JP5013795B2 - Carbapenem for oral administration - Google Patents

Description

  The present invention relates to an ester-type prodrug of a carbapenem compound having an excellent antibacterial action, and in particular, (1R, 5S, 6S) -2- [1- (1,3-thiazoline-2-yl) azetidine-3 It relates to an ester-type prodrug of -yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid.

  Carbapenem antibiotics exhibit strong antibacterial activity and a broad antibacterial spectrum, and thus many studies have been conducted, and imipenem, panipenem, meropenem, biapenem, and doripenem are already on the market.

  The above-mentioned carbapenem antibiotics on the market are all injections, and there are no carbapenem antibiotics that can be administered orally, and there are only a few compounds under development. In clinical practice, it is desirable to be able to select several administration routes for drug administration, depending on the purpose of treatment and patient circumstances. In particular, oral preparations are extremely useful clinically because they are easier and simpler to administer than injections and can be administered at home. Therefore, development of a carbapenem antibiotic having strong antibacterial activity and a wide antibacterial spectrum and excellent in oral absorption is strongly desired.

  (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1- represented by the following formula (II) Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (hereinafter referred to as the compound of formula (II)) is a compound disclosed in JP-A-8-53453 (Patent Document 1). It has high stability against β-lactamase and a strong affinity for mutated penicillin-binding proteins, so it has significant antibacterial activity against penicillin-resistant pneumococci and ampicillin-resistant Haemophilus influenzae that are currently clinical Is a carbapenem compound that is improved and also has very high stability to renal dehydropeptidase.

  However, the compound of the formula (II) has low absorbability from the gastrointestinal tract and is considered to be administrable only as an injection in clinical practice.

  With the aim of improving the oral absorbability of the compound of formula (II), several reports have been made on ester derivatives obtained by esterifying the carboxyl group at the 3-position (Patent Documents 2 and 3). For example, Patent Document 3 discloses a compound in which the 3-position carboxyl group of the compound of formula (II) is esterified with a cyclohexylcarboxymethyl group. However, these prior art documents do not disclose any compounds in which the carboxyl group at the 3-position of the compound of formula (II) is esterified with a group having a carbamate bond.

JP-A-8-53453 Japanese National Patent Publication No. 11-504039 JP-A-9-110869

  The present inventors have aimed to create a carbapenem antibiotic having a strong antibacterial activity and a wide antibacterial spectrum and excellent in oral absorbability. The compound of the formula (II) has high stability against β-lactamase and strong affinity for mutated penicillin-binding protein, so that it is currently against clinically problematic penicillin-resistant pneumococci and ampicillin-resistant Haemophilus influenzae. However, the antibacterial activity is greatly improved, and the kidney dehydropeptidase is extremely stable. Therefore, the present inventors have made it an object of the present invention to improve the oral absorbability of the compound of formula (II).

  The inventors of the present invention have intensively studied to improve the oral absorbability of the compound of formula (II). As a result, it was found that oral absorption is improved by protecting the 3-position carboxyl group of the compound of formula (II) with a specific ester-forming group, and the present invention has been completed.

[式中、R¹及びR²は同一または異なって、水素原子若しくはC₁−C₆アルキル基を表し、
R³及びR⁴は同一または異なって、水素原子、C₁−C₆アルキル基、またはR³とR⁴が隣接する窒素原子と一緒になって、置換されていてもよい複素環を形成する]、
２）R¹及びR²が水素原子を表し、
R³及びR⁴は同一または異なって、C₁−C₆アルキル基、またはR³とR⁴が隣接する窒素原子と一緒になって、1個以上のC₁−C₆アルキル基で置換されていてもよいピペリジニル基を形成する、１）に記載の化合物またはその薬学上許容される塩、
３）(1R, 5S, 6S)-2-[1-(1,3-チアゾリン-2-イル)アゼチジン-3-イル]チオ-6-[(R)-1-ヒドロキシエチル]-1-メチルカルバペン-2-エム-3-カルボン酸(N,N-ジイソプロピルカルバモイルオキシ)メチル、または、(1R, 5S, 6S)-2-[1-(1,3-チアゾリン-2-イル)アゼチジン-3-イル]チオ-6-[(R)-1-ヒドロキシエチル]-1-メチルカルバペン-2-エム-3-カルボン酸(cis-2,6-ジメチルピペリジン-1-イル)カルボニルオキシメチル、
４）１）乃至３）のいずれか１に記載の化合物またはその薬学上許容される塩を含んでなる、抗菌剤、
を提供するものである。 That is, the present invention
1) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ and R ⁴ are the same or different, and a hydrogen atom, a C ₁ -C ₆ alkyl group, or R ³ and R ⁴ together with the adjacent nitrogen atom form an optionally substituted heterocycle ],
2) R ¹ and R ² represent a hydrogen atom,
R ³ and R ⁴ are the same or different, together with the C ₁ -C ₆ alkyl group or a nitrogen atom to which R ³ and R ⁴ are adjacent, substituted with one or more C ₁ -C ₆ alkyl group Which forms an optionally piperidinyl group, or a pharmaceutically acceptable salt thereof,
3) (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl Carbapen-2-em-3-carboxylic acid (N, N-diisopropylcarbamoyloxy) methyl or (1R, 5S, 6S) -2- [1- (1,3-thiazoline-2-yl) azetidine- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl ,
4) An antibacterial agent comprising the compound according to any one of 1) to 3) or a pharmaceutically acceptable salt thereof,
Is to provide.

  The compound of formula (I) of the present invention is hydrolyzed in vivo and converted to the compound of formula (II) which is an active substance, and therefore has excellent oral absorbability and useful as a carbapenem agent for oral administration It is. Furthermore, the compound of the present invention is expected to be useful in clinical settings because of its low toxicity and high safety.

In the present specification, the “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, i-pentyl, t-pentyl, n-hexyl, i -Hexyl and the like.

In the present specification, the “heterocycle” is the same or different and is a 4-7 membered ring (preferably 5-6 membered) having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Ring). Therefore, the “heterocycle” of “the heterocycle optionally substituted by R ³ and R ⁴ together with the adjacent nitrogen atom” described in claim 1 has at least one nitrogen atom. Means heterocycle. Pyrrolidine, piperidine, piperazine, morpholine and the like are preferable, and piperidine is more preferable.

In the present specification, examples of the substituent of the heterocyclic ring in the “optionally substituted heterocycle” include a hydroxyl group, a C ₁ -C ₆ alkyl group, an amino group, a C ₁ -C ₆ alkoxy group, and the like. is C ₁ -C ₆ alkyl group.

  The general formula (I) according to the present invention can be preferably prepared from the general formula (I ′) according to the following scheme.

[In the above scheme, R ¹ , R ² , R ³ and R ⁴ represent the same meaning as defined in formula (I), R ⁵ represents a hydrogen atom or a metal ion such as potassium or sodium, X is present in the general formula (III) represents _{Cl, Br, I, -OSO 2} CF 3, -OSO 2 CH 3, a leaving group such as -OSO ₂ PhCH _3. ]

  (I ′), if necessary, 1 equivalent or an excess of a base (organic bases such as diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine and the like, inorganic bases such as water Sodium oxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.) and, if necessary, catalytic to excess quaternary ammonium salts (eg, tetra-n-butyl) In the presence of ammonium bromide, tetra-n-ethylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium bromide, cetyltrimethylammonium bromide, etc.) (eg, (N, N-Diisopropylcarbamoyloxy) methyl Loride, [(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] methyl chloride, (N, N-diisopropylcarbamoyloxy) ethane-1-yl chloride, [(cis-2,6-dimethylpiperidine- 1-yl) carbonyloxy] ethane-1-yl chloride, (piperidin-1-yl) carbonyloxymethyl iodide, (N, N-di-n-propylcarbamoyloxy) methyl iodide, (N, N-di) -n-butylcarbamoyloxy) methyl chloride, (Nn-hexyl-N-methylcarbamoyloxy) methyl chloride, (N, N-diisobutylcarbamoyloxy) methyl chloride, (N-cyclohexyl-N-methylcarbamoyloxy) methyl chloride, (N-Pentan-1-ylcarbamoyloxy) methyl chloride, (N-cyclohexyl-N-ethylcarbamoyloxy) methyl chloride (N-isobutyl-N-isopropylcarbamoyloxy) methyl chloride, (Nt-butyl-N-ethylcarbamoyloxy) methyl chloride, (N-ethyl-N-isoamylcarbamoyloxy) methyl chloride, etc. are preferred) alone or in combination An inert solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylformamide, N, N-diethylacetamide, N-methylpyrrolidinone, N, N-dimethylimidazolidinone, dimethyl Sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, diethyl ether, anisole, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, hexame Le triamide, methanol, ethanol, etc.) in, is -70 ℃ ~ + 70 ℃ (preferably, can be obtained at the -30 ° C. + 50 ° C.), by reacting 10 min to 48 hours (I).

  The ester obtained as described above can be isolated and purified by precipitation, gel filtration using Sephadex, etc., silica gel column chromatography, reverse phase column chromatography or the like.

  The salt of formula (I) is a pharmaceutically acceptable salt, for example, an inorganic salt such as lithium, sodium, potassium, calcium, magnesium, or a salt with an organic base such as ammonium salt, triethylamine, diisopropylethylamine. Or a salt with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, or a salt with an organic acid such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid or methanesulfonic acid. Sodium salt, potassium salt, or hydrochloride is preferable.

  The compound of formula (I) exhibits excellent antibacterial activity by being rapidly hydrolyzed in the body and converted to the active compound of formula (II). Therefore, the compound of formula (I) is extremely useful clinically as a prodrug for enabling oral administration of the compound of formula (II).

  The compounds of the present invention can be used for the prevention or treatment of bacterial infections and associated symptoms. Examples of the bacteria causing such bacterial infection include those selected from the group consisting of pneumococci, Haemophilus influenzae, Moraxella catarrhalis, and β-lactamase producing bacteria. That is, according to the present invention, an antibacterial agent comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof is provided.

  When the compound of the formula (I) of the present invention is orally administered, it can be administered to mammals including humans in the form of a composition for oral administration containing an antibacterial effective amount thereof. The dosage can vary over a wide range depending on the age, weight, symptoms, dosage form of the drug, doctor's diagnosis, etc. of the patient to be treated, but is generally about 200-3000 mg per day for an adult. Doses within the range are standard and can usually be administered once or in several divided doses per day.

  EXAMPLES Next, although an Example demonstrates this invention, this invention is not limited to these.

[Comparative Example 1] (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methylcarbapene-2-em-3-carboxylic acid (compound of formula (II))
The compound of the formula (II) is known and can be obtained by the method described in Example 2 (Compound 28) of JP-A-8-53453.

  [Example 1] (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methylcarbapene-2-em-3-carboxylic acid (N, N-diisopropylcarbamoyloxy) methyl

  (1R, 5S, 6S) -2- [1- (1,3-Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene -2-M-3-carboxylic acid tetrahydrate (911 mg) in N, N-dimethylacetamide (3 mL) solution at 30 ° C. with stirring, benzyltriethylammonium chloride (569 mg, (N, N-diisopropylcarbamoyl) 484 mg of oxymethyl) chloride and 0.435 mL of N, N-diisopropylethylamine were sequentially added, and the mixture was stirred as it was for 2.5 hours. After the reaction solution was washed with 4 mL of n-heptane, the N, N-dimethylacetamide layer was diluted with 20 mL of ethyl acetate and washed twice with 20 mL of deionized water and once with 20 mL of half-saturated saline. did. The organic layer was dried over anhydrous magnesium sulfate, filtered off, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 770 mg of the title compound.

NMR (CDCl ₃ ) δ: 1.23-1.26 (15H, m), 1.33 (3H, d, J = 6.0 Hz), 2.56 (1H, br.s), 3.14-3.19 (1H, m), 3.21-3.24 ( 1H, m), 3.37 (2H, t, J = 7.6 Hz), 3.80 (1H, br.s), 3.92-3.98 (1H, m), 3.99-4.03 (2H, m), 4.10-4.15 (1H, m), 4.22-4.25 (2H, m), 4.35-4.41 (2H, m), 4.47 (1H, br.s), 5.88 (1H, d, J = 5.6 Hz), 5.99 (1H, d, J = (5.6 Hz).
MS (ES +): m / z = 541 (M + + H).

  [Example 2] (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methylcarbapen-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl

a) [(cis-2,6-Dimethylpiperidin-1-yl) carbonyloxy] methyl chloride
24 mL of toluene solution of 2.39 mL of chloromethyl chloroformate was added dropwise to 46 mL of toluene solution of 9.11 mL of cis-2,6-dimethylpiperidine for 10 minutes under ice cooling, and the mixture was stirred at room temperature for 16 hours. After adding 60 mL of 1N hydrochloric acid to separate the layers, the organic layer was washed with 60 mL each of 5% aqueous sodium hydrogen carbonate solution and 20% brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain 12.7 g of [(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] methyl chloride.

NMR (CDCl ₃ ) 1.23 (6H, d, J = 7.1 Hz), 1.46-1.81 (6H, m), 4.34 (2H, m), 5.83 (2H, s)

b) (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl Carbapen-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl
(1R, 5S, 6S) -2- [1- (1,3-Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene -2-M-3-carboxylic acid tetrahydrate (911 mg) in N, N-dimethylacetamide (3 mL) solution at 30 ° C. with stirring, benzyltriethylammonium chloride 569 mg, [(cis-2,6 -Dimethylpiperidin-1-yl) carbonyloxymethyl] chloride 514 mg and N, N-diisopropylethylamine 0.435 mL were sequentially added, and the mixture was stirred as it was for 15 hours. After the reaction solution was washed twice with 8 mL of n-heptane, the N, N-dimethylacetamide layer was diluted with 20 mL of ethyl acetate, and three times with 20 mL of deionized water and once with 20 mL of half-saturated saline. Washed twice. The organic layer was dried over anhydrous magnesium sulfate, filtered off, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to give the title compound (774 mg).

NMR (CDCl ₃ ) δ: 1.20-1.23 (9H, m), 1.33-1.35 (3H, d, J = 6.4 Hz), 1.44-1.77 (7H, m), 3.15 (1H, quintet, J = 3.3 Hz) , 3.19-3.18 (1H, m), 3.37 (2H, t, J = 7.6 Hz), 3.93-3.98 (2H, m), 4.01 (2H, t, J = 7.6 Hz), 4.10-4.16 (2H, m ), 4.18-4.27 (2H, m), 4.32-4.35 (3H, m), 5.91 (1H, d, J = 5.6 Hz), 5.99 (1H, d, J = 5.6 Hz).
MS (ES +): m / z = 553 (M + + H).

[Test Example 1] Rat Oral Absorption Test The compounds of Examples 1 and 2 of the present invention and the active compound of Comparative Example 1 were orally administered to rats, respectively, and the compound of Comparative Example 1 in plasma was used. The concentration was measured by high performance liquid chromatography, and the area under the plasma concentration-time curve (AUC) was compared.

(1) Specimen Compound of Example 1 of the present invention: (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6-[(R ) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid (N, N-diisopropylcarbamoyloxy) methyl compound of Example 2 of the present invention: (1R, 5S, 6S) -2 -[1- (1,3-Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid (cis-2,6-Dimethylpiperidin-1-yl) carbonyloxymethyl Compound of Comparative Example 1: (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidine-3 -Il] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid

(2) Specimen administration Specimen 10 mg titer / kg was dissolved in 5% HCO-60 aqueous solution (in the case of the compounds of Example 1 and Example 2) or 0.5% CMC aqueous solution (in the case of the compound of Comparative Example 1), respectively. Then, it was orally administered to male rats (n = 3) intravenously administered with cilastatin sodium 30 mg titer / kg.

(3) Blood sampling and measurement of active substance concentration in plasma After sample administration, blood is collected every 5, 15, 30, 60, 120, 180 minutes, and the resulting blood is centrifuged to obtain plasma. The compound concentration of Comparative Example 1 was measured by high performance liquid chromatography.

(4) Calculation of plasma concentration-time curve area (AUC) The plasma concentration measurement value was plotted against the time after sample administration, and the plasma concentration-time curve area (AUC) was determined.

The area under the plasma concentration-time curve from 0 to infinity after sample administration (AUC _{0 → ∞} , μg · min / mL) was 99.0 for the compound of Example 1, 125.5 for the compound of Example 2, and Comparative Example One compound was 0.5.

  The compounds of Example 1 and Example 2 of the present invention had oral absorbability, and showed a significant improvement in oral absorbability compared to the compound of Comparative Example 1 which is the active form.

Claims (4)

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ and R ⁴ are the same or different, and a hydrogen atom, a C ₁ -C ₆ alkyl group, or R ³ and R ⁴ together with the adjacent nitrogen atom form an optionally substituted heterocycle ] R ¹ and R ² represent a hydrogen atom,
R ³ and R ⁴ are the same or different, together with the C ₁ -C ₆ alkyl group or a nitrogen atom to which R ³ and R ⁴ are adjacent, substituted with one or more C ₁ -C ₆ alkyl group The compound or pharmaceutically acceptable salt thereof according to claim 1, which forms an optionally piperidinyl group. (1R, 5S, 6S) -2- [1- (1,3-Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapene 2-M-3-carboxylic acid (N, N-diisopropylcarbamoyloxy) methyl or (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidine-3- Yl] thio-6-[(R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl. An antibacterial agent comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.