KR810000004B1 - Preparing method of 6-methoxy alpha -carboxy penicillins - Google Patents

Abstract

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Description

Method for preparing 6-methoxy-α-carboxy penicillin series as an antibacterial agent

The present invention relates to a method for the preparation of penicillin-based compounds having antimicrobial activity that is valuable for the treatment of infections occurring in animals including humans and poultry by a wide range of gram negative bacteria.

In particular, the present invention relates to a method for preparing a 6-methoxy-α-carboxyphenicillin-based compound.

The 6-substituted acylamino phenylsilins of the following general formula (A) are known.

Wherein R _A is an acyl group, R _B is a hydroxy or mercapto group, substituted or unsubstituted methoxy, ethoxy, methyl, ethyl, methylthio, or ethyl thiogi, carbamoyloxy, carbamoylthio, C _1-6 alkanoyloxy, C _1-6 alkanoylthio, cyano, or a derivative of a carboxyl group such as a carboxyl or carbamoyl, and R _C is a hydrogen atom or an esterification group or cation that can be used as a medicament.

Known α-carboxy substituted acyl groups R _A are 2-carboxy phenylacetamido and specific examples of such side chains are shown with the following R _B groups: methyl, cyano, aminomethyl and 2-carboxy. 6-methoxy substituted penicillins with side chains of 2-aminoethoxy, α-carboxy-substituted acyl have not been published.

In addition, single 6-methoxy penicillin, ie, 6α-methoxy-6β- (2-carboxyphenylacetamido) peniclanic acid, is known in General Formula (A). We have now found that the new esters of 6-methoxy-α-carboxy phenylsilanes containing the above compounds have better oral absorption than free α-carboxy compounds.

According to this invention, the compound of the following general formula (I) is provided.

In the above formula, R is phenyl or 2- or 3-thienyl, R ² is hydrogen or salting ion which can be used as a drug, or an ester group which can be hydrolyzed in vivo, and R ¹ can be used as a drug. It can be substituted by any ester group which can be hydrolyzed in vivo, or by alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclic group.

Suitable salt ions for the R ² group include metal ions, such as aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, and lower alkylamines such as ammonium or substituted ammonium ions, for example triethylamine, From hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, cycloalkyls such as bicyclohexylamine Or furocaine, dibenzylamine, N, N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-β-phenethylamine, dehydroabiethyl adine, N, N ' There are other amines that come from bis-dehydro abiethylene diamine or which form a salt with pyridine, collidine or quinoline and ground pyridine or benzylphenicillin.

Ester groups that can be hydrolyzed in vivo to the R ₁ and R ₂ groups can be hydrolyzed in the human body to produce the original acid.

Suitable examples include acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-acetoxybenzyl and α-pivaloyloxyethyl groups: in ethoxycarbonyl oxymethyl and α- Alkoxycarbonyloxy alkyl groups such as oxycarbonyloxyethyl: and lactone, thiolactone and dithiolactone groups, ie ester groups of the general formula:

Wherein X 'and Y' are oxygen or sulfur and Z 'is a 1,2-phenylene group optionally substituted by ethylene or lower-alkoxy, halogen or nitro.

Better ester groups include phthalides and 5,6-dimethoxyphthalide esters.

In addition, the R ¹ group is an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclic group which may be substituted. Such suitable groups are as follows:

(a) alkyl, in particular lower alkyl such as methyl, ethyl, n- and iso-furophyll, n-, Sec-, iso- and tert-butyl pentyl:

(b) substituted lower alkyl wherein the substituent is at least one of the following: chloro, bromo, fluoro, nitro, carbo (lower alkoxy), lower alkanoyl, lower alkoxy, cyano, (lower) alkyl Mercapto, (lower) alkylsulfinyl, (lower) alkylsulfonyl, 1-indanyl, 2-indanyl, huryl, pyridyl, 4-imidazolyl, phthalimido, azetidino, aziridino, pi Lolidino, piperidino, morpholino, thiomolpoulino, N- (lower alkyl) piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethylpyrrolidino, 1, 4,5,6-tetrahydro pyrimidino, 4-methylpiperidino, 2,6-dimethylpiperidino, alkylamino, dialkylamino, alkanoylamino, alkylanilio or substituents are chlorine, clear, lower Substituted alkylamino which is alkyl or lower alkoxy:

(c) Substituted cycloalkyl and (2,2-di (loweralkyl) -1,3-dioxolon-4-yl) methyl of C _3-7 (with lower alkyl) in the cycloalkyl and cycloalkyl groups:

(d) alkenyl up to C ₈ :

(e) alkynyl up to C ₈ :

(f) phenyl and substituted phenyl wherein the substituents are at least one of chloro, bromo, fluoro, lower alkyl, lower alkoxy, lower alkanoyl, carbo (lower) alkoxy, nitro or di (lower) alkyl amino. Aryl group: And those having the following general formula.

In the formula, Y ² is

In the above formula Z ² is lower alkylene such as (CH ₂ ) ₃ -or-(CH ₂ ) ₄ -and substituted derivatives thereof whose substituent is methyl, chloro or bromo:

(g) aralkyl groups, such as substituted benzene, wherein the benzyl or substituent is chloro, bromo, fluoro, lower alkyl, lower alkoxy, lower alkanoyl, carbo (lower) alkoxy, nitro or di (lower) alkylamino;

(h) huryl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolyl, 3- (2-methyl-4-pyronyl), 3- (4 pyronyl) or N- (methyl Heterocyclic groups such as pyridyl)

(i) other hydrocarbyl groups, such as: ac-indanyl and substituted derivatives thereof, wherein the substituents are methyl, chloro or bromo: ac-tetrahydro naphthyl and substituted derivatives thereof, wherein the substituents are methyl, chloro or bromo : Benzohydroyl, trityl, cholesteryl, bicyclo [4,4,0] decyl.

Preferred groups for R ¹ include lower alkyl, benzyl, phthalyl, indanyl, phenyl, mono-, di- and 0-, m-, or p-methylphenyl, ethyl phenyl, n- or iso-propylphenyl, n-, tri- (lower) alkyl substituted phenyl groups such as sec-, iso- or t-butylphenyl.

Specific compounds in the present invention include the following.

6-α-methoxy, 6β- (D, L-2-phenoxycarbonyl-thien-2'-yl acetamido) peniclanic acid:

6-α-methoxy, 6β- (2'-phenoxycarbonylthien-3-yl acetamido) peniclanic acid:

6-β- [D, L-2- (iso-butyloxycarbonyl) thien-3-yl acetamido] -6-α-methoxy-phenicylic acid:

6-β- [D, L-2- (Indan-5-yl oxycarbonyl) -thien-3-yl acetamido] -6-α-methoxyphenicylanic acid:

6-α-methoxy-6-β- [D, L-2- (4-methylphenoxycarbonyl) -thien-3-yl acetamido] peniclanic acid:

6-α-methoxy-6-β- [D, L-2- (phthalide-3-yl oxycarbonyl) -thien-3'-yl acetamido] penicilanic acid:

6-β- (D, L-2- (2-sec-butyl phenoxycarbonyl) thien-3'-yl acetamido] -6-α-methoxy phenysilane acid:

6-β- [D, L-2- (2-ethyl phenoxycarbonyl) thien-3'-yl acetamido] -6-α-methoxyphenicylanic acid:

6- [alpha] -methoxy-6- [beta]-[D, L-2- (4-isofurophylphenoxycarbonyl) thien-3'-yl acetamido] peniclanic acid:

6-β- [D, L-2- (3,4-dimethylphenoxycarbonyl) -phenylacetamido] -6α-methoxy peniclanic acid:

6-α-Methoxy-6-β- [D, L-2- (4-methyl phenoxycarbonyl) -phenylacetamido] -phenoxysilane:

6α-methoxy-6-β- [D, L-2-phenoxycarbonyl-phenyl acetamido) -pheny silane acid:

6-α-methoxy-6-β- [D, L-2- (3-methylphenoxycarbonyl) -2-phenylacetamido] peniclanic acid:

6-β- [D, L-2- (5-indanyloxycarbonyl) -2-phenylacetamido] -6-α-methoxyphenicylanic acid:

6-β- [D, L-2-isobutoxycarbonyl-2-phenylacetamido-6-α-methoxyphenicylanic acid:

The process for preparing the compound of general formula (I) may be carried out by using a compound of general formula (XIII) as a metal ion such as tellurium (III), lead (IV), bismuth (V) mercury, lead, silver, cadmium or thallium salt. Reacts with methanol in the presence of:

Wherein R, R ¹ and R ² are as defined in formula (I) and R ³ is lower alkyl or benzyl.

This reaction is preferably carried out at -50 °-+ 25 ° C in a solvent.

Then if necessary,

(j) remove the carboxyl protecting group:

(ii) the product is converted to its salt or ester.

The antibiotic compound according to the present invention may be prepared to be administered in a convenient manner for use in medicine or veterinary medicine similar to the following antibiotics and thus the present invention consists of the above general formula (I) and a compound together with a pharmaceutical carrier or excipient Provides pharmaceutical composition.

Although oral administration is good, the composition can be formulated by the route of administration. The composition may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration are in unit dosage form and contain the following conventional excipients.

Excipients include binders such as syrup, acacia, gelatin, sorbet, tragacanth or polyvinyl-pyrrolidone: diluents such as lactose, sucrose, maize-starch, calcium phosphate, sorbitol or glycine: tablet lubricants such as magnesium Wetting agents such as stearates, talc, polyethylene glycols or silicas: disintegrants, for example potato starch: or sodium lauryl sulfate.

Tablets may also be removed by methods well known in the manufacture of conventional pharmaceuticals. Oral liquid preparations are, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or are given as a product which is dried to re-form before use with water or other suitable solvent.

Such liquid preparations include the following conventional additives.

Additives include suspending agents such as sorbet, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxy methyl cellulose, aluminum stearate or hydrogenated edible fats: emulsifying agents such as lecithin, sorbitan, Monooleates or acacias: Oily esters such as non-aqueous solvents (including cooking oils), such as almond oil, fractionated coconut oil, glycerin, porphylene glycol or ethyl alcohol: preservatives such as methyl or furo There is a fill P-hydroxy benzoate or sorbic acid, and if desired, conventional flavors or pigments may be added.

Suppositories include conventional suppositories, such as cocoa, butter or other glycerides.

For parenteral use, the liquid unit dosage form is prepared using the compound and a sterile solvent, preferably water.

Depending on the solvent and concentration used, the compound may be suspended or dissolved in the solvent. In preparing solutions, the compounds may be dissolved in water for injection and filled into suitable vials or ampoules and filtered sterilized prior to sealing. The advantage is that auxiliaries such as local anesthetics, preservatives and buffers can be dissolved in the solvent. To increase the safety, the ingredients can be filled in vials and then frozen to remove water under vacuum.

The lyophilized powder is then sealed in a vial and attached for re-formation of the distilled water for injection before use. Parenteral suspensions are actually prepared in the same manner except in suspension in a solvent instead of dissolving the compound and sterilization cannot be achieved by filtration.

Compounds are sterilized by exposure to ethylene oxide prior to suspension in sterile solvent. Surfactants or wetting agents are included in the components to promote even distribution of the compound.

The composition contains 0.1 wt% to 99 wt%, preferably 10 to 60 wt% of the active substance, depending on the method of administration. When the composition is made in unit doses, preferably each unit contains 50-500 mg of the active ingredient.

The therapeutic dose of an adult is preferably in the range of 100-3,000 mg per day, for example 1,500 mg per day, depending on the route and frequency of administration.

It will be clear that the side chains of penicillins of formula (I) have strong asymmetric carbon atoms. The present invention is intended to include not only mixtures of compounds (I) but also all possible epimers thereof.

The preparation of the compounds of the present invention will be described in the following examples.

Example

중탄산소다 용액(75밀리리터)와 함께 모든것이 녹을때까지 진탕했다.(a) benzyl 6-α-methylthio-6-β- (D, L-2-phenoxy carbonyl-2-phenylacetamido) penicilanate benzyl 6-β-amido-6-α-methyl Thiofenisylate toluene-4-sulfonate (1.57 grams, 3.0 mmol) was added to ethyl acetate (100 milliliters) and 0.5

It was shaken with sodium bicarbonate solution (75 milliliters) until everything melted.

중탄산 소다용액 및 포화소금물로 세척하고 건조한후 증발 농축하여 유를 얻었다. 실리카겔상의 크로마토 그래피를 행하여 표제의 화합물을 담황색 포말상으로 1.32그람, 74.5% 얻었다.The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 25 ml), and the combined extracts were dried (MgSO ₄ ) and concentrated by evaporation to obtain benzyl 6-β-amino-6-α-methylthio penicilanate. This containing pyridine (0.67 ml) was dissolved in dichloromethane (60 ml) and cooled in an ice bath and treated with 2-phenoxycarbonyl-2-phenyl acetyl chloride (phenyl hydrogen phenylmalo in dichloromethane (20 milliliters)). Nate, 1.28 grams, from 5.0 mmol) The solution was stirred for 2 hours, concentrated by evaporation to give an oil, dissolved in ethyl acetate, water, 10% citric acid solution, water,

Washed with bicarbonate soda solution and saturated brine, dried, and evaporated to give an oil. Chromatography on silica gel yielded the title compound (1.32 grams, 74.5%) in a pale yellow foam.

t. 1.c (SiO ₂ : ethyl acetate / 69-80 ° gasoline: 1: 3) Rf = 0.16: V max (nujolmull), 3300, 1780, 1740 and 1690 (m ⁻ ).

), 4.50, 4.47(1H,2×S,C₃프로톤), 2.25, 2.22 (3H,2×SiCH₃), 1.35, 1.30 (6H,2xS,gem dmethyls)nmr (CDCl ₃ ), δ = 7.90 (1H, S, -NH (0-), 7.0-7.8 (15H, m, 3 × PH-), 5.67, 5.63 (1H, 2 × S, (5 protons), 5.23 (2H, S, -CO ₂ CH ₂ Ph), 4.95 (1H, S,

), 4.50, 4.47 (1H, 2 × S, C ₃ protons), 2.25, 2.22 (3H, 2 × SiCH ₃ ), 1.35, 1.30 (6H, 2xS, gem dmethyls)

(b) benzyl 6-α-methoxy-6-β- (D, L-2-phenoxycarbonyl-2-phenylacetamido) phenylsilanate

Acetic acid in benzyl 6-α-methylthio-6-β- (D, L-2-phenoxycarbonyl-2-phenylacetamido) peniclanate (0.523 grams, 0.91 mmol) and methanol (4 ml) The second mercury (0.29 grams) was stirred for 1.5 hours at room temperature under a stream of nitrogen. Methanol was removed in vacuo, the residue was scrubbed with ether, filtered through celite and the filtrate was evaporated to straw straw foam. Chromatography on silica gel yielded 0.270 g, or 52.7% of this product:

), 4.49(1H,S,C₃푸로톤), 3.50, 3.47(4H,2×S, -OCH₃), 1.33(6H, S, gem dimethyls).(SiO ₂ : ethyl acetate / 60-80 ° petrol: 1: 3) Rf = 0.14: nmr (CDCl ₃ ), δ = 8.12, 8.02 (1H, 2 x S, -NHCO-), 7.9-7.0 (12H, m, 3 × Ph-), 5.70 (1H, S, C ₅ proton), 5.25 (2H, S, -CO ₂ CH ₂ Ph) 5.00 (1H, S,

), 4.49 (1H, S, C ₃ proton), 3.50, 3.47 (4H, 2 × S, -OCH ₃ ), 1.33 (6H, S, gem dimethyls).

(C) 6α-methoxy-6β- (D, L-phenoxycarbonylphenyl acetamido) phenic carboxylic acid

Benzyl ester was removed as follows to yield the title compound.

-중탄산소다(0.92밀리리터)로 처리하고, 10% 탄소상의 팔라디움(620밀리그람)을 질소공기 속에서 가하고, 이 혼합물을 1시간동안 수소화시켰다. 이 혼합물을 셀라이트(celite)를 통하여 여과하고 잔액을 50% 수용성 에탄올(10ml)로 세척했다. 촉매(0.7g)를 더가하고 클로로포름/아세톤/초산-50 : 50 : 7 용매로 실리카겔상에서 t.l.c에서 보여주듯이 벤질 에스테르가 완전히 제거될 때까지 가수소분해를 계속했다. 반응 혼합물을 셀라이트를 통해 여과하고 진공에서 증발농축하여 에탄올을 제거한 후 동결 건조하여 생성물을 그것의 소듐염으로 얻었다.Benzyl 6α-methoxy-6-β- (D, L-2-phenoxycarbonyl-phenylacetamido) phenylsilanate (620 mg) dissolved in distilled ethanol (4.5 ml) and freshly prepared One

Treated with sodium bicarbonate (0.92 milliliters), palladium on 10% carbon (620 milligrams) was added in nitrogen air and the mixture was hydrogenated for 1 hour. The mixture was filtered through celite and the residue was washed with 50% aqueous ethanol (10 ml). Catalyst (0.7 g) was further added and hydrolysis continued until the benzyl ester was completely removed as shown by tlc on silica gel with chloroform / acetone / acetic acid-50: 50: 7 solvent. The reaction mixture was filtered through celite and concentrated in vacuo to remove ethanol and freeze dried to afford the product as its sodium salt.

T.1.c: Rf = 5.69 (SiO ₂ : chloroform / acetone / acetic acid-50: 50: 7) ν max (kBr): 3420 (broad), 2967, 1710, 1597, 1680, 1490, 1190, 690 cm ^-1 .

N.m.r indicated that benzyl isster was removed.

[Biological data]

1. Antimicrobial Screening

The antimicrobial activity of the various compounds of the present invention in terms of MIC values is shown in Tables 1,2 and 3.

Table 1 relates to the α-esters of 6-methoxycarbenicillin (General Formula (I), R = Ph, R ² = H):

Table 2 relates to α-esters of 6-methoxy ticarcillin (General formula (I), R = 3-thienyl, R ² = H).

Table 3 shows phenyl esters of 6α-methoxy, 6β- (2-carboxy-2-thien-2'-yl acetamido) peniclanic acid (formula (I), R = 2-thienyl, R ² = H, R ¹ = Ph).

TABLE 1

[Α-esters of 6-α-methoxycarbenicillin]

(System dilution method of 5% blood agar)

TABLE 2

[Α-esters of 6-α-methoxy ticarcillin]

(System dilution of 5% blood agar)

TABLE 3

(System dilution of 5% blood agar)

2. Oral Absorption

Blood concentrations in mice of 6-methoxy ticarcillin and 6-methoxy carbenicillin were measured after oral administration of esters. Urine may also be collected from mice and subjected to biochromatograms to determine whether non-hydrolyzed esters are secreted. During the microbial analysis, the degree of hydrolysis of the esters was measured in the blood and salt of mice. The following method was used.

Species: Albino male (S1 strain 18-22 g)

Route of administration: Oral

Dose: Each ester was dosed to contain 100 mg / kg of oral penicillin free acid.

Analysis: Specimens were analyzed as oral penicillin using Neisseria catarrhalis as the analytical microorganism.

Chromatography: Urine was collected from the mice receiving the compound. The samples were subjected to biochromatogram.

Butanol: ethanol: water system (4: 1: 5) was used and strips were observed on agar plates seeded with Nigeria catalanis.

Results for blood concentrations in mice are shown in Tables 4 and 5.

Blood concentration was not detected after 6-methoxycarbenicillin was administered at the dose of 100 mg / kg under the same conditions.

TABLE 4

[Blood Concentration in Mice of 6-methoxy Tikarsin after Oral Administration of α-carboxyesters at 100 mg / kg]

TABLE 5

[Blood Concentration in Mice of 6-methoxy Carbenicillin after Oral Administration of α-carboxyesters at 100 mg / kg]

Claims (1)

A process for preparing 6-methoxy-α-carboxyphenicillins of formula (I), wherein the compound of formula (XIII) is reacted with methanol in the presence of a metal ion.

Wherein R is phenyl or 2- or 3-thienyl, R ² is hydrogen or salting ion or a group which can be hydrolyzed in vivo, and R ¹ is an ester group or alkyl which can be hydrolyzed in vivo , Cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or a heterocyclic group, which groups may be optionally substituted, and R ³ is lower alkyl or benzyl.