HK1067116A - Carbapenem compound - Google Patents
Carbapenem compound Download PDFInfo
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- HK1067116A HK1067116A HK04109961.2A HK04109961A HK1067116A HK 1067116 A HK1067116 A HK 1067116A HK 04109961 A HK04109961 A HK 04109961A HK 1067116 A HK1067116 A HK 1067116A
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- methylpenam
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- hydroxyethyl
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- dimethylaminocarbonyl
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Description
Technical Field
The present invention relates to a novel carbapenem compound useful as a prophylactic and therapeutic agent for bacterial infections, etc. More particularly, the present invention relates to a compound having excellent oral absorbability and exhibiting sufficient antibacterial activity, and an antibacterial agent containing the compound as an active ingredient.
Background
Heretofore, many compounds having carbapenem skeleton have been found as therapeutic agents for infectious diseases, and several carbapenem compounds having excellent antibacterial activity have been used or developed for practical use. For example, carbapenem compounds represented by the formula (A) (isomeric penems) have been put to practical use for clinical use. The isomeric penems have a broad antibacterial spectrum and a strong antibacterial activity, and overcome the disadvantages of the conventional carbapenem compounds, namely instability to renal dehydropeptidase, and have the excellent characteristic of being administered alone without using a stabilizer.
However, the isomeric penems lack absorbability in the digestive tract and are only administered clinically as injections. The oral preparation is easy and convenient to administer as compared with injection, and has high clinical applicability. Therefore, there is a strong demand for the development of carbapenem compounds for oral administration which have potent antibacterial activity and broad antibacterial spectrum and have excellent absorbability into the digestive tract.
Disclosure of the invention
The present invention addresses the problem of providing a useful compound that has excellent absorbability in the digestive tract and exhibits a strong antibacterial activity when hydrolyzed after absorption.
The present inventors have conducted extensive studies to achieve the above object and found that a specific carbapenem compound (prodrug) represented by the following formula (I') is superior in absorbability into the digestive tract compared to a carbapenem compound for oral administration which has been proposed so far, and can exhibit antibacterial activity by being deesterified in vivo to a carbapenem compound having antibacterial activity, thereby completing the present invention.
That is, the present invention relates to the following.
(1) A carbapenem compound represented by the formula (I').
[ in the formula, R1represents-CH2OCOC(CH3)3、-CH2OCO2CH(C2H5)2、-CH(CH3)OCO2CH(C2H5)2、
Or
R2represents-CH2CH2CH3、-CH2CH3、-CH(CH3)2，
However, (i) R1is-CH2OCOC(CH3)3When R is2is-CH2CH2CH3；
(ii)R1is-CH2OCO2CH(C2H5)2or-CH (CH)3)OCO2CH(C2H5)2When R is2is-CH2CH2CH3、-CH2CH3or-CH (CH)3)2；(iii)R1Is that
Or
When R is2is-CH2CH2CH3or-CH (CH)3)2。]
(2) The compound of the above (1) is
Pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate, or
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate.
(3) An antibacterial agent comprising the compound according to the above (1) or (2) as an active ingredient.
(4) The antibacterial agent according to the above (3) is for oral administration.
(5) A carbapenem compound represented by formula (I)
(6) The compound according to the above (5) is pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate.
(7) An antibacterial agent comprising the compound according to (5) or (6) as an active ingredient.
(8) The antibacterial agent according to (7) above is for oral administration.
Detailed description of the invention
Using the following formula (I')
(wherein each symbol is as defined above) represents, for example, a compound (I),
the carbapenem compound is superior in absorbability into the digestive tract compared with conventional carbapenem compounds for oral administration. The antibacterial agent of the present invention contains the above-mentioned compound (I') as an active ingredient.
Compound (I') can be produced, for example, by the following production method or a method according to it. The other compounds contained in the compound (I') can also be produced according to the following production method of the compound (I).
[ wherein X represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an alkanesulfonyloxy group such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group or a butanesulfonyloxy group, or a digestive group such as an arylsulfonyloxy group such as a benzenesulfonyloxy group or a tolylsulfonyloxy group, and Y represents a chlorine atom, an imidazol-1-yl group, a p-nitrophenyloxy group or a digestive group such as a 2-phenylacetonitrile-2-yl-iminoxy group. ]
Step 1
The compound (II-2) is obtained by reacting the compound (II-1) or a salt thereof with the compound (III) in a solvent which does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture of these). The amount of the compound (III) to be used is usually about 1 to 5 moles, preferably about 1 to 2 moles, based on 1 mole of the compound (II-1). Further, the compound (II-1) can be obtained, for example, by the method described in Japanese patent publication No. 1988-55514, etc.
Examples of the salt of the compound (II-1) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, triethylamine salt, dicyclohexylamine salt, and pyridine salt.
The reaction of step 1 may be carried out in the presence of a base. The base to be used is not particularly limited, but is preferably an inorganic base such as sodium hydrogencarbonate and potassium carbonate or an organic base such as triethylamine, diisopropylethylamine, and pyridine.
The reaction temperature in the step 1 is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature for suppressing side reactions, and usually, the reaction is carried out at-30 to 40 ℃ and preferably at-10 to 10 ℃. The reaction time varies depending on the reaction temperature, the kind of the reaction reagent, and the like, but is usually from 30 minutes to 10 hours.
Step 2
The compound (I) is obtained by reacting the compound (II-2) or a salt thereof with the compound (IV) in a solvent which does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture of these), preferably in the presence of a base. The amount of the compound (IV) to be used is usually about 1 to 5 mol, preferably about 1 to 2 mol, based on 1 mol of the compound (II-2).
The reaction in step 2 is carried out in the presence of a base when the compound (II-2) is not in the form of a salt. The base to be used is not particularly limited, but is preferably an inorganic base such as sodium hydrogencarbonate and potassium carbonate or an organic base such as triethylamine, diisopropylethylamine, and pyridine. The amount of the base used is usually about 1 to 5 moles, preferably about 1 to 2 moles, based on 1 mole of the compound (II-2).
The reaction temperature in the step 2 is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature for suppressing side reactions, and usually, the reaction is carried out at-30 to 40 ℃, preferably-10 to 10 ℃. The reaction time varies depending on the reaction temperature, the kind of the reaction reagent, and the like, but is usually from 30 minutes to 10 hours.
Examples of the salt of the compound (II-2) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, triethylamine salt, dicyclohexylamine salt, and pyridine salt.
The compound (I'), for example, the compound (I), can be purified by a conventional method, for example, recrystallization, separation thin layer chromatography, column chromatography, etc., as required.
The compound (I ') having an excellent configuration is a compound represented by the following formula (I' -a)
(wherein each symbol is as defined above.)
A compound (I) having an excellent configuration is represented by the following formula (I-a)
The compound shown in the specification. Namely trimethylacetoxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate.
The compound (I') is rapidly absorbed into the blood by oral administration, and the metabolite thereof is a carbapenem compound represented by the above formula (II-1), and shows a high blood concentration. That is, the compound (I') is excellent in absorbability in the digestive tract and is useful as a prodrug of a carbapenem compound (particularly, isomeric penems).
Therefore, the prophylactic and therapeutic agent for infectious diseases containing the compound (I') has the above-mentioned excellent effect by oral administration, and is usually administered as an oral agent.
The agent for preventing and treating infectious diseases can be prepared by diluting with a pharmaceutically acceptable excipient according to a known method. Examples of the excipient include starch, lactose, granulated sugar, calcium carbonate, and calcium phosphate.
The agent for the prophylaxis or treatment of infectious diseases may further contain other additives as needed, and examples thereof include additives excellent in a binder (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), a lubricant (e.g., magnesium stearate, talc, etc.), and a disintegrant (e.g., calcium carboxymethyl cellulose, talc, etc.). After mixing the components, the mixture is prepared into a dosage form suitable for oral administration, such as a capsule, a tablet, a fine granule, a dry syrup, and the like, according to a known method, and an agent for preventing and treating infectious diseases for oral administration is produced.
The compound (I') of the present invention is useful for the prevention and/or treatment of an infectious disease (particularly, a bacterial infectious disease) in a mammal (e.g., a human, a cow, a horse, a dog, a cat, a white mouse, a mouse, or a hamster). Examples of the infection include suppurative diseases, respiratory infection, biliary tract infection, urinary tract infection, and the like.
The amount of the compound (I '), particularly the compound (I), to be administered varies depending on the subject, symptoms, and the like, and when administered to, for example, a suppurative disease of an adult, the compound (I') is administered orally 1 time about 1 to 40mg/kg body weight (preferably about 1 time about 1 to 10mg/kg body weight) about 1 time about 1 day to 4 times.
The compound (I') of the present invention can exhibit an excellent antibacterial action in vivo with a smaller amount of administration than the carbapenem compounds for oral administration which have been proposed in the past.
In addition, the compound (I') may be used in combination with other antibacterial active substances, for example, antibacterial agents (penicillins, aminoglycosides, cephalosporins, etc.) or therapeutic agents for systemic symptoms due to bacterial infections (antipyretics, analgesics, anti-inflammatory agents, etc.).
Examples
The physical properties and production method of the compound of the present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.
Example 1
Trimethylacetyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
21.1g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 80ml of N, N-dimethylformamide, and 16.3g of butyryloxymethyl-p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Next, the reaction mixture was cooled to 5 ℃ and 21.4g of pivaloyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 400ml of ethyl acetate was added thereto, and the mixture was washed with 400ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 40ml of ethyl acetate. Further, 60ml of isopropyl ether was added thereto, and after stirring for 1 hour, the precipitated crystals were filtered to obtain 19.7g of the title compound.
IR(Nujol，cm-1)：3395，1794，1753，1728，1636
1H-NMR(CDCl3，δppm)：0.94(3H，t)，1.22(9H，s)，1.26(3H，d)，1.33(3H，d)，1.65(2H，m)，2.34(2H，t)，1.7～2.8(3H，m)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.71(1H，m)，5.6～5.8(2H，m)，5.89(2H，ABq).
Example 2
1-Ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of isobutyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃, 1.42g of 1-ethylpropyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 50ml of ethyl acetate was added thereto, washed with 50ml of 5% saline solution, and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 2.5ml of ethyl acetate. Further, 5.5ml of isopropyl ether was added thereto, and after stirring for 1 hour, the precipitated crystals were filtered to obtain 1.22g of the title compound.
IR(Nujol，cm-1)：3395，1759，1724，1651
1H-NMR(CDCl3，δppm)：0.91(6H，t)，1.17(6H，d)，1.25(3H，d)，1.33(3H，d)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.8(2H，m)，5.6～6.0(4H，m).
Example 3
1-Ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 5ml of N, N-dimethylformamide, and 813mg of butyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃, 1.47g of 1-ethylpropyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, and the mixture was washed with 50ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and after stirring for 1 hour, the precipitated crystals were filtered to obtain 1.02g of the title compound.
IR(Nujol，cm-1)：3400，1761，1722，1651
1H-NMR(CDCl3，δppm)：0.92(6H，t)，0.94(3H，t)，1.26(3H，d)，1.33(3H，d)，1.63(4H，qui)，2.34(2H，t)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.8(2H，m)，5.6～6.0(4H，m).
Example 4
1-Ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyri-dinol-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 773mg of propionyloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃, 1.42g of 1-ethylpropyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, washed with 100ml of 5% saline solution, and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 4ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated crystals were collected by filtration to obtain 1.13g of the title compound.
IR(Nujol，cm-1)：3395，1761，1717，1653
1H-NMR(CDCl3，δppm)：0.92(6H，t)，1.14(3H，t)，1.26(3H，d)，1.33(3H，d)，1.64(4H，qui)，2.39(2H，q)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.6～4.8(2H，m)，5.6～6.0(4H，m).
Example 5
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of isobutyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction mixture was cooled to 5 ℃ and 1.49g of 1- (1-ethylpropyloxycarbonyloxy) ethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, and the mixture was washed with 50ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 810mg of the title compound.
IR(Nujol，cm-1)：3395，1755，1728，1651
1H-NMR(CDCl3，δppm)：0.91(6H，t)，1.18(6H，d)，1.26(3H，d)，1.33(3H，d)，1.5～1.7(4H，m)，1.58，1.59(3H，d)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.8(2H，m)，5.6～5.8(2H，m)，6.86(1H，q).
Example 6
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of butyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction mixture was cooled to 5 ℃ and 1.49g of 1- (1-ethylpropyloxycarbonyloxy) ethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, and the mixture was washed with 50ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 650mg of the title compound.
1H-NMR(CDCl3，δppm)：0.91，0.92(6H，t)，0.94(3H，t)，1.25(3H，d)，1.33(3H，d)，1.58(3H，d)，2.34(2H，t)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.8(2H，m)，5.6～5.8(2H，m)，6.86(1H，q).
Example 7
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 773mg of propionyloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction mixture was cooled to 5 ℃ and 1.49g of 1- (1-ethylpropyloxycarbonyloxy) ethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, and the mixture was washed with 50ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 790mg of the title compound.
IR(Nujol，cm-1)：3395，1759，1728，1651
1H-NMR(CDCl3，δppm)：0.91(6H，t)，1.14(3H，d)，1.26(3H，d)，1.33(3H，d)，1.59，1.60(3H，d)，2.39(2H，q)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.8(2H，m)，5.6～5.8(2H，m)，6.86(1H，q).
Example 8
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of isobutyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Further, the reaction mixture was cooled to 5 ℃ and 1.48g of cyclohexyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, and the mixture was washed with 50ml of 5% saline solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 1.19g of the title compound.
IR(Nujol，cm-1)：3395，1796，1751，1728，1638
1H-NMR(CDCl3，δppm)：1.18(6H，d)，1.0～2.1(11H，m)，1.26(3H，d)，1.33(3H，d)，2.4～2.9(2H，m)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.6～4.8(2H，m)，5.6～6.0(4H，m).
Example 9
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of butyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃, 1.64g of cyclohexyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added thereto, washed with 50ml of 5% saline solution, and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 1.10g of the title compound.
IR(Nujol，cm-1)：3400，1760，1715，1653
1H-NMR(CDCl3，δppm)：0.95(3H，t)，1.1～2.2(13H，m)，1.30(3H，d)，1.34(3H，d)，2.34(2H，t)，2.5～2.9(1H，m)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.9(2H，m)，5.6～5.9(2H，m)，5.84，5.92(2H，ABq).
Example 10
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of isobutyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃ and 1.45g of cyclopentyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added, and the mixture was washed with 50ml of 5% aqueous sodium chloride solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 1.01g of the title compound.
1H-NMR(CDCl3，δppm)：1.18(6H，d)，1.0～2.1(9H，m)，1.26(3H，d)，1.33(3H，d)，2.4～2.9(2H，m)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.6～4.8(2H，m)，5.6～6.0(4H，m).
Example 11
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate
1.06g of sodium (1R, 5S, 6S) -2- [ (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate was suspended in 4ml of N, N-dimethylformamide, and 813mg of butyryloxymethyl p-nitrophenylcarbonate was added thereto at 5 ℃ and the mixture was stirred at room temperature for 1 hour.
Then, the reaction solution was cooled to 5 ℃ and 1.45g of cyclopentyloxycarbonyloxymethyl iodide was added thereto, and after stirring at room temperature for 1 hour, 100ml of ethyl acetate was added, and the mixture was washed with 50ml of 5% aqueous sodium chloride solution and dried with thenardite.
Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a solid substance, which was dissolved in 5ml of ethyl acetate. Further, 20ml of isopropyl ether was added thereto, and the precipitated powder was filtered to obtain 0.95g of the title compound.
1H-NMR(CDCl3，δppm)：0.95(3H，t)，1.1～2.2(11H，m)，1.30(3H，d)，1.34(3H，d)，2.34(2H，t)，2.5～2.9(1H，m)，2.9～3.2(6H)，3.1～3.9(4H，m)，3.9～4.4(3H，m)，4.5～4.9(2H，m)，5.6～6.0(4H，m).
The chemical structural formulas of the compounds obtained in examples 1 to 11 are shown in table 1.
TABLE 1
Test examples
Next, in order to confirm the excellent properties of the compound of the present invention, the following oral absorption test was performed.
Test example 1
The compound of the present invention (compound of example 1) was orally administered at 20mg/kg in pre-dosed 50mg/kg of enzyme inhibitor (cilastatin) in white mice (group 1, 3). The concentrations of the isomeric penems formed by hydrolysis in each plasma after 0.125, 0.25, 0.5, 1.0, 1.5, 2.0 and 3.0 hours were measured by HPLC, and the area under the plasma concentration-time curve (AUC) was determined. The results are shown in Table 2.
TABLE 2
| Test compounds | Mean plasma concentration (. mu.g/ml) | AUC 0-3hr(μg·hr/ml) | ||||||
| 0.125hr | 0.25hr | 0.5hr | 1.0hr | 1.5hr | 2.0hr | 3.0hr | ||
| Experimental example 1 | 0.62 | 1.31 | 2.31 | 2.59 | 2.27 | 1.56 | 0.55 | 5.06 |
Industrial applicability of the invention
The compound (I') of the present invention has superior absorption in the digestive tract upon oral administration as compared with the carbapenem compounds for oral administration which have been proposed so far, and the active form produced in vivo exhibits sufficient antibacterial activity against a wide range of bacterial species, and is extremely useful for the prevention and treatment of infectious diseases (particularly bacterial infections).
This application is based on Japanese patent application No. 2001-150874, the contents of which are fully included in this specification.
Claims (8)
1. A carbapenem compound represented by the formula (I'),
[ in the formula, R1represents-CH2OCOC(CH3)3、-CH2OCO2CH(C2H5)2、-CH(CH3)OCO2CH(C2H5)2、
Or
R2represents-CH2CH2CH3、-CH2CH3、-CH(CH3)2，
However, (i) R1is-CH2OCOC(CH3)3When R is2is-CH2CH2CH3；
(ii)R1is-CH2OCO2CH(C2H5)2or-CH (CH)3)OCO2CH(C2H5)2When R is2is-CH2CH2CH3、-CH2CH3or-CH (CH)3)2；
(iii)R1Is that
Or
When R is2is-CH2CH2CH3or-CH (CH)3)2]。
2. The compound of claim 1 which is
Pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1-ethylpropyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
1- (1-ethylpropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidine-3-thio ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate,
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate, or
Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate.
3. An antibacterial agent comprising the compound according to claim 1 or 2 as an active ingredient.
4. The antibacterial agent according to claim 3, which is for oral administration.
5. A carbapenem compound represented by formula (I)
6. The compound of claim 5, which is pivaloyloxymethyl (1R, 5S, 6S) -2- [ (3S, 5S) - (5-N, N-dimethylaminocarbonyl-1-butyryloxymethyloxycarbonyl) pyrrolidin-3-sulfanyl ] -6- [ (1R) -1-hydroxyethyl ] -1-methylpenam-2-m-3-carboxylate.
7. An antibacterial agent comprising the compound according to claim 5 or 6 as an active ingredient.
8. The antibacterial agent according to claim 7, which is for oral administration.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP150874/2001 | 2001-05-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1067116A true HK1067116A (en) | 2005-04-01 |
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