JPS59502063A - chemical compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] chemical compound This invention relates to a new β-lactam antibacterial agent, its production method, and its uses. , specifically penicillins that are active against β-lactamase-producing bacteria. It is related to.

British Patent No. 2,044,255 (corresponding to U.S. Patent No. 4,342,772) Formula (A): (In the formula, Ra is phenyl, 4-hydroxyphenyl, 1.4=cyclohexage Nyl or 3-chenyl group, Rb is the 17th amino or carboxy group r RC is hydrogen atom or lower alkyl, aryl or aralkyl group and Rd is β-lactamase It is the basis of inhibition. ) Compounds have been disclosed.

This invention has the formula (I): or an acid addition salt thereof, R1 is alkyl of 01-6, Ca -6 cycloalkyl, 05-8 cycloalkenyl or aromatic group.

R2 is a primary amino or carboxy group or an ester thereof.

R3 is hydrogen or a hydrocarbon moiety; all the above groups R1, R2 and R3 are optional may be substituted; and R4 is the formula (■): (wherein R represents an inert organic group having up to 18 carbon atoms).

Suitable inert organic groups R in the residues of the formula (ml) include hydrocarbon groups as well as halide groups. became rogene, ether group, acyloxy, acyl, ester, carboxy, salt Carboxy, hydroxy, nitro, cyano, amino and substituted amino groups, etc. is an inertly substituted hydrocarbon group. Therefore, suitable groups R include hydrocarbon groups, and halogen and/or by-product OR5,0HXOCOR5, COR5, C02R 1NR6COR6, NR6Co 2 R5, 5OR5, 5O2R5, NR2, N R5R6, NO2, CN or C0NR5R6 (in the formula, R5 has 8 carbon atoms and R6 is a hydrocarbon group having up to 4 carbon atoms) There are hydrocarbon groups.

In the term ``inert organic group'' used herein, the organic group is means that it does not make the compound inherently unstable or unsuitable for use.

Similar terms 1 Inertly substituted '' means that the introduction of a substituent is useful for pharmaceutical use. This means that the compound does not become an inherently unstable compound that cannot be used.

When the term 5 hydrocarbon is used herein, it includes alkyl, alkenyl and and alkynyl groups as well as those substituted with phenyl or hydrocarbon-substituted phenyl Including groups, etc.

Suitable inert organic groups R included in the residue of formula (n) include hydrocarbon groups, as well as Halo and/or sub-products OR5,0COR6, C0R5, C02R5 (wherein R5 is a hydrocarbon group having up to 8 carbon atoms, inertly substituted with including.

The most suitable R5 is an alkyl group having 1 to 4 carbon atoms or phenyl or benzene. is a group. A preferred group R6 is a methyl group. A preferred group R6 is a methyl group. Ru.

Further suitable subgroups of residues of formula (II) include R in the group CR8R9R10 [in the formula , R8 and R9 are independently an alkyl group having up to 8 carbon atoms or a halogen or by the formula R11 or 0RII (wherein R11 is an alkyl group having up to 3 carbon atoms) The optionally substituted phenyl group and RIO are hydrogen atoms or atom atoms having up to 8 carbon atoms. alkyl group or halogen or formula R12 or 0R12 (wherein R12 is carbon a phenyl group optionally substituted with an alkyl group having up to 8 atoms] .

A further suitable R is the group CH2R18, where R18 is naphthyl, phenyl, or halo. or a group R14 or 0R14 (wherein R14 is an alkyl group having up to 8 carbon atoms) phenyl group].

In addition, a particularly suitable R is R11>-coon (wherein R15 is a halogen and/or 0R16, 0COR16, COR16 or OH group (wherein R1 6 is a carbon atom optionally inertly substituted with an alkyl group 9 having 1 to 4 carbon atoms; hydrocarbon group having 1 to 8 molecules].

The most appropriate R15 is an alkylene group having 1 to 4 carbon atoms, a phenylene group, or a hafe group. C1-C4 alkylene group substituted with nyl or phenylene group It is.

Preferably R15 has 1 to 4 carbon atoms, such as -CH2- or -CH2CH2- group. is an alkylene group.

A particularly suitable group of residues of formula (II) is a group of the formula ([[D: (wherein R16 has 1 carbon atom ~4 alkylene group and R17 can also be a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. or an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group). It is what is expressed.

Preferred R16 is -CH2- or -CH2CH2-.

Particularly suitable residues thereon are of the formula (■): In the formula, R18 is a divalent hydrocarbon group having 2 to 8 carbon atoms, R19 is a hydrogen atom or An alkyl group having 1 to 4 carbon atoms and R20 are hydrogen atoms, or R21 and COR21 are also or Co2R21 group (wherein R21 (ephenyl group) δ5 is an alkyl group having 1 to 4 carbon atoms). ] It is expressed as

The most suitable R21 is an alkylene group having 2 to 4 carbon atoms, a phenylene group, or a phenylene group. C2-4 alkylene group substituted with nyl or phenylene group It is.

Certain desirable residues of 2fII) include (wherein R22 is hydrogen, 1 carbon atom ~4 alkyl group or phenyl group, or carboxylic acid group or salt or C1~ one of the aforementioned groups substituted by an alkyl ester of 4, otherwise R22 is a salt of carbon # group or its Ci~4 alkyl ester. ) Ru. Particularly desirable groups are generally hydrogen or unsubstituted alkyl groups, preferably hydrogen. There are many things.

In formula (I), suitable R1 is C1-6 alkyl such as methyl or ethyl. , fLc8-8 cycloalkyl or cyclohexenyl such as cyclohexyl 06-8 cycloalkenyl such as or 1,4-cyclohexagenyl It is cyclohexagenyl.

Similarly suitable R1 is phenyl or naphthyl or heterosubstituted phenyl. Teroaryl (wherein the heteroaryl ring consists of 5 to 7, preferably 5 to 6 atoms) , up to circle 4 may be a heteroatom selected from oxygen, sulfur, and nitrogen. It is an aromatic group such as

When R1 is an aromatic group, more suitable R1 is 1 selected from oxygen, sulfur and nitrogen. an optionally substituted five-membered heterocyclic ring consisting of one or two heteroatoms; Bare rings include furyl, chenyl such as cheny-3-yl, oxacylyl, thiazolyl. These ring systems include If any of the stems is a halogen, hydroxy, amine, or alkyl 01-6, or 01-6 alkoxy.

When R1 is an aromatic group, suitable R1 is phenyl, monosubstituted phenyl (such as Substituents include halogen, hydroxy, 01-6 alkoxy, nitro, amino , C1-6 alkyl, 01-6 haloalkyl, C1-6 alkanoyl group or a di-substituted phenyl sulfonylamine) (in which substituents include hydroxy, halogen, methoxy, acetoxy and amino ).

When R1 is an aromatic group, more suitable R1 is phenyl; fluoro, chloro, hydrogen. droxy, methoxy, nitro, amino, acetoxy or trifluoromethane phenyl monosubstituted by, or from acetoxy, hydroxy and methoxy phenyl di-substituted with selected substituents.

Preferred R1 is 1,4-cyclohexagenyl, phenyl, p-hydroxyphenyl. phenyl, p-aminophenyl, p-acetoxyphenyl, chenyl-2-yl, Cheny-3-yl or ha-2-7minothiazin-4-yl.

More preferable R1 is phenyl, p-hydroxyphenyl, 1,4-cyclohexyl Sagenyl or 8-chenyl.

When R2 is amino, preferred R1 is phenyl or p-hydroxyphenyl. substituted phenyl, and R2 is a carboxyl group or optionally substituted Its esters such as phenyl esters, benzyl or indanyl esters In this case, R1 is phenyl or chenyl, such as 3-chenyl.

When R2 is an amine, it may be in the form of its acid addition salt such as hydrochloride.

In the compound of formula (I), a suitable R8 is a hydrogen atom or an alkyl group of 01-6. , aryl or arylC1-6 alkyl group. In the definition of R8, The alkyl moiety of 01-6 may be linear or branched, and the alkyl moiety of 01 to 6 may be linear or branched. The lyl moiety is a monocyclic or bicyclic carbocyclic group.

Further suitable R8 is hydrogen, methyl, ethyl, phenyl or benzyl. preferred R8 is a hydrogen atom, methyl, phenyl or benzyl group.

Particularly preferred compounds of formula (I) are those in which R1 is phenyl p-hydroxy-phenyl, 1,4-cyclohexagenyl or 3-chloro It's Niru.

R2 is amino, carboxyl, phenoxycarbonyl or a formula such as [1 This is the residue of clavanerad in No. 1.

If a carboxy group is present as a substituent in any compound of this invention If so, it is its free acid, salted, esterified or zwitterionic form. It can exist as a state.

The salt is suitably in a pharmaceutically acceptable form, for example aluminum metal salts such as sodium or potassium, alkali metal salts such as sodium or potassium, calcium alkaline earth metal salts such as aluminum or magnesium, and ammonium salts; ammonium salts, e.g. C1-6 alkaline salts such as triethylamine. Kylamines, 2-hydroxyethylamine, bis(2-hydroxyethyl)a Min Or)! Hydroxy-C1 such as J(2-hydroxyethyl)amine ~6 alkylamines, cycloalkylamides such as bicyclohexylamine There are salts with procaine and salts with procaine. Sodium or potassium salts are preferred stomach.

Also, any carboxyl present in the compounds of this invention may be alkyl, alkyl, esters with pharmaceutically acceptable esterifying groups such as aryl or aralkyl groups; may be Preferred esterification groups include methyl, ethyl, etc. C1-6 alkyl, phenyl, benzyl; or nitrobenzyl, bromobenzi C1-6 alkoxycarbonylbenzyl, C1-6 alkoxybenzyl and substituted benzyls such as C1-6 alkylbenzyls, and phthalates. These are esters that can be hydrolyzed in vivo, such as Zyl.

The compounds of this invention may be used if a basic group (e.g. -NH2) is present as a substituent. If desired, they can optionally be present in the form of their acid addition salts. used for salt formation The acid is most preferably a pharmaceutically acceptable one, although non-pharmaceutically acceptable acid addition salts are also suitable. For example, it can be considered as an intermediate in the production of pharmaceutically acceptable salts by ion exchange. It will be done. Suitable pharmaceutically acceptable acid addition salts include hydrochloric acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. acid, toluenesulfonic acid, citric acid, maleic acid, acetic acid, lactic acid, tartaric acid, pro- Includes acid addition salts with inorganic and organic acids such as pionic acid and succinic acid.

Certain compounds of this invention may exist in diastereomeric forms, which The invention covers all such diastereomers, separated or mixed. It includes.

According to another aspect of the invention, a compound of formula (I) and a pharmaceutically acceptable carrier thereof; A pharmaceutical composition comprising:

The compositions of this invention can be manufactured by conventional methods for making antibiotic compositions. can be adapted for oral, topical or parenteral administration in the usual manner.

A unit dosage form according to the invention includes, for example, about 62.5.100.150.2 00.250.500 or 750 mg. ~100011y included. Such compositions are usually administered one to six times per day, more conveniently. may be administered 2.8 or 4 times per day, thus giving a total daily dose to 70 to 9 adults. The output amount is, for example, about 400.600.750.1000 or 1500q. It is about 200-2000 Da.

Suitable pharmaceutically acceptable carriers for use in the compositions of this invention include Contains diluents, binders, disintegrants, lubricants, colorants, flavorings, or preservatives. It will be done. Therefore, suitable agents include lactose, starch, sucrose, calcium phosphate, Sorbitol, polyvinylpyrrolidone, gum arabic, gelatin, tragacanth, Potato starch or polyvinylpolypyrrolidone, magnesium stearate Contains sodium lauryl sulfate.

The composition of this invention may be administered in a single form such as a tablet or capsule. The form of single-dose units is most suitable.

Certain compounds of this invention tend to be poorly soluble and therefore may be used in pharmaceutical formulations. In one embodiment, if it is desirable to increase their solubility for use in compositions, If a suitable amino or carboxylic acid group is present, acid addition salts or carboxylic acid salts can be used. It is preferable to use

One feature of the compounds of this invention is that they degrade in vivo and are antibacterial. It is thought to liberate the penicillin and β-lactamase inhibitor moieties. be. This is believed to occur more easily by the oral route. Thus, Compounds of formula (I) are precursor drugs to penicillin and precursors to β-lactamase inhibitors. Can be considered as a medicine.

Furthermore, the invention provides a pharmaceutical composition as described above together with a penicillin or a cephalosporin. Provided is a synergistic pharmaceutical composition comprising:

Suitable penicillins for inclusion in the synergistic compositions of this invention include benzyl penicillin. Sirin, phenoxymethylpenicillin, ampicillin, amoxicillin, tical Cilin, sancillin, sulpenicillin, ampicillin, or mezlocillin are listed. and especially amoxicillin, its sodium salt or trihydrate being preferred.

Suitable cephalosporins for inclusion in the synergistic compositions of this invention include cephalosporins. These are lysine, cefazolin and cefrazine.

Penicillins or cephalosporins generally include those normally administered. .

The 11 ratio of the compounds of this invention to the penicillin or cephalosporin is generally 20 :1 to 1:5, more usually 10:1 to 1:2, and usually 5:1 to 1:1. It is surrounded.

The compounds and compositions of this invention can be used, for example, in the respiratory system, urinary system or soft tissues. or the treatment of bacterial infections in animals such as mammals, including humans, such as the mammary glands of cows. suitable for use as an agent.

Therefore, in a further aspect, the invention provides a method for treating bacterial infections in animals in need thereof. The present invention also provides methods for treating diseases (such as those described above), which methods to administer an effective antibacterial amount in the manufacture of a compound of formula CI) or a pharmaceutical preparation thereof. It will be.

Furthermore, in a further aspect, the present invention also provides a method for producing the compound of formula (I). and the method provides a source of the side chain R1-CHR2-C0-, 6-aminopenicillane. Source of the acid moiety and source of the ester group -CHR8-()-CO-R4, where RO1R 3 and R4 are the same as defined above).

As a specific example of the method of this invention, the formula (VO:H (In the formula, RIXR2 and R3 are the same as defined above and Y is the group to be removed) A compound represented by or a salt thereof or a reactive derivative thereof and formula (2): % formula % (10 (In the formula, R4 is the same as the previous definition) (However, all functional groups in R1-CHR2- and amino groups in R4 are shall be strictly protected. ) or a salt thereof. , then if necessary, (1) remove all protecting groups, (11) Formation of formula (I) consisting of converting the product into a pharmaceutically acceptable salt. A method for producing the compound is provided.

Suitable Y is removed such as a halogen atom, for example chlorine, bromine or iodine. It is a good basis for

The reaction is suitably carried out in dimethylformamide, acetone, ethyl acetate or halogen Substances known to be favorable for esterification reactions, such as esterified hydrocarbons. The method is carried out in an inert organic solvent. Such reactions are carried out between 0°C and 50°C. Preferably, the reaction is carried out at a reduced, room temperature or an elevated temperature, such as room temperature.

The compound of formula (■) need not be pharmaceutically acceptable, but may be It is appropriate to Suitable salt deposits include, for example, metal salts; lithium, potassium or are inorganic salts such as alkali metal salts such as sodium salts, or tertiary amine salts. Includes types.

The compound of the formula (■ is a compound of the formula ~l): Y-CHR3-Z @ (In the formula, Y and R3 are the same as the previous definitions, and Z is a transverse group than Y) It can be produced by reaction with a compound represented by: Such a reaction is expressed by the formula (VrJ and This reaction can be easily carried out under conditions similar to those described for the reaction of compounds (2) and (2).

Compounds of formula (2) are described, for example, in British Patent No. 1,565,209. It can be manufactured by the method described.

As another specific example of the method of this invention, formula@: (wherein R3 and R4 are the same as defined above) or N-acylated a derivative thereof that causes a reaction; Formula (X): R1-C)IR2-CO21((X) (wherein R1 and R2 are as defined above) and (reactive groups are optionally protected) ) is reacted with an N-acylated derivative of a carboxylic acid represented by , (1) removing the protecting group, (11) Formation of formula (I) consisting of converting the product into a pharmaceutically acceptable salt A method for producing the compound is provided.

The acylation reaction is caused to occur, and a suitable Groups include N-silyl, N-tin, N-IJ groups, such as trimethylsilyl, trialkylsilyl groups such as ru, trialkyltin groups such as tri-n-butyltin group, or a group of formula -PRaRb (wherein Ra is alkyl, haloalkyl, aryl , aralkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy or is a dialkylamino group, Rb is the same as Ha or halogen yc, 5Zu Ra and and Rb together form a ring), suitable examples of such phosphorus groups include -P(O C2H5)2, -P(C2H5)2 The reactive N-acylated derivative of the acid of formula (X) is , used in the above process. Suitable fjN-acylated derivatives include acid halides. , preferably acid chlorides and acid bromides. Acylation with acid halides For example, tertiary amines ( triethylamine or dimethylaniline), inorganic bases (such as calcium carbonate), or acid binders such as oxiranes) or oxiranes. It can be done in the presence of Ethylene oxide or propylene oxide is used as oxirane. (C1-6)-1,2-alkylene oxides such as lene oxide are preferred. stomach. Acylation reactions using acid halides can be performed using aqueous acetone, ethyl acetate, dimethyl Ruacetamide, dimethylformamide, acetonitrile, dichloromethane, 1 ．． -5 in an aqueous or non-aqueous medium such as 2-dichloroethane or mixtures thereof. The temperature range is 0°C to +50°C, preferably -20°C to +20°C.

Alternatively, the reaction may be carried out in a water-immiscible solvent, especially methyl isobutyl ketone or butyl acetate. carried out in unstable emulsions of aliphatic esters or ketones such as Ru.

The acid halide may be phosphorus pentachloride, thionyl chloride or oxalyl chloride. For the reaction of a halogenating agent (e.g. chlorination or bromination) with an acid of formula (Xl) or a salt thereof Alternatively, the N-acylated derivatives of acids of formula (X) can be prepared from symmetrical or mixed An acid anhydride may also be used. Mixed acid anhydrides include alkoxyformic anhydrides, carboxylic acid monoesters, trimethylacetic acid, thioacetic acid, diphenylacetic acid, Zozoic acid, phosphorous acids (phosphoric acid or phosphorous acid, sulfuric acid or 1)-) luensul anhydrides such as aliphatic or aromatic sulfonic acids such as fonic acid are suitable. be. The mixed or symmetric acid anhydrides include N-ethoxycarbonyl-2-ethoxy Can be generated using syl-2-ethoxy-1,2-dihydroquinoline .

If a symmetrical acid anhydride is used, the reaction (2,4-lutidine as a catalyst) can be carried out in the presence of

Other N-acylated derivatives of acids of formula α) include acid azides; or 2-mercap Topyridine, cyanomethanol, p-nitrophenol, 2,4-dinitrophe Nols: thiophenol, methanethiol, ethanethiol and propanethiol thioalcohols such as alcohol, halophenols including pentachlorophenol , monomethoxyphenol, 8-hydroxyquinoline, N-hydroxysuccine Active esters such as imides or esters with 1-hydroxybenzotriazole or amines such as N-acyl saccharins or N-acyl phthalimides; Alkylidine iminoesters produced by the reaction of amides or acids and oximes There is a le.

Other reactive N-acylated derivatives of acids of formula (Xl) include, for example, N,N-diethyl - a carbodiimide such as dipropyl or diisopropyl-carbo, e.g. , N-carbonyldiimidazole or N,N''-carbonylditriazole. suitable carbonyl compounds such as N-ethyl-5-phenylisoxazo Linium-8-sulfonate or N-t-butyl-5-methylisoxazolini Inoxazinonium salts such as Umberchlorate or N-ethoxyca N-alkoxylic acid such as carbonyl-2-ethoxy-1,2-dihydroquinoline Reaction with a condensing agent such as carbonyl-2-alkoxy-1,2-dihydroquinoline Includes reaction intermediates generated in situ. Other condensing agents include Lewis soaps (e.g. BBra C6H6), mini or diethylphosphoryl cyanide Contains a phosphoric acid condensing agent. For example, methylene chloride, dimethyl Formamide, acetonitrile, alcohol, benzene, dioxane or tet Preference is given to carrying out in an organic reaction medium such as hydrofuran.

As another specific example of the method of this invention, (a) Formula l: (In the formula, R3 and R4 are the same as defined above, and R2g is an acyl group. (b) the resulting iminohalide. QRf group on the imino carbon atom (where Q is oxygen, sulfur or nitrogen and R 4 is an alkyl group having 5 to 14 carbon atoms). minoester, iminothioether or amidine (where Q is 0, S or N, respectively) form), (C) React with the N-acylated derivative of the acid of the above formula (d) Treat with water , Then, if necessary, (1) removing the protecting group, (11) A compound of formula (I) consisting of converting the product into a pharmaceutically acceptable salt. A method of manufacturing a product is provided.

Suitable agents for preparing halogenated iminos include tertiary amines such as pyridine. , in the presence of an acid binder such as triethylamine or N,N-dimethylaniline. It is an acid halide.

Examples of suitable acid halides include phosphorus pentachloride, phosgene, phosphorus pentabromide, oxychloride, Phosphorous cyclochloride, oxalyl chloride and p-toluenesulfonic acid chloride are included. . Preferred are phosphorus pentachloride and phosphorus oxychloride. If phosphorus pentachloride is used, The reaction is carried out under cooling, preferably at a temperature between O''C and -80°C. The amount is preferably 8 to 5 moles per mole of phosphorus pentachloride. Also less than the starting material Preferably, an excess amount of phosphorus halide is used.

Next, the generated imino compound is created by introducing a QR1 group onto the imino carbon atom. It is processed. This is done by reacting the iminohalide with the corresponding alcohol. It is preferable to do so. Examples of suitable alcohols to react with iminohalides include is methanol, ethanol, propatool, isopropyl alcohol, amyl 1 to 12 carbon atoms, preferably 1 to 5 carbon atoms, such as alcohol and butyl alcohol aliphatic alcohols containing benzyl alcohol and 2-phenyletha There are aralkyl alcohols like nol.

The reaction between an alcohol and an iminohalide is performed using an 8th amine, preferably pyridine. The reaction is preferably carried out in the presence of an acid binding agent, and the reaction is usually The imino compound is then isolated from the N-acyl of the acid of formula (X). react with the chemical conductor.

Comments above regarding N-acylated derivatives and conditions for carrying out the acylation also applies to this case. In particular, pyridine and N,N-dimethylalcohol are present in the reaction system. Preferably, an 8th amine such as niline is present.

Finally, the product is treated with water. Treatment of water should be carried out together with isolation of the desired substance. I can do it. That is, water or a saturated aqueous solution of sulfur chloride is added to the reaction mixture. is added and the resulting aqueous layer is then separated from the organic solvent layer.

In the above reaction, the functional group or reactive group is protected, and the protecting group is Benzyl or substituted benzyl esters for xyl groups, and amino groups N-benzyloxycarbonyl or substituted benzyloxycarbonyl for Contains groups. Deprotection can be performed by standard methods such as catalytic hydrogenolysis .

The invention will now be illustrated by examples.

Example 1 iodomethyl 6-(D-α) dissolved in hexamethylphosphoric triamide (12d) -azido-α-phenylacetamido)benicilanato (1.2 g, 2.8 ml A solution of calcium 9-〇-methylclavalanate (o, asg, 1.5 mmol) and the mixture was stored at room temperature for 1 hour. Add ethyl acetate, The organic phase was washed thoroughly with water and dried over anhydrous magnesium sulfate. evaporation A brown oil was obtained. Ethyl acetate-petroleum ether (boiling point 60-80"C) ( 1:1) on silica gel to produce a colorless oil. The title compound (0.86f, 46%) was obtained.

The physical properties were as shown below.

1, R, Niji max (CHCLa) 2100, 1800, 1700 and 15000.

Methylclavalanyloxymethyl-6-( D-α-azido-α-phenylacetamide) benicilanato (OJ62f, 0 ．． A solution of 6 mmol) in water (40 gt) and 10% palladium-charcoal catalyst (0, 1362f). The system is flushed with nitrogen and hydrogen is passed through the solution. The pH of the solution was maintained at 2.5 by simultaneous addition of 0.1 molar aqueous hydrochloric acid. of acid When the treatment was complete, the flask was flushed with nitrogen and the catalyst was removed. the aqueous layer Separate, filter and lyophilize 1 The title compound was obtained as its hydrochloride.

The physical properties were as shown below.

Yield: 0.2649 Proton-N, M, R,: a (CD3)2 So 1.3 (8H, s, 2-CHs).

1.45 (3H, s, 2-CHa), 8.05-8.65. (2H, m, 6 a and 6β-H), 8.15 (8H,s, 9-OCHa), 8.9 (2H, d, 9-CH2).

4.4 (LH, s, 5-CH), 4.71 (LH, t, 8-CH), 5 ．． 12 (2H.

s, 3-CH and 5-CH), 5.3-5.75 (8H, m, 5-C H, 6-CH, and CH-Ph), 5.84 (2H, S, -0-CH2-O ), 7.4 (5H, br,, s.

Ar-H).

International investigation report

Claims (1)

[Claims] [In the formula, Bl is alkyl of 01 to 6, cycloalkyl of 03 to 6, cycloalkyl of 05 to 8 chloroalkenyl or aromatic group R2 is 17th amino or carboxy group or R3 is the hydrogen or hydrocarbon fraction as described above. of the groups R11λ2 and R8 Either is optionally substituted; and R4 is of formula 0: (In the formula, the symbol represents a carbon atom '?ii, and up to 18 inert organic groups). ] combination of substance or its acid addition salt. 2. Ordinary 4 is 2〇D= [In the formula, R16 is a 7p kylene group having 1 to 4 carbon atoms and 11? is a hydrogen atom or carbon Number of carbon atoms substituted by an alkyl group having 1 to 4 atoms or a phenyl group 1 to 4 alkyl groups. ) The compound according to claim 1, which is a group of 8. R4 is the formula (g): [In the formula, R18 is a divalent hydrocarbon group having 2 to 8 carbon atoms, B19 is a hydrogen atom or The alkyl group having 1 to 4 carbon atoms and RffiO are hydrogen atoms or R'', Co, and 21 groups (wherein R21 is a group of 1 to 1 carbon atoms optionally substituted with a phenyl group) 4 is an alkyl group. ] The compound according to claim 1, which is a group of (In the formula, R22 is hydrogen, an alkyl group having 1 to 4 carbon atoms, or phenylene) V group, or Substituted with carboxylic acid group or salt or alkyl ester of 01-4 One of the above is a carboxylic acid group or a salt of its 01-4 alkyl ester. grow old ) is a group according to claim 1. 5. Compound 06 of Claim 4, wherein 22 is hydrogen, and R1 is phenyl or monosubstituted phenyl group and R2 is amino or an acid salt thereof. Compounds described in Nos. 1 to 5 below. 7. Methylclaparanyloxymethyl-3-(I)-α-amino-α-phenylene Ruacetamide] Benicilanato. 8, IA) Formula (VD: (In the formula, R1, R2 and C8 are the same as defined in claim 1, and Y is excluded. This is the group to be removed. ) or a salt thereof or a reactive conductor thereof; ceremonial hat R'-CO-Of ((ro) (In the formula, R4 is 0, which is the same as defined in claim 1.) (However, R' The functional group at -C112- and the amino group at R4 are appropriately protected). or (to) Formula (2): (wherein R3 and R4 are the same as defined in claim 1) or a derivative thereof which undergoes N-acylation and the formula α): R”-CnH2-00□Hα) (wherein and R2 are the same as defined in claim 1, and a reactive group is voluntarily insured. ) with N-acylated derivatives of carboxylic acids. , or 0(a) formula ω): (In the formula, R8 and R4 are the same as defined in claim 1, and R2B is a It is a V group. ) and treated with an iminohalide forming agent, (b) The resulting iminohalide is attached to the imino carbon atom with a QRf group [wherein Q is oxygen] , sulfur or nitrogen and 1Lf is an alkyl group having 5 to 14 carbon atoms]. iminoether, iminothioether or amidine (where Q is OlS or N, respectively), (0) Reacting the N-acylated derivative of the acid of formula (to) above, and (d) treatment with water. death, And then if necessary, (1) removing the protecting group, (B) a compound of formula (I) comprising converting the product into a pharmaceutically acceptable salt; manufacturing method. 9. from a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition. 10. Formula % formula % defined in claim 1 used for treatment of N4B silent infection