であり、従って必要により常法にて、夫々の保護基
の除去を行なう。カルボキシル保護基及びアミノ保護基
の除去の方法は脱離される保護基の種類により適宜選択
される。アミノ保護基の脱離反応には加水分解、還元及
び保護基がアシル基である化合物に対してはイミノハロ
ゲン化剤、次いでイミノエーテル化剤を作用させた後、
必要に応じて加水分解する方法等の慣用される任意の方
法を適用できる。酸を用いた加水分解の方法は一般的な
方法の一つであり、たとえばアルコキシカルボニル基、
ホルミル基、トリチル基等の基の脱離に適用される。ま
た使用される酸としては、ギ酸、トリフルオル酢酸、塩
酸等がアミノ保護基の種類に応じて適宜選択される。反
応は無溶媒下又は水、親水性有機溶媒もしくはそれらの
混合溶媒の存在下のいずれでも行なうことができる。ま
たトリフルオル酢酸を用いる場合はアニソールの存在下
に反応を行なってもよい。カルボキシル保護基の脱離反
応には加水分解、還元等慣用される任意の方法を適用で
きる。酸を用いた加水分解は一般的方法の一つであり、
たとえばシリル基、ｐ−メトキシベンジル基、ジフェニ
ルメチル基等の脱離に適用される。ピリドン環上の水酸
基の保護基の脱離反応についても加水分解、還元等慣用
される任意の方法が適用できる。酸あるいは塩基を用い
た加水分解は一般的方法の一つであり、例えばｐ−メト
キシベンジル基、ジフェニルメチル基等の脱離には酸
が、アセチル基、ベンゾイル基等のアシル基の脱離には
塩基が適用される。The product obtained by these methods is the objective compound (I) of the present invention or a protected form of the amino group, the carboxyl group and the hydroxyl group on the pyridone ring of the objective compound (I), and therefore, if necessary, Each protecting group is removed by a conventional method. The method for removing the carboxyl protecting group and the amino protecting group is appropriately selected depending on the type of the protecting group to be eliminated. For the elimination reaction of the amino protecting group, hydrolysis, reduction, and after applying an imino halogenating agent to a compound in which the protecting group is an acyl group and then an imino etherifying agent,
Any conventional method such as a method of hydrolysis can be applied if necessary. The hydrolysis method using an acid is one of the general methods, for example, an alkoxycarbonyl group,
It is applied to elimination of groups such as formyl group and trityl group. As the acid to be used, formic acid, trifluoroacetic acid, hydrochloric acid or the like is appropriately selected according to the kind of amino protecting group. The reaction can be carried out without solvent or in the presence of water, a hydrophilic organic solvent or a mixed solvent thereof. When trifluoroacetic acid is used, the reaction may be performed in the presence of anisole. For the elimination reaction of the carboxyl protecting group, any conventional method such as hydrolysis and reduction can be applied. Hydrolysis with acid is one of the common methods,
For example, it is applied to elimination of silyl group, p-methoxybenzyl group, diphenylmethyl group and the like. For the elimination reaction of the protective group for the hydroxyl group on the pyridone ring, any conventional method such as hydrolysis or reduction can be applied. Hydrolysis using an acid or a base is one of the general methods. For example, for elimination of p-methoxybenzyl group, diphenylmethyl group and the like, acid is used for elimination of acyl group such as acetyl group and benzoyl group. Base is applied.
以上の如くして得られた一般式（Ｉ）の化合物は反応混
合物中より常法により採取される。The compound of general formula (I) thus obtained is collected from the reaction mixture by a conventional method.
例えば、アンバーライトXAD-2（ロームアンドハース社
製）、ダイアイオンHP-20又はセビビーズSP207（三菱化
成（株）製）等の吸着製レジンによる精製、沈澱法、結
晶化法等を適宜組合せることにより達成される。For example, a purification using an adsorption resin such as Amberlite XAD-2 (manufactured by Rohm and Haas), Diaion HP-20 or Sevibeads SP207 (manufactured by Mitsubishi Kasei Co., Ltd.), a precipitation method, a crystallization method, etc. are appropriately combined It is achieved by
一般式（Ｉ）で示される化合物又はその塩を主成分とし
て含有する抗菌剤は主として静注、筋注等の注射剤、カ
プセル剤、錠剤、散剤等の経口剤もしくは直腸投与剤、
油脂性座薬、水溶性座薬等の種々の剤形で使用される。
これらの各種製剤は通常用いられている賦型剤、増量
剤、結合剤、湿潤化剤、崩壊剤、表面活性剤、滑沢剤、
分散剤、緩衝剤、保存剤、溶解補助剤、防腐剤、矯味矯
臭剤、無痛化剤等を用いて常法により製造することがで
きる。製剤法の具体例は後記の実施例によってさらに詳
細に説明する。The antibacterial agents containing the compound represented by the general formula (I) or a salt thereof as a main component are mainly injections such as intravenous injection and intramuscular injection, oral agents such as capsules, tablets and powders, or rectal administration agents,
It is used in various dosage forms such as oily suppositories and water-soluble suppositories.
These various preparations are usually used excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants,
It can be produced by a conventional method using a dispersant, a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent and the like. A specific example of the formulation method will be described in more detail with reference to Examples below.
投与量は症状や年齢、性別等を考慮して、個々の場合に
応じて適宜決定されるが、通常成人１日あたり250-3000
mgであり、これを１日１−４回に分けて投与する。The dose is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc., but is usually 250-3000 per adult per day.
mg, which is administered in 1 to 4 divided doses daily.
［発明の効果］ 本発明の目的化合物（Ｉ）又はその塩類は新規化合物で
あり、グラム陽性菌及び陰性菌を含む広範囲の病原性微
生物の発育を阻止する高い抗菌活性を示す。目的化合物
（Ｉ）の有用性を示すために、この発明の化合物（Ｉ）
の中のいくつかについて寒天希釈法により測定した抗菌
活性を第１表に示す。[Effect of the Invention] The object compound (I) of the present invention or a salt thereof is a novel compound, and exhibits high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive bacteria and negative bacteria. In order to show the usefulness of the target compound (I), the compound (I) of the present invention
Table 1 shows the antibacterial activity measured by the agar dilution method for some of the above.
［実施例］ 本発明は、更に以下の製造例及び実施例で詳しく説明さ
れるが、これらは本発明を限定するものではなく、本発
明の範囲を逸脱しない範囲で種々の変形及び修正が可能
である事は言うまでも無い。 [Examples] The present invention will be further described in detail in the following production examples and examples, but these do not limit the present invention, and various variations and modifications can be made without departing from the scope of the present invention. Needless to say.
なお、実施例中のNMRデータは断りのない限り90M Hzを
用い、重水中の場合には、水のピークをδ値4.82とした
時のδ値を示し、他の重溶媒の場合には、TMSを基準と
した時のδ値を示した。The NMR data in the examples used 90 MHz unless otherwise specified, in the case of heavy water, showing the δ value when the water peak is δ value 4.82, in the case of other heavy solvents, The δ value based on TMS is shown.
製造例１ ２−メチルアミノメチル−１−ジフェニルメ
チルオキシ−５−ｐ−メトキシベンジルオキシ−４−ピ
リドン １−ジフェニルメチルオキシ−２−ヒドロキシメチル−
５−ｐ−メトキシベンジルオキシ−４−ピリドン13.3g
をジクロルメタン300mlに懸濁し、−10〜−15℃でN,N−
ジメチルホルムアミド0.3ml及び塩化チオニル6.6mlを加
えた。Production Example 1 2-Methylaminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone 1-Diphenylmethyloxy-2-hydroxymethyl-
13.3 g of 5-p-methoxybenzyloxy-4-pyridone
Was suspended in 300 ml of dichloromethane, and N, N-at −10 to −15 ° C.
0.3 ml of dimethylformamide and 6.6 ml of thionyl chloride were added.
氷冷下1.5時間反応させた後飽和炭酸水素ナトリウム水
溶液300mlで洗浄し無水MgSO4で乾燥した。溶媒を減圧下
留去し、２−クロルメチル誘導体を得た。精製する事な
しにこの２−クロルメチル体をジクロルメタン100mlに
溶解し更に40％のメチルアミン水溶液100mlを加え室温
で17時間攪拌した。反応終了後有機層を水洗し、溶解
し、無水MgSO4で乾燥後溶媒を減圧下留去した。得られ
た残渣をカラムクロマトグラフィー［Wakogel C-300（W
ako），(CHCl3-CH3OH)］で精製し、表題の化合物8.3gを
油状物として得た。After reacting for 1.5 hours under ice cooling, the mixture was washed with 300 ml of a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure to obtain a 2-chloromethyl derivative. Without purification, the 2-chloromethyl derivative was dissolved in 100 ml of dichloromethane and 100 ml of 40% aqueous methylamine solution was added, followed by stirring at room temperature for 17 hours. After completion of the reaction, the organic layer was washed with water, dissolved, dried over anhydrous MgSO4, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography [Wakogel C-300 (W
ako), (CHCl 3 -CH 3 OH)] to give the title compound (8.3 g) as an oil.
NMR(CDCl3)δ： 2.32(3H,s,NCH3),3.50(2H,s,NCH2),3.80(3H,s,OCH3),4.
68(2H,s,OCH2),6.18（1H,s,pyridone 3-H）,6.29（1H,
s,pyridone 6-H）,6.65(1H,s,CHPh2),6.84,7.17（4H,AB
q,arom）,7.2-7.5（10H,m,arom） 製造例２ ２−ｎ−ヘキシルアミノメチル−１−ジフェ
ニルメチルオキシ−５−ｐ−メトキシベンジルオキシ−
４−ピリドン 製造例１に準じて、１−ジフェニルメチルオキシ−２−
ヒドロキシメチル−５−ｐ−メトキシベンジルオキシ−
４−ピリドン1g及びｎ−ヘキシルアミンより表題の化合
物720mgを得た。NMR (CDCl 3 ) δ: 2.32 (3H, s, NCH 3 ), 3.50 (2H, s, NCH 2 ), 3.80 (3H, s, OCH 3 ), 4.
68 (2H, s, OCH 2 ), 6.18 (1H, s, pyridone 3-H), 6.29 (1H,
s, pyridone 6-H), 6.65 (1H, s, C H Ph 2 ), 6.84,7.17 (4H, AB
q, arom), 7.2-7.5 (10H, m, arom) Production Example 2 2-n-hexylaminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-
4-Pyridone According to Production Example 1, 1-diphenylmethyloxy-2-
Hydroxymethyl-5-p-methoxybenzyloxy-
720 mg of the title compound was obtained from 1 g of 4-pyridone and n-hexylamine.
NMR(CDCl3)δ： 0.80(3H,br t,CH3),1.1-1.3(8H,m,(CH2)4),2.4(2H,m,NC
H2),3.45(2H,s,NCH2),4.60(2H,s,OCH2),6.12（1H,s,pyr
idone 3-H）,6.20（1H,s,pyridone 6-H）,6.65(1H,s,CH
Ph2),6.75,7.10（4H,ABq,J＝8 Hz arom）,7.1-7.3（10
H,m,arom） 製造例３ ２−ヒドロキシエチルアミノメチル−１−ジ
フェニルメチルオキシ−５−ｐ−メトキシベンジルオキ
シ−４−ピリドン 製造例１に準じて、１−ジフェニルメチルオキシ−２−
ヒドロキシメチル−５−ｐ−メトキシベンジルオキシ−
４−ピリドン1g及びモノエタノールアミンより表題の化
合物520gを無色結晶として得た。NMR (CDCl 3 ) δ: 0.80 (3H, brt, CH 3 ), 1.1-1.3 (8H, m, (CH 2 ) 4 ), 2.4 (2H, m, NC
H 2 ), 3.45 (2H, s, NCH 2 ), 4.60 (2H, s, OCH 2 ), 6.12 (1H, s, pyr
idone 3-H), 6.20 (1H, s, pyridone 6-H), 6.65 (1H, s, C H
Ph 2 ), 6.75,7.10 (4H, ABq, J = 8 Hz arom), 7.1-7.3 (10
H, m, arom) Production Example 3 2-Hydroxyethylaminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone According to Production Example 1, 1-diphenylmethyloxy-2-
Hydroxymethyl-5-p-methoxybenzyloxy-
From 1 g of 4-pyridone and monoethanolamine, 520 g of the title compound was obtained as colorless crystals.
NMR(CDCl3)δ： 2.15(2H,m,CH2),2.55(2H,m,CH2),3.50(2H,s,NCH2),3.70
(3H,s,OCH3),4.60(2H,s,OCH2),6.05（1H,s,pyridone 3-
H）,6.25（1H,s,pyridone 6-H）,6.60(1H,s,CHPh2),6.7
5（2H,d,arom）,7.1-7.4（12H,m,arom） 製造例４ ２−イソプロピルアミノメチル−１−ジフェ
ニルメチルオキシ−５−ｐ−メトキシベンジルオキシ−
４−ピリドン 製造例１に準じて、１−ジフェニルメチルオキシ−２−
ヒドロキシメチル−５−ｐ−メトキシベンジルオキシ−
４−ピリドン1g及びイソプロピルアミンより表題の化合
物620mgを油状物として得た。NMR (CDCl 3 ) δ: 2.15 (2H, m, CH 2 ), 2.55 (2H, m, CH 2 ), 3.50 (2H, s, NCH 2 ), 3.70
(3H, s, OCH 3 ), 4.60 (2H, s, OCH 2 ), 6.05 (1H, s, pyridone 3-
H), 6.25 (1H, s, pyridone 6-H), 6.60 (1H, s, C H Ph 2 ), 6.7
5 (2H, d, arom), 7.1-7.4 (12H, m, arom) Production Example 4 2-isopropylaminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-
4-Pyridone According to Production Example 1, 1-diphenylmethyloxy-2-
Hydroxymethyl-5-p-methoxybenzyloxy-
620 mg of the title compound was obtained as an oil from 1 g of 4-pyridone and isopropylamine.
NMR(CDCl3)δ： 0.95（6H,d,J＝6.4 Hz,CH(CH3)2),2.55(1H,m,CH(C
H3)2),3.45(2H,s,NCH2),3.70(3H,s,OCH3),4.65(2H,s,OC
H2),6.15（1H,s,pyridone 3-H）,6.22（1H,s,pyridone
6-H）,6.60(1H,s,CHPh2),6.75（2H,d,arom）,7.1-7.4
（12H,m,arom） 製造例５ ２−アリルアミノメチル−１−ジフェニルメ
チルオキシ−５−ｐ−メトキシベンジルオキシ−４−ピ
リドン 製造例１に準じて、１−ジフェニルメチルオキシ−２−
ヒドロキシメチル−５−ｐ−メトキシベンジルオキシ−
４−ピリドン1g及びアリルアミンより表題の化合物600m
gを油状物として得た。NMR (CDCl 3 ) δ: 0.95 (6H, d, J = 6.4 Hz, CH (CH 3 ) 2 ) , 2.55 (1H, m, C H (C
H 3) 2), 3.45 ( 2H, s, NCH 2), 3.70 (3H, s, OCH 3), 4.65 (2H, s, OC
H 2 ), 6.15 (1H, s, pyridone 3-H), 6.22 (1H, s, pyridone
6-H), 6.60 (1H, s, C H Ph 2 ), 6.75 (2H, d, arom), 7.1-7.4
(12H, m, arom) Production Example 5 2-allylaminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone According to Production Example 1, 1-diphenylmethyloxy-2-
Hydroxymethyl-5-p-methoxybenzyloxy-
4-pyridone 1g and the title compound 600m from allylamine
g was obtained as an oil.
NMR(CDCl3)δ： 3.05（2H,m,CH2 CH=),3.48(2H,s,NCH2),3.72(3H,s,OC
H3),4.62(2H,s,OCH2),4.9-5.2（2H,m,＝CH2）,5.65(1H,
m,CH2CH=),6.10（1H,s,pyridone 3-H）,6.25（1H,s,pyr
idone 6-H）,6.75（2H,d,arom）,7.1-7.4（12H,m,aro
m） 実施例１ ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−メトキシイミノアセトアミド］−３−
（Ｎ−メチル−Ｎ−（１−ジフェニルメチルオキシ−５
−ｐ−メトキシベンジルオキシ−４−ピリドン−２−イ
ルメチル）アミノメチル−３−セフェム−４−カルボン
酸 ｐ−メトキシベンジルエステル ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−メトキシイミノアセトアミド］−３−
クロルメチル−３−セフェム−４−カルボン酸 ｐ−メ
トキシベンジルエステル 800mgを窒素置換下アセトン1
5mlに溶解しヨウ化ナトリウム160mgを加え室温で１時間
攪拌する。この溶液を５℃に冷却後、参考例１で得た２
−メチルアミノメチル−１−ジフェニルメチルオキシ−
５−ｐ−メトキシベンジルオキシ−４−ピリドン480mg
を加え５℃で４時間攪拌する。反応終了後反応液を濃縮
乾固し残渣を塩化メチレン50mlに溶解し、水及び５％亜
硫酸水素ナトリウム水で洗浄し硫酸マグネシウムで乾燥
する。減圧下溶媒を留去し残渣をカラムクロマトグラフ
ィー［Wakogel C-300（Wako），CHCl3-CH3OH）］で精製
し、表題の化合物850mgを得た。NMR (CDCl 3 ) δ: 3.05 (2H, m, C H 2 CH =), 3.48 (2H, s, NCH 2 ), 3.72 (3H, s, OC
H 3 ), 4.62 (2H, s, OCH 2 ), 4.9-5.2 (2H, m, = CH 2 ), 5.65 (1H,
m, CH 2 C H =), 6.10 (1H, s, pyridone 3-H), 6.25 (1H, s, pyr
idone 6-H), 6.75 (2H, d, arom), 7.1-7.4 (12H, m, aro
m) Example 1 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
(N-methyl-N- (1-diphenylmethyloxy-5
-P-Methoxybenzyloxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
Chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 800 mg was replaced with acetone 1 under nitrogen substitution.
Dissolve in 5 ml, add 160 mg of sodium iodide and stir at room temperature for 1 hour. This solution was cooled to 5 ° C. and then obtained in Reference Example 1-2.
-Methylaminomethyl-1-diphenylmethyloxy-
5-p-methoxybenzyloxy-4-pyridone 480mg
Is added and the mixture is stirred at 5 ° C. for 4 hours. After completion of the reaction, the reaction solution is concentrated to dryness, the residue is dissolved in 50 ml of methylene chloride, washed with water and 5% aqueous sodium hydrogen sulfite and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography [Wakogel C-300 (Wako), CHCl 3 -CH 3 OH)] to obtain 850 mg of the title compound.
NMR(CDCl3)δ： 2.05(3H,s,NCH3),3.0-3.6（6H,m,2-H,3′‐H,NCH2),3.7
0(6H,br s,OCH3×２）,4.00(3H,s,OCH3),4.68(2H,s,C
H2),4.85(1H,d,J=5 Hz,6-H),5.05（1H,dd,J＝5 Hz,J＝8
Hz,7-H）,5.80（1H,s,pyridone 3-H）,6.3−7.3（37H,
m） 実施例２ ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−ｔ−ブトキシカルボニルメトキシイミ
ノアセトアミド］−３−（Ｎ−メチル−Ｎ−（１−ジフ
ェニルメチルオキシ−５−ｐ−メトキシベンジルオキシ
−４−ピリドン−２−イルメチル）アミノメチル−３−
セフェム−４−カルボン酸 ｐ−メトキシベンジルエス
テル ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−ｔ−ブトキシカルボニルメトキシイミ
ノアセトアミド］−３−クロルメチル−３−セフェム−
４−カルボン酸 ｐ−メトキシベンジルエステル及び２
−メチルアミノメチル−１−ジフェニルメチルオキシ−
５−ｐ−メトキシベンジルオキシ−４−ピリドンを用い
て実施例１と同様に処理して表題の化合物を得た。NMR (CDCl 3 ) δ: 2.05 (3H, s, NCH 3 ), 3.0-3.6 (6H, m, 2-H, 3′-H, NCH 2 ), 3.7
0 (6H, br s, OCH 3 × 2), 4.00 (3H, s, OCH 3 ), 4.68 (2H, s, C
H 2 ), 4.85 (1H, d, J = 5 Hz, 6-H), 5.05 (1H, dd, J = 5 Hz, J = 8
Hz, 7-H), 5.80 (1H, s, pyridone 3-H), 6.3−7.3 (37H,
m) Example 2 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-t-butoxycarbonylmethoxyiminoacetamide] -3- (N-methyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridon-2-ylmethyl) aminomethyl -3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-t-butoxycarbonylmethoxyiminoacetamido] -3-chloromethyl-3-cephem-
4-carboxylic acid p-methoxybenzyl ester and 2
-Methylaminomethyl-1-diphenylmethyloxy-
Treatment with 5-p-methoxybenzyloxy-4-pyridone in the same manner as in Example 1 gave the title compound.
NMR(CDCl3)δ： 1.35(9H,s,(CH3)3),2.00(2H,s,NCH3),3.1−3.6（6H,m,2
-H,3′‐H,NCH2),3.72(6H,s,OCH3×２）,4.68(4H,br s,
CH2×２）,4.85(1H,d,J=5 Hz,6-H),5.10(1H,s,CH2),5.8
0（1H,dd,J＝5 Hz,J＝8 Hz,7-H）,5.90（1H,s,pyridone
3-H）,6.3−7.3（37H,m）,8.45（1H,d,J＝8 Hz,CONH） 実施例３ ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−メチル−Ｎ−（１−ジフェニルメチルオキシ−５
−ｐ−メトキシベンジルオキシ−４−ピリドン−２−イ
ルメチル）アミノメチル−３−セフェム−４−カルボン
酸 ｐ−メトキシベンジルエステル ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−ク
ロルメチル−３−セフェム−４−カルボン酸 ｐ−メト
キシベンジルエステル及び２−メチルアミノメチル−１
−ジフェニルメチルオキシ−５−ｐ−メトキシベンジル
オキシ−４−ピリドンを用いて実施例１と同様に処理し
て表題の化合物を得た。 NMR (CDCl 3) δ: 1.35 (9H, s, (CH 3) 3), 2.00 (2H, s, NCH 3), 3.1-3.6 (6H, m, 2
-H, 3′-H, NCH 2 ), 3.72 (6H, s, OCH 3 × 2), 4.68 (4H, br s,
CH 2 × 2), 4.85 (1H, d, J = 5 Hz, 6-H), 5.10 (1H, s, CH 2 ), 5.8
0 (1H, dd, J = 5 Hz, J = 8 Hz, 7-H), 5.90 (1H, s, pyridone
3-H), 6.3-7.3 (37H, m), 8.45 (1H, d, J = 8 Hz, CONH) Example 3 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N-methyl-N- (1-diphenylmethyloxy-5
-P-Methoxybenzyloxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester and 2-methylaminomethyl-1
This was treated with -diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone in the same manner as in Example 1 to obtain the title compound.
NMR(CDCl3)δ： 1.60(6H,s,(CH3)2),2.00(3H,s,NCH3),3.1-3.6(6H,m,2-
H,3′-H,NCH2),3.70(3H,s,OCH3×２）,4.70(2H,s,C
H2）,4.80(1H,d,J=5 Hz,6-H),5.10(2H,s,CH2),5.80（1
H,dd,J＝5 Hz,J＝8 Hz,7-H）,5.90（1H,s,pyridone 3-
H）,6.3-7.3（48H,m） 実施例４ ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−ｎ−ヘキシル−Ｎ−（１−ジフェニルメチルオキ
シ−５−ｐ−メトキシベンジルオキシ−４−ピリドン−
２−イルメチル）アミノメチル−３−セフェム−４−カ
ルボン酸 ｐ−メトキシベンジルエステル ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−ク
ロルメチル−３−セフェム−４−カルボン酸 ｐ−メト
キシベンジルエステル及び参考例２で得た、２−ｎ−ヘ
キシルアミノメチル−１−ジフェニルメチルオキシ−５
−ｐ−メトキシベンジルオキシ−４−ピリドンを用いて
実施例１と同様に処理して表題の化合物を得た。NMR (CDCl 3 ) δ: 1.60 (6H, s, (CH 3 ) 2 ), 2.00 (3H, s, NCH 3 ), 3.1-3.6 (6H, m, 2-
H, 3′-H, NCH 2 ), 3.70 (3H, s, OCH 3 × 2), 4.70 (2H, s, C
H 2 ), 4.80 (1H, d, J = 5 Hz, 6-H), 5.10 (2H, s, CH 2 ), 5.80 (1
H, dd, J = 5 Hz, J = 8 Hz, 7-H), 5.90 (1H, s, pyridone 3-
H), 6.3-7.3 (48H, m) Example 4 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(Nn-hexyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone-
2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester and obtained in Reference Example 2, 2- n-hexylaminomethyl-1-diphenylmethyloxy-5
Treatment with -p-methoxybenzyloxy-4-pyridone in the same manner as in Example 1 gave the title compound.
NMR(CDCl3)δ： 1.62(3H,s,CH3),1.70(3H,s,CH3),2.40(2H,m,NCH2),3.1-
3.6（8H,m,2-H,3′‐H,CH2,NCH2),3.70(3H,s,OCH3),3.7
2（3H,s,OCH3）,4.72(2H,s,CH2),4.80(1H,d,J=5 Hz,6-
H),5.10(2H,s,CH2),5.78（1H,s,pyridone 3-H）,5.80
（1H,dd,J＝5 Hz,J＝8 Hz,7-H）,6.3-7.3（48H,m） 実施例５ ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−（２−ヒドロキシエチル）−Ｎ−（１−ジフェニ
ルメチルオキシ−５−ｐ−メトキシベンジルオキシ−４
−ピリドン−２−イルメチル）アミノメチル−３−セフ
ェム−４−カルボン酸 ｐ−メトキシベンジルエステル ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−ク
ロルメチル−３−セフェム−４−カルボン酸 ｐ−メト
キシベンジルエステル及び参考例３で得た、２−（２−
ヒドロキシエチル）アミノメチル−１−ジフェニルメチ
ルオキシ−５−ｐ−メトキシベンジルオキシ−４−ピリ
ドンを用いて実施例１と同様に処理して表題の化合物を
得た。NMR (CDCl 3 ) δ: 1.62 (3H, s, CH 3 ), 1.70 (3H, s, CH 3 ), 2.40 (2H, m, NCH 2 ), 3.1-
3.6 (8H, m, 2- H, 3'-H, CH 2, NCH 2), 3.70 (3H, s, OCH 3), 3.7
2 (3H, s, OCH 3 ), 4.72 (2H, s, CH 2 ), 4.80 (1H, d, J = 5 Hz, 6-
H), 5.10 (2H, s, CH 2 ), 5.78 (1H, s, pyridone 3-H), 5.80
(1H, dd, J = 5 Hz, J = 8 Hz, 7-H), 6.3-7.3 (48H, m) Example 5 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N- (2-hydroxyethyl) -N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4
-Pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester and obtained in Reference Example 3, 2- (2-
Hydroxyethyl) aminomethyl-1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone was treated in the same manner as in Example 1 to obtain the title compound.
NMR(CDCl3)δ： 1.62(3H,s,CH3),1.70(3H,s,CH3),2.40(2H,m,NCH2),3.1-
3.6（8H,m,2-H,3′‐H,CH2,NCH2),3.70(3H,s,OCH3),3.7
2(3H,s,OCH3),4.72(2H,s,CH2),4.80（1H,d,J＝5 Hz,6-
H）,5.10(2H,s,CH2),5.78（1H,s,pyridone 3-H）,5.80
（1H,dd,J＝5 Hz,J＝8 Hz,7-H）,6.3-7.3（48H,m） 実施例６ ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−メトキシイミノアセトアミド］−３−（Ｎ−
メチル−Ｎ−（1,5−ジヒドロキシ−４−ピリドン−２
−イルメチル）アミノメチル−３−セフェム−４−カル
ボン酸 実施例１で得た、７−［（Ｚ）−２−（２−トリチルア
ミノチアゾール−４−イル）−２−メトキシイミノアセ
トアミド］−３−（Ｎ−メチル−Ｎ−（１−ジフェニル
メチルオキシ−５−ｐ−メトキシベンジルオキシ−４−
ピリドン−２−イルメチル）アミノメチル−３−セフェ
ム−４−カルボン酸 ｐ−メトキシベンジルエステル10
0mgを塩化メチレン0.5mlに溶解しアニソール0.5mlを加
え氷冷する。トリフルオル酢酸3mlを加え５℃で１時間
攪拌する。NMR (CDCl 3 ) δ: 1.62 (3H, s, CH 3 ), 1.70 (3H, s, CH 3 ), 2.40 (2H, m, NCH 2 ), 3.1-
3.6 (8H, m, 2- H, 3'-H, CH 2, NCH 2), 3.70 (3H, s, OCH 3), 3.7
2 (3H, s, OCH 3 ), 4.72 (2H, s, CH 2 ), 4.80 (1H, d, J = 5 Hz, 6-
H), 5.10 (2H, s, CH 2 ), 5.78 (1H, s, pyridone 3-H), 5.80
(1H, dd, J = 5 Hz, J = 8 Hz, 7-H), 6.3-7.3 (48H, m) Example 6 7-[(Z) -2- (2-aminothiazol-4-yl) 2-Methoxyiminoacetamide] -3- (N-
Methyl-N- (1,5-dihydroxy-4-pyridone-2
-Ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamide] -3 obtained in Example 1. -(N-methyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-
Pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 10
Dissolve 0 mg in 0.5 ml of methylene chloride, add 0.5 ml of anisole, and cool with ice. Add 3 ml of trifluoroacetic acid and stir at 5 ° C. for 1 hour.
反応終了後イソプロピルエーテル50mlを加え析出する沈
殿を濾取しイソプロピルエーテルで洗浄後氷水1.5mlに
懸濁させ氷冷下５％炭酸水素ナトリウム水でpHを7.2に
調整し溶解させる。After completion of the reaction, 50 ml of isopropyl ether is added and the deposited precipitate is collected by filtration, washed with isopropyl ether, suspended in 1.5 ml of ice water and adjusted to pH 7.2 with 5% aqueous sodium hydrogen carbonate under ice cooling to dissolve.
DIAION HP-20 20mlに展開し溶離液を凍結乾燥し表題の
化合物のナトリウム塩42mgを粉末として得た。It was developed in 20 ml of DIAION HP-20 and the eluate was freeze-dried to obtain 42 mg of the sodium salt of the title compound as a powder.
NMR(D2O)δ： 2.65(3H,s,NCH3),3.42,3.80（2H,ABq,J＝16 Hz,2-H）,
3.7-4.2（4H,m,3′‐H,NCH2),4.05(3H,s,OCH3),5.25（1
H,d,J＝5 Hz,6-H）,5.85（1H,d,J＝5 Hz,7-H）,6.65（1
H,s,pyridone 3-H）,7.05（1H,s,thiazole 5-H）,7.65
（1H,s,pyridone 6-H） 実施例７ ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−カルボキシメトキシイミノアセトアミド］−
３−（Ｎ−メチル−Ｎ−（1,5−ジヒドロキシ−４−ピ
リドン−２−イルメチル）アミノメチル−３−セフェム
−４−カルボン酸 実施例２で得た、７−［（Ｚ）−２−（２−トリチルア
ミノチアゾール−４−イル）−２−ｔ−ブトキシカルボ
ニルメトキシイミノアセトアミド］−３−（Ｎ−メチル
−Ｎ−（１−ジフェニルメチルオキシ−５−ｐ−メトキ
シベンジルオキシ−４−ピリドン−２−イルメチル）ア
ミノメチル−３−セフェム−４−カルボン酸 ｐ−メト
キシベンジルエステルを用いて実施例６と同様に処理し
て表題の化合物のナトリウム塩を粉末として得た。NMR (D 2 O) δ: 2.65 (3H, s, NCH 3 ), 3.42,3.80 (2H, ABq, J = 16 Hz, 2-H),
3.7-4.2 (4H, m, 3′-H, NCH 2 ), 4.05 (3H, s, OCH 3 ), 5.25 (1
H, d, J = 5 Hz, 6-H), 5.85 (1H, d, J = 5 Hz, 7-H), 6.65 (1
H, s, pyridone 3-H), 7.05 (1H, s, thiazole 5-H), 7.65
(1H, s, pyridone 6-H) Example 7 7-[(Z) -2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamide]-
3- (N-Methyl-N- (1,5-dihydroxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2 obtained in Example 2 -(2-Tritylaminothiazol-4-yl) -2-t-butoxycarbonylmethoxyiminoacetamido] -3- (N-methyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-) Pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was treated in the same manner as in Example 6 to obtain the sodium salt of the title compound as a powder.
NMR(D2O)δ： 2.80(3H,s,NCH3),3.35-4.30（6H,m,2-H,3′‐H,NCH2),
4.62(2H,s,OCH2),5.30（1H,d,J＝5 Hz,6-H）,5.90（1H,
d,J＝5 Hz,7-H）,6.70（1H,s,pyridone 3-H）,7.10（1
H,s,thiazole 5-H）,7.68（1H,s,pyridone 6-H） 実施例８ ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−（１−メチル−１−カルボキシエトキシイミ
ノ）アセトアミド］−３−（Ｎ−メチル−Ｎ−（1,5−
ジヒドロキシ−４−ピリドン−２−イルメチル）アミノ
メチル−３−セフェム−４−カルボン酸 ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−メチル−Ｎ−（１−ジフェニルメチルオキシ−５
−ｐ−メトキシベンジルオキシ−４−ピリドン−２−イ
ルメチル）アミノメチル−３−セフェム−４−カルボン
酸 ｐ−メトキシベンジルエステルを用いて実施例６と
同様に処理して表題の化合物のナトリウム塩を粉末とし
て得た。NMR (D 2 O) δ: 2.80 (3H, s, NCH 3 ), 3.35-4.30 (6H, m, 2-H, 3′-H, NCH 2 ),
4.62 (2H, s, OCH 2 ), 5.30 (1H, d, J = 5 Hz, 6-H), 5.90 (1H,
d, J = 5 Hz, 7-H), 6.70 (1H, s, pyridone 3-H), 7.10 (1
H, s, thiazole 5-H), 7.68 (1H, s, pyridone 6-H) Example 8 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-methyl) -1-Carboxyethoxyimino) acetamide] -3- (N-methyl-N- (1,5-
Dihydroxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N-methyl-N- (1-diphenylmethyloxy-5
-P-Methoxybenzyloxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid Treated as in Example 6 with p-methoxybenzyl ester to give the sodium salt of the title compound. Obtained as a powder.
NMR(D2O)δ： 1.55(6H,s,(CH3)2),2.78(3H,s,NCH3),3.4-4.25（6H,m,2
-H,3′‐H,NCH2),5.30（1H,d,J＝5 Hz,6-H）,5.90（1H,
d,J＝5 Hz,7-H）,6.72（1H,s,pyridone 3-H）,7.05（1
H,s,thiazole 5-H）,7.70（1H,s,pyridone 6-H） 実施例９ ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−（１−メチル−１−カルボキシエトキシイミ
ノ）アセトアミド］−３−（Ｎ−ｎ−ヘキシル−Ｎ−
（1,5−ジヒドロキシ−４−ピリドン−２−イルメチ
ル）アミノメチル−３−セフェム−４−カルボン酸 ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−ｎ−ヘキシル−Ｎ−（１−ジフェニルメチルオキ
シ−５−ｐ−メトキシベンジルオキシ−４−ピリドン−
２−イルメチル）アミノメチル−３−セフェム−４−カ
ルボン酸 ｐ−メトキシベンジルエステルを用いて実施
例６と同様に処理して表題の化合物のナトリウム塩を粉
末として得た。NMR (D 2 O) δ: 1.55 (6H, s, (CH 3 ) 2 ), 2.78 (3H, s, NCH 3 ), 3.4-4.25 (6H, m, 2
-H, 3′-H, NCH 2 ), 5.30 (1H, d, J = 5 Hz, 6-H), 5.90 (1H,
d, J = 5 Hz, 7-H), 6.72 (1H, s, pyridone 3-H), 7.05 (1
H, s, thiazole 5-H), 7.70 (1H, s, pyridone 6-H) Example 9 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-methyl) -1-Carboxethoxyimino) acetamide] -3- (N-n-hexyl-N-
(1,5-Dihydroxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(Nn-hexyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone-
2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was treated in the same manner as in Example 6 to obtain the sodium salt of the title compound as a powder.
NMR(D2O)δ： 0.85(3H,m,CH3),1.2-1.7(8H,m,(CH2)4）,1.50(6H,br,(C
H3)2),2.80(2H,m,NCH2),3.4-4.1（6H,m,2-H,3′‐H,NCH
2）,5.20（1H,d,J＝5 Hz,6-H）,5.82（1H,d,J＝5 Hz,7-
H）,6.70（1H,s,pyridone 3-H）,7.00（1H,s,thiazole
5-H）,7.55（1H,s,pyridone 6-H） 実施例10 ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−（１−メチル−１−カルボキシエトキシイミ
ノ）アセトアミド］−３−（Ｎ−（２−ヒドロキシエチ
ル）−Ｎ−（1,5−ジヒドロキシ−４−ピリドン−２−
イルメチル）アミノメチル−３−セフェム−４−カルボ
ン酸 ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−（２−ヒドロキシエチル）−Ｎ−（１−ジフェニ
ルメチルオキシ−５−ｐ−メトキシベンジルオキシ−４
−ピリドン−２−イルメチル）アミノメチル−３−セフ
ェム−４−カルボン酸 ｐ−メトキシベンジルエステル
を用いて実施例６と同様に処理して表題の化合物のナト
リウム塩を粉末として得た。NMR (D 2 O) δ: 0.85 (3H, m, CH 3 ), 1.2-1.7 (8H, m, (CH 2 ) 4 ), 1.50 (6H, br, (C
H 3) 2), 2.80 ( 2H, m, NCH 2), 3.4-4.1 (6H, m, 2H, 3'-H, NCH
2 ), 5.20 (1H, d, J = 5 Hz, 6-H), 5.82 (1H, d, J = 5 Hz, 7-
H), 6.70 (1H, s, pyridone 3-H), 7.00 (1H, s, thiazole
5-H), 7.55 (1H, s, pyridone 6-H) Example 10 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-methyl-1-carboxyethoxy) Imino) acetamido] -3- (N- (2-hydroxyethyl) -N- (1,5-dihydroxy-4-pyridone-2-
Ilmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N- (2-hydroxyethyl) -N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4
-Pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was treated in the same manner as in Example 6 to obtain the sodium salt of the title compound as a powder.
NMR(D2O)δ： 1.50(6H,br s,(CH3)2),2.70(2H,m,NCH2),3.3-1.8（8H,
m,2-H,3′‐H,CH2,NCH2),5.15（1H,d,J＝5 Hz,6-H）,5.
80（1H,d,J＝5 Hz,7-H）,6.72（1H,s,pyridone 3-H）,
7.00（1H,s,thiazole 5-H）,7.62（1H,s,pyridone 6-
H） 実施例11 ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−（１−メチル−１−メカルボキシエトキシイ
ミノ）アセトアミド］−３−（Ｎ−アリル−Ｎ−（1,5
−ジヒドロキシ−４−ピリドン−２−イルメチル）アミ
ノメチル−３−セフェム−４−カルボン酸 ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−アリル−Ｎ−（１−ジフェニルメチルオキシ−５
−ｐ−メトキシベンジルオキシ−４−ピリドン−２−イ
ルメチル）アミノメチル−３−セフェム−４−カルボン
酸 ｐ−メトキシベンジルエステルを用いて実施例６と
同様に処理して表題の化合物のナトリウム塩を粉末とし
て得た。NMR (D 2 O) δ: 1.50 (6H, br s, (CH 3 ) 2 ), 2.70 (2H, m, NCH 2 ), 3.3-1.8 (8H,
m, 2-H, 3′-H, CH 2 , NCH 2 ), 5.15 (1H, d, J = 5 Hz, 6-H), 5.
80 (1H, d, J = 5 Hz, 7-H), 6.72 (1H, s, pyridone 3-H),
7.00 (1H, s, thiazole 5-H), 7.62 (1H, s, pyridone 6-
H) Example 11 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-methyl-1-mecarboxyethoxyimino) acetamido] -3- (N-allyl-N − (1,5
-Dihydroxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N-allyl-N- (1-diphenylmethyloxy-5
-P-Methoxybenzyloxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid Treated as in Example 6 with p-methoxybenzyl ester to give the sodium salt of the title compound. Obtained as a powder.
NMR(D2O)δ： 1.52(3H,s,CH3),1.54(3H,s,CH3),3.5(2H,m,NCH2 CH=),3.
7-4.3（6H,m,2-H,3′‐H,NCH2),5.25（1H,d,J＝5 Hz,6-
H）,5.55(1H,m,=CH2),5.90（1H,d,J＝5 Hz,7-H）,6.00
（1H,m,CH＝）,6.75（1H,s,pyridone 3-H）,7.05（1H,
s,thiazole 5-H）,7.65（1H,s,pyridone 6-H） 実施例12 ７−［（Ｚ）−２−（２−アミノチアゾール−４−イ
ル）−２−（１−メチル−１−カルボキシエトキシイミ
ノ）アセトアミド］−３−（Ｎ−イソプロピル−Ｎ−
（1,5−ジヒドロキシ−４−ピリドン−２−イルメチ
ル）アミノメチル−３−セフェム−４−カルボン酸 ７−［（Ｚ）−２−（２−トリチルアミノチアゾール−
４−イル）−２−（１−メチル−１−ジフェニルメトキ
シカルボニル）エトキシイミノアセトアミド］−３−
（Ｎ−イソプロピル−Ｎ−（１−ジフェニルメチルオキ
シ−５−ｐ−メトキシベンジルオキシ−４−ピリドン−
２−イルメチル）アミノメチル−３−セフェム−４−カ
ルボン酸 ｐ−メトキシベンジルエステルを用いて実施
例６と同様に処理して表題の化合物のナトリウム塩を粉
末として得た。NMR (D 2 O) δ: 1.52 (3H, s, CH 3 ), 1.54 (3H, s, CH 3 ), 3.5 (2H, m, N CH 2 CH =), 3.
7-4.3 (6H, m, 2-H, 3'-H, NCH 2 ), 5.25 (1H, d, J = 5 Hz, 6-
H), 5.55 (1H, m, = CH 2 ), 5.90 (1H, d, J = 5 Hz, 7-H), 6.00
(1H, m, CH =), 6.75 (1H, s, pyridone 3-H), 7.05 (1H,
s, thiazole 5-H), 7.65 (1H, s, pyridone 6-H) Example 12 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-methyl-1) -Carboxyethoxyimino) acetamide] -3- (N-isopropyl-N-
(1,5-Dihydroxy-4-pyridon-2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3-
(N-isopropyl-N- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridone-
2-ylmethyl) aminomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was treated in the same manner as in Example 6 to obtain the sodium salt of the title compound as a powder.
NMR(D2O)δ： 1.4(6H,m,CH(CH3)2 ),1.52(3H,s,CH3),1.54(3H,s,CH3),
3.3-4.5（7H,m,2-H,3′‐H,NCH2,CH(CH3)2),5.15（1H,
d,J＝5 Hz,6-H）,5.85（1H,d,J＝5 Hz,7-H）,6.65（1H,
s,pyridone 3-H）,7.00（1H,s,thiazole 5-H）,7.65（1
H,s,pyridone 6-H）NMR (D 2 O) δ: 1.4 (6H, m, CH ( CH 3 ) 2 ), 1.52 (3H, s, CH 3 ), 1.54 (3H, s, CH 3 ),
3.3-4.5 (7H, m, 2- H, 3'-H, NCH 2, C H (CH 3) 2), 5.15 (1H,
d, J = 5 Hz, 6-H), 5.85 (1H, d, J = 5 Hz, 7-H), 6.65 (1H,
s, pyridone 3-H), 7.00 (1H, s, thiazole 5-H), 7.65 (1
H, s, pyridone 6-H)
───────────────────────────────────────────────────── フロントページの続き (72)発明者 柴原 聖至 神奈川県横浜市港北区師岡町760 明治製 菓株式会社薬品総合研究所内 (72)発明者 井上 重治 神奈川県横浜市港北区師岡町760 明治製 菓株式会社薬品総合研究所内 審査官 池田 正人 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiji Shibahara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Shigeharu Inoue 760 Meiji, Kohoku-ku, Yokohama-shi, Kanagawa Masato Ikeda Examiner, Pharmaceutical Research Institute, Inc.
Claims (2)
ル基、又はカルボキシ基又は保護されたカルボキシ基で
置換されている低級アルキル基、低級アルケニル基、R2
は水素原子又は置換基を有しても良い低級アルキル基、
低級アルケニル基を表す。］で表される新規セファロス
ポリン系化合物及びその薬理上許容される塩、又はエス
テル。1. A general formula (1) [Wherein R 1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkyl group, a lower alkenyl group, or a R 2 which is substituted with a carboxy group or a protected carboxy group.
Is a hydrogen atom or a lower alkyl group which may have a substituent,
Represents a lower alkenyl group. ] The novel cephalosporin compound represented by these, and its pharmacologically acceptable salt or ester.
効成分として含有する抗菌剤。2. An antibacterial agent containing the compound of general formula (I) according to claim 1 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15407190A JPH075606B2 (en) | 1990-06-14 | 1990-06-14 | New cephalosporin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15407190A JPH075606B2 (en) | 1990-06-14 | 1990-06-14 | New cephalosporin compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0446181A JPH0446181A (en) | 1992-02-17 |
| JPH075606B2 true JPH075606B2 (en) | 1995-01-25 |
Family
ID=15576260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15407190A Expired - Lifetime JPH075606B2 (en) | 1990-06-14 | 1990-06-14 | New cephalosporin compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH075606B2 (en) |
-
1990
- 1990-06-14 JP JP15407190A patent/JPH075606B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0446181A (en) | 1992-02-17 |
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