Derivatives carbapenem, antibacterial based on it and its intermediate connection

 

(57) Abstract:

The invention relates to new derivatives carbapenem formula I, where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino; or its pharmaceutically acceptable salt. Antibacterial agent containing the derivative carbapenem formula I and pharmaceutically acceptable carrier or diluent. The intermediate connection representing a derivative carbapenem formula II, where R2represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino;5presented is; what if his salt. The technical result of new derivatives carbapenem that have antibacterial properties. 6 c. and 13 C. p. F.-ly, 3 tables.

The technical field

This invention relates to a new derived carbapenem and its pharmaceutically acceptable salts that can be used as agents for the prevention and treatment of bacterial infectious diseases. More specifically, this invention relates to a new derived carbapenem and its pharmaceutically acceptable salts, which possess antibacterial activity and which are absorbed when administered orally; oral antibacterial agent containing the specified connection as the active ingredient, and an intermediate connection to obtain the derived carbapenem and its salts.

Background of the invention

As a means for the treatment of infectious diseases was discovered, many compounds having a skeleton carbapenem, of which some derivatives carbapenem with excellent antibacterial activity, have been proposed for practical use or under development for practical is imeneniya and used in clinical situations. It is derived carbapenem has a broad spectrum antibacterial, strong antibacterial activity and is devoid of instability under the action of renal dehydropeptidase, which is considered a disadvantage of conventional derivatives carbapenem. An excellent feature of this coupling is that it can be inserted without the use of a stabilizer.

However, these derivatives carbapenem show weak absorption from the digestive tract, which limits their clinical route of administration only by injection. Oral means in comparison with injections and easy to enter and it is very suitable for use in clinical situations. Thus, there is a need to develop a derivative carbapenem for oral administration, which has strong antibacterial activity and broad spectrum antibacterial and which exhibits excellent absorption from the digestive tract.

Thus, the purpose of this invention is derived carbapenem, which has an excellent antibacterial activity and which shows excellent absorption from the digestive tract.

Others the second aim of the present invention is an intermediate product, suitable to receive the specified derived carbapenem.

Description of the invention

The authors of this invention have conducted intensive studies to achieve the above objectives and found that the new derived carbapenem the following formula (I) and its pharmaceutically acceptable salt demonstrated superior absorption from the digestive tract, have a fairly strong antibacterial activity and is very useful as an oral antibacterial agents. In addition, the authors of this invention have discovered a new intermediate compound that can be used to obtain the specified connection that led to the creation of this invention.

Accordingly, this invention relates to the next.

(1) Derived carbapenem formula (I)

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where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different, and each represents a lower ALK is asepticheski acceptable salt.

(2) the Above derivative carbapenem (1), where R1and R2may be the same or different, and each represents modifitsiruyutsya group which can be hydrolyzed in the body, and R3and R4may be the same or different, and each represents lower alkyl and pharmaceutically acceptable salt.

(3) the Above derivative carbapenem (1), where R2represents 5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl and R3and R4each is methyl, and pharmaceutically acceptable salt.

(4) the Above derivative carbapenem (1), where R1is pivaloyloxymethyl and R2represents 5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl, and its pharmaceutically acceptable salt.

(5) the Above derivative carbapenem (1), where R1and R2each represent pivaloyloxymethyl, and its pharmaceutically acceptable salt.

(6) the Above derivative carbapenem (1), which is selected from the group including

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1, 3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl is karbapin-2-em-3-carboxylate,

hydrochloride pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-diethylaminomethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-methylaminomethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1 - pyrrolidinylcarbonyl)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-piperidinylcarbonyl)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate and

pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-azetidinone)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

or their pharmaceutically acceptable salts.

(7) an Antibacterial agent comprising the above derivative carbapenem (I), P CLASS="ptx2">

(8) the Above antibacterial agent (7) which is suitable for oral administration.

(9) Derivative carbapenem formula (II)

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where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different, and each represents lower alkyl, or

R3and R4together with the adjacent nitrogen atom form a cyclic amino,

or its salt.

(10) the Above derivative carbapenem (9), which is selected from the group including

p-nitrobenzyl (1R, 5S, 65)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate and

sodium (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

or its salt.

Each term used in this description may be explained as follows.

Modified gr is Nike or blood and are presented as examples of optionally substituted aryl (for example, the phenyl, talila, xilian, indayla and the like), 1-alkanoyloxy-alkyl, 1-alkoxycarbonylmethyl, phthalidyl, 5-methyl-2-oxo-1,3-dioxolan-4-elmetron and the like. Particularly preferred 1-alkanoyloxy, 1-alkoxycarbonyl-oxyalkyl and 5-methyl-1,3-dioxolan-2-he-4-ylmethyl.

Optionally substituted aryl, preferably not substituted or is substituted by from 1 to 3 substituents, which may be the same or different. Examples of the substituent include alkyl having from 1 to 4 carbon atoms, such as methyl, ethyl and the like.

The number of carbon atoms alkanoyloxy part 1-alkanoyl-oxyalkyl preferably ranges from 2 to 10, more preferably from 2 to 7, and it may be unbranched, branched or cyclic. The number of carbon atoms of alkyl part preferably is from 1 to 3, more preferably 1 or 2.

Examples 1-alkanoyloxy include acetoxymethyl, propionyloxy, n-butyryloxy, isobutyryloxy, pivaloyloxymethyl, n-valerolactone, 2-methylbutyronitrile, isovaleramide, n-hexanolactone, 3-methylvaleramide, neodecanoate, 2-methyl-hexanolactone, 2,2-dimethylaminocarbonylmethyl, 1-n-butyrylacetate, 1-isobutyrylacetate, 1-n-valeriansee, 1-pivaloyloxymethyl, 1-isovalerianic, 1-n-hexaniacinate, 1-cyclohexanecarbonitrile and the like.

The number of carbon atoms alkoxides 1-alkoxy-carbonyloxy preferably ranges from 1 to 10, more preferably from 2 to 7, and it may be unbranched, branched or cyclic. The number of carbon atoms of alkyl part preferably is from 1 to 3, more preferably 1 or 2.

Examples 1-alkoxycarbonylmethyl are 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-n-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-n-butoxycarbonylmethyl, 1-second-butoxycarbonylmethyl, 1-tert-butoxycarbonylmethyl, 1-ventilatsioonisusteemi and 1-cyclohexyloxycarbonyloxy.

Lower alkyl, R3and R4represents an unbranched or branched alkyl having from 1 to 6 carbon atoms, an example is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and the like. Especially preferred methyl, ethyl, propyl and butyl. cyclic amino, having from 4 to 6 members in the loop. Examples of the above cyclic amine include azetidine, pyrrolidine, piperidinyl and the like.

Carboxyamide group R5includes, for example, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzoyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethanediisocyanate, dimethylaminoethyl and the like. One of them is particularly preferred p-nitrobenzyl, p-methoxybenzyl and diphenylmethyl.

Derived carbapenem (I) and derivative carbapenem (II) can form pharmaceutically acceptable salts.

Insofar as derived carbapenem (I) and derivative carbapenem (II) contain the main group, they can form acid additive salt. The acid used for the formation of such acid additive salt is not specially limited, while it is pharmaceutically acceptable. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, organic acids such as oxalic acid, fumaric acid, maleic acid, libopenal (II) has a carboxyl group (so that is, when R5represents a hydrogen atom), a salt can be formed with the above carboxyl group. Examples of salts of carboxyl group include alkali metal salts (e.g. sodium salt, potassium salt and the like), salts of alkaline earth metals (e.g. calcium salt, magnesium salt and the like), salts with organic bases (for example, salt of triethylamine, salt dicyclohexylamine, salt of pyridine) and the like.

Preferred examples derived carbapenem (I) and derivative carbapenem (2) are the following compounds:

pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-acetoxyethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-isopropoxycarbonyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)-methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-cyclohexyloxycarbonyloxy(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)-methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,< / BR>
p-nitrobenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

diphenylmethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

p-methoxybenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-CA is one-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-pivaloyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-acetoxyethyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-isopropoxycarbonyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-ethoxycarbonylmethyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

1-cyclohexyloxycarbonyloxy(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)-pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

p-nitrobenzyl (1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

diphenylmethyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethyln the BR> p-methoxybenzyl(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(1R, 5S, 6S)-2-[(3S, 5S)-(5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylic acid,

hydrochloride pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-methylaminomethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-pyrrolidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-piperidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

Derived carbapenem (I) and its pharmaceutically acceptable salt and a derivative carbapenem (II) and its pharmaceutically acceptable salt can be obtained by any of the following ways to get from 1 to 4.

The method of obtaining 1

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where R1, R2, R3and R4such as defined above, and X represents a leaving group such as halogen atom (e.g. chlorine, bromine, and iodine), alkanesulfonyl (for example, methanesulfonate, econsultancy, propanesulfonate, butanesulfonate), arylsulfonate (for example, phenylsulfonyl, tolilsulfonil) and the like.

The compound (I) can be obtained by dissolving compound (IIA) (compound of formula (II), where R5represents a hydrogen atom) in a solvent that does not inhibit the reaction (e.g., dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylthiourea, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and mixtures and reaction of this compound with approximately 1-5-fold, preferably, approximately 1-2-fold, molar amount of compound (III) in the presence of a base.

The Foundation, which use special oont potassium and the like, organic base such as triethylamine and Diisopropylamine and the like.

The temperature of the reaction is not specifically limited, but the reaction is preferably carried out at a relatively low temperature to suppress the side reaction temperature is usually from -30 to -40oC, preferably from -20 to 0oC. Although the reaction time varies depending on the reaction temperature, the type of reagents for the reaction, and the like, it is usually from 30 minutes to 12 hours or so.

When necessary, the compound (IIA) can be converted into its reactive derivative such as a salt of an alkali metal (e.g. sodium salt, potassium salt and the like), alkali earth metal salt (e.g. calcium salt), salt, triethylamine salt of dicyclohexylamine, salt of pyridine, and the like, and subjected to reaction with compound (III).

The method of obtaining 2

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where R1, R2, R3and R4and X are such as defined above.

The compound (I) can be obtained by dissolving the compound (IV) in a solvent that does not inhibit the reaction (e.g., dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylenimmonium this connection approximately 1-5-fold, preferably, 1-2-fold, molar amount of compound (V). The compound (IV) can be obtained by the interaction of carboxylic acids, not described in the examined publications Japan patent 233076/1985 and the like, and compound (III) using the same method as in method a 1.

This reaction can also be carried out in the presence of a base. The Foundation, which use not specifically limited, but is preferably an inorganic base, such as sodium bicarbonate, potassium carbonate and the like, or an organic base such as triethylamine and Diisopropylamine and the like.

The temperature of the reaction is not specifically limited, but the reaction is preferably carried out at a relatively low temperature to suppress the side reaction temperature is usually from -30 to -40oC, preferably from -20 to 0oC. Although the reaction time varies depending on the reaction temperature, the type of reagents for the reaction, and the like, it is usually from 30 minutes to 12 hours or so.

The method of obtaining 3

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where R2, R3, R4and R5such as defined above, and R6is alconsult is l, such as phenylsulfonyl, tamilselvan and the like, dialkylphosphate, such as dimethylphosphoric, diethylphosphate, diisopropoxyphosphoryl, dibutylester and the like, or dealkylated, such as diphenylphosphoryl, detailsfull and the like.

The compound (II) can be obtained by dissolving compound (VI), not described in the examined publications Japan patent 12676/1996 and the like, in a solvent that does not inhibit the reaction (e.g., dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylthiourea, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and mixtures) and the interaction of this compound with approximately 1-5 times, preferably 1-2 times, the molar amount of mercaptoethane (VII) in the presence of a base.

The Foundation, which use not specifically limited, but is preferably an inorganic base, such as sodium bicarbonate, potassium carbonate and the like or an organic base such as triethylamine and Diisopropylamine and the like.

The reaction temperature is not specifically limited, but the reaction is preferably carried out n theoC, preferably from -20 to 0oC. Although the reaction time varies depending on the reaction temperature, the type of reagents for the reaction, and the like, it is usually from 30 minutes to 12 hours or so.

The original compound (VII) for the synthesis of compound (II) can be obtained as follows.

The method of obtaining the compound (VII)

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< / BR>
where R2, R3, R4and X are such as defined above, R7is toolsedit group, and R8is aminosidine group.

The compound (VII) can be obtained by removing R8that is aminosidine group to compound (IX), not described in the examined publications Japan patent 233076/1985 and the like, in a known manner to obtain the compound (X), the interaction of the compounds (X) and compound (V) in the same way as the method of obtaining 2, to obtain the compounds (XI) and remove7that is toolsedit group, in a way known in itself. As thiol - and aminosidine groups you can use the protective groups are generally known in the appropriate field.

The method of obtaining 4

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where R2, R3, R4, R5and X t is th not in the examined publications Japan patent 233076/1985 and the like, and compound (V) in the same manner as in the production method of 2.

When necessary, thus obtained derivative carbapenem (II) can be converted into a carboxylic acid derivative, where R5represents a hydrogen atom, removing carboxyamide group conventional method. Although the method of removing the protective group varies depending on its nature, can be used in the manner commonly known in this field.

Derived carbapenem (I) and derivative carbapenem (II) if necessary, you can clean conventional means such as recrystallization, preparative thin layer chromatography, column chromatography and the like. Alternatively, if you want, you can clean it in the form of its salts.

Derived carbapenem (I) and derivative carbapenem (II) can be converted into a pharmaceutically acceptable salt by a method known per se.

The target compound (I) and the compound (II) according to this invention, preferably have the configuration of the following compounds (Ia) and compound (IIb)

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where R1, R2, R3and R4such as described above.

< / BR>
where R2, R3, R4and R5such katsa in the blood when administered orally and is metabolized in the derived carbapenem formula (I), where R1and R2represents a hydrogen atom, or its pharmaceutically acceptable salt and reveal a high concentration in the blood.

In addition, the derived carbapenem (I) when converted to its pharmaceutically acceptable salt detect an increased solubility in the digestive tract, which, in turn, further enhances the effect of absorption and, thus, the adsorption capacity.

Therefore, the remedy for the prevention and treatment of infectious diseases, including derivative carbapenem (I) or its pharmaceutically acceptable salt, detects a superior effect by oral administration, as described above, and can usually be entered as an oral drug.

This tool for the prevention and treatment of infectious diseases can be obtained by dilution of the compounds of pharmaceutical excipients known manner. Examples of usable fillers include starch, lactose, sugar, calcium carbonate, calcium phosphate and the like.

In addition, this tool for the prevention and treatment of infectious diseases, preferably contains an organic acid, resulting in prolinol tract, thus facilitating its absorption into the blood.

The organic acid may be any acid, while it is pharmaceutically acceptable and, preferably, presents examples of such organic acids as maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, maleic acid, oxalic acid, mandelic acid, malonic acid, benzoic acid and the like. The organic acid is usually added in an amount of 0.01-20 mol, preferably 0.02 to 2 mol, per mol of compound carbapenem (I) or its pharmaceutically acceptable salt.

In addition, this tool for the prevention and treatment of infectious diseases may contain, if necessary, other additives, such as binders (e.g., starch, Arabic gum, carboxymethyl cellulose, hydroxypropylcellulose, crystalline cellulose and the like), lubricants (e.g. magnesium stearate, talc and the like), leavening agents (e.g. calcium salt of carboxymethylcellulose, talc and the like) and the like. After adding the various ingredients of the mixture is converted into dosage form suitable for oral administration, such as xeba, receiving means for oral administration, which are suitable for the prevention and treatment of infectious diseases.

Although the dose derived carbapenem (I) and its pharmaceutically acceptable salts varies depending on the purpose of administration, symptoms and other factors, for example, when the compound is administered for the treatment of purulent diseases of the adult, the daily dose is about 1-40 mg/kg of body weight, which is administered orally 1 to 4 times a day.

The specified derived carbapenem (I) and its pharmaceutically acceptable salt can be introduced in combination with other antibacterial substances such as antibacterial drugs (e.g. penicillin, aminoglycosides, cephalosporins and the like), or a therapeutic agent for systemic symptoms caused by bacterial infection (e.g., antipyretic, analgesic, anti-inflammatory drug, and the like).

Properties and methods of making compounds of this invention are illustrated by the examples, which is not limited to this invention.

Example 1

p-Nitrobenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-noncarbonyl-4-mercapto-1-(5-methyl-2-oxo-1/3-dioxolan-4-yl)methylpyrrolidine (867 mg) was dissolved in acetonitrile (11 ml) in nitrogen atmosphere at a temperature of from -40 to -30oWith was added dropwise a solution of p-nitrobenzyl(1R, 5S, 6S)-2-diphenylphosphino-6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate (1.5 g) and diisopropylethylamine (1,05 ml) in acetonitrile (15 ml). The mixture was stirred at the same temperature for one hour and was added ethyl acetate (200 ml). The reaction mixture was washed with saturated saline (100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate evaporated under reduced pressure and the residue was purified column chromatography on silica gel, receiving 1.0 g specified in the connection header.

1H NMR (DMSO-d6) memorial plaques : 1,06 (d, J= 7.5 Hz, 3H), of 1.16 (d, J= 6.5 Hz, 3H), 1,30~ of 1.80 (m, 1H), 2,02 (s, 3H), 2,50~ 4,30 (m, N), 2,82 (s, 3H), 3,01 (s, 3H), of 3.57 (s, 2H), free 5.01 (d, J= 5.0 Hz, 1H), 5.25-inch, 5,50 (Avcv, J= 13.5 Hz, 2H), to 7.67, by 8.22 (Avcv, J= 8.5 Hz, 4H).

Example 2

(1R, 5S, 6S)-2-{ (3S/5S)-[5-N, N-Dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate sodium

p-Nitrobenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate (730 mg) was dissolved in a mixed solution of tetrahydrofuran (22 ml) and 0.1 M phosphate buffer (pH 7.0, 33 ml) and add filtered through cellit and the obtained filtrate was washed diethyl simple ether and concentrated under reduced pressure to about 5 ml The resulting solution was subjected to chromatography on Dia Ion HP-21 (produced by Mitsubishi Chemical). After concentration under reduced pressure the residue liofilizirovanny, receiving 300 mg specified in the connection header.

IR (nujol, cm-1): 3385, 1815, 1750, 1600.

1H NMR (DMSO-d6) memorial plaques : 1,05 (d, J= 7.5 Hz, 3H) and 1.15 (d, J= 6.5 Hz, 3H), 1,20~ 1,70 (m, 1H), 2,03 (s, 3H), 2,50~ 4,20 (m, N), of 2.81 (s, 3H), 3,01 (s, 3H), of 3.60 (s, 2H), 4,40-5,50 (Shir. , 1H).

Example 3

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-Dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate sodium (500 mg) was dissolved in N, N-dimethylformamide (2.5 ml) and the mixture was cooled to -5oC. was Added pivaloyloxymethyl (350 mg) and the mixture was stirred at the same temperature for one hour. Added ethyl acetate (100 ml) and the reaction mixture is washed with 5% saturated saline solution (100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate evaporated under reduced pressure and the residue was purified by chromatography on silica gel, getting 370 mg decree is B>6) memorial plaques : 1,00~ of 1.30 (m, 15 NM), 1,30~ of 1.80 (m, 1H), 2,03 (s, 3H), 2,50~ 4,30 (m, N), 2,82 (s, 3H), 3,01 (s, 3H), 3,55 (s, 2H), 5,00 (d, J= 5.0 Hz, 1H), 5,70, by 5.87 (Avcv, J= 5.5 Hz, 2H).

Example 4

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

(1) (1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-Dimethylaminocarbonylmethyl-lidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate sodium (580 mg) suspended in N, N-dimethylformamide (2.9 ml) and the mixture was cooled to -5oC. was Added pivaloyloxymethyl (520 mg) and the mixture was stirred at the same temperature for one hour. Added ethyl acetate (150 ml) and the mixture washed with 5% saturated brine (150 ml) and dried over anhydrous sodium sulfate. The ethyl acetate evaporated under reduced pressure and the residue was purified column chromatography on silica gel, receiving 350 mg pivaloyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminocarbonylmethyl-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate.

1H NMR (DMSO-d6) memorial plaques : 1,02~ of 1.30 (m, 15 NM), 1,30~ of 1.80 (m, 1H), 2,50~ and 4.40 (m, 10H), 2,87 (s, 3H), 2,99 (s, 3H), 4,90~ 5,10 (m, 1H), 5,70, 5,85 (Avcv, J= 6.0 Hz, 2H).

(2) Compound (330 mg) obtained in REC-2-he-4-yl)methyl bromide (190 mg) and triethylamine (0,11 ml) and the mixture was stirred at the same temperature for 1.5 hours. Added ethyl acetate (150 ml) and the mixture washed with 5% saturated saline solution (100 ml) and the aqueous layer was extracted twice with ethyl acetate (150 ml). Layers of ethyl acetate were combined and dried over anhydrous sodium sulfate. The ethyl acetate evaporated under reduced pressure and the residue was purified by chromatography on silica gel, getting 2330 mg specified in the connection header.

IR and1H NMR spectra were identical with the spectra of the compound of example 3.

Example 5

Pivaloyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate.

Pivaloyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminocarbonylmethyl-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate (400 mg) obtained in example 4(1), and pivaloyloxymethyl (290 mg) was subjected to interact in the same manner as in example 4(2), getting 190 mg specified in the connection header.

1H NMR (DMSO-d6) memorial plaques : 1,02~ of 1.30 (m, 24N), 1,30~ of 1.80 (m, 1H), 2,50~ and 4.40 (m, 10H), 2,87 (s, 3H), 2,99 (s, 3H), 4,90~ 5,10 (m, 1H), 5,70, 5,85 (Avcv, J= 6.0 Hz, 2H).

Example 6

Hydrochloride pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxo the Teal (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate (1,49 g) obtained in example 3 was dissolved in ethyl acetate (30 ml) and the mixture was cooled to 5oC. was Added a solution of 0.35 ml) of hydrogen chloride dissolved in 2-propanol at 8,68 h, and the mixture was stirred at the same temperature for 15 minutes. The resulting crystals were collected by filtration, washed with ethyl acetate and then diethyl simple ether, receiving 1.2 g specified in the connection header.

IR (nujol, cm-1): 3355, 1825, 1700, 1740, 1660.

1H NMR (DMSO-d6) memorial plaques : 1,10~ of 1.40 (m, 6N), 1,19 (s, N), 1,70~ 2,10 (m, 1H), 2,19 (s, 3H), 2,80~ 3,20 (m, 1H), 2,99 (s, 3H), to 3.09 (s, 3H), 3,30~ 3,70 (m, 2H), 3,80~ 4,10 (m, 2H), 4,10~ 4,50 (m, 5H), 4,80~ 5,00 (m, 1H), 5,86, 5,96 (Avcv, J= 6.0 Hz, 2H).

The compounds of examples 7 to 11 were synthesized in the same manner as in any of examples 1 to 5 were identified and their properties.

Example 7

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-diethylaminomethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

1H NMR (DMSO-d6) memorial plaques : 1,10~ of 1.30 (m, N), 1,30~ of 1.80 (m, 1H), 2,03 (s, 3H), 2,50~ 4,30 (m, 13H), N-dimethylthiocarbamyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

1H NMR (DMSO-d6) memorial plaques : 1,10~ of 1.30 (m, N), 1,30~ of 1.80 (m, 1H), 2.05 is (s, 3H), 2,50~ 4,30 (m, 11N), 2,93, 3,03 (s, 3H), to 3.58 (s, 2H), of 5.05 (d, J= 5.0 Hz, 1H), 5,68, by 5.87 (Avcv, J= 5.5 Hz, 2H).

Example 9

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-pyrrolidinylcarbonyl)-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

1H NMR (DMSO-d6) memorial plaques : 1,00~ of 1.30 (m, 15 NM), 1,30~ of 1.80 (m, 1H), 1,80~ 2,10 (m, 4H), of 2.05 (s, 3H), 2,50~ 4,30 (m, 13H), to 3.58 (s, 2H), 5,07 (d, J= 5.0 Hz, 1H), 5,67, of 5.83 (Avcv, J= 5.5 Hz, 2H).

Example 10

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-piperidinyl-carbonyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

1H NMR (DMSO-d6) memorial plaques : 1,00~ of 1.30 (m, 15 NM), 1,30~ of 1.80 (m, 7H), 2,03 (s, 3H), 2,50~ 4,30 (m, 13H), of 3.57 (s, 2H), 5,10 (d, J= 5.0 Hz, 1H), 5,66, of 5.83 (Avcv, J= 5.5 Hz, 2H).

Example 11

Pivaloyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-azetidine-carbonyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate

1H NMR (DMSO-d6) memorial plaques : 1,00~ of 1.30 (m, 15 NM), 1,30~ of 1.80 (m, 1H), 2.05 is (s, 3H), 2,50~ 4,50 (m, 15 NM), of 3.57 (s, 2H), of 5.05 (d, J= 5.0 Hz, 1H), 5,68, 5,85 (Avcv, J= 5.5 Hz, 2H).

The following compounds were obtained by the method, opisannyj-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(2) 1-acetoxyethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(3) 1-isopropoxycarbonyloxymethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl] -pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(4) 1-ethoxycarbonylmethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-yl)-methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(5) 1-cyclohexyloxycarbonyloxy(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(6) (5-methyl-2-oxo-1,3-dioxolan-yl)methyl(1R, 5S, 6S)-2-{ (33, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1, 3-dioxolan-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxy-ethyl] -1-methylcarbamyl-2-em-3-carboxylate,< / BR>
(7) diphenylmethyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-dioxolan-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(8) p-methoxybenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-2-oxo-1,3-diox ITIL(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(10) 1-acetoxyethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(11) 1-isopropoxycarbonyloxymethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(12) 1-ethoxycarbonylmethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(13) 1-cyclohexyloxycarbonyloxy(1R, 5S, 6S)-2-[ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(14) (5-methyl-1,3-dioxolan-2-he-4-yl)methyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)-pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(15) p-nitrobenzyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(16) diphenylmethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminocarbonylmethyl(1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate,

(18) (1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-em-3-carboxylate.

Then carried out the following tests on oral absorption to clarify excellent properties of the compounds of this invention.

Experimental example 1

(test on oral absorption)

The connection according to this invention (the compound of example 6, 20 mg/kg) orally was administered to dogs (3 per group) and were measured concentration in the urine hydrolyzed derivative carbapenem (A) through 0-3, 3-6 and 6-24 hours by the method of paper disks with the use of the tested bacteria Escherichia coli NIHJ and nutrient agar medium (Difco). Determined the percentage of extraction from the urine. The results are shown in table 1.

Experimental example 2

(test on oral absorption)

The connection according to this invention (the compound of example 6, 20 mg/kg) orally was administered to dogs (3 per group) and measured the plasma concentration of hydrolyzed compounds carbapenem (A) through 0,25, 0,5, 1,0, 1,5, 2,0, 3,0, 4,0 and the s (Difco). The results are given in table. 2 and 3.

Derived carbapenem (I) and its pharmaceutically acceptable salt according to this invention detects the excellent absorption from the gastrointestinal tract when administered orally and sufficient antibacterial activity against a large number of bacterial species. Thus, they are highly useful as a means for the prevention and treatment of infectious diseases, especially bacterial infections. These funds for the prevention and treatment of infectious diseases can be used for the prevention and treatment of diseases caused by bacteria (for example, pyogenic diseases, respiratory infectious diseases, inflammatory diseases of the biliary tract, urinary tract infections, and the like) in warm-blooded animals, including humans (e.g., dogs, cats, cows, horses, rats, mice and the like).

This invention is based on the applications 25671/1997 and 248903/1997 filed in Japan, the contents of which are incorporated herein by reference.

The example of the pharmaceutical composition

The following components were used to prepare tablets usual method:

Componet magnesium - 20

1. Derived carbapenem formula (I)

< / BR>
where R1and R2may be the same or different and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a 4-6-membered cyclic amino,

or its pharmaceutically acceptable salt.

2. Derived carbapenem under item 1, where R3and R4may be the same or different and each represents lower alkyl, or its pharmaceutically acceptable salt.

3. Derived carbapenem under item 1, where R2represents 5-methyl-1,3-dioxolan-2-he-4-ylmethyl, and3and R4each represents methyl, or its pharmaceutically acceptable salt.

4. Derived carbapenem under item 1, where R1is pivaloyloxymethyl and R2represents 5-methyl-1,3-dioxolan-2-he-4-ylmethyl, or its pharmaceutically acceptable salt.

5. Derived karbapin is acceptable salt.

6. Derived carbapenem under item 1, which is selected from the group comprising the hydrochloride pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-diethylaminomethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-methylaminomethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-pyrrolidinylcarbonyl)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-piperidinylcarbonyl)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate and pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-(1-azetidinone)-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate or its pharmaceutically acceptable salt.

7. Antibacterial containing Akti the main ingredient it contains is derived carbapenem by p. 1, which is represented by formula I, or its pharmaceutically acceptable salt.

8. Antibacterial under item 7, which is suitable for oral administration.

9. Derived carbapenem formula II

< / BR>
where R2represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different, and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a 4-6 membered cyclic amino;

R5represents a hydrogen atom or carboxyamide group selected from p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl,

or its salt.

10. Derived carbapenem formula I

< / BR>
where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different and each represents Zobeide R3and R4may be the same or different and each represents lower alkyl, or its pharmaceutically acceptable salt.

12. Derived carbapenem under item 10, where R2represents 5-methyl-1,3-dioxolan-2-he-4-ylmethyl and3and R4each represents methyl, or its pharmaceutically acceptable salt.

13. Derived carbapenem under item 10, where R1is pivaloyloxymethyl and R2represents 5-methyl-1,3-dioxolan-2-he-4-ylmethyl, or its pharmaceutically acceptable salt.

14. Derived carbapenem under item 10, where R1and R2each represents pivaloyloxymethyl, or its pharmaceutically acceptable salt.

15. Derived carbapenem under item 10, which is selected from the group including pivaloyloxymethyl (1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate and pivaloyloxymethyl (1R, 5S, 6S)-2-[(3S, 5S)-[5-N, N-dimethylaminoethyl-1-pivaloyloxymethyl)pyrrolidin-3-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate or its pharmaceutically acceptable salt.

16. Antibacterial, soda is the amount of active ingredient it contains is derived carbapenem by p. 10, which is represented by formula I, or its pharmaceutically acceptable salt.

17. Antibacterial under item 16, which is suitable for oral administration.

18. Derived carbapenem formula II

< / BR>
where R2represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl;

R3and R4may be the same or different and each represents lower alkyl, and

R5represents a hydrogen atom or carboxyamide group selected from p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl,

or its salt.

19. Derived carbapenem under item 18, which is selected from the group comprising p-nitrobenzyl(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate and sodium(1R, 5S, 6S)-2-{ (3S, 5S)-[5-N, N-dimethylaminoethyl-1-(5-methyl-1,3-dioxolan-2-he-4-yl)methyl] pyrrolidin-3-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methylcarbamyl-2-EN-3-carboxylate or its salt.

Priority points:

12.09.1997 - PP. 1-9;

07.02.1997 - PP. 10-19.

 

Same patents:

The invention relates to (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S)-2-[(3R)-3-methylaminomethyl-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylic acid or its pharmaceutically acceptable salts, method of treatment a pharmaceutical composition based on it

The invention relates to a new method of obtaining new hyalinella formula I

where In represents the structure of the General formula II

Q represents the structure of General formula III,

where R1- lower alkyl or a saturated or unsaturated WITH3- C6carbocycle, optionally substituted with halogen;

R2is hydrogen or amino group;

And - nitrogen or the group CR4where R4represents halogen, hydrogen;

R - piperazinil, unsubstituted or substituted lower alkyl or a group of formula IV

Наl - fluorine, chlorine, bromine or iodine,

or their salts, characterized in that conduct the reaction interaction lactam compounds IN IT, where has the above significance, in which optional pre-protected hydroxy and carboxyl functional group, with phosgene at a temperature of from -80oC to about 0oC with formation of an intermediate product of the formula V

where have the above values,

and the resulting intermediate product is subjected to interaction with the compound of General formula HQ, where Q have the above meanings, in which optional pre-protected carboxyl functional group, to follow the

The invention relates to a new group of antibiotics, the carbapenems and their non-toxic pharmaceutically acceptable salts, having antimicrobial activity, which can be used both separately and in combination with other antibiotics to treat bacterial infections in humans and animals

The invention relates to new antibiotics that have carbapenemases skeleton

The invention relates to new derivatives of 1-methylcarbamate General formula (I) described in the claims

The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the General formula:

A-B (Groups I and II) or

< / BR>
where is a

< / BR>
n = 1 or 2; m = 0, 1, or 2; NH or NR, where R = lower alkyl(C-C);

A is attached to Y;

-Y = -N, -CH, or C (when-CO group, A substituted group CH= CF,=),

R=H, CN, CHO, B(OH)2CC-R7or CH=N-R8;

R7=H, F, lower alkyl(C1-C6), CN, NO2OR9, CO2R9or COR9;

R8=Ph, HE, OR9, OCOR9or OBn;

R9= lower alkyl (C1-C6); and either oneor bothmay be missing

The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

The invention relates to methods for selection of individual amino acids from the mixture and can be used in chemical, medical, food and other industries

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I)

The invention relates to new derivatives of cephalosporin of the General formula I and II where R1selected from the group consisting of-NНС(O)ZR3, -NR4R5; Z is selected from the group consisting of-CH2(X)m-, -C(NОR6)-; X is a sulfur atom; m = 0 - 1; R3- thiazolyl substituted by chlorine or amino group, and (CH2)T, where n = 1 to 6; T - guanidino; R4and R5each hydrogen; R6is hydrogen or may be a group which with the adjacent oxygen atom forms a protected hydroxyl group,2is hydrogen; each of G, H, L, and M - carbon; J is nitrogen; rings a, b, D and E are selected from the group consisting of thiazolyl and thiadiazolyl; R11is hydrogen; alk1- C1-6alkyl; alk2- C1-6alkyl, optionally substituted by a group selected from hydroxyl, amino, carboxamido; p is 0 to 1; R99selected from the group consisting of sulfur and SO2; q is 1; r = 1 - 3; R12- NR13R14group (a) or (b); R13-R17each is hydrogen, or its pharmaceutically acceptable salt

Cyclopeptide // 2171260
The invention relates to cyclopeptides and to their therapeutic use as inhibitors of the expression of adhesion molecules
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