CN1194977C - Tetracyclic fluoroquinolone carboxylic acid, its preparation method and its pharmaceutical composition as active ingredient - Google Patents

Abstract

The present invention discloses tetracyclic fluorine quinolone carboxylic acid, particularly a 1, 9-bridge 5-oxy-5H-thiazole-[3, 2-a] quinolyl-4-carboxylic acid derivative (wherein substituted radials Z, B and R1 have definition described in the specification), a preparing method thereof and medicine compounds of the derivative. The antibacterial activity of the derivative is better than that of ofloxacin.

Description

Tetracyclic fluoroquinolone carboxylic acid, its preparation method and its pharmaceutical composition as active ingredient

The present invention is a divisional application of the 00112170.7 patent application. The application date of the original application is March 24, 2000. The application number is 00112170.7. The invention name is "tetracyclic fluoroquinolone carboxylic acid, its preparation method and its active ingredient drug combination".

technical field

The present invention relates to tetracyclic fluoroquinolone carboxylic acids, namely 1,9-bridged 5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid derivatives, processes for their preparation and their activity as Ingredients of pharmaceutical composition.

Background technique

5-Oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids have been disclosed to have antibacterial activity, examples of which are listed below:

EP 286,089

JP 03,190,883

DE 4,431,122

J. Med chem 1993, 36(18): 2621

Quinolone drugs can strongly inhibit bacterial DNA gyrase and interfere with the DNA replication of bacterial cells, because these drugs have broad-spectrum antibacterial activity and a unique mechanism of action different from penicillins and cephalosporins, and can be administered orally. The fourth-generation cephalosporins are comparable, occupy a considerable amount of clinical use, and develop rapidly. But there are some obvious deficiencies in the existing medicines. Firstly, the antibacterial effect on some G ⁺ and anaerobic bacteria is not ideal. Secondly, it has side effects on the central nervous system. In addition, photosensitivity and bacterial resistance are the main problems in some quinolones. increasingly apparent. The purpose of the present invention is to further improve the antibacterial activity, especially enhance the activity against Gram ⁺ bacteria, anaerobic bacteria and chlamydia, overcome CNS system and photosensitive side effects, and drug resistance to bacteria.

Contents of the invention

Compounds having the general formula (I) have now been invented:

Wherein, ^R represents hydrogen, an alkyl group with 1 to 4 carbon atoms optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino;

B represents O or NCH ₃ ;

Z represents a group of the following structure:

Wherein, R ² represents hydrogen, straight or branched C ₁ -C ₃ alkyl;

R ³ represents hydroxyl or -NR ₈ R ₉ ;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ : represent hydrogen, straight chain or branched C ₁ -C ₃ alkyl.

Particularly preferred compounds of formula (I) are compounds of formula (I) as defined below and pharmaceutically acceptable hydrates and acid addition salts thereof, as well as alkali metal, alkaline earth metal salts of carboxylic acids based on these compounds:

Wherein, ^R represents hydrogen, methyl or ethyl;

B represents O or NCH ₃ ;

Z represents a group of the following structure:

Among them, R ² : represents hydrogen, methyl or ethyl;

R ³ represents hydroxyl or -NR ⁸ R ⁹ ;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ : represent hydrogen, methyl or ethyl.

A pharmaceutical preparation, which comprises an effective amount of formula (I) 1,9-bridged 5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid derivative or its pharmaceutically acceptable salts and pharmaceutically acceptable carriers or diluents.

Some compounds of formula (I) are listed below:

Compound B Z R ¹

No.1 O h

No.2 NCH ₂₃ h

No.3 O HOCH ₂ CH ₂ NH-H

No.4 NCH ₃ HOCH ₂ CH ₂ NH-H

No.5 O h

No.6 NCH ₃ h

      EtNo.7 O

Et

      EtNo.8 NCH ₃

Et

              HNo.9 O

h

No.10 NCH ₃ h

The preparation of the compound of formula (I) is carried out by making the compound of formula (II) react with the compound of formula (III):

Wherein, R ¹ and B are as defined above; Y represents fluorine or chlorine.

Z-H (III)

Wherein, Z is as defined above.

For example, the compound of formula (II) 7,8-difluoro-9,1-(episulfomethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid can be used And the preparation of formula (III) compound (1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptane (III) can be according to literature (1) J org chem, 1966,31 : 1059; 1990, 55: 1684. (2) J medchem, 1974, 17: 481. (3) EurPat Appl 1991: 925, (4) Eur Pat Appl 1990: 397351 (5) Synthesis 1990: 925 Chinese Journal of Pharmaceutical Industry , 1999, 30(9): 416. Reaction to prepare formula (I) compound 7-fluoro-8-[(1S, 4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane Alkane-2]-9,1-(epoxymethylene)-5-oxygen-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid, the reaction process can be represented by the following reaction formula:

The compounds of formula (II) used as starting compounds are known and/or can be prepared by known methods, some examples of which can be enumerated are as follows:

7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

7,8-Difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

7,8-Difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

The amines of the formula (III) used as starting compounds are known and/or can be prepared by known methods. Among them, the salt forms of compound (III) such as hydrochloride and hydrobromide can be used; for chiral amines, racemates can be used, and their optical antipodes can also be used. Some examples that can be cited are as follows :

(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane

ethanolamine

Isopropanolamine

Piperazine

2-amino-2-methyl-propanol; imidazole; methylimidazole

The method for preparing the pharmaceutically acceptable salt of the compound of the formula (I) is to react the compound of the general formula (I) with a solution of an inorganic acid or an organic acid to form an addition salt; it is also possible to react the compound of the general formula (I) with an alkali metal , alkaline earth metal hydroxide solution, and basic amino acid solution react to form basic salts. It is prepared by adding the compound of formula (II) and compound of formula (III) into a polar aprotic solvent, adding a basic acid absorbing agent, stirring and heating. The solvent suitable for the reaction of compound (II) and compound (III) is an aprotic polar solvent, such as DMSO, DMF, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, tetrahydrofuran, chloroform, acetonitrile, water, alcohol Such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol-methyl ether or pyridine, picoline, mixed solvents of these solvents can also be used. If desired, the reaction can be carried out in the presence of acid binders, all commonly used inorganic and organic acid binders can be used as acid binders, including alkali metal hydroxides, alkali metal carbonates, organic amines and amidines, Particularly suitable specific compounds are: triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine (III). The reaction temperature can be varied within relatively wide ranges. The reaction is generally carried out at about 20-200°C, preferably 80-180°C; the pressure can be normal pressure or 1-30 atmosphere. In the reaction, 1-15 moles, preferably 1-6 moles of compound (III) can be used per mole of compound (II). In addition, if necessary, the free amino group can be protected with a suitable amino protecting group such as tert-butoxycarbonyl, and the amino group can be released by treating with a suitable acid such as hydrochloric acid or trifluoroacetic acid after the reaction. The ester compound of the present invention can be prepared by the alkali metal salt of its corresponding carboxylic acid (if necessary, its nitrogen atom can be protected by a protecting group such as tert-butoxycarbonyl) and the appropriate haloalkyl derivative in DMF, dimethyl ethyl amide, N-methylpyrrolidone, dimethyl sulfoxide and other solvents, and react at about 0-100 ° C.

These compounds of the present invention can form pharmaceutically acceptable salts, such as addition salts and/or basic salts. They can be prepared by conventional methods. For example, the betaine compound can be dissolved in a sufficient amount of aqueous acid solution, and then the salt can be precipitated with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile; The water or alcohol such as ethylene glycol monoethyl ether solution is heated, and then the mixture is evaporated to dryness or the precipitated salt is collected by filtration. Pharmaceutically acceptable salts are understood as salts of the following acids: hydrochloric acid, sulfuric acid, acetic acid, malonic acid, lactic acid, Succinic Acid, Citric Acid, Tartaric Acid, Fumaric Acid, Maleic Acid. Methanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, galacturonic acid, gluconic acid, glutamic acid or aspartic acid, ascorbic acid, malic acid, salicylic acid, oxalic acid, etc. The alkali metal or alkaline earth metal salts of carboxylic acids of the present invention can be obtained as follows: the betaine compound is dissolved in less than an equivalent amount of alkali metal or alkaline earth metal hydroxide solution, the undissolved betaine is removed by filtration, and then The filtrate was evaporated to dryness. Pharmaceutically suitable salts are sodium, potassium or calcium salts.

The compound of the invention has powerful broad-spectrum antibacterial activity, has strong antibacterial effect on various G ⁺ and G ^- bacteria including penicillin-resistant bacteria, and has very low toxic and side effects. These compounds are particularly active against bacteria resistant to multiple antibiotics, such as penicillins, cephalosporins, aminoglycosides, sulfonamides, and tetracyclines. These compounds can become highly valuable anti-infective drugs in medicine, can be used as prevention, alleviation and treatment of diseases caused by human and veterinary pathogens, and can be used as preservatives for inorganic and organic materials, such as organic polymers, lubricants, coatings , fiber, leather, paper, wood, food and water, etc.

For example, these compounds can be administered locally and/or systemically to treat and/or prevent the following pathogens, or mixed infections caused by: Gram ⁺ bacteria, such as Staphylococcus and Streptococcus, etc.; Gram ^- cocci and Gram ^- bacteria, such as Escherichia coli, Haemophilus influenzae, Citrobacter, Salmonella and Shigella. In addition, Klebsiella, Enterobacter, Hafnia, Serratia, Proteus, Astrobacter, Acinetobacter, Pseudomonas; anaerobic bacteria such as Bacteroides fragilis; and Mycoplasma; Mycobacteria, such as Mycobacterium tuberculosis.

The above pathogenic bacteria are purely illustrations and are not limited scope of the present invention. The compounds of the present invention can prevent, alleviate and/or treat diseases, such as pneumonia, pharyngitis, otitis, peritonitis, pyelonephritis, cystitis vaginitis, enteritis, endocarditis, bronchitis, arthritis, bone and Systemic infection, topical and superficial infection.

Animals mentioned in the present invention include domestic animals and raised livestock, such as mammals: cattle, horses, donkeys, sheep, pigs, dogs, cats, rabbits, deer; birds, chickens, ducks, geese; and aquatic products species, such as fish, shrimp, and crab; and other animals and birds, such as tigers, lions, leopards, and ostriches.

The compounds of the present invention can be administered directly or orally in the form of appropriate pharmaceutical preparations, or administered enterally, parenterally, dermally, or nasally. Preferred pharmaceutical preparations that may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, injections, orally administrable solutions, suspensions, emulsions, pastes, ointments, gels Lotions, creams, lotions, powders, and sprays; oral administration can also take the form of food or drinking water containing the drug.

The preparation of the dosage forms such as injections is as follows: the active compound is dissolved in a suitable solvent, and if necessary, some auxiliary materials such as cosolvents, acid-base buffer salts, antioxidants, preservatives can be added, and then the solution is sterile filtered and subpackaged in the container.

Solvents that may be mentioned are: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methylpyrrolidone and mixtures thereof, if desired, active The compounds can also be dissolved in physiologically compatible vegetable or synthetic oils suitable for injection.

Co-solvents are used to facilitate the dissolution of the active compound in the main solvent or to prevent the precipitation of the active compound. Examples are polyvinylpyrrolidone, polyoxyethylated sorbitan esters.

Preservatives are benzyl alcohol, chlorobutanol, parabens, n-butanol.

The adjuvant of the present invention's preparation preparation is not limited to the above-mentioned example, according to the present invention: 1. filler and swelling agent have: starch, lactose, sucrose, glucose, mannitol, silicon dioxide etc.; In addition to carboxymethyl cellulose, there are also alginate gelatin and polyvinylpyrrolidone; 3. Wetting agents include: glycerin; 4. Disintegrants include: agar, calcium carbonate, sodium carbonate; 5. Absorption enhancers include: quaternary Ammonium compounds; 6. Wetting agents include: cetyl alcohol and glyceryl stearic acid; 7. Adsorbents include kaolin, bentonite; 8. Lubricants include talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol wait. Each of the above substances can be arbitrarily matched with the main drug as required to make a dosage form for use.

The suppository also contains conventional water-soluble or water-insoluble forming agents except the main medicine or compound medicine of the present invention, which are polyethylene glycol and fat (coconut fat and higher fat are 16-carbon fatty acid and 14-carbon alcohol).

For parenteral administration, such as injections, freeze-dried powder injections, emulsions, etc., excipients should be non-toxic and isotonic with blood.

The total weight of administration of one or more compounds of the present invention to human or veterinary administration is generally: 0.5 to about 500 mg per kilogram of body weight, preferably 5-100 mg/kg in 24 hours, and various dosage forms can be used. medicine way. According to the present invention, it is suitable for one administration to contain one or several active compounds in an amount of 1-250 mg/kg, preferably 3-60 mg/kg, although not limited to the above range.

Furthermore, in various formulations, the active compounds according to the invention can also be present in combination with synergists or other active compounds.

The minimum inhibitory concentration (MICS) of the compound of the present invention was determined by standard agar plate two-fold serial dilution method. For each test compound, a series of agar plates are prepared, each plate containing a two-fold dilution of the active compound in decreasing concentration. Inoculation was performed with an overnight pathogen culture, activated. Dilute the activated bacterial solution so that the bacterial inoculum amount is 10 ⁴ -10 ⁵ CFU/point, and use a multi-point inoculator to plant it on the above-mentioned drug-containing plate. After the agar plate inoculated with bacteria was incubated at 37°C for about 20 hours, the growth of bacteria was observed with the naked eye, and compared with the control plate (no drug), the lowest concentration of the drug effect that could inhibit the visible growth of bacteria was used as the concentration of the compound Minimum Inhibitory Concentration (MIC).

The following table lists the MICS (μg/ml) of some compounds of the present invention:

Table MICS(μg/ml) Compound MIC (μg/ml) strain No.1 No.2 No.4 No.9 No.10 *ofloxacin Staphylococcus aureus ATCC25923 ≤0.025 ≤0.025 0.1 0.1 0.05 0.2 Staphylococcus aureus (clinical) ≤0.025 ≤0.025 0.05 0.1 ≤0.025 0.2 Staphylococcus aureus (beta-lactamase producing) ≤0.025 ≤0.025 0.1 0.05 ≤0.025 0.2 Staphylococcus epidermidis (clinical) ≤0.025 ≤0.025 0.05 0.05 0.05 0.4 Escherichia coli ATCC25922 ≤0.025 ≤0.025 0.05 0.05 0.05 0.05 Escherichia coli (clinical) ≤0.025 ≤0.025 0.05 ≤0.025 0.05 0.05 Salmonella typhi (clinical) ≤0.025 ≤0.025 0.05 ≤0.025 0.1 0.1 Shigella flexneri (clinical) ≤0.025 ≤0.025 0.05 ≤0.025 ≤0.025 0.2 Klebsiella pneumoniae 46117 0.025 ≤0.025 0.05 ≤0.025 ≤0.025 0.05 C.freundii ≤0.025 ≤0.025 0.4 0.05 0.1 0.05

* Ofloxacin (produced by Kunshan Pharmaceutical Factory, Jiangsu Province, commercially available) is a known reference substance, which has been widely used clinically for many years, with excellent curative effect and few side effects. It is a tricyclic fluoroquinolone drug.

Examples of the preparation of active compounds are as follows:

example 1

7-fluoro-8-[(1S,4S)5-methyl-2,5-diazabicyclo[2,2,1]heptane-2-]-9,1-(epoxymethylene) -5-Oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate hydrochloride

With 7,8-difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid 0.31g (1.1mmol), ( 1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide 0.30g (1.1mmol), 1,8-diazabicyclo[5,4, 0] The mixture of undecane-7-ene (DBU) 0.70ml (4.4mmol) and DMSO 10ml was stirred at 80°C for 1 hour under nitrogen protection, concentrated under high vacuum and reduced pressure, dilute hydrochloric acid was added to the residue, and filtered Precipitate, recrystallize from water-ethanol, and dry to obtain 0.32 g of light yellow crystals; yield: 73%; mp>280°C.

IR (cm-1): 3469, 2800, 2656, 2524, 1679, 1620, 1599, 1518, 1473.

¹ HNMR (D ₂ O): δ2.35-2.50 (m, 2H, -CHCH ₂ CH-), 3.10 (s, 3H, CH ₃ ) 3.34-4.92 (m, 6H, 2×(-NCH ₂ CHN- ), 5.12-5.37 (m, 2H, -NOCH ₂ -,), 6.64 (d, 1H, H-6, JH _{-6, F} = 11 Hz), 7.38 (s, 1H, H-2).

MS (SCI, m/z): 402, 384, 358, 276, 82 (base peak)

Example 2

7-fluoro-8-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-]-9,1-[(N-methylimine Base) methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid 0.32 g (1.0mmol), (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide 0.30g (1.1mmol), 1,8-diazo The mixture of heterobicyclo[5.4.0]undec-7-ene (DBU) 0.70ml (4.4mmol) and DMSO 10ml was stirred at 140°C for 9 hours under nitrogen protection, concentrated under high vacuum and reduced pressure, and the residue was dissolved in DMSO Recrystallized and dried to obtain 0.30 g of pale yellow crystals; yield: 72%; mp.255-257°C (dec).

IR (cm ⁻¹ ): 3400, 3078, 1701, 1610, 1572, 1490, 1445.

¹ HNMR (DMSO-d ₆ ): δ1.74-1.95 (m, 2H, -CHCH ₂ CH-), 2.35 (s, 3H, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 2.45-4.61 ( m, 8H, 2×(-NCH2CHN-) and H- ₁₁ ), 7.50 (s, 1H, H-2), 7.59 (d, 1H, H-6, JH _{-6, F} = 14Hz), 15.99 (br, 1H, -COOH).

MS (SCI, m/z): 415, 397, 371, 333, 259, 82 (base peak).

Example 3

7-Fluoro-8-hydroxyethylamino-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

By a method similar to Example 2, with 7,8-difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid Prepared by reacting with ethanolamine, yield: 78%, mp: 265～266°C (dec).

IR (cm-1): 3266, 2926, 1673, 1629, 1596, 1518, 1486.

¹ HNMR (DMSO-d ₆ ): δ3.60 (m, 4H, HOCH ₂ CH ₂ NH-), 5.51 (s, 2H, -OCH ₂ -), 7.50 (d, 1H, H-6, J _{H- 6, F} = 13 Hz), 7.57 (s, 1H, H-2), 15.81 (brs, 1H, -COOH).

MS (EI, m/z): 350, 306, 275 (base peak).

Example 4

-7-fluoro-8-hydroxyethylamino-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline-4 -carboxylic acid

By a method similar to Example 2, with 7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a] Quinoline-4-carboxylic acid was prepared by reaction with ethanolamine, yield: 69%; mp>280°C.

IR (cm ⁻¹ ): 3350, 3295, 1674, 1614, 1592, 1515, 1473.

¹ HNMR (DMSO-d ₆ ): δ2.54 (s, 3H, CH ₃ ), 3.61 (m, 4H, HOCH ₂ CH ₂ NH-), 4.39 (s, 2H, H-11), 5.94 (br, 1H, -NH-), 7.53 (s, 1H, H-2), 7.64 (d, 1H, H-6, JH _{-6, F} =13.5HZ), 15.99 (brs, 1H, -COOH).

MS (EI, m/z): 363, 319 (base peak), 272.

Example 5

7-Fluoro-8-(2-hydroxy-propylamino)-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

By a method similar to Example 2, with 7,8 difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid and Prepared by reaction of isopropanolamine, yield: 75%; mp: 250-252°C (dec.).

IR (cm ⁻¹ ): 3500, 3400, 1673, 1628, 1587, 1481, 1451.

¹ HNMR (DMSO-d ₆ ): δ1.1 (d, 3H, CH ₃ ), 3.0-4.0 (m, 4H, CH ₃ CH(OH)CH ₂ NH-), 5.5 (s, 2H, -OCH ₂ -) 5.7 (br, 1H, -NH-), 7.4 (d, 1H, H-6, _{JH-6, F} = 12Hz), 7.5 (s, 1H, H-2), 15.7 (brs, 1H, -COOH).

MS (EI, m/z): 364, 320, 275, 73 (base peak).

Example 6

7-fluoro-8-(2-hydroxy-propylamino)-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinone Phenyl-4-carboxylic acid

By a method similar to Example 2, with 7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a] Quinoline-4-carboxylic acid was prepared by reaction with isopropanolamine, yield: 67%; mp: 253-255°C (dec).

IR (cm ⁻¹ ): 3429, 3278, 2945, 1682, 1614, 1591, 1506, 1470.

¹ HNMR (DMSO-d ₆ ): δ1.12 (d, 3H, CH ₃ ), 2.51 (S, 3H, N-CH ₃ ), 3.36-3.87 (m, 3H, CH ₃ CH(OH)CH ₂ NH -), 4.39(s, 2H, H-11), 4.90(br, 1H, -OH), 5.87(br, 1H, -NH-), 7.53(s, 1H, H-2), 7.63(d, 1H, H-6, JH _{-6, F} = 13.5 Hz), 15.99 (s, 1H, -COOH).

MS (EI, m/z): 377, 333, 288, 272 (base peak).

Example 7

7-fluoro-8-(1-imidazolyl)-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid

By a method similar to Example 2, with 7,8-difluoro-9,1-(epoxymethylene)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid Prepared by reacting with imidazole, yield: 75%; mp: >280°C.

IR (cm-1): 3450, 1705, 1630, 1596, 1492, 1486.

¹ HNMR (DMSO-d ₆ ): δ5.69 (s, 2H, -OCH ₂ -), 7.22 (s, 1H, H-2), 7.60-7.72 (d, 2H, -CH=CH-), 7.82 (d, 1H, H-6, JH _{-6, F} = 12 Hz), 8.10 (s, 1H, -NCH = N-), 15.28 (br, s, 1H, -COOH).

MS (EI, m/z): 357,313,284.

Example 8

7-Fluoro-8-(1-imidazolyl)-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a]quinoline- 4-carboxylic acid

By a method similar to Example 2, with 7,8-difluoro-9,1-[(N-methylimino)methylene]-5-oxo-5H-thiazolo[3,2-a] Quinoline-4-carboxylic acid reacted with imidazole, yield: 54%; mp>280°C.

IR (cm ⁻¹ ): 3400, 1683, 1618, 1600, 1518, 1470.

¹ HNMR (DMSO-d ₆ ): δ2.49 (s, 3H, CH ₃ ), 4.67 (s, 2H, H-11), 7.20 (s, 1H, H-2), 7.597 (m, 3H, - CH=CH- and H-2), 8.04 (s, 1H, -NCH=N-), 15.57 (brs, 1H, -COOH).

MS (EI, m/z): 370, 326 (base peak), 298.

Example 9

According to the present invention, an example of a tablet

Contents per tablet:

Example 1 compound 100mg

Hypromellose E ₅ 30mg

Hypromellose E ₅₀ 10mg

Sodium carboxymethyl starch 15mg

Pregelatinized starch 5mg

8% povidone K ₃₀ qs

Magnesium stearate 2mg

Talc powder 1mg

Example 10

According to the invention, examples of capsules

Content per capsule:

Example 2 Compound 100mg

Hypromellose E ₅₀ 10mg

Hypromellose K _4M 12mg

Sodium carboxymethyl starch 5mg

Pregelatinized starch 10mg

Talc powder 1mg

8% povidone K ₃₀ qs

Example 11

According to the present invention, examples of injection

Contents per ampoule:

Example 1 compound 100mg

Lactic acid Appropriate amount

Add water for injection to 2ml

Example 12

According to the present invention, the example of transfusion

Contents of each bottle (bag):

Example 2 compound 200mg

Lactic acid Appropriate amount

Sodium chloride 850mg

Add water for injection to 100ml

Example 13

Examples of creams according to the invention

Each content:

Component A Component B

White vaseline 1.0g Example 1 compound 100mg

Liquid paraffin 0.9g glycerin 1000g

Octadecanol 0.4g Diethanolamine 10mg

Cetyl alcohol 0.4g distilled water 5.89ml

Polyoxyethylene cetyl ether 0.3g

Heat Component A to about 80°C to melt, dissolve Component B, heat to 80°C, mix with A, cool, and it will be external bactericidal ointment.

Claims (7)

1. 1 of general formula (I), 9-bridge-type 5-oxygen-5-H-thiazole is [3,2-a] quinoline 4-carboxylic acid derivative also:

Wherein, R ¹The alkyl that represent hydrogen, is replaced arbitrarily by hydroxyl, methoxyl group, amino, methylamino or dimethylin with 1 to 4 carbon atom;

B represents NCH ₃

The Z representative is the group of array structure down:

Wherein, R ²: the C that represents hydrogen, straight or branched ₁～C ₃Alkyl;

R ³Representation hydroxy or-NR ⁸R ⁹

R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹: the C that represents hydrogen, straight or branched ₁～C ₃Alkyl;

Formula (I) compound be with its racemic modification or optical antipode form and with they pharmaceutically acceptable water compound and acid salt form and exist with their an alkali metal salt, alkaline-earth metal salt form.

2. according to the compound of claim 1, wherein

R ¹Represent hydrogen, methyl or ethyl;

B represents NCH ₃

The Z representative is the group of array structure down:

Wherein, R ²Represent hydrogen, methyl or ethyl;

R ³Representation hydroxy or-NR ⁸R ⁹

R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹: represent hydrogen, methyl or ethyl.

3, according to the compound of claim 2, R wherein ¹Represent H; B represents NCH ₃

The Z representative

4, the formula of claim 1 (I) 1,9-bridge-type 5-oxygen-5H-thiazole is the preparation method of [3,2-a] Cinchonic Acid's derivative also:

Wherein, R ¹The alkyl that represent hydrogen, is replaced arbitrarily by hydroxyl, methoxyl group, amino, methylamino or dimethylin with 1～4 carbon atom;

B represents NCH ₃

The Z representative is the group of array structure down:

Wherein, R ²Represent the C of hydrogen, straight or branched ₁～C ₃Alkyl;

R ³Representation hydroxy or-NR ⁸R ⁹

R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹: the C that represents hydrogen, straight or branched ₁～C ₃Alkyl;

It is characterized in that formula (II) compound and formula (III) compound added that alkaline acid-acceptor stirs and reacting by heating makes in polar aprotic solvent:

R wherein ¹The same with the B definition, Y represents fluorine or chlorine;

Z-H (III)

Wherein the Z definition is the same;

If desired, reaction can be carried out in the presence of acid binding agent.

5, the preparation described formula of claim 1 (I) but the method for the salt of compound hyoscine, with general formula (I) compound and mineral acid or organic acid solution reaction formation additive salt; Also the solution reaction of general formula (I) compound and basic metal, alkaline earth metal hydroxides solution, basic aminoacids can be formed basic salt.

6, according to the described preparation formula of claim 5 (I) but the method for the salt of compound hyoscine it is characterized in that: used mineral acid is hydrochloric acid, sulfuric acid; Organic acid is methylsulfonic acid, tosic acid, lactic acid, aspartic acid.

7, a kind of pharmaceutical preparation, wherein comprise significant quantity the disclosed formula of claim 1 (I) 1,9-bridge-type 5-oxygen-5H-thiazole also [3,2-a] but but the salt of Cinchonic Acid's derivative or its hyoscine and hyoscine carrier or thinner.