JPS58116418A - Antimicrobial pharmaceutical composition - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R<1> is H or hydroxyl group; R<2> is -CO-CH(NH2)-CH2COR<3> (R<3> is hydroxyl group, lower alkylamino, dilower alkylamino, etc. when R<1> is H, and amino or lower alkoxyl when R<1> is hydroxyl group), etc.]or a salt thereof. EXAMPLE:Potassium 6-[D-2-(D-2-amino-3-carbamoyl-propionamido)-2-p-hydroxyphenylacetamido ]penicillanate. USE:An antimicrobial agent and chemotherapeutic agent useful for infectious diseases due to Gram-positive and Gram-negative bacteria, etc. PROCESS:A compound of formula II (Y<1> is H or a protecting roup) is reacted with a compound of the formula R<2>'-OH[R<2>' is CO-CH(NHZ)-CH2COR<3> (Z is a protecting group), etc.]to give a compound of formula III. The protecting group is then removed to afford the aimed compound of formulaI.

Description

[Detailed description of the invention] The present invention is based on the general formula (However, R1 represents a hydrogen atom or a hydrogen atom.

R2 represents a group represented by the formula %, where Ha is a water a group or a lower alkylamino group when R1 is a hydrogen atom.

It is a di-lower alkylamino group, a lower alkoxy group, or a hydroxy-substituted lower alkylamino group.
* 6-CD-2 represented by "When it is a swimsuit group, it represents an amine 7 group or a lower alkoxy group"
The present invention relates to an antibacterial pharmaceutical composition comprising a therapeutically effective amount of a penicillane compound (acylamido-2-phenylacetamide) or a pharmacologically acceptable salt thereof.

U.S. Patent No. 326851: i'l-' and 3340
Product No. 252 is 6-CD-2-(DL-2-aminoglutaric acid)-2- produced from 6-(D-2-amino-2-phenylacetamido)penicillanic acid and DI,-glutamine. It has been described that phenylacedoide] penicillanic acid has antibacterial activity against Durham-positive and Gram-negative bacteria. It was heavy. N German Patent Application No. 193
No. 4783 discloses that 6-CD-2-(L-2- Amino-3-
It is described that penicillanic acid (carbamoyl-propionamide)-2-phenylacetothymide] can be prepared.

The chemical compounds of the present invention are all new compounds, and can be used as a countermeasure against infectious diseases spread by Durham positive 1 and Durham negative farms.
It is useful as a drug or chemotherapeutic agent. That is, compound CI)
It has high anti-microbial activity against various microorganisms, and when used in humans and animals, it is very well absorbed whether administered orally or parenterally.Especially the compounds of the present invention [!] is characterized by exhibiting high antibacterial activity against bacteria belonging to the genus Pseudomonas and the genus Staphylococcus.
Esierici γ, Klebsiella spp.

It also shows high antibacterial activity against Durham-positive bacteria and Durham-negative bacteria such as Salmonella and Bacillus. Moreover, the compound (
The toxicity of I) is very low.

Compound CI) of the present invention can be used for pharmaceutical purposes either as a free acid or as a salt. Examples of pharmacologically acceptable non-toxic salts of the compound include non-toxic metal salts such as sodium, potassium, calcium and aluminum;
Ammonium salts and trialkylamines, including triethylamine.

Procaine, dibenzylamine, N-pendyludiβ-7enethylamine, 1-F-teimine, N, N/
Non-toxic substituted ammonium salts such as -dibenzylethylenediamine, tehydroabiethylamine, H,Ml-bisude-1hydroabiethylethylenediamine, and salts with amines used to make salts with benzylpenicillin. Furthermore, since the metal compound CI) itself is very soluble in water, it can be administered either orally or parenterally, such as intravenously, intramuscularly, or subcutaneously. The daily dose for adults of compound CI) is approximately 0.25
1! ~202, preferably 0.5F-111, more preferably lf~4F is suitable. Furthermore, compound (I) can also be used as a drug with excipients and binders suitable for oral or parenteral administration. Suitable excipients include gelatin, lactose, glucose, salt, starch,
Examples include magnesium stearate, talc, vegetable oil and other commonly used excipients. Examples of the drug include solid preparations such as bare tablets, coated tablets, pills, and capsules, and liquid preparations such as solutions, suspensions, and emulsions. The drug may also contain adjuvants such as stabilizers, wetting agents or emulsifying agents. Moreover, it is also possible to sterilize drugs. The compound CI) of the present invention has the general formula (where yl represents a hydrogen atom or a protective group).

R1 has the same meaning as above) 6-(D-2-chominnow-2-phenylacetamido)penicillanic acid compounds [phantom and general formula % formula % (1) (However, R2 has the formula -Go-Cfl (NH2)-(HsCOR” e>t
, <bar GOCIIIs -CH(NHz) -C
OR'', where 2 represents a protecting group, and R'' is 1
6-CD-2-azilua mido-2-thenylacetamide, which is obtained by condensation with the N-protected amino acid represented by (having the same meaning as in the following) or its reactive derivative at the carboxyl group (6-CD-2-azilua mido-2-thenylacetamide) It can be produced by removing various protective groups from penicillanic acid compounds. On the other hand, the compound CII in which the symbol R3 is a hydroxyl group is the above-mentioned compound [πco and the general formula % formula % () (However, f' is the formula -Co-CH(IIiZ)-CFfbirdC00Y" 4L
lt-C0CHz-, CH(NFIK)-C00
Y", where Yl represents a protecting group, and 2 has the same meaning as above). The general formula ( However, 6-CD-2-acylamido-2-phenylacedore (Hl, R/ and Yl have the same meanings as above) is produced by removing various protecting groups from penicillanic acid compounds. I can do it.

The 0-line method will be explained in detail below.

The binding reaction between mass, penicillanic acid compound Cl0) and amino acid compound CM3 or [v] can be easily carried out. For example, this condensation reaction can be carried out using Schifnyl phosphoryl azide (+1m PO(0CsHs )s) in a suitable solvent.
] and in the presence of an organic tertiary amine. In addition, amino acid compounds [■] and [v
] can also be converted into a reactive derivative at its carboxyl group prior to the condensation reaction, suitable examples of which include the corresponding mixed acid anhydrides, active esters, azides and acid halides, which can be converted by conventional methods. can be manufactured. The condensation reaction between these reactive derivatives and the penicillanic acid compound (II) is carried out using a suitable solvent width of about -30 to
It is best to carry out at 40°C.

Next, the protective group can be removed from the 6-(D-2-acylamido-2-phenyl T-cetamido]penicillanic acid compound α] or [field] obtained as described above by various methods depending on the type of the protecting group used. It can be carried out by a removal method, for example.

1i [Group Z,! l: When L, TeO-nitrophenylsulfenyl group is used, the protecting group can be removed by reacting the compound [old or country] with 2 to 3 times the mole of thioamide in an appropriate solvent. can. Soda. Protecting group 2 is a benzyloxycarbonyl group,
Yasumoto! 1 and! In cases such as when each of 3 is a benzyl group, the removal of the WaS group can be carried out by stirring the compound [old or ■] in a hydrogen stream in the presence of a catalyst. On the other hand, when the protecting group 2 is a 1-methyl-2-lower alkoxycarbonylvinyl group or the protecting group Y1 is a trimethylsilyl group, the protecting group is treated with a dilute mineral acid in an appropriate solvent for 5 to 10 It is removed by contact treatment at °C. Even more blind protecting groups! 1 is 7 enacyl group, 7
In the case of a tal-imidomethyl group or a succinimidomethyl group, the li protecting group is removed by reacting with a thiool compound or a thiophyl alkali metal salt. In addition, when the protecting group Y1 is a 2.2.2-trichloroethyl group, the protecting group can be removed by reducing the compound [2] or [■] with 90% formic acid and zinc powder according to a conventional method. I can do it.

One of the starting materials compounds (II) and (V) of the present invention can be easily obtained by a method known per se. For example, W-
Hotan Ami/class compounds
It can also be produced by reacting t-noic acid with a compound represented by the general formula (where ?-logen atom is represented, and 2 has the same meaning as above). The raw material compound [v] is an amino acid represented by the general formula % formula % (where YS has the same meaning as above) and a compound represented by the general formula % formula % (however, 2 and X have the same meaning as above) It can be produced by reacting with and in the same manner as above.

In this specification, the terms "lower alkyl group" and "lower alkoxy group" refer to alkyl groups and alkoxy groups having 1 to 6 carbon atoms, which may be separated.

Production Example 1 (1) Dissolve 5F of D-2-Areino 3-carbamoyl propion, salt, and salt in 40% of water, neutralize it with 5.6F of potassium carbonate, and add TEHF2G-. There,
0-Nitrophenylsul 7enyl chloride 8.5F 5
During the reaction, add at ~10°C and stir at the same temperature for 2 hours.
Keep the - of the reaction solution at 8 with potassium carbonate After the reaction 1 Add 40 - of water to the reaction mixture, filter off the insoluble matter, wash the filtrate twice with ethyl acetate, acidify with citric acid and add acetic acid. Extract three times with ethyl chloride. After washing the extract with water and drying, the solvent was distilled off to obtain 6.7 t of D-2-(0-nitrophenylsul7enyl-aden))-3-carbamoyl-propionic acid at 163°C ( Decomposition] (2) Ru of ice crystal 2.859
Dicyclohexylcarbodiimide (hereinafter referred to as DCCD) 2.289 and N-hydroxysuccinimide are distilled off under reduced pressure at 2.7θ°C or less to the F50-solution, and the remaining crystals are washed with a benzene/ether mixture to obtain N-CD. -2
-(0-nitrophenylsulfenylamino)-3-,
fJ lupamoylprobiodyloxy]succinimide 39 is obtained as crystals. 1Ilp, 13◆~136℃ (
(decomposition) (3) Ice crystal 380'W and 6-(El-2-amino-
2-(p-Hydroxyphenyl)acetothymide] penicillanic acid triethylamine jJ [500 Mt was dissolved in a mixture of chloroform 4- and DMF 4-, and the mixture was heated to 26°C at 0 to 5°C.
Stir for a while. After the reaction, the solvent was distilled off under reduced pressure at about 30 DEG C., 1 ml of aqueous citric acid solution was added to the residue, and the mixture was extracted with a mixture of 20 ml of ethyl acetate and 10 ml of ethyl acetate. Wash the extracted layer with water. After drying, the solvent was distilled off under reduced pressure at a temperature below about 30°C to obtain crude 6-[D-2-(D-2-0-nitrophenylsul-7enyl〒2])-3-carbamoyl-propionamide 1/ )-2-P-hydroxyphenyl T-zdoamide]penicillanic acid 80 Q"l is obtained.

(4) Dissolve this product (8t) O”f in a mixture of 2- TIIF and 8wJ of ethanol, add thiobenzamide 41Q, and stir at room temperature for 15 minutes. Distill under reduced pressure, add 20% of TeiiF to the residue, and take the pale yellow precipitate.
Dissolve to remove insoluble matter, and freeze-dry the solution. The resulting colorless amorphous powder was suspended in methanol to 300 ml, and 100 ml of triethylamine and 180 ml of potassium 2-ethylhexanoate were added, followed by 2 ml of ether. If the colorless precipitate is taken, 6-(t)-2-CD-2-amino-3-carbamoyl-propionamide)-2-p
-Hydroxyphenyltacetamide] 370q of potassium penicillanate are obtained. llp, 213-115°C (decomposition).

fit-to 5 za: 330α, 17g0, 1660.1
590TLC: Rf = a0.30 (silica gel;
Solvent, n-butanol:acetic acid:water-4:1:1
) Production Example 2 In the same manner as Production Example 1, N-[DL-3-(.

6-(D-2-(DL-2-(0-nitrophenylsulfenylamino)-3-N-methyl Carbamoyl-propionamide)-2-phenylacetamido] penicillanic acid [yellow crystals; I!lp, 135-140°C (
decomposition)].

Then, the protecting group is removed to obtain 6-CD-2-(DL-2-amino-3-N-methylcarbamoyl-propionamide)-2-phenylacetamido]penicillanic acid as a colorless powder. Peng p, 193-195°C (decomposed).

Production Example 3 In the same manner as in Production Example 1, H-CD-2-(0-nitrophenylsulfenylamino-3-H-metallic acid, carbamoyl-propionic acid imide, sycosuccinic acid ionic acid and D-α
- React with aminobenzylpenicillin triethylamine salt, 5! -(D-2-CD-2-(0-nitrophenylsulfenyl γ-electrode)-3-M-methylcarbamoyl-propionamide)-2-7enyl acetate-electrode]pes+tyshun[゛yellow needles+mp , 145-147
°C (decomposition)] was then removed to give 6-[D-
Obtain 2-CD-2-aminoto 1-methylcarpamoylprobionamide]-2-7enylacetamide]penicillanic acid as a colorless powder. Table p, 1 9 3
~195°C (decomposition).

Production Example 4 In the same manner as in Production Example 1, 0M-[:L-2-(o-nitrophenylsulfenylamino)-3-M-methylcarbamoyl-propioic acid imide sycosuccinic acid ionic acid and D
-6-CD-2-(L-2-(0-nitrophenylsulfenylamino)-3-M-methylcarbamoyl-propionamide)-2-yenylacetamito]penicillane from α-aminobenzylpenicillin triethylamine salt The protecting group was removed in step 9 to obtain 6-CD-2-(L
-2-amino-3-)l-methylcarbamoyl-propionamide)-2-phenylacetamide] penicillane is obtained as a colorless powder. tap, 191-193℃ (
Disassembly).

Production Example 5 In the same manner as in Production Example 1, 6-(
D-2-(DL-2-(0-nitrophenylsulfenylamino)-3-M-ethylcarbamoyl-propionamide)-2-7dynylT-cetamido]penicillanic acid was obtained and the 0-th protecting group 6-[D-2-(DL-2
-amino-3-N-ethylcarbamoyl-propionamido)-2-phenylacetamido]penicillanic acid is obtained. mp, 190-193°C (decomposed).

Production Example 6 In the same manner as Production Example 1, DL-2-amino-3-N-n
- From propylcarbamoyl-propionic acid * 6-
(D-3-(D L-2-(0-nitrophenylsulfenylamino)-3-N-n-propylcarbamoyl-propionamide]-2-phenylacetate)
Remove the protecting group from penicillin prell with 111c and 6-C
D-2-(DL-2-ami)-3-N-n-propylcarbamoyl-≠propionamide)-2-phenylacetoy(de)penicillanic acid obtained, ridge 175
~178°C (decomposition).

Production example 7 (1) DL-N-(O-nitro-7-enylsulfenyl)
Asparagine anhydride 13.5 fit: TF1?20
- and methanol 30- dissolved in a mixture of 50-b and 30-b.
IF 10 G- and N-hydroxysuccinimide 5. Added IP and DCCD 9.1 f.

Leave at room temperature for 17 hours. The precipitate was plugged and the solvent was distilled off from the solution to obtain H-(DL-3-(o-nitrophyl-nylsulfenyl T-electron)-3-methoxycarponyloop a biote-thioxy) Kohata. Obtain Sunimide at 1.42 F.mp, 158-160°C (decomposition).

(2) 2.4 g of crystal and 1.52 T of n-butylamine
The HF25-solution is left at room temperature for 20 hours. When the solvent is distilled off from the reaction solution under reduced pressure, 1.8 g of T)L-2-(0-nitrophenylsulfenylamino)-3-N-n-butylcarpamoylpropionic acid methyl ester is obtained. n
ap, 104-105°C.

(3) Hydratinhydride 2- is added to a solution of 1.7 g of crystal in methanol 30-. After 1 hour, the precipitated yellow crystals are taken, and DL-2-(o-nitrophenylsulfenylamino)-3-N-n-butylcarbamoyl-
Obtain 1.2 p of propionic acid hydrachitite. mp, 1
80-182℃.

(4) Dissolve 888 q of crystal in a mixture of 15 yd of THF, 10 g of sulfuric acid, and 5 g of acetic acid, and gradually add 345 ml of sodium nitrite to the dough at -5 to -10°C. After 20 minutes, cold water was added to the two reactants, and the mixture was extracted with ethyl acetate. The extracted layer was dried with anhydrous magnesium sulfate,
By distilling off the solvent under reduced pressure, DL-2-(0-nitrophenylsulfenylamino)-3-N-n-butylcarbamoyl-propionite was converted into a yellow caramel with 700%
"?obtain.

(5) Crystal 7001W and. D-α-γ Minobenzylpenicillin triethylamine salt 900 kg of chloroform 15s+JII solution is stirred at 0 to 5°C for 48 hours. If the reaction solution is treated in the same manner as in Production Example 1-(3), e
6-CD-2-(DL-2-(o-nitrophenylsulfenylamino)-3-H-n-ph'Pcarpamoylpropionamide)-2-phenylacetamide] penicillanic acid as yellow caramel 210"f0 is then removed from this compound (200 Cape) to give 5-(D-2-(OL-2-amino-3-N-n-butylcarbamoyl-propionamide)-2- Phenylacetamide] Penicillanic acid as colorless powder 85”f
obtain.

Roof, 190-193°C (decomposition).

Production Example 8 In the same manner as Production Example 1, DL-2-7mi/-3-M-β
-Hydroxyethylcarbazoyl-propionic acid,
6-CD-2-(0-nitrophenylsulfenylamino)-3-N-β-hydroxyethylcarbamoyl-propionamido)-2-phenyltincetamide]penicillanic acid was obtained.

Then, the protecting group is removed to form @-(D-2-(DL-2-
Amino-3-N-β-droxyethylcarbamoyl-
Penicillanic acid (propionamide)-2-phenylchocetamide V] is obtained as a colorless powder.

ff1p, 177-180°C (decomposed).

Production Example 9 In the same manner as Production Example 1, DL-2-Ryo Minnow 3-N, N
-Dimethylcarbamoyl-propionic acid/resistant salt-
6-(''-2-(DL-2-(o-nitrophenylsulfenylTt/)-3-N,N-dimethylcarbamoyl-propionamide)-2-phenyldosetomide]
Obtain penicillanic acid.

Then, the protecting group was removed to give 6-(T), 2-(DL-2-
Ding minnow 3-11. ti-dimethylcarbamoyl-propionamide)-2-phenylacetotomide] penicillanic acid is obtained. nap, 192-194°C (decomposed).

Production example] 0 (1) DL-2-benzyloxycarbonylamino-3
-To a solution of 20q of benzyloxycarbonyl-propion and 210"f of triethylamine in dichloromethane, 2 dll of a solution of 270"f of inbutylchlorocarbonate in dichloromethane is added at -20 to -15°C. 1
After 0 minutes, to this solution.

A solution of D-α-aminobenzylpenicillin triethylamine salt 740"F in DMF4j was added dropwise and evaporated under reduced pressure at -15%, and to the residue was added 5% aqueous citric acid and 10% ethyl acetate, and the mixture was shaken. The organic solvent layer was separated. After taking the sample, washing it with water and drying it, 200q of triethylamine is added thereto.The solvent is distilled off under reduced pressure at about 30°C or less to obtain 16-CD-
2-(DL-2-benzyloxycarbonylTi)-3
-benzyloxycarbonyl-propion y(do)-2
-Penylacetamide] penicillanic acid triethylamine salt is obtained as colorless crystals at 970"F.

mp, 110-113°C (5+ solution).

121 Into an ethanol 6-solution of 200η of crystal, 30
Add 300 cm of palladium-barium carbonate.

Incubate in a hydrogen stream at room temperature and pressure for 4 hours.

After the reaction, insoluble matter is removed and the solvent is distilled off from the first solution under filtration pressure at about 30°C or lower. Add ether 5- to the resulting residue,
The white precipitate was collected, washed with chloroform, and dried to give 6-(D-2-(DL-2-amino-3-hydroxycarbonyl-propionamide)-2-phenylacetoTmide)penicillanic acid. Triethylamine salt 6011I9 is obtained, mP.

189~] 91°C (5+ solution).

Production Example 11 In the same manner as in Production Example 1, 6-(:D
-2-<0L-2-(0-nitrophenylsulfenylamino)-3-methoxycarbonyl-propionamide to 2-phenyldicetamido]penicillanic acid 1
The protecting group was then removed to give 6-CD-2-(DL-2-ami/-3-methoxycarbonyl-propionamide)-
2-phenylacetamido]penicillanic acid is obtained as a colorless powder. mp, 185-188°C (decomposition) The following compound was prepared in the same manner.

6-CD-2-(n-2-amino-3-methoxycarbonyl-propionamide)-2-p-hydroxyphenylacetamide] penicillanic acid.

Crystalline powder, mp, 170-173°C (decomposed).

Production Example] 2 In the same manner as in Production Example 1, D-2-ami/-3-methoxycarbonyl-propionic acid hydrochloride Jsu6-CD-2-
CD-2-(o-nitrophenylsulfenylamino)
-3-methoxycarbonyl-fropionamide)-2-
7-ethyl acetolymide] penicillanic acid was obtained 9 and then the protecting group was removed to give 6-[D+2-(D-2-γmino-3-
Methoxycarbonyl-propionamido-2-phenyl-propionamido]penicillane is obtained. q, 185-1
88°C (decomposition).

Production Example 13 In the same manner as in Production Example 10, 6-(D-2-(DL-3-benzyloxycarbonylamino-3- Benzyloxycarbonyl-propionamide)-2-phenylacetamide]penicillanic acid triethylamine salt was obtained as a colorless powder.The protecting group was then removed to obtain 6-CD-2-(DL-
3-Amino-3-hydroxycarbonyl-propionamide)-2-phenylacetamide penicillanic acid triethylamine salt is obtained as a light gray powder. ap, 1
85-188°C (decomposition).

Production Example 14 Same as Production Example 1, but from DL-3-amino-3-N-ethylcarbamoyl-propionic acid.

6- (D -2-(TI I, -3-(o-2)
o 7 z Nylsulfenylamino 3-3-N-ethylcarbamoylpropionamide)-2-phenylacetamide]penicillanic acid and then remove the protecting group to give 6-CD-2-CDL-3-amino-3 -! 1-Ethylcarbamoyl-propionamide)-2-phenylacetamide] penicillanic acid is obtained.

mp, 2oo-203°C (decomposed).

Production Example 15 Same as Production Example 1, DL-3-amino-3-N-n
-f From ropylcarbamoylpropionic acid, 6-[
D-2-(DL-3-(o-nitrophenylsulfenylamino)-3-)i-n-propylcarbamoyl-propionamido)-2-phenylacetamido]penicillane 11-4, and then the protecting group was removed. 6-1″D
-2-(DL-3-ami)-3-N-n-propylcarbamoyl-propionamide)-2-phenylacetamide]henisilane 117e. mp, 181-184
℃(＞+solution).

Production Example 16 In the same manner as Production Example 1, D[, -3-7mi/-3-N,
From N-dimethylcarbamoyl-propion hydrochloride, 6-(D-2-(t)L-(O-nitrophenylsulfenylamino)-3-N,N-dimethylcarbamoyl Propionamide F)-2-phenylacetamide] penicillanic acid was obtained.

The protecting group is then removed to obtain 6-CD-2-(DL-3-ami/-3-N,N-dimethylcarbamoyl-propionamide)-2-phenylacetamido]penicillanic acid as a colorless powder. mp, 207-210°C (decomposed).

Claims (4)

[Claims] (1) General formula (where R1 is a hydrogen atom or hydroxyl group, R3 is the formula = G
o-CH(MHz)-CHsCOR" l)l, (bar C0CE1*-CH(MHz)-COR", where R3 is a hydroxyl group, lower Alkylamino II represents a di-lower alkylamino group, a lower alkoxy group, or a hydroxy-substituted lower alkylamino group, and when R1 is a hydroxyl group, it represents an amino group or a lower alkoxy group] An anti-inflammatory pharmaceutical composition comprising a therapeutically effective amount of a newly synthesized penicillanic acid compound or a pharmacologically acceptable salt thereof. (2) R'' represents a hydrogen atom, R'' represents a group represented by the formula %, R8 is a lower alkyl T-electro group,
The antibacterial acid compound according to claim 1, which is a di-lower alkyl group, a lower alkoxy group, or a hydroxy-substituted lower alkylamino group. (3) The antibacterial pharmaceutical composition according to claim tmwixJJie, wherein R'' is a hydroxyl group, R3 is a group represented by the formula %, and R1 is an ami7 group or a lower alkoxy group. (4) R'' is a hydrogen atom, f represents a group represented by the formula %, and the furnace is a hydroxyl group, a lower alkylamino group, or a di-lower T-alkylaino group, according to claim 1 Antibacterial pharmaceutical composition.