CN1190439C - Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component - Google Patents

Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component Download PDF

Info

Publication number
CN1190439C
CN1190439C CNB031004180A CN03100418A CN1190439C CN 1190439 C CN1190439 C CN 1190439C CN B031004180 A CNB031004180 A CN B031004180A CN 03100418 A CN03100418 A CN 03100418A CN 1190439 C CN1190439 C CN 1190439C
Authority
CN
China
Prior art keywords
acid
compound
formula
alkyl
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB031004180A
Other languages
Chinese (zh)
Other versions
CN1425668A (en
Inventor
王尔华
张秀芝
吴问根
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CNB031004180A priority Critical patent/CN1190439C/en
Publication of CN1425668A publication Critical patent/CN1425668A/en
Application granted granted Critical
Publication of CN1190439C publication Critical patent/CN1190439C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses tetracyclic fluoroquinolone carboxylic acid namely a 1, 9-bridge 5-oxy-5H-thiazole-[3, 2-a]quinolyl-4-carboxylic acid derivative (wherein substituted groups Z, B, R1 have definition disclosed in the specification), a preparation method thereof and a medical composition capable of being used by people and animals, which has better antibacterial activity than ofloxacin.

Description

The tetracyclic fluoquinolone carboxylic acid, its preparation method and be the pharmaceutical composition of active ingredient
The present invention is dividing an application of 00112169.3 patent application, and the applying date of original application is on March 24th, 2000, and application number is 00112169.3, and denomination of invention is " tetracyclic fluoquinolone carboxylic acid, its preparation method and be the pharmaceutical composition of active ingredient ".
Technical field
The present invention relates to Fourth Ring fluoroquinolone compounds, promptly 1,9-bridge-type 5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's derivative also, its preparation method and be the pharmaceutical composition of activeconstituents with them.
Background technology
Disclose 5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid's compounds have anti-microbial activity, the example is listed below:
EP 286,089
JP 03,190,883
DE 4,431,122
J.Med chem 1993，36(18)：2621
Quinolone medicine can strongly inhibited DNA of bacteria gyrase, disturb the dna replication dna of bacterial cell, because of these medicines have broad spectrum antibiotic activity and the unique effect mechanism that is different from penicillin, cynnematin, and can be oral, the status of occupying suitable consolidation clinically may compare favourably with third and fourth cynnematin in generation, also has the impetus of fast development, however, clinically these medicines of usefulness still exist some obvious defects: at first these medicines are to some G +Antibacterial effect such as bacterium, anerobe is undesirable; Secondly toxic side effect of human body is comprised that CNS system toxicity, phototoxicity and bacterial drug resistance problem manifest day by day and be on the rise.The objective of the invention is to the especially anti-G of these contrivance anti-microbial activities +The bacterium activity has strengthened greatly, and in addition, they further reduce CNS system and the photosensitive side effect of human and beasts, have overcome bad defectives such as bacterial resistance.
Summary of the invention
Now invented compound with general formula (I):
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 S or NCH 2CH 3
The Z representative is the group of array structure down:
Wherein, R 2, R 3, R 4: the C that represents hydrogen, straight or branched 1～C 3Alkyl; Or R 3R 4Represent CH 2X represents O, S or NH; R 5R 6: the alkyl that represent hydrogen, is replaced arbitrarily by hydroxyl, methoxyl group, amino, methylamino or dimethylin with 1～4 carbon atom;
R 7Representation hydroxy or-NR 11R 12
R 8, R 9, R 10, R 11, R 12: the C that represents hydrogen, straight or branched 1～C 3Alkyl.Compare with the known representative of homogenous configuration type, The compounds of this invention is to various G +, G -Bacterium all has higher anti-microbial effect.Particularly preferred formula (I) compound for as formula (I) compound and the pharmaceutically acceptable water compound and the acid salt of giving a definition, and based on an alkali metal salt, the alkaline earth salt of the carboxylic acid of these compounds:
Figure C0310041800063
Wherein, R 1Represent hydrogen, methyl or ethyl; B represents S or NCH 2CH 3
The Z representative is the group of array structure down:
Wherein, R 2, R 3, R 4: represent hydrogen, methyl or ethyl; Or R 3R 4Represent CH 2X represents O, S or NH; R 5, R 6Represent hydrogen, methyl or ethyl; R 7Representation hydroxy or-NR 11R 12R 8, R 9, R 10, R 11, R 12: represent hydrogen, methyl or ethyl.
Segment bounds (I) compound is listed as follows:
Compd B Z R 1
No.1 NCH 2CH 3
Figure C0310041800071
H
No.2 NCH 2CH 3 H
No-3 NCH 2CH 3 H
No.4 NCH 2CH 3
Figure C0310041800074
H
No.5 NCH 2CH 3
Figure C0310041800075
H
No.6 NCH 2CH 3
Figure C0310041800076
H
No.7 S H
No.8 S
Figure C0310041800078
H
No.9 S H
No.10 S H
No.11 NCH 2CH 3 HOCH 2CH 2NH- H
No.12 NCH 2CH 3 H
No.13 NCH 2CH 3 Et
No.14 S HOCH 2CH 2NH- H
No.15 S
Figure C03100418000713
H
No.16 S
Figure C03100418000714
Et
The preparation of formula (I) compound is to make through acid or basic hydrolysis with the reaction of formula (III) compound after making the reaction of formula (II) compound and formula (III) compound or using nitrilotriacetic boric anhydride, fluoroboric acid with formula (II) compound chelating again:
Wherein, R 1The same with the B definition; Y represents fluorine or chlorine.
Z-H (III)
Wherein, the Z definition is the same.
For example, can use the nitrilotriacetic boric anhydride with formula (II) compound 7,8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole also [3,2-a] behind Cinchonic Acid's chelating with formula (III) compound cis-2, (Henan Kangtai Pharmacy Group Company produces the 6-lupetazin, commercially available) reaction, get formula (I) compound 7-fluoro-8-(suitable-3 through acid hydrolysis again, 5-dimethyl-1-piperazinyl)-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also, and reaction process can be represented by the formula:
Formula (II) compound as initial compounds is known and/or available currently known methods preparation, and adducible part example is as follows:
7,8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also
7,8-two fluoro-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H thiazole [3,2-a] Cinchonic Acid also
7,8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's ethyl ester also
7,8-two fluoro-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's ethyl ester also
Formula (III) amine as initial compounds is known and/or available currently known methods preparation.Wherein, can use form for example hydrochloride, the hydrobromate of the salt of compound (III); For Chiral Amine, can use its racemic modification, also can use its optical antipode, adducible part example is as follows:
(1S, 4S)-5-methyl-2,5-diazabicyclo [2,2,1] heptane; Piperazine;
The 2-methylpiperazine; Cis 2, the 6-lupetazin;
The 3-amino-pyrrolidine; Morpholine; Thanomin;
Yi Bingchunan; 2-amino-2-methyl-propyl alcohol
The reaction of compound (II) or its inner complex and compound (III) can be as DMSO in polar aprotic solvent, DMF, N-Methyl pyrrolidone, HMPA, tetramethylene sulfone, acetonitrile, ethylene glycol-methyl ether carry out, or in water, alcohols such as methyl alcohol, ethanol, n-propyl alcohol, Virahol or pyridine, picoline, carry out, also can use the mixed solvent of above these solvents.If desired, reaction can be carried out in the presence of acid binding agent, and all inorganic and organic acid wedding agents commonly used all can be used as acid binding agent, comprise alkali metal hydroxide, alkaline carbonate, organic amine and amidine class, specially suitable particular compound is: triethylamine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) or excessive amine (III).Temperature of reaction can change in the scope of relative broad.Described reaction is generally carried out under about 20-200 ℃ preferred 80-180 ℃; Pressure can be normal pressure or 1-30 normal atmosphere.In the reaction, every mole compound (II) can use the compound (III) of the preferred 1-6 mole of 1-15 mole.In addition, if desired, available suitable amino protecting group such as tertbutyloxycarbonyl protection free amino can handle after reaction finishes that amino is discharged by suitable sour example hydrochloric acid or trichoroacetic acid(TCA).
Ester compound of the present invention can be by its corresponding carboxylic acid an alkali metal salt (if desired, available protecting group such as uncle's fourth oxygen carboxyl are protected its nitrogen-atoms) and suitable haloalkyl derivative in DMF, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide equal solvent and about 0～100 ℃ down reaction make.
Acid salt of the present invention can make with ordinary method.For example the betaine compound can be dissolved in the aqueous acid of q.s, then with going out salt with the miscible organic solvent of water such as methyl alcohol, ethanol, acetone, acetonitrile precipitation; Also the betaine compound of equivalent and the water or the alcohol of acid can be heated as ethylene glycol monoethyl ether solution, then mixture is evaporated to and does or the sedimentary salt of leaching, pharmacologically acceptable salt is interpreted as the salt of following acid: hydrochloric acid, sulfuric acid, acetate, lactic acid, succsinic acid, citric acid, tartrate, fumaric acid, toxilic acid, hydroxyl naphthoic acid, methylsulfonic acid, ethane disulfonic acid, tosic acid, galacturonic acid, glyconic acid, L-glutamic acid or aspartic acid etc.
Preparing described preparation formula (I) but the method for the salt of compound hyoscine, is that general formula (I) compound and mineral acid or organic acid solution reaction are formed 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.Its used mineral acid is haloid acid, hydrochloric acid, sulfuric acid; Organic acid is methylsulfonic acid, tosic acid, lactic acid, Aspartic Acid; Basic aminoacids is arginine, Methionin.
The basic metal of carboxylic acid of the present invention or alkaline earth salt can followingly make: the betaine compound is dissolved in the basic metal or alkaline earth metal hydroxides solution that is less than equivalent, removes by filter not molten betaine, then filtrate is evaporated to dried.Pharmaceutically suitable salt is sodium, potassium or calcium salt.
The compounds of this invention is administration or oral with suitable pharmaceutical dosage forms directly, through intestines, parenteral, skin, intranasal administration.The preferred drug substances that can mention is solution, suspension agent, emulsion, paste, ointment, gelifying agent, creme, lotion, pulvis and the sprays of tablet, coated tablet, capsule, pill, granula, suppository, injection, Orally-administrable; Oral administration also can adopt forms such as the food that contains medicine or tap water.
Pharmaceutical preparation of the present invention, wherein comprise significant quantity formula (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.
Being prepared as follows of described formulation such as injection: active compound is dissolved in the appropriate solvent, can adds some auxiliary materials such as solubility promoter if desired, soda acid buffering salt, oxidation inhibitor, sanitas are then with solution sterile filtration and be sub-packed in the container.The solvent that can mention is: the solvent of physical compatibility such as water, alcohols such as ethanol, butanols, benzylalcohol, glycerine, propylene glycol, polyethylene glycols, N-Methyl pyrrolidone and their mixture, if desired, active compound also dissolves in the vegetables oil or synthetic oil of the physical compatibility that is applicable to injection.Solubility promoter is in order to promote active compound to dissolve in main solvent or to prevent the active compound precipitation.Example is polyvinylpyrrolidone, polyoxyethylene sorbitan ester class.Sanitas is benzylalcohol, Trichloroisobutyl Alcohol, parabens, propyl carbinol.
Therefore, The compounds of this invention can be used for killing G +Bacterium, G -Bacterium and some other microorganism, and be used to prevent, improve and/or cure the disease that causes by these pathogenic agent; Be particularly suitable for the chemotherapy active compound with medicine, with people and beastly part and/or the systemic infection that is used to prevent cause by these pathogenic agent with chemotherapy as people and animal doctor.Mentioned beasts comprise the domestic animal of domestic animal and raising, as Mammals ox, horse, donkey, sheep, pig, cat, dog, rabbit, deer; In addition, also comprise birds, fishery products such as fish, shrimp, crab, soft-shelled turtle etc.
Patent of the present invention relates to and can be used for oral formula of medicine, by weight: containing example 1 compound is 25.0-90.0%, the dry adhesives that contains based on cellulose family is 4.7-22.0%, the disintegrating agent that contains based on starch is 0.8-9.0%, the auxiliary disintegrating agent that contains based on derivatived cellulose and/or cross-linked polyvinylpyrrolidone is 0.8-9.5%, containing Cetyl Alcohol is that main wetting agent is 0.5-2.8%, and containing Magnesium Stearate is that main lubricant is 0.1～2.8%.
Tablet, Drug coating, capsule, pill, granula, electuary contain active compound of the present invention, and the forming agent that also need add has in addition: 1. weighting agent, flow control agent, swelling agent such as lactose, sucrose, glucose, seminose, silicon-dioxide, starch; Wedding agent, help and collapse agent such as carboxymethyl cellulose, alginate gelatin, interlinkage Polyvinylpyrolidone (PVP); 3. wetting agent such as Cetyl Alcohol and glycerine stearic acid; 4. disintegrating agent such as agar, lime carbonate and yellow soda ash; 5. wetting agent such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol etc.Above-mentioned each forming agent can make up as required.Above-mentioned formulation can dressing or casing, can be transparent or opaque.
Suppository also contains habitual water-soluble binder except The compounds of this invention or compound compound, as polyoxyethylene glycol, fat is as the mixture of cupraol and senior fat or these materials.
Ointment, paste, emulsifiable paste, gel are except containing active compound of the present invention or compound compound, also contain habitual binder, as animals and plants fat, wax, paraffin, starch, tragacanth gum, derivatived cellulose, polyoxyethylene glycol, silicon-dioxide, talcum powder, zinc oxide or their composition.
Pulvis, sprays also contain habitual binder except containing active compound of the present invention or compound compound, as lactose, talcum powder, aluminium hydroxide, silicon-dioxide, Silon, or their composition.In addition, sprays also can contain common propelling agent fluorochlorohydrocarbon.
Solution, emulsion also contain common binder except containing active compound of the present invention or compound compound, as water, alcohol, ester, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, DMF; Oils such as Oleum Gossypii semen, peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame oil, glycerine, tetrahydrofuran (THF), methyl alcohol, polyoxyethylene glycol, anhydro sorbitol, fatty acid ester or their mixture.
The auxiliary material of injection, freeze-dried powder, infusion solution also will wait except that nontoxic and ooze.
Prescription of the present invention can contain tinting material, sanitas and improve the additive of aroma and flavor, be spearmint oil and Oil of Eucalyptus, and sweeting agent is an asccharin.
The active compound that is used for the treatment of is used for all kinds of preparations that the present invention mentions as prescription, and concentration is approximately the 0.2-99.0% of whole mixture weight, and optimum concn is 1.0-95%.
Active compound of the present invention or by the medicament of formulated can local application, oral, non-oral administration, intraperitoneal administration and/or rectal administration, preferably oral and non-per os such as intravenous drip administration.
One or more compounds of the present invention are by the gross weight administration, and its amount is per kilogram of body weight 0.5-450mg, and preferably 24 hours consumption is per kilogram of body weight 4-90mg, also can adopt medication several times arbitrarily.
Preferred plan is that the amount that once gives one or more active compounds of the present invention is 1-200mg/kg, and special excellent dosage is 2-50mg/kg.In order to meet people or ideal occlusion regimen for animals, also can fluctuate up and down, or follow the doctor's advice.
What especially be worth to praise highly is that active compound of the present invention can be used by common concentration and poultry, domestic animal, aquatic product feed, or adds in the feed for preparing or the drinking-water and use, and can prevent, alleviates and/or treat G +, G -, multiple infection such as chlamydozoan, mycoplasma.
Range of application of the present invention is generally: the part that causes by following pathogenic agent or by following pathogenic agent mixture and/or the disease of system can be treated and/or prevented.These pathogenic agent are: microballoon bacterial classification, streptococcus aureus and staphylococcus epidermidis; Lactobacillus species, as streptococcus pyogenes, α and beta hemolytic streptococcus and non--gamma-Hemolytic streptococcus, faecalis and pneumococcus, the enterobacteria kind is as intestinal bacteria, enteroaerogen and enterobacter cloacae, Klebsiella pneumonia, serratia marcescens, Bacillus proteus, the pseudomonas kind, bacterioide kind, Mycoplasma such as mycoplasma pneumoniae, mycobacterium such as Mycobacterium tuberculosis, hansen's bacillus etc. and atypical microorganism.Pathogenic agent listed above is only done for example but not only is confined to above-mentioned example.
One or more make compound of the present invention the disease example that various prescriptions can prevent, alleviate and/or cure and are: otitis, pharyngitis, rhinitis, pneumonia, enteritis, peritonitis, urocystitis, pyelonephritis, endocarditis, bronchitis, sacroiliitis, vaginitis, urethritis, part and skin infections, soft tissue and infection of bone, septicemia and systemic infection.
Measure the minimum inhibitory concentration (MIC) of The compounds of this invention with two times of serial dilution methods of agar plate of standard.For each test compound, prepare a series of agar plates, each plate contains the active compound that the concentration gradient of at every turn carrying out twice dilution is successively decreased.Inoculate activation with the pathogen culture thing that spends the night.With the dilution of the bacterium liquid after the activation, making bacterial load is 10 4-10 5The CFU/ point, adopt the multiple spot inoculator with its dibbling to above-mentioned pastille flat board.The agar plate of inoculating bacterium is after cultivating about 20 hours under 37 ℃, whether the visual inspection bacterial growth, and compare with control board (no medicine), with the minimum concentration of the drug effect that can suppress the bacterium visible growth minimum inhibitory concentration (MIC) as this compound.
Following table is listed the MIC of part of compounds of the present invention s(μ g/ml)
Compound MIC (μ g/ml) bacterial strain No.1 No.4 No.6 No.9 No.11 *Ofloxacine USP 23
Streptococcus aureus ATCC25923 0.05 0.1 ≤0.025 0.1 0.1 0.2
Streptococcus aureus (clinical) ≤0.025 0.1 ≤0.025 0.1 0.05 0.2
Streptococcus aureus bacterium (product β-Nei Xiananmei) 0.1 0.1 0.05 0.1 0.05 0.2
Staphylococcus epidermidis (clinical) 0.05 0.1 ≤0.025 0.1 0.05 0.4
Intestinal bacteria ATCC25922 0.05 0.1 0.4 0.1 0.1 0.05
Intestinal bacteria (clinical) 0.05 ≤0.025 0.05 0.05 0.05 0.05
Corynebacterium diphtheriae (clinical) ≤0.025 ≤0.025 0.05 ≤0.025 0.1 0.1
Shigella flexneri (clinical) ≤0.025 ≤0.025 0.05 0.05 0.05 0.2
Cray Bai Shi pneumobacillus 46117 0.1 ≤0.025 0.05 0.05 0.05 0.05
The Fu Shi bacillus citrate 0.1 0.1 1.6 0.05 0.4 0.05
*Ofloxacine USP 23 (Jiangsu Province Kunshan Pharmaceutical Factory produces, and is commercially available) is the contrast medicine, and it is for many years clinical that this medicine has been widely used in, and curative effect is good, and side effect is little, is three ring fluoroquinolones medicines.
Embodiment
The preparation example of active compound is as follows:
Example 1
(±)-7-fluoro-8-(3-amino-1-pyrrolidyl)-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's hydrochloride also
Boric acid 105mg (1.7mmol) is added among the aceticanhydride 1.2ml, being warming up to 110 ℃ of stirring reactions all dissolves until solid, add 7 again, 8-two fluoro-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid's ethyl ester 400mg (1.1mmol), temperature stirs after 3 hours and is chilled to room temperature, leaching precipitation and with aceticanhydride and isopropyl ether wash 7,8-two fluoro-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid's root diethyl acid group close boron 450mg.With this inner complex and 3-amino-pyrrolidine 100mg (1.2mmol), 1; 8-diazabicyclo [5; 4; 0] mixture of undecane-7-alkene (DBU) 0.35ml (2.2mmol), DMSO 5ml under nitrogen protection in 80 ℃ stir 1 hour after; the high vacuum concentrating under reduced pressure; resistates is with dilute hydrochloric acid hydrolysis 30 minutes, leaching crystallization 1The NHCl recrystallization, drying gets yellow crystals 300mg; Yield 68%; Mp235～237 ℃ (dec).
IR(cm -1)：3413，2877，1686，1612，1513，1451。
1HNMR(DMSO-d 6)：δ0.90(t，3H，CH 3)，2.10(m，2H，-CH 2CH 2-CH-)2.85(q，2H，-NCH 2CH 3)，3.15-4.05(m，5H-NCH 2，-NCH)，4.45(S，2H，H-11)，7.50(S，1H，H-2)，7.60(d，1H，H-6，J H-6，F＝12Hz)，8.50(br，3H，-NH 3 +)，15.80(br，1H，-COOH)。
MS(SCI，m/z)：403，385，359，341(base peak)。
Example 2
7-fluoro-8-[(1S, 4S)]-and 5-methyl-2,5-diazabicyclo [2,2,1] heptane-2-]-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 1, with inner complex with (1S, 4S)-5-methyl-2, the reaction of 5-diazabicyclo [2,2,1] heptane two hydrobromates makes yield: 66%; Mp258-260 ℃ (dec)
IR(cm -1)：3413，2573，1680，1613，1593，1453。
1HNMR (DMSO-d 6): δ 0.82 (t, 3H ,-NCH 2CH 3), 2.11-2.47 (m, 2H ,-CHCH 2CH-), 2.78 (m, 2H ,-NCH 2CH 3), 2.88 (s, 3H ,-NCH 3), 3.22-4.91 (m, 8H, 2 * (NCH 2CHN-) and H-11),
7.56(s，1H，H-2)，7.65(d，1H，H-6，J H-6，F＝14Hz)，11.02(br，1H，-NH +-)，15.87(br，1H，-COOH)。
MS(SCI，M/Z)：429(base peak)，411，112。
Example 3
7-fluoro-8-(1-piperazinyl)-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 1, make yield: 69%mp＞280 ℃ with the reaction of inner complex and Piperazine anhydrous.
IR(cm -1)：3393，2707，2472，1707，1616，1594，1493。
1HNMR(D 2O)：δ1.01(t，3H，CH 3)，3.10(q，2H，-NCH 2CH 3)，3.52-3.75(m，8H，2×(-NCH 2CH 2N-))，4.52(s，2H，H-11)，7.07(d，1H，H-6，J H-6，F＝12Hz)，7.43(s，1H，H-2)。
MS(EI，m/z)：402，385，373，358，286(base peak)。
Example 4
(±)-7-fluoro-8-(3-methyl isophthalic acid-piperazinyl)-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 1, make yield 74% with inner complex and the reaction of 2-methylpiperazine; Mp＞280 ℃.
IR(cm -1)：3350，2703，2475，1687，1614，1589，1526。
1HNMR(D 2O)：δ0.96(t，3H，-NCH 2CH 3)，1.46(d，3H，-CHCH 3)，3.02(q，2H，-NCH 2CH 3)，3.36～3.75(m，7H，-CH 2CH 2NCHCH 2-)，4.48(s，2H，H-11)，6.96(d，1H，H-6，J H-6，F＝10Hz)，7.39(s，1H，H-2)。
Ms(EI，m/z)：416，387，329，286(base peak)。
Example 5
7-fluoro-8-(suitable-3,5-dimethyl-1-piperazinyl)-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 1, with inner complex and cis-2, the reaction of 6-lupetazin makes yield: 73%; Mp＞280 ℃.
IR(cm -1)：3429，2711，2466，1683，1611，1591。
1HNMR(DMSO-d 6)：δ0.96(t，3H，-NCH 2CH 3)1.28(d，6H，2×(-CHCH 3))，3.06(q，2H，-NCH 2CH 3)，3.16～3.64(m，6H，2×(-NCH 2CHN-))，4.52(s，2H，H-11)，7.55(s，1H，H-2)，7.73(d，1H，H-6，J H-6，F＝12Hz)，15.78(s，1H，-COOH)。
MS(EI，m/z)：430，401，286(base peak)。
Example 6
7-fluoro-8-hydroxyethylamine-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 1, make yield 76% by reaction with inner complex and thanomin; Mp:258～260 ℃ (dec).
IR(cm -1)：3385，1665，1615，1592，1512。
1HNMR(DMSO-d 6)：δ1.04(t，3H，CH 3)，2.77(q，2H，-NCH 2CH 3)，3.60(a，4H，HOCH 2CH 2NH-)，4.44(s，2H，H-11)，5.74(br，1H，-NH-)，7.51(s，1H，H-2)，7.64(d，1H，H-6，J H-6，F＝13.5Hz)，15.98(s，1H，-COOH)。
MS(EI，m/z)：377，333，272(base peak)。
Example 7
7-fluoro-8-(2-hydroxy-propylamine base)-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 1, make yield with inner complex and Yi Bingchunan reaction: 68%; Mp:215～218 ℃ (dec).
IR(cm -1)：3323，1683，1615，1589，1509。
1HNMR (DMSO-d 6): δ 1.04 (t, 3H ,-NCH 2CH 3), 1.44 (d, 3H, CH 3CH (OH) CH 2NH-), 2.79 (q, 2H ,-NCH 2CH 3), 3.56-3.85 (m, 3H, CH 3CH (OH) CH 2NH-), 4.44 (s, 2H, H-11), 4.94-5.68 (2 * br, 2H ,-OH and-NH-), 7.51 (s, 1H, H-2), 7.65 (d, 1H, H-6, J H-6, F=13Hz), 15.97 (s, 1H ,-COOH).
MS(EI，m/z)：391，347(base peak)，302。
Example 8
7-fluoro-8-morpholinyl-9,1-[(N-ethyl imido grpup) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 1, make yield 82% with inner complex and morpholine reaction; Mp:260～262 ℃ (dec).
IR(cm -1)：3400，1696，1611，1585，1522。
1HNMR(DMSO-d 6)：δ0.99(t，3H，CH 3)，3.12(q，2H，-NCH 2CH 3)，3.37～3.74(m，8H，-CH 2CH 2OCH 2CH 2-)，4.50(s，2H，H-11)，7.52(s，1H，H-2)，7.61(d，1H，H-6，J H-6，F＝13Hz)，15.77(s，1H，-COOH)。
MS(EI，m/z)：403，359，286
Example 9
7-fluoro-8-(1-piperazinyl)-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's hydrochloride also
Boric acid 115mg (1.9mmo1) is added among the aceticanhydride 1.4ml, be warming up to 110 ℃ of stirring reactions and all dissolve, add 7 again until solid, 8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid 400mg (1.2mmol) also, and equality of temperature stirred after 3 hours, cooling, leaching precipitation, with aceticanhydride and normal hexane wash 7,8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid's root diethyl acid group closes boron 440mg.With this inner complex and Piperazine anhydrous 110mg (1.3mmol), 1,8-diazabicyclo [5,4,0] undecane-7-alkene (DBU) 0.35ml (2.2mmol), the mixture of DMSO 5ml under nitrogen protection in 140 ℃ stir 10 hours after, the high vacuum concentrating under reduced pressure.Resistates is with dilute hydrochloric acid hydrolysis 1 hour, the leaching crystallization, the 1NHCl recrystallization, drying, light yellow crystal 275mG, yield: 62%; Mp＞280 ℃.
IR(cm -1)：3429，2700，2455，1692，1608，1574，1508。
1HNMR(D 2O)：δ3.54(m，8H，4×CH 2)4.23(s，2H，-SCH 2-)，7.06(d，1H，H-6，J H-6，F＝12Hz)，7.35(s，1H，H-2)。
MS(EI，m/z)：391，347，305(base peak)。
Example 10
(±) 7-fluoro-8-(3-methyl isophthalic acid-piperazinyl)-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 9, make yield 68% with inner complex and the reaction of 2-methylpiperazine; Mp＞280 ℃.
IR(cm -1)：3350，2712，2470，1701，1577，1499。
1HNMR(DMSO-d 6)：δ1.33(d，3H，CH 3)，3.10～3.50(m，7H，-CH 2CH 2NCHCH 2-)，4.49(s，2H，-SCH 2-)，7.65(s，1H，H-2)，7.82(d，1H，H-6，J H-6，F＝12Hz)，9.43～9.82(br，2H，NH 2 +，exchange with D 2O)，15.54(brs，1H，-COOH)。
MS(EI，m/z)：405，361，305(base peak)。
Example 11
7-fluoro-8-(suitable-3,5-dimethyl-1-piperazinyl)-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's hydrochloride also
By the method that is similar to example 9, with inner complex and cis-2, the reaction of 6-lupetazin makes yield: 70%; Mp＞280 ℃
IR(cm -1)：3400，2717，2471，1701，1600，1575，1521。
1HNMR(DMSO-d 6)：δ1.25(m，6H，2×CH 3)，2.78～3.53(m，6H，2×(-NCH 2CHN-))，4.48(s，2H，-SCH 2-)，7.65(s，1H，H-2)，7.94(d，1H，H-6，J H-6，F＝12Hz)，15.64(brs，1H，-COOH)。
MS(EI，m/z)：419，349，305(base peak)。
Example 12
7-fluoro-8-morpholinyl-9,1-(epithio methylene radical)-5-oxygen-5H thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 9, make yield with inner complex and morpholine reaction: 76%; Mp:275～276 ℃ (dec)
IR(cm -1)：3400，1696，1611，1575，1506。
1HNMR(DMSO-d 6)：δ3.18～3.77(m，8H，-CH 2CH 2OCH 2CH 2-)，4.46(s，2H，-SCH 2-)，7.63(s，1H，H-2)，7.83(d，1H，H-6，J H-6，F＝12Hz)，15.61(brs，1H，-COOH)。
MS(EI，m/z)：392，348，290(base peak)。
Example 13
7-fluoro-8-hydroxyethylamine-9,1-(epithio methylene radical)-5-oxygen-5H thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 9, make yield with inner complex and thanomin reaction: 68%; Mp＞280 ℃
IR(cm -1)：3369，3263，1670，1613，1573，1506。
1HNMR(DMSO-d 6)：δ3.59(m，4H，HOCH 2CH 2NH-)，4.45(s，2H，-SCH 2-)，5.58(brs，1H，-NH-)，7.56(s，1H，H-2)7.74(d，1H，H-6，J H-6，F＝13Hz)，15.94(brs，1H，-COOH)。
MS(EI，m/z)：366，322，291(base peak)。
Example 14
7-fluoro-8-(2-hydroxy-propylamine base)-9,1-(epithio methylene radical)-5-oxygen-5H thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 9, make yield with inner complex and Yi Bingchunan reaction: 66%; Mp＞280 ℃
IR(cm -1)：3495，3324，1684，1614，1574，1498。
1HNMR (DMSO-d 6): 81.12 (d, 3H, CH 3), 3.33～3.52 (m, 2H, CH 3CH (OH) CH 2NH-), 3.83 (m, 1H, CH 3CH (OH) CH 2NH-), 4.46 (s, 2H ,-SCH 2-), 4.80～5.50 (2 * br, 2H ,-OH and-NHH-), 7.58 (s, 1H, H-2), 7.78 (d, 1H, H-6, J H-6, F=13Hz), 15.97 (S, 1H-COOH).
MS(EI，m/z)：380，336，291(base peak)。
Example 15
According to the present invention, the example of tablet,
Every content: 100mg
Example 1 compound 100mg
HPMC E 510mg
HPMC E 5010mg
Give gelling starch 30mg
Microcrystalline Cellulose 12mg
Magnesium Stearate 2mg
Talcum powder 1mg
30 POVIDONE K 30 BP/USP 30In right amount
Example 16
According to the present invention, the example of emulsion
Every content: 100mg
Component A component B
White vaseline 10.0g example 1 compound 5.0g
Liquid paraffin,light 9.0g propylene glycol 10.0g
Stearyl alcohol 4.0g diethanolamine 1.2g
Cetyl alcohol 4.0g distilled water 54g
Polyoxyethylene margaron 3.0g
Component A is heated to 80 ℃ melts, with component B dissolving, mix, be heated to 80 ℃, mix with A, cooling promptly mixes emulsion.
Example 17
According to the present invention, capsular example
Every content: 100mg
Compound 100mg
HPMC E 505mg
HPMC K 4M15mg
Give gelling starch 10mg
Celluloasun Microcrystallisatum 10mg
Talcum powder 1mg
30 POVIDONE K 30 BP/USP 30In right amount
Example 18
According to the present invention, the example of injection
Per ampoule content: 100mg
Example 1 compound 100mg
Lactic acid is an amount of
Water for injection 2ml
Example 19
According to the present invention, the example of transfusion
Every bottle of content: 200mg
Example 1 compound 200mg
Lactic acid is an amount of
Sodium-chlor 0.88g
Water for injection 100ml

Claims (7)

1,1 of Fourth Ring fluoroquinolone compounds general formula (I), 9-bridge-type 5-oxygen-5H-thiazole is [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 to 4 carbon atom;
B represents NCH 2CH 3
The Z representative is the group of array structure down:
Figure C031004180002C2
Wherein, R 2, R 3, R 4: the C that represents hydrogen, straight or branched 1～C 3Alkyl or R 3R 4Represent CH 2
X represents O, S or NH;
R 5, R 6The alkyl that represent hydrogen, is replaced arbitrarily by hydroxyl, methoxyl group, amino, methylamino or dimethylin with 1～4 carbon atom;
R 7Representation hydroxy or-NR 11R 12
R 8, R 9, R 10, R 11, R 12: the C that represents hydrogen, straight or branched 1～C 3Alkyl, or (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, shine the compound of claim 1, wherein
R 1Represent hydrogen, methyl or ethyl;
B represents NCH 2CH 3
The Z representative is the group of array structure down:
Wherein, R 2, R 3, R 4: represent hydrogen, methyl or ethyl; Or R 3, R 4Represent CH 2
X represents O, S or NH;
R 5, R 6Represent hydrogen, methyl or ethyl;
R 7Representation hydroxy or-NR 11R 12
R 8, R 9, R 10, R 11, R 12: represent hydrogen, methyl or ethyl.
3, according to the compound of claim 2, R wherein 1Represent H; B represents NCH 2CH 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:
Figure C031004180003C3
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 2CH 3
The Z representative is the group of array structure down:
Wherein, R 2, R 3, R 4: the C that represents hydrogen, straight or branched 1～C 3Alkyl; Or R 3R 4Represent CH 2
X represents O, S or NH;
R 5, R 6The alkyl that represent hydrogen, is replaced arbitrarily by hydroxyl, methoxyl group, amino, methylamino or dimethylin with 1～4 carbon atom;
R 7Representation hydroxy or NR 11R 12
R 8, R 9, R 10, R 11, R 12: the C that represents hydrogen, straight or branched 1～C 3Alkyl;
It is characterized in that making through acid or basic hydrolysis again with the reaction of formula (IH) compound with formula (II) compound and the reaction of formula (III) compound or after using nitrilotriacetic boric anhydride, fluoroboric acid with formula (II) compound chelating:
Wherein, R 1The same with the B definition, Y represents fluorine or chlorine;
Z-H(III)
Wherein, the Z definition is the same;
If desired, the reaction of formula (II) compound or its inner complex and formula (III) compound can be carried out in the presence of acid binding agent.
5, the preparation described formula of claim 1 (I) but change the method for the salt contain the thing 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 haloid acid, sulfuric acid; Organic acid is methylsulfonic acid, tosic acid, lactic acid, Aspartic Acid; Basic aminoacids is arginine, Methionin.
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.
CNB031004180A 2000-03-24 2000-03-24 Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component Expired - Fee Related CN1190439C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB031004180A CN1190439C (en) 2000-03-24 2000-03-24 Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB031004180A CN1190439C (en) 2000-03-24 2000-03-24 Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN 00112169 Division CN1116300C (en) 2000-03-24 2000-03-24 Tetracyclic fluoquinolone carboxylic acid, its preparing process and medicinal composition containing it as active component

Publications (2)

Publication Number Publication Date
CN1425668A CN1425668A (en) 2003-06-25
CN1190439C true CN1190439C (en) 2005-02-23

Family

ID=4789823

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB031004180A Expired - Fee Related CN1190439C (en) 2000-03-24 2000-03-24 Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component

Country Status (1)

Country Link
CN (1) CN1190439C (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1332670C (en) * 2005-09-29 2007-08-22 周卓和 Baloxin capsule and preparing method
WO2011031745A1 (en) 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs

Also Published As

Publication number Publication date
CN1425668A (en) 2003-06-25

Similar Documents

Publication Publication Date Title
CN1046162A (en) The 5-Alkylquinolonecarboxacids acids
CN88101741A (en) Quinolinone one and azanaphthalenes keto carboxylic acid derivatives that 5-replaces
CN1009930B (en) Novel quinoline derivatives and process for prepn. thereof
CN1914180A (en) Indazole derivatives as inhibitors of hormone-sensitive lipases
CN1019668B (en) Quinolone acid derivatives and process for preparing them
CN1414964A (en) Antibacterial heterobicyclic substituted phenyl oxazolidinones
CN1708481A (en) N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones as antimicrobials
CN100341855C (en) 7-substituted-8-methoxy fluoroquinolone carboxylic derivatives, preparing process, preparation and use thereof
CN1918172A (en) Rifamycin analogs and uses thereof
CN86104479A (en) The preparation method of pyridone carboxylic acid derivatives
CN1051176A (en) Quinolone compounds and preparation method thereof
CN1543465A (en) Novel heterocyclic compounds as selective bacterial DHFR inhibitors and their uses thereof
CN87100354A (en) The derivative of 7-(azabicycloalkyl)-quinolone carboxylic acid and 7-(azabicycloalkyl)-naphthyridonecarboxylic
CN86100126A (en) 6, the two replacement-1-cyclopropyl of 7--1,4 dihydro-4-oxo-1, the preparation method and the application thereof of 8-naphthyridines-3-carboxylic acid
CN1190439C (en) Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component
CN1116300C (en) Tetracyclic fluoquinolone carboxylic acid, its preparing process and medicinal composition containing it as active component
CN1237056C (en) Oxazolidone compound, preparing method and use thereof
CN1021967C (en) Ouinoline derivatives and processes for preparation thereof
CN1183115C (en) 5-amino-8-methoxy quinolone carboxylic acid derivatives and its preparation
CN1914206A (en) 7-phenylamino-4-quinolone-3-carboxylic acid derivatives, methods for production and use thereof as medicaments
CN1056420A (en) Preparation contains the Pharmaceutical composition method of 2-methoxy-penem derivatives
CN1025196C (en) Quinoline carboxylic acid derivatives
CN1194977C (en) Tetracyclic fluoroquinolone carboxylic acid, its preparing method and medicinal composition with it as active component
CN1094941C (en) Pyridobenzoxazine derwatives
CN1112364C (en) 1,3,4-thiadiazole carbapenem compound and its preparing process and usage

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee