CN1194977C - Tetracyclic fluoroquinolone carboxylic acid, its preparing method and medicinal composition with it as active component - Google Patents
Tetracyclic fluoroquinolone carboxylic acid, its preparing method and medicinal composition with it as active component Download PDFInfo
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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
The present invention is dividing an application of 00112170.7 patent application, and the applying date of original application is on March 24th, 2000, and application number is 00112170.7, 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 the tetracyclic fluoquinolone carboxylic acid, 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 Orally-administrable, may with the 3rd, the 4th generation cynnematin compare favourably, occupy sizable usage quantity clinically, and growth momentum is swift and violent.But existing medicine also exists some obviously not enough, at first to some G
+, the anerobe antibacterial effect is not satisfactory, secondly, central nervous system had side effect, in addition, photosensitized reaction and bacterial drug resistance manifest in some quinolone medicine day by day.The objective of the invention is to further improve anti-microbial activity, particularly strengthen G
+Bacterium, anerobe and chlamydozoan isoreactivity overcome CNS system and photosensitive side effect, and to drug-resistance of bacteria.
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 O or 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.
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:
Wherein, R
1Represent hydrogen, methyl or ethyl;
B represents O or NCH
3
The Z representative is the group of array structure down:
Wherein, R
2: represent hydrogen, methyl or second its;
R
3Representation hydroxy or-NR
8R
9
R
4, R
5, R
6, R
7, R
8, R
9: represent hydrogen, methyl or ethyl.
A kind of pharmaceutical preparation wherein comprises the formula (I) 1 of significant quantity, 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.
Segment bounds (I) compound is listed as follows:
Compd B Z R
1
No.1 O
H
No.2 NCH
23 H
No.3 O HOCH
2CH
2NH- H
No.4 NCH
3 HOCH
2CH
2NH- H
No.5 O
H
No.6 NCH
3 H
No.7 O
Et
No.8 NCH
3 
Et
No.9 O
H
No.10 NCH
3 H
The preparation of formula (I) compound is undertaken by making the reaction of formula (II) compound and formula (III) compound:
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 formula (II) compound 7,8-two fluoro-9,1-(epithio methylene radical)-5-oxygen-5H-thiazole also [3,2-a] and Cinchonic Acid and Shi (III) compound (1S, 4S)-5-methyl-2, the preparation of 5-diazabicyclo [2.2.1] heptane (III) can be by document (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 Pharmaceuticals, 1999,30 (9): 416. reactions come preparation formula (I) compound 7-fluoro-8-[(1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptane-2]-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also, and reaction process can be represented with following reaction 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-[(N-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
7,8-two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also
7,8-two fluoro-9,1-[(N-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid's ethyl ester also
7,8-two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [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 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
Thanomin
Yi Bingchunan
Piperazine
2-amino-2-methyl-propyl alcohol; Imidazoles; Methylimidazole
Prepare described formula (I) but the method for the salt of compound hyoscine, 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.Formula (II) compound and formula (III) compound added in polar aprotic solvent alkaline acid-acceptor stirs and reacting by heating makes.Being suitable for compound (II) is aprotic polar solvent with the solvent that compound (III) reacts, DMSO for example, DMF, N-Methyl pyrrolidone, HMPA, carry out in tetramethylene sulfone, tetrahydrofuran (THF), chloroform, acetonitrile, water, alcohols such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, ethylene glycol-methyl ether or pyridine, the picoline, also can use the mixed solvent of above these solvents.If desired, reaction can be carried out in the presence of acid binding agent, 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 at approximately 20-200 ℃, carries out under preferred 80-180 ℃; Pressure can be normal pressure or 1-30 normal atmosphere.In the reaction, every mole compound (II) can use the 1-15 mole, the compound (III) of preferred 1-6 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 trifluoroacetic acid.Ester compound of the present invention can be by its corresponding carboxylic acid an alkali metal salt (if desired; available protecting group such as tertbutyloxycarbonyl are protected its nitrogen-atoms) with suitable haloalkyl derivative in DMF, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide equal solvent, and about 0～100 ℃ down reaction make.
These compounds of the present invention can both form pharmaceutically useful salt, as additive salt and/or alkali salt.Their available ordinary methods make.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, propanedioic acid, lactic acid, succsinic acid, citric acid, tartrate, fumaric acid, toxilic acid.Methylsulfonic acid, ethane disulfonic acid, tosic acid, galacturonic acid, glyconic acid, L-glutamic acid or aspartic acid, xitix, oxysuccinic acid, Whitfield's ointment, oxalic acid etc.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 has the strong effect wide-spectrum antibacterial activity, to various G
+And G
-Bacterium comprises that the penicillin resistant bacterioid all has very strong anti-microbial effect, and toxic side effect is very low.These compounds especially multiplely antibioticly have chemical sproof germ activity are arranged those, for example: penicillin, cynnematin, aminoglycosides antibiotics, sulfanilamide (SN) and tsiklomitsin etc.These compounds can become pharmaceutically extremely valuable anti-infectives, can be used as prevention, alleviate and treat the disease that the mankind and beasts pathogenic agent cause, and can be used as inorganic and sanitas organic materials, as organic polymer, lubricant, coating, fiber, leather, paper, wood, food and water etc.
For example, these compounds can the part and/or systemic administration treat and/or prevent following pathogenic agent, or the polyinfection that causes of following pathogenic agent: G
+Bacterium is as Staphylococcus and streptococcus etc.; G
-Coccus and G
-Bacillus, as bacillus coli, hemophilus influenzae, citric acid bacterium, salmonella and shigella.In addition, Cray Bai Shi bacillus, intestinal bacilli, Hafnia, Serratia, Bacillus proteus, God's will Pseudomonas, acinetobacter Rhodopseudomonas; Anerobe such as bacteroides fragilis; Also has mycoplasma; Mycobacterium is as Mycobacterium tuberculosis.
Above pathogenic bacteria sheerly illustrates, is not institute of the present invention limit scope.The disease that compound of the present invention can prevent, alleviates and/or treat has for example: pneumonia, pharyngitis, otitis, peritonitis, pyelonephritis, urocystitis vaginitis, enteritis, endocarditis, bronchitis, sacroiliitis, bone and systemic infection, part and epidermis infect.
The mentioned beasts of the present invention comprise the livestock of domestic animal and raising, as mammal: ox, horse, donkey, sheep, pig, dog, cat, rabbit, deer; Birds and chicken, duck, goose; Aquatic products category in addition is as fish, shrimp, crab; Also has some other animal bird, as tiger, lion, leopard, ostrich etc.
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.
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 suitable for injecting.
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.
The auxiliary material of formulated of the present invention is not confined to above-mentioned cited example, and according to the present invention: 1. weighting agent and swelling agent have: starch, lactose, sucrose, glucose, N.F,USP MANNITOL, silicon-dioxide etc.; 2. tackiness agent also has the alginate gelatin, polyvinylpyrrolidone except that carboxymethyl cellulose; 3. drawing humectant has: glycerine; 4. disintegrating agent has: agar, lime carbonate, yellow soda ash; 5. short vapor has: quaternary ammonium compounds; 6. wetting agent has: Cetyl Alcohol and glycerine stearic acid; 7. sorbent material has kaolin, wilkinite; 8. lubricant has talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol etc.More than each material can be as required cooperate arbitrarily and make formulation and use with main ingredient.
Suppository also contains habitual water-soluble or water-insoluble binder except main ingredient of the present invention or compound medicine, be polyoxyethylene glycol, fat (cupraol and senior fat are 16 carbon fatty acids, 14 carbon alcohol).
For para-oral administration, as injection, freeze-dried powder, emulsion etc., auxiliary material should be nontoxic and ooze with blood etc.
Use one or more compounds of the present invention that people's clothes or administration gross weight for animals are generally: per kilogram of body weight 0.5 is to about 500mg, and best 24 hours consumption is 5-100mg/kg, can adopt multiple administering mode.According to the present invention, being suitable for the amount that single administration contains one or more active compounds is 1-250mg/kg, and preferably 3-60mg/kg is not limited to above-mentioned scope certainly.
In addition, in each several formulations, active compound of the present invention also can be used as the form existence with synergistic agent or other active ingredient compound pharmaceuticals.
Measure the minimum inhibitory concentration (MICS) 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 contrast dull and stereotyped (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 MICS (μ g/ml) of part of compounds of the present invention:
Table MICS (μ g/ml)
| Compound MIC (μ g/ml) bacterial strain | No.1 | No.2 | No.4 | No.9 | No.10 | * Ofloxacine USP 23 |
| Streptococcus aureus ATCC25923 | ≤0.025 | ≤0.025 | 0.1 | 0.1 | 0.05 | 0.2 |
| Streptococcus aureus (clinical) | ≤0.025 | ≤0.025 | 0.05 | 0.1 | ≤0.025 | 0.2 |
| Streptococcus aureus bacterium (product β-Nei Xiananmei) | ≤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 |
| Intestinal bacteria ATCC25922 | ≤0.025 | ≤0.025 | 0.05 | 0.05 | 0.05 | 0.05 |
| Intestinal bacteria (clinical) | ≤0.025 | ≤0.025 | 0.05 | ≤0.025 | 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 | ≤0.025 | ≤0.025 | 0.2 |
| Cray Bai Shi pneumobacillus 46117 | 0.025 | ≤0.025 | 0.05 | ≤0.025 | ≤0.025 | 0.05 |
| The Fu Shi bacillus citrate | ≤0.025 | ≤0.025 | 0.4 | 0.05 | 0.1 | 0.05 |
* as known reference substance, this medicine has been widely used in for many years clinical Ofloxacine USP 23 (Jiangsu Province Kunshan Pharmaceutical Factory produces, and is commercially available), and curative effect spy is good, and side effect is little, and it is three ring fluoroquinolones medicines.
The preparation example of active compound is as follows:
Example 1
7-fluoro-8-[(1S, 4S) 5-methyl-2,5-diazabicyclo [2,2,1] heptane-2-]-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid's hydrochloride also
With 7,8-two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid 0.31g (1.1mmol), (1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptane two hydrobromate 0.30g (1.1mmol), 1,8-diazabicyclo [5,4,0] undecane-7-alkene (DBU) 0.70ml (4.4mmol), the mixture of DMSO 10ml under nitrogen protection in 80 ℃ stir 1 hour after, the high vacuum concentrating under reduced pressure adds dilute hydrochloric acid in the resistates, the leaching precipitation, the water-ethanol recrystallization, drying gets light yellow crystal 0.32g; Yield: 73%; Mp＞280 ℃.
IR(cm-1)：3469，2800，2656，2524，1679，1620，1599，1518，1473。
1HNMR(D
2O)：δ2.35-2.50(m，2H，-CHCH
2CH-)，3.10(s，3H，CH
3)3.34-4.92(m，6H，2×(-NCH
2CHN-)，5.12-5.37(m，2H，-NOCH
2-，)，6.64(d，1H，H-6，J
H-6，F＝11Hz)，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-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
With 7,8-two fluoro-9,1-[(N-methylene imine base) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid 0.32g (1.0mmol), (1S, 4S)-5-methyl-2,5-diazabicyclo [2.2.1] heptane two hydrobromate 0.30g (1.1mmol), 1, the mixture of 8-diazabicyclo [5.4.0] undecane-7-alkene (DBU) 0.70ml (4.4mmol), DMSO 10ml under nitrogen protection in 140 ℃ stir 9 hours after, the high vacuum concentrating under reduced pressure, resistates is with the DMSO recrystallization, drying gets light yellow crystal 0.30g; Yield: 72%; Mp.255～257 ℃ (dec).
IR(cm
-1)：3400，3078，1701，1610，1572，1490，1445。
1HNMR (DMSO-d
6): δ 1.74-1.95 (m, 2H ,-CHCH
2CH-), 2.35 (s, 3H, CH
3), 2.43 (s, 3H, CH
3), 2.45-4.61 (m, 8H, 2 * (NCH
2CHN-) and H-11), 7.50 (s, 1H, H-2), 7.59 (d, 1H, H-6, J
H-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-hydroxyethylamine-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 2, with 7,8-two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole also reaction of [3,2-a] Cinchonic Acid and thanomin make yield: 78%, mp:265～266 ℃ (dec).
IR(cm-1)：3266，2926，1673，1629，1596，1518，1486。
1HNMR(DMSO-d
6)：δ3.60(m，4H，HOCH
2CH
2NH-)，5.51(s，2H，-OCH
2-)，7.50(d，1H，H-6，J
H-6，F＝13Hz)，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-hydroxyethylamine-9,1-[(N-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 2,, 8-two fluoro-9,1-[(N-methylene imine base with 7) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid and thanomin reaction make yield: 69%; Mp＞280 ℃.
IR(cm
-1)：3350，3295，1674，1614，1592，1515，1473。
1HNMR(DMSO-d
6)：δ2.54(s，3H，CH
3)，3.61(m，4H，HOCH
2CH
2NH-)，4.39(s，2H，H-11)，5.94(br，1H，-NH-)，7.53(s，1H，H-2)，7.64(d，1H，H-6，J
H-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-propylamine base)-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 2, with 7,8 two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid and Yi Bingchunan reaction makes yield: 75%; Mp:250-252 ℃ (dec.).
IR(cm
-1)：3500，3400，1673，1628，1587，1481，1451。
1HNMR(DMSO-d
6)：δ1.1(d，3H，CH
3)，3.0-4.0(m，4H，CH
3CH(OH)CH
2NH-)，5.5(s，2H，-OCH
2-)5.7(br，1H，-NH-)，7.4(d，1H，H-6，J
H-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-propylamine base)-9,1-[(N-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 2,, 8-two fluoro-9,1-[(N-methylene imine base with 7) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid and Yi Bingchunan reaction make yield: 67%; Mp:253-255 ℃ (dec).
IR(cm
-1)：3429，3278，2945，1682，1614，1591，1506，1470。
1HNMR(DMSO-d
6)：δ1.12(d，3H，CH
3)，2.51(S，3H，N-CH
3)，3.36-3.87(m，3H，CH
3CH(OH)CH
2NH-)，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，J
H-6，F＝13.5Hz)，15.99(s，1H，-COOH)。
MS(EI，m/z)：377，333，288，272(base peak)。
Example 7
7-fluoro-8-(1-imidazolyl)-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole is [3,2-a] Cinchonic Acid also
By the method that is similar to example 2, with 7,8-two fluoro-9,1-(epoxy methylene radical)-5-oxygen-5H-thiazole also reaction of [3,2-a] Cinchonic Acid and imidazoles make yield: 75%; Mp:＞280 ℃.
IR(cm-1)：3450，1705，1630，1596，1492，1486。
1HNMR(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，J
H-6，F＝12Hz)，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-methylene imine base) methylene radical]-5-oxygen-5H-thiazole [3,2-a] Cinchonic Acid also
By the method that is similar to example 2,, 8-two fluoro-9,1-[(N-methylene imine base with 7) methylene radical]-5-oxygen-5H-thiazole also [3,2-a] Cinchonic Acid and imidazoles reaction make yield: 54%; Mp＞280 ℃.
IR(cm
-1)：3400，1683，1618，1600，1518，1470。
1HNMR (DMSO-d
6): δ 2.49 (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, the example of tablet
Every content:
Example 1 compound 100mg
HPMC E
530mg
HPMC E
5010mg
Sodium starch glycolate 15mg
Give gelling starch 5mg
8% 30 POVIDONE K 30 BP/USP
30In right amount
Magnesium Stearate 2mg
Talcum powder 1mg
Example 10
According to the present invention, capsular example
Every content:
Example 2 compound 100mg
HPMC E
5010mg
HPMC K
4M12mg
Sodium starch glycolate 5mg
Give gelling starch 10mg
Talcum powder 1mg
8% 30 POVIDONE K 30 BP/USP
30In right amount
Example 11
According to the present invention, the example of injection
Per ampoule content:
Example 1 compound 100mg
Lactic acid is an amount of
Water for injection adds to 2ml
Example 12
According to the present invention, the example of transfusion
The content of every bottle (bag):
Example 2 compound 200mg
Lactic acid is an amount of
Sodium-chlor 850mg
Water for injection adds to 100ml
Example 13
According to the present invention, the example of emulsifiable paste
Every content:
Component A component B
White vaseline 1.0g example 1 compound 100mg
Whiteruss 0.9g glycerine 1000g
Stearyl alcohol 0.4g diethanolamine 10mg
Cetyl alcohol 0.4g distilled water 5.89ml
Polyoxyethylene n-Hexadecane ether 0.3g
Component A is heated to about 80 ℃ melts, with component B dissolving, and be heated to 80 ℃, mix with A, cooling is external application sterilization missible oil cream.
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.
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|---|---|---|---|
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|---|---|
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