JP2005097195A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition usable as an antibacterial agent having no drug tolerance to bacteria causing infectious diseases. <P>SOLUTION: This pharmaceutical composition comprises a compound of formula(1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle. In formula(1), each R<SP>1</SP>is a halogen group, (substituted) lower alkyl, (substituted) lower alkenyl, (substituted) lower alkynyl, (substituted) lower alkoxy, OH or a (substituted) amino; R<SP>2</SP>is H, a (substituted) lower alkyl, (substituted) lower alkenyl or (substituted) lower alkynyl; and (n) is 0, 1, 2, 3, 4 or 5. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical composition containing a bicyclo [2.2.1] heptane compound as an active ingredient, and particularly relates to an antibacterial agent containing such a compound.

  As therapeutic agents for infectious diseases in humans and livestock, antibiotics such as penicillins, cephalosporins, penems, macrolides, tetracyclines, aminoglycosides, or synthetic antibacterial agents based on pyridone carboxylic acids have been used.

  The long-term use or large-scale use of conventional antibiotics or synthetic antibacterial agents imparts drug resistance to the causative bacteria of the infectious disease, resulting in a situation that makes treatment difficult. Therefore, it is desirable to cope with bacteria resistant to existing antibacterial agents by developing compounds having a skeleton that has not been attempted as antibacterial agents.

（式中、各Ｒ¹は、独立して、ハロゲン基、置換されてもよい低級アルキル基、置換されてもよい低級アルケニル基、置換されてもよい低級アルキニル基、置換されてもよい低級アルコキシ基、水酸基又は置換されてもよいアミノ基であり；Ｒ²は水素原子、置換されてもよい低級アルキル基、置換されてもよい低級アルケニル基又は置換されてもよい低級アルキニル基であり；そしてｎは０、１、２、３、４又は５である）で表される化合物又はその薬学的に許容され得る塩、及び薬学的に許容され得る担体を含有してなる医薬組成物を提供する。 The present invention has been made in view of the above-mentioned problems of the prior art, and has been completed by finding a group of bicyclo [2.2.1] heptane compounds having antibacterial activity by multi-sample screening.
That is, the present invention provides the following formula (1):

(In the formula, each R ¹ independently represents a halogen group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, or an optionally substituted lower alkoxy group. R ² is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group or an optionally substituted lower alkynyl group; and and n is 0, 1, 2, 3, 4 or 5), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier. .

In the compound (1) which is an active ingredient of the pharmaceutical composition of the present invention, preferably, each R ¹ is independently a halogen group or an optionally substituted lower alkyl group; R ² is a hydrogen atom or a substituted A lower alkyl group which may be substituted; and n is 0, 1 or 2.

In the compound (1) which is an active ingredient of the pharmaceutical composition of the present invention, more preferably, each R ¹ is independently a halogen atom, methyl, ethyl, propyl or butyl; R ² is a hydrogen atom, methyl , Ethyl, propyl or butyl; and n is 0, 1 or 2.

The compound (1) which is an active ingredient of the pharmaceutical composition of the present invention is preferably a compound represented by the formula (I):
(1) 3- [4- (4-Chlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 1, R ¹ = 4-chloro, R ² = H );
(2) 3- [4- (2,5-Dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 2, R ¹ = 2-methyl and 5 -Methyl, R ² = H);
(3) 3- [4- (3,4-Dichlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 2, R ¹ = 3-chloro and 4- Chloro, R ² = H);
(4) 3- [4- (3,4-Dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 2, R ¹ = 3-methyl and 4 -Methyl, R ² = H);
(5) 3- [4- (4-Bromophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 1, R ¹ = 4-bromo, R ² = H);
(6) 3- [4- (2,4-Dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 2, R ¹ = 2-methyl and 4 -Methyl, R ² = H);
(7) 3- [4- (4-Isopropylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 1, R ¹ = 4-isopropyl, R ² = H);
(8) 3- [4- (4-Butylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 1, R ¹ = 4-butyl, R ² = Methyl);
(9) 3- [4- (4-Isopropylphenyl) -5-methylthiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 1, R ¹ = 4-isopropyl , R ² = H); and
(10) 3- [5-Methyl-4- (2,5-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid (n = 2, R ¹ = 2) -Methyl and 5-methyl, R ² = methyl);
Is a compound selected from

The compound (1) that is an active ingredient of the pharmaceutical composition of the present invention is particularly preferably
(1) 3- [4- (4-Chlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(2) 3- [4- (2,5-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(3) 3- [4- (3,4-Dichlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(4) 3- [4- (3,4-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid; and
(5) 3- [4- (4-Bromophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
Is a compound selected from

  And since the compound of said Formula (1) has antibacterial activity, the preferable pharmaceutical composition of this invention is an antibacterial agent.

で表される。 Moreover, the preferable three-dimensional structure of the compound of Formula (1) is the following (1a):

It is represented by

  In addition, each term in the said general formula is defined as follows. “Halogen” means a radical derived from fluorine, chlorine, bromine and iodine. “Lower” means having 1 to 6 carbon atoms.

  “Alkyl” means a monovalent linear or branched hydrocarbon radical, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t -Butyl etc. are mentioned, However, It is not limited to these.

  “Alkenyl” is used as a term for monovalent straight-chain and branched-chain hydrocarbon groups having a double bond, and includes ethenyl, 1- and 2-propenyl, 2-methyl-1 -Including but not limited to propenyl, 1- and 2-butenyl and the like. “Alkynyl” is used as a term for monovalent straight chain and branched chain hydrocarbon groups having a triple bond, and includes, but is not limited to, ethynyl, propynyl, butynyl, and the like. It is not something.

  “Alkoxy” is used as a term for —O-alkyl and includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, and the like. It is not a thing.

  Examples of the group that may be substituted with the above substituent include halogen, a lower alkyl group, a hydroxyl group, and an amino group. These groups can be bonded to the above substituents in a number that can be substituted from 1 to 1, preferably 1 to 3, more preferably 1 to 2.

  Since all the compounds that are active ingredients of the pharmaceutical composition of the present invention have at least one asymmetric center, various optical isomers or arrangements may exist. Thus, the compounds of the present invention can exist as separate optically active forms of (+) and (−) and as racemates or (±) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism may also exist. The present invention includes all these types within its scope. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.

  Since the pharmaceutical composition of the present invention exhibits a broad antibacterial spectrum against Gram-negative bacteria, Gram-positive bacteria, filamentous fungi and / or yeasts, various infectious diseases in humans, livestock, etc. caused by these fungi It can be used as a prophylactic or therapeutic drug. Further, since the active ingredient used in the pharmaceutical composition of the present invention has a novel skeleton as an antibacterial agent, its basic skeleton structure is useful for the design of a novel antibacterial agent.

  Hereinafter, the pharmaceutical composition of the present invention will be described in detail.

  The bicyclo [2.2.1] heptane compounds of general formula (I) according to the invention are known and are commercially available, for example, from SPECS. Moreover, the compound of the general formula (I) of the present invention can be prepared by various synthetic methods known to those skilled in the art. For example, it can be prepared by the synthesis method (A) and synthesis method (B) shown below.

（ここで、Ｒ¹、Ｒ²及びnは上述の通りである） Synthesis method (A):

(Where R ¹ , R ² and n are as described above)

  In the synthesis method (A), first, the compound (4) is prepared by subjecting the dicarboxylic anhydride compound (2) and the amine compound (3) to a coupling reaction in the presence of a coupling agent. This coupling reaction is usually a reaction such as aqueous or non-aqueous organic solvents (eg tetrahydrofuran, DMF, dioxane, dimethoxyethane and acetonitrile); halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane). In an inert solvent.

  Examples of the coupling agent used here include dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, benzotriazol-1-yloxy-tris ( Dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop ™), Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexa Examples thereof include fluorophosphate (PyBOP), 2- (1-H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), ethyl chloroformate and the like. This reaction is carried out at a temperature in the range from −30 to 40 ° C., usually from 0 ° C. to 25 ° C. for 10 minutes to 96 hours, usually 30 minutes to 24 hours.

  Next, the compound (4) is subjected to a known reduction reaction to obtain the target compound (1). For example, the reduction reaction may be carried out at a temperature in the range of 10 to 60 ° C., usually 20 to 30 ° C., 1 hour to 3 days, usually 3 hours to 10 hours, an inert solvent such as ethanol and ethyl acetate, usually ethyl acetate. In particular, it can be carried out by hydrogenation in the presence of a suitable catalyst such as palladium on carbon and platinum (IV) oxide, usually platinum oxide.

Synthesis method (B):

  In the synthesis method (B), first, the dicarboxylic anhydride compound (5) is obtained by subjecting the compound (2) to the reduction reaction used in the second step of the synthesis method (A). And the target compound (1) can be obtained by using a compound (5) and a compound (3) for coupling reaction in presence of a coupling agent. This coupling reaction can be performed under the same conditions as in the reaction between the compound (2) and the compound (3).

  The intermediates and final products in the above synthesis methods (A) and (B) can be isolated and purified by known methods such as recrystallization and chromatography.

  Moreover, the compound (I) which is an active ingredient of this invention can be made into a "pharmaceutically acceptable salt" as needed. “Pharmaceutically acceptable salt” refers to, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate, ethanesulfonic acid Sulfonates such as salts, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, Acid addition salts such as organic acid salts such as ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, amino acid salt such as glutamate, aspartate, Or inorganic salt such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt or ammonium salt, triethylamine salt, diisopropylamine salt, cyclohexyl It can be a salt with an organic base such as a min salt, preferably hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartaric acid Salt, citrate, acetate, lactate, glutamate, aspartate, sodium salt, potassium salt, ammonium salt or triethylamine salt, more preferably sodium salt, hydrochloride or sulfate.

  In addition, the compound (1) which is an active ingredient of the present invention may be lyophilized from an aqueous solution or recrystallized to absorb moisture or adsorbed water to become a hydrate. Such salts are also included in the active ingredient of the present invention.

  The dosage, dosage form, and administration method of the antibacterial agent of the present invention can be appropriately selected according to the subject such as humans or livestock, as in the case of conventionally used antibacterial agents. For example, the compounds of the present invention can be administered by oral, parenteral, topical or other suitable route to prevent or treat human and other animal diseases caused by various pathogenic bacteria. In general, the most desirable dosage of these compounds is between about 300 mg and about 3000 mg per day, but will of course vary depending on the weight and symptoms of the patient and the particular route of administration. However, a dosage of about 5 mg to about 50 mg per kg body weight per day is most desirable. When administered to an animal, the dose varies depending on the kind of animal to be treated and the difference in sensitivity of the animal to the drug, the manner of drug formulation, the administration period and the administration interval. In some cases, a dose lower than the lower limit of the above range may be appropriate, and even if the dose is increased from the above range, it may cause harmful side effects if administered in small portions in several times a day. There may be no.

  The compound of the present invention can be administered alone or in combination with a pharmaceutically or pharmaceutically acceptable carrier or diluent by any of the above three administration routes, and the administration is divided into one or several times. It can be carried out. More specifically, the novel therapeutic agent of the present invention can be administered in various types of administration forms, such as tablets, capsules, medicinal products in combination with various pharmaceutically acceptable inert carriers. Drops, troches, hard candy, powders, sprays, creams, salves, suppositories, jelly, gels, pastes, lotions, ointments, aqueous suspensions, injection solutions, elixirs, syrups and the like can be used. These carriers include solid diluents or excipients, sterile aqueous media, various non-toxic organic solvents and the like.

  In the case of a drug for oral administration, it may be appropriately sweetened and / or flavored. Generally, the therapeutically effective compounds of this invention are administered in a concentration range of about 5% to 70% by weight in the form as described above. For oral administration, various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, glycine are added to starch, preferably corn, potato or tapioca starch, and alginic acid and certain species. It can be used with various disintegrants such as silicate double salts and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very effective for tablet formation. The same kind of solid composition can also be used by filling gelatin capsules. Suitable substances in this connection include lactose or lactose as well as high molecular weight polyethylene glycols. When an aqueous suspension and / or elixir is desired for oral administration, the active ingredient is used in combination with various sweeteners or flavors, colorants or dyes, and if necessary, an emulsifier and / or suspending agent is also used. And can be used with water, ethanol, propylene glycol, glycerin, and the like, and diluents that combine them.

  In the case of parenteral administration, a solution in which the active ingredient of the present invention is dissolved in either sesame oil or peanut oil or dissolved in an aqueous propylene glycol solution can be used. The aqueous solution should be appropriately buffered as necessary (preferably pH 8 or more), and the liquid diluent must first be made isotonic. Such aqueous solutions are suitable for intravenous injection and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. All these solutions can be prepared aseptically by standard pharmaceutical techniques well known to those skilled in the art. Furthermore, the active ingredient of the present invention can also be administered locally such as on the skin. In this case, topical administration in the form of creams, jellies, pastes, ointments is desirable according to standard pharmaceutical practice.

The antibacterial activity measurement of the compounds of the present invention was described in the methods described in the Examples, known literatures (for example, HM Ericsson and JCScherris, Acta Pathol. Microbiol. Scand., Suppl. 217B, 64-68, 1971) and the like. It can be performed according to a known technique.

Example (1) Test Bacteria The following 6 strains received from the University of Tokyo Graduate School of Agricultural and Life Sciences, Fushiya Lab.
(Gram negative bacteria) Pseudomonas aeruginosa IAM1052
(Gram-positive bacteria) Batillus subtilis PCI219, Staphylococcus aureus 209P
(Fungus fungus) Penicillium chrysogenum Q176, Mortiellera remmaniana IAM6128
(Yeast (mold)) Candida albicans

(2) Test method The test medium was inoculated into a liquid medium, and liquid shaking culture was performed at 37 ° C. for bacteria and 26 ° C. for mold / yeast for 16 to 20 hours. In the case of bacteria, malt extract was used as the medium, and in the case of fungi / yeast, bouillon was used. Pre-cultured bacteria were applied to agar plates prepared with these media, and the antibacterial activity was determined by the diameter of the inhibition circle by the paper disk method. As a sample, 20 μL of 10 mg / mL (23-27 mM) DMSO solution was absorbed on a paper disk having a diameter of 8 mm. The results are shown in Table 1.

[Note 1] The diameter of the blocking circle is 25 mm or more, +++, 15 mm or more and less than 25 mm, ++, 10 mm or more and less than 15 mm, +, and less than 10 mm-.
[Note 2] PA: Pseudomonas aeruginosa IAM1052, BS: Bacillus subtilis PCI219, SA: Staphylococcus aureus 209P, PC: Penicillium chrysogenum Q176, MR: Mortiellera remmaniana LAM6128, CA: Candida albicans.
The above compound has been confirmed to have low toxicity to mammals.

  As is apparent from Table 1, the compound which is an active ingredient of the present invention is effective against gram-negative bacteria, gram-positive bacteria, filamentous fungi and / or yeasts, and particularly the compounds of compound numbers 1 to 5 have a broad antibacterial spectrum. showed that.

Since the pharmaceutical composition of the present invention contains a compound having a broad antibacterial spectrum as an active ingredient, it is particularly effective as an antibacterial agent. In particular, the pharmaceutical composition of the present invention can be used as an effective antibacterial agent against causative bacteria having drug resistance.

Claims (7)

The following formula (1):

(In the formula, each R ¹ independently represents a halogen group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, or an optionally substituted lower alkoxy group. R ² is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group or an optionally substituted lower alkynyl group; and n is 0, 1, 2, 3, 4 or 5) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Each R ¹ is independently a halogen group or an optionally substituted lower alkyl group; R ² is a hydrogen atom or an optionally substituted lower alkyl group; and n is 0, 1 or 2 The pharmaceutical composition according to claim 1. Each R ¹ is independently a halogen atom, methyl, ethyl, propyl or butyl;
The pharmaceutical composition according to claim 1, wherein R ² is a hydrogen atom, methyl, ethyl, propyl or butyl; and n is 0, 1 or 2. The compound represented by formula (I) is:
(1) 3- [4- (4-Chlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(2) 3- [4- (2,5-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(3) 3- [4- (3,4-Dichlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(4) 3- [4- (3,4-Dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(5) 3- [4- (4-Bromophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(6) 3- [4- (2,4-Dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(7) 3- [4- (4-Isopropylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(8) 3- [4- (4-Butylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(9) 3- [4- (4-Isopropylphenyl) -5-methylthiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid; and
(10) 3- [5-Methyl-4- (2,5-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
The pharmaceutical composition according to claim 1, selected from: The compound represented by formula (I) is:
(1) 3- [4- (4-Chlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(2) 3- [4- (2,5-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(3) 3- [4- (3,4-Dichlorophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
(4) 3- [4- (3,4-dimethylphenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid; and
(5) 3- [4- (4-Bromophenyl) thiazol-2-ylcarbamoyl] bicyclo [2.2.1] heptane-2-carboxylic acid;
The pharmaceutical composition according to claim 1, selected from: The pharmaceutical composition according to claim 1, which is an antibacterial agent. The three-dimensional structure of the compound of formula (1) is the following (1a):

The pharmaceutical composition of Claim 1 represented by these.