JP2761566B2 - Pyridonecarboxylic acid compound - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid compound and a salt thereof which are extremely excellent as an antibacterial agent.

[Prior art] As a pyridonecarboxylic acid compound substituted by fluorine, norfloxane, ofloxacin, ciprofloxacin and the like are known. Also, JP-A-62-228063
No. 6-fluoro-substituted with a methoxy group at the 8-position.
An 8-methoxy-4-oxoquinoline-3-carboxylic acid compound is disclosed.

[Problems to be solved by the invention]

An object of the present invention is to provide a novel pyridonecarboxylic acid compound and a salt thereof, which maintain a strong antibacterial activity against Gram-negative bacteria and have a clinically satisfactory antibacterial activity against Gram-positive bacteria. I do.

[Means for solving the problem]

The present invention maintains a strong antibacterial action against Gram-negative bacteria, and against Gram-positive bacteria, especially methicillin and cephem-resistant Staphylococcus aureus, Staphylococcus such as Staphylococcus epidermidis, Pneumococcus, and Gram-positive bacteria such as enterococci. The present invention also relates to a novel pyridonecarboxylic acid compound having a very strong antibacterial activity and a clinically satisfactory antibacterial activity.

That is, the present invention relates to the general formula (Wherein, R ¹ represents alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl or a phenyl group having 1 to 3 halogen, alkyl, alkoxy, hydroxyl, nitro, amino as substituents, R ² represents hydrogen, Alkyl, cycloalkyl, acyl or alkoxycarbonyl group, R ³ represents hydrogen, alkyl or aralkyl group, or R ² , R ³ is bonded to each other and adjacent nitrogen atom together with pyrrolidine, piperidine, morpholine, thiomorpholine, R ⁴ represents hydrogen or an alkyl group, R ⁵ represents hydrogen, alkyl, aralkyl, or alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, phthalidyl, dimethoxy Phthalidyl, carbamoyl alk Represents alkoxyalkyl and 5-methyl-1,3-dioxolen-2-one-4-ylmethyl ester residue which can be hydrolyzed in vivo selected from, R ⁶ is an alkyl, R ⁷ is hydrogen or an amino And m represents an integer of 2 or 3, and n represents an integer of 1 to 3.) and a salt thereof.

In the present specification, halogen is chlorine, bromine, fluorine, iodine, and alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, octadecyl. Alkyl having 1 to 18 carbon atoms such as
Alkoxy is alkoxy having 1 to 18 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, alkenyl Is alkenyl having 2 to 8 carbon atoms such as vinyl, allyl, butenyl, pentenyl, hexenyl and octenyl;
Haloalkyl is an alkyl having 1 to 8 carbon atoms substituted by at least one halogen, and includes difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and the like, and cycloalkyl is cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl,
Acyl is cycloalkyl having 3 to 7 carbon atoms such as cycloheptyl, acyl is acyl having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, and alkoxycarbonyl is alkyl having 1 to 4 carbon atoms. Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc., as a substituent, halogen, alkyl, alkoxy, trifluoromethyl Phenyl having 1 to 3 hydroxyl, nitro, and amino means 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3-
Or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-amino Phenyl, 2,4-, 2,3
-Or 3,4-difluorophenyl, 2,4-, 2,3- or 3,4-dimethylphenyl, 2,4-, 2,3- or 3,4-dimethoxyphenyl, 2,4-, 2, 3- or 3,4-ditrifluoromethylphenyl, 2,4-, 2,3- or 3,4-dihydroxyphenyl, 2,4-, 2,3- or 3,4-dinitrophenyl, 2,4- , 2,3- or 3,4-diaminophenyl, 2,4,6-trifluorophenyl and the like, aralkyl is selected from halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, amino on the aromatic ring Benzyl optionally having 1 to 3 substituents, 2-,
3- or 4-chlorobenzyl, 2-, 3- or 4-
Methylbenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-trifluoromethylbenzyl, 2-, 3- or 4-hydroxybenzyl, 2-,
3- or 4-nitrobenzyl, 2-, 3- or 4-
Aminobenzyl, phenylethyl, phenylpropyl,
The heterocycle which forms phenylbutyl, naphthylmethyl or the like together with an adjacent nitrogen atom by bonding to R ² and R ³ is a 5- to 7-membered heterocycle containing at least one nitrogen atom, , Piperidine, morpholine, thiomorpholine, piperazine or 4-methylpiperazine,
An ester residue that can be hydrolyzed in a living body is a compound that can be easily decomposed in a living body into a free carboxylic acid or a salt thereof, and is acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl, Alkanoyloxyalkyl esters such as -pivaloyloxyethyl, ethoxycarbonyloxymethyl, alkoxycarbonyloxyalkyl esters such as 1-ethoxycarbonyloxyethyl, phthalidyl, esters such as dimethoxyphthalidyl, carbamoylmethyl, carbamoylethyl,
Carbamoyl alkyl esters such as N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, N, N-diethylcarbamoylmethyl, methoxymethyl, alkoxyalkyl esters such as methoxyethyl or 5-methyl-1,3-dioxolen-2- On-4-ylmethyl ester can be mentioned.

Salts of the compound of the general formula (I) include acid addition salts, metal salts and the like. Examples of the acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, lactic acid, Salts with organic acids such as acetic acid, citric acid, tartaric acid, etc., are mentioned. As metal salts, alkali metal salts or alkaline earth metal salts (sodium, potassium, calcium, magnesium etc. salts), or heavy metal salts such as copper, Examples include salts of zinc, iron, gold, silver, platinum, manganese, and the like.

The compounds of general formula (I) of the present invention may also exist as their corresponding hydrates (monohydrate, hemihydrate, 3/2 hydrate, etc.) or other solvates.

In the compound of the general formula (I), since one or two asymmetric carbons are present on the morpholine ring of the 7-position substituent or on the hexahydro-1,4-oxazepine ring, optical isomers and stereoisomers based on the asymmetric carbons are present. The isomers exist, but these isomers and mixtures thereof are all included in the present invention.

According to the present invention, the compound of the general formula (I) is prepared by the following method.

Method 1 General formula (Wherein X ¹ represents a halogen, and other symbols are as defined above) (for example, JP-A-62-228063).
It is manufactured by the method described in the item. ) And general formula (Wherein each symbol has the same meaning as described above).

This condensation reaction is carried out by reacting compound (II) with compound (III)
Is carried out at 0 to 200 ° C., preferably 30 to 150 ° C. for 1 to 48 hours in the absence of a solvent or in the presence of a suitable solvent. Suitable solvents include water, alcohols (eg, methanol, ethanol, propanol), acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoricamide, 1-methyl-2-pyrrolidone, and the like. At this time, 1,8-diazabicyclo [5.4.0] undeca-4 was used as a deoxidizing agent.
Organic bases such as -ene and triethylamine or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate may be used.

Method 2 General formula (Wherein each symbol has the same meaning as described above). A compound represented by the general formula MOR ⁶ (V) (where M represents an alkali metal such as sodium, potassium and lithium, and R ⁶ has the same meaning as described above) A method of reacting with a compound represented by the following formula:

In this reaction, compound (V) is added to compound (IV) for 2 to 2 hours.
The reaction is carried out at a temperature of 0 to 200 ° C, preferably 50 to 150 ° C, for 1 to 48 hours, using a 3-fold molar amount in the presence of a suitable solvent. Suitable solvents include methanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like.

Method 3 A compound of the formula (I) wherein R ⁵ is alkyl or aralkyl is converted into a compound of the formula (I) wherein R ⁵ is hydrogen by deprotection according to a conventional method. can do.

This reaction can be carried out using hydrolysis or catalytic reduction using an acid or an alkali.

Further, among the compounds of the general formula (I), R ² is acyl, alkoxycarbonyl (ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.) and R ³
Is hydrogen, alkyl, or a compound in which R ² is hydrogen and R ³ is aralkyl, can be deprotected according to a conventional method by hydrolysis or catalytic reduction using an acid or an alkali to obtain a compound represented by the general formula (Wherein R ^{2 ′} represents hydrogen, R ^{3 ′} represents hydrogen and alkyl, and other symbols have the same meanings as described above.).

The compound in which the general formula (I) is an ester which can be easily hydrolyzed in vivo is a compound in which R ^{5 in the} general formula (I) is hydrogen and a compound represented by the general formula R ^{5 ′} -X ² (VII) , R ^{5 ′,} in the definition of R ^5, an ester residue which can be easily hydrolyzed in vivo, and X ² represents a halogen.)

Further, acid addition salts and metal salts of compound (I) can also be produced by a conventional method. Further, the optical isomer can also be resolved by a conventional method or can be produced using an optically active starting compound.

When the compound of the present invention is used as an antibacterial agent, it is orally administered in the form of a conventional preparation containing a therapeutically effective amount of the compound of the present invention and an organic or inorganic, solid or liquid pharmaceutically acceptable carrier. It can be administered parenterally or externally.

Such formulations include, for example, tablets, granules,
Solid and suspensions such as powders and capsules, and solutions such as syrups, emulsions and lemonades are included. further,
Auxiliaries, stabilizers, wetting agents, other lactose, magnesium stearate, clay, sucrose,
Commonly used additives such as corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cocoa oil, ethylene glycol and the like can be included.

The dosage varies depending on the age and symptoms of the patient, or on the type of disease and the type of compound administered.
An amount of 1 mg to about 4000 mg or more per day can be administered to the patient. The average single dose of a compound of the present invention may be about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 200 mg.
0 mg.

[Action]

The compound of the general formula (I) of the present invention and its salts, hydrates, alkyl esters, aralkyl esters or its in vivo hydrolysable esters or their optical isomers can be prepared by various methods including the experimental examples described below. Pharmacological experiments show that while maintaining the strong antibacterial activity of conventional pyridonecarboxylic acid antimicrobial agents against Gram-negative bacteria, it has enhanced potency and broad antibacterial activity against Gram-positive bacteria in vitro and in vivo . In addition, oral administration to experimental animals shows better absorption, has almost no problematic side effects, and shows low toxicity, so that it is expected to be more clinically useful as an antibacterial agent.

The compounds of the present invention have a particularly strong antibacterial activity against gram-positive bacteria such as methicillin and cephem-resistant Staphylococcus aureus, Staphylococcus epidermidis, pneumococci, enterococci, etc. It can also be used for the purpose of various infectious diseases caused by.

〔Example〕

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [2- (methylaminomethyl) monophorino]-
A mixture of 3.9 g of 4-oxoquinoline-3-carboxylic acid, 1.2 g of sodium methylate and 39 ml of dimethylformamide is stirred at 80 DEG C. for 9 hours. After completion of the reaction, the solvent is concentrated under reduced pressure, water is added to the residue, and the pH is adjusted to 6.5 with acetic acid. HP-20
After purification by column chromatography, recrystallization from ethanol gave 1-cyclopropyl-1,4-dihydro-
6-Fluoro-8-methoxy-7- [2- (methylaminomethyl) morpholino] -4-oxoquinoline-3-carboxylic acid is obtained. 208-210 ° C IR (cm ^-1 , KBr) 3400,1640 NMR (CDCl ₃ ), δ (ppm): 0.9-1.3 (m, 4H), 2.46
(S, 3H), 2.5 to 4.1 (m, 10H), 3.8 (s, 3H), 7.86 (d, 1H,
12 Hz), 8.76 (s, 1H) Example 2 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 2.95 g, 2- (dimethylamino Methyl) morpholine 1.5
9 g, and 1,8-diazabicyclo [5.4.0] undec-7
2.77 g of ene are stirred at reflux for 8 hours in 30 ml of acetonitrile. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was HP-20
Purify by column chromatography. Recrystallization from ethanol gives 1-cyclopropyl-1,4-dihydro-7.
-[2- (dimethylaminomethyl) morpholino] -6
Fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid is obtained. Mp 162-163 ° C IR (cm ^-1 , KBr) 3400,1735,1620 NMR (CDCl ₃ ), δ (ppm): 0.9-1.3 (m, 4H), 2.2-4.
1 (m, 10H), 2.32 (s, 6H), 3.8 (s, 3H), 7.86 (d, 1H, 12H
z), 8.8 (s, 1H) The following compounds can be produced in the same manner as in Example 1 and Example 2.

(A) 7- [2- (aminomethyl) morpholino] -1
-Cyclopropyl-1,4-dihydro-6-fluoro-8
-Methoxy-4-oxoquinoline-3-carboxylic acid, mp 174-177 ° C (b) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2-methyl-6- ( Methylaminomethyl) morpholino] -4-oxoquinoline-
3-carboxylic acid (c) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2- (2-methylaminoethyl) morpholino] -4-oxoquinoline-3-carboxylic acid (D) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2- (methylaminomethyl) hexahydro-1,4-oxazepin-4-yl]-
4-oxoquinoline-4-carboxylic acid (e) 7- [2- (ethylaminomethyl) morpholino] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxoquinoline-3 -Carboxylic acid (f) 1-cyclopropyl-7- [2- (diethylaminomethyl) morpholino] -1,4-dihydro-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid (g) 1 -Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-7- [2- (1-
Pyrrolidinylmethyl) morpholino] quinoline-3-carboxylic acid (h) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-7- [2- (piperidinomethyl) morpholino] quinoline -3-carboxylic acid (i) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2- (morpholinomethyl) morpholino] -4-oxoquinoline-3-carboxylic acid (j ) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2- (N-methyl-1-
Piperazinylmethyl) morpholino] -4-oxoquinoline-3-carboxylic acid (k) 7- [2- (aminomethyl) morpholino] -1
-Cyclopropyl-1,4-dihydro-8-ethoxy-6
-Fluoro-4-oxoquinoline-3-carboxylic acid (l) 1-cyclopropyl-1,4-dihydro-8-ethoxy-6-fluoro-7- [2- (methylaminomethyl) morpholino] -4-oxo Quinoline-3-carboxylic acid (m) 1-cyclopropyl-1,4-dihydro-7-
[2- (dimethylaminomethyl) morpholino] -8-ethoxy-6-fluoro-4-oxoquinoline-3-carboxylic acid (n) 7- [2- (aminomethyl) morpholino] -1,
4-dihydro-1-ethyl-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid (o) 1,4-dihydro-1-ethyl-6-fluoro-
8-methoxy-7- [2- (methylaminomethyl) morpholino] -4-oxoquinoline-3-carboxylic acid (p) 1,4-dihydro-7- [2- (dimethylaminomethyl) morpholino] -1- Ethyl-6-fluoro-8
-Methoxy-4-oxoquinoline-3-carboxylic acid (q) 7- [2- (aminomethyl) morpholino] -1
-(2,4-difluorophenyl) -1,4-dihydro-6
Fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid (r) 1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-8-methoxy-7- [2- (methyl Aminomethyl) morpholino] -4-oxoquinoline-
3-carboxylic acid (s) 1- (2,4-difluorophenyl) -1,4-dihydro-7- [2- (dimethylaminomethyl) morpholino] -6-fluoro-8-methoxy-4-oxoquinoline- 3-carboxylic acid (t) 7- [2- (aminomethyl) morpholino] -1,
4-dihydro-6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxoquinoline-3-carboxylic acid (u) 1,4-dihydro-6-fluoro-1- (2-fluoroethyl ) -8-Methoxy-7- [2- (methylaminomethyl) morpholino] -4-oxoquinoline-3-
Carboxylic acid (v) 1,4-dihydro-7- [2- (dimethylaminomethyl) morpholino] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxoquinoline-3
-Carboxylic acid (w) 1-ethoxycarbonyloxyethyl / 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- [2- (methylaminomethyl) morpholino] -4-oxoquinoline- 3-carboxylate (x) 1-allyl-1,4-dihydro-6-fluoro-
8-Methoxy-7- [2- (methylaminomethyl) morpholino] -4-oxoquinoline-3-carboxylic acid [Effect of the Invention] Experimental Example The in vitro antibacterial activity of the compound of the present invention was determined by the standard method of the Japanese Society of Chemotherapy ( Chemotherapy, Vol. 23, p. 1126, 1974). Test compounds include 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-
7- [2- (methylaminomethyl) morpholino] -4-
Using oxoquinoline-3-carboxylic acid (compound A) as a target compound, 9-fluoro-3-methyl-10- (4-
Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [2,2,3-de] [1,4] -benzoxazine-6-carboxylic acid (ofloxacin), 1-cyclopropyl -6-Fluoro-1,4-dihydro-7- (1-
Piperazinyl) -4-oxoquinoline-3-carboxylic acid (ciprofloxacin) was used. The results are as summarized in Table 1.

As is evident from Table 1, the compound of the present invention had much better antibacterial activity against Gram-positive bacteria than ofloxacin and ciprofloxacin.

Also, in particular, methicillin and cephem resistant Staphylococcus aureus, staphylococci such as S. epidermidis, pneumococci,
It had very strong antibacterial activity against Gram-positive bacteria such as enterococci.

Therefore, the compound of the general formula (I) and its salt, hydrate, alkyl ester, aralkyl ester or its in vivo hydrolysable ester obtained in the present invention, or its optical isomer is a conventional pyridonecarboxylic acid In vitro and in vitro against gram-positive bacteria compared to
It has enhanced efficacy and wide antibacterial activity in vivo, shows better absorption by oral administration to experimental animals, has few problematic side effects, and shows low toxicity, so it has better clinical utility. Be expected.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Takashi Ikeda 914-2 Nagazo, Oaza, Nakatsu-shi, Oita (56) References JP-A-63-198664 (JP, A) JP-A-1-135770 (JP, A) JP-A-2-11517 (JP, A) JP-A-2-19380 (JP, A) JP-A-2-115182 (JP, A) JP-B4-13355 (JP, B2) JP-B5-41633 (JP, B2) JP 7-20941 (JP, B2) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 413/00-413/14 CA (STN) REGISTRY (STN) WPI / L (QUESTEL)

Claims (1)

(57) [Claims] (1) General formula (Wherein, R ¹ represents alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl or a phenyl group having 1 to 3 halogen, alkyl, alkoxy, hydroxyl, nitro, amino as substituents, R ² represents hydrogen, Alkyl, cycloalkyl, acyl or alkoxycarbonyl group, R ³ represents hydrogen, alkyl or aralkyl group, or R ² , R ³ is bonded to each other and adjacent nitrogen atom together with pyrrolidine, piperidine, morpholine, thiomorpholine, R ⁴ represents hydrogen or an alkyl group, R ⁵ represents hydrogen, alkyl, aralkyl, or alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, phthalidyl, dimethoxy Phthalidyl, carbamoyl alk Represents alkoxyalkyl and 5-methyl-1,3-dioxolen-2-one-4-ylmethyl ester residue which can be hydrolyzed in vivo selected from, R ⁶ is an alkyl, R ⁷ is hydrogen or an amino And m represents an integer of 2 or 3, and n represents an integer of 1 to 3.) A pyridonecarboxylic acid compound represented by the formula: