CN1183115C - 5-Amino-8-methoxyquinolone carboxylic acid derivatives and its preparation method - Google Patents
5-Amino-8-methoxyquinolone carboxylic acid derivatives and its preparation method Download PDFInfo
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- CN1183115C CN1183115C CNB031600077A CN03160007A CN1183115C CN 1183115 C CN1183115 C CN 1183115C CN B031600077 A CNB031600077 A CN B031600077A CN 03160007 A CN03160007 A CN 03160007A CN 1183115 C CN1183115 C CN 1183115C
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- amino
- carboxylic acid
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- 238000002360 preparation method Methods 0.000 title abstract description 62
- RAUKXRNOCZERAV-UHFFFAOYSA-N 5-amino-8-methoxy-2-oxo-1H-quinoline-3-carboxylic acid Chemical class NC1=C2C=C(C(NC2=C(C=C1)OC)=O)C(=O)O RAUKXRNOCZERAV-UHFFFAOYSA-N 0.000 title description 2
- -1 quinolone compound Chemical class 0.000 claims abstract description 21
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 110
- 238000000034 method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 21
- 239000003814 drug Substances 0.000 abstract description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 5
- 241000192125 Firmicutes Species 0.000 abstract description 4
- 239000004599 antimicrobial Substances 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 abstract 2
- 239000003674 animal food additive Substances 0.000 abstract 1
- MAEBCGDGGATMSC-OSHGGGOQSA-N cyclamine Chemical group O([C@H]1CO[C@H]([C@@H]([C@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CCC45OCC6([C@@H](C[C@@]4(C)[C@]3(C)CCC2C1(C)C)O)CC[C@@](C[C@@H]65)(C)C=O)[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O MAEBCGDGGATMSC-OSHGGGOQSA-N 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 229940072132 quinolone antibacterials Drugs 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 241000894006 Bacteria Species 0.000 description 12
- 239000003999 initiator Substances 0.000 description 10
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- 241000607762 Shigella flexneri Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new quinolone compound with good antibacterial activity and a preparation method thereof, and also relates to an antimicrobial agent and feed additive containing the quinolone compound. More specifically, the present invention relates to a new quinoline carboxylic acid derivative of the formula (I) (disclosed in the specification). The 5-position of a quinolone core has an amino group, the 7-position has various cyclamine substituted groups, and the 8-position has a methoxy group. Compared with the existing quinolone antibacterial medicine having weak activity to gram-positive bacteria, the quinoline carboxylic acid derivative has superior activity resisting the gram-positive bacteria and broad-spectrum antibacterial activity, and the groups of the formula are disclosed in the specification.
Description
Technical field
The present invention relates to have active new carbostyril compound of excellent antibacterial and preparation method thereof, relate to the antibacterial combination and the fodder additives that contain them.
Background technology
Quinolones was from Nalidixic Acid (nalidixic acid in 1962, see G.Y.Lesher etc., J.Med.Chem.5,1063-1065 (1962)) Moxifloxacin (moxifloxacin that went on the market by 1999, the open NO.1074218 (1993) of Chinese patent), with regard to anti-microbial activity, experienced the transformation of only most of Gram-negative bacteria effectively being arrived broad-spectrum antimicrobial.
According to the existing structure activity relationship of quinolones, the 5-bit substituent is NH
2The time can improve the activity of compound resisting gram-positive bacteria, reduce the phototoxicity of compound simultaneously.
Sanchez J.P. etc. are at J.Med.Chem.1995,38, report among the 4478-4487: a series of 8-alkoxyl groups and a series of corresponding 5-amino-8-alkoxyl group carbostyril compound have carried out the structure activity relationship evaluation, with regard to external activity, the activity of anti-Gram-negative bacteria, 5-amino-8-alkoxyl group quinolone and 8-alkoxyl group quinolone quite or slightly inferior, and the activity of resisting gram-positive bacteria is better than the latter.In their the synthetic 5-of institute amino-8-BAY 128039 analogue, 7-position side chain only is the common substituted-piperazinyl of part, the amino piperidine of substituted aminopyrrolidine and replacement, and other 7-position ring ammonia side chain is not estimated.
The present invention is incorporated into these side chains in 5-amino-8-BAY 128039 parent nucleus, and measures the pharmacologically active of formed compound, seeks new quinolones.Beat all is that these compounds of the present invention are compared with corresponding similar compound, and the wide spectrum pathogenic strains has been demonstrated stronger anti-microbial activity, have good pharmacokinetics performance, and toxicity are very low.
Summary of the invention
Therefore, the invention provides formula (I) compound of following structure,
Wherein
R
1And R
2Coupled nitrogen-atoms forms single or two heterocycle together, can also further have nitrogen, oxygen or sulfur heteroatom on described ring, and can selectedly replace.For R
1And R
2Coupled nitrogen-atoms forms single or two heterocycle together, the preferably following group of the present invention:
Or
With the corresponding concrete formulas of these groups (I) compound be:
5-amino-1-cyclopropyl-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-6-fluoro-7-(3-methyl isophthalic acid-piperazinyl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-6-fluoro-7-(5-methyl-2,5-diazabicyclo [2,2,1] heptane-2-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-6-fluoro-7-(7-amino-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-6-fluoro-7-(7-aminomethyl-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-6-fluoro-7-(7-methyl aminomethyl-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-7-(3-aminomethyl-4-methoxy imino-1-pyrrolidyl)-1-cyclopropyl-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-7-[(R, R)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-7-[(S, S)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
5-amino-1-cyclopropyl-7-(2,8-diazabicyclo [4,3,0] nonane-8-yl)-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid.
Formula of the present invention (I) compound also comprises their pharmacy acceptable salts and hydrate.
The present invention also provides the preparation method of formula (I) compound and pharmacy acceptable salt and hydrate.
The present invention also provides and comprises (I) compound and pharmacy acceptable salt and hydrate thereof the antibacterial combination as active ingredient.
Formula of the present invention (I) compound can form pharmaceutically acceptable non-toxic salt.These salt comprise the salt with mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc., salt with organic carboxyl acid such as acetate, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid, or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc., and with common known and conventional other sour salt that is applied in the quinolone compounds technical field.These acid salt of conversion processes routinely.
The invention still further relates to the preparation method of formula (I) compound.
According to the present invention, shown in following reaction scheme 1, formula (I) but compound through type (II) compound and formula (III) compound or its salt react and prepare.
Reaction scheme 1
In above route, R
1, R
2Definition as previously mentioned; X represents halogen atom, is preferably chlorine, bromine or fluorine; Y represents alkyl or (replacement) benzyl of H, a 1-6 carbon atom.
According to reaction scheme 1, can be by in the presence of solvent and add suitable alkali, room temperature to 200 ℃ temperature understirring type (II) compound and formula (III) compound 1-20 hour, come preparation formula (I) compound.In this reaction, can use formula (III) compound of free cpds form, or its salt that is become with example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred pyridine, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, the hexamethylphosphoramide of using.
This reaction is generally carried out in the presence of acid acceptor.In this case, in order to improve the reaction efficiency of expensive initiator (II), use excessive reactant (III), for example initiator (II) is equimolar amount to 10 a times molar weight relatively, preferred equimolar amount to 5 times molar weight.When using excess reactant (III), unreacted formula (III) compound that stays after the reaction is recyclable and be reused for another reaction.The acid acceptor that is preferred for this reaction comprises mineral alkali such as sodium bicarbonate and salt of wormwood etc., with following organic bases: pyridine, triethylamine, diisopropylethylamine, N, accelerine, N, N-dimethyl aminopyridine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene and 1,4-diazabicyclo [2.2.2] octane.
Formula of the present invention (I) compound also can by with reaction scheme 1 in identical condition following formula (II) compound and amino formula (III) compound reaction with amino protecting group P protection, remove amino protecting group P then and form target formula (I) compound.Can get target formula (I) compound through hydrolysis or hydrogenolysis more in case of necessity.
That routine is used for organic chemistry filed and after reaction, be easy to remove and do not decompose any protecting group of the structure of target compound, all can be used to formula (III) compound is carried out amido protecting, form formula (III) compound with amino protecting group P.The specific examples that can be used for the protecting group of this purpose comprises formyl radical, ethanoyl, trifluoroacetyl group; benzoyl, right-nitro benzoyl, ptoluene-sulfonyl; methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl; carbobenzoxy-(Cbz); right-methoxyl group benzyloxy carbonyl, trichloro-ethoxycarbonyl, benzyl; right-methoxy-benzyl, trityl or tetrahydrofuran base etc.
After reaction was finished, the amino protecting group P that exists in the compound of formation can be according to the relevant nature of protecting group, and by hydrolysis, solvolysis or hydrogenolysis reducing are removed.For example, can be in solvent have or anacidity or alkali in the presence of under 0-130 ℃ of temperature, handle, slough protecting group.The acid that can be used for this purpose comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc., organic acid such as acetate, trifluoroacetic acid, formic acid, toluenesulphonic acids etc., or Lewis acid is as boron tribromide, aluminum chloride etc.The alkali that is used for this purpose can use the oxyhydroxide of basic metal or alkaline-earth metal, as sodium hydroxide, hydrated barta etc., alkaline carbonate such as yellow soda ash, lime carbonate etc.Alkali metal alcoholates such as sodium methylate, sodium ethylate etc., or sodium acetate etc.Reaction can be carried out in the presence of solvent.For example, water or organic
Solvent such as ethanol, tetrahydrofuran (THF), dioxan, ethylene glycol, acetate etc., or the mixture of this organic solvent and water.As needs, this reaction also can be carried out in the presence of no any solvent.
In addition, when protecting group is a ptoluene-sulfonyl, carbobenzoxy-(Cbz), right-methoxyl group benzyloxy carbonyl, trichloro-ethoxycarbonyl, benzyl, right-methoxy-benzyl, during trityl etc., these groups can be removed effectively by reduction.Though removing the reduction reaction conditions of protecting group changes along with the character of relevant protecting group; but hydrogen stream is generally used in this reduction; in inert solvent, in the presence of catalyzer such as platinum, palladium, Raney nickel etc., under 10-100 ℃ of temperature, carry out, or in ammoniacal liquor, react under in-50 to-10 ℃ of temperature with sodium Metal 99.5 or metallic lithium.
Formula (II) compound as initiator is a known compound in the present invention, and can easily make (seeing Sanchez J.P. etc., J.Med.Chem.38,4478-4487 (1995)) by known method in the existing publication.
Formula (III) compound as initiator is a known compound in the present invention, and the example can comprise following patent publication: CN 87100580, EP-A-523512, EP-A-230 295, EP-A-357 047, CN1400209, CN 1114959, CN 1074218 and EP-A-241.
In known amine groups,
Preferred expression:
Or
Particularly preferred
Expression:
The present invention also provides and contains formula (I) compound or its pharmacy acceptable salt and the hydrate antibacterial combination as activeconstituents, when this antimicrobial compound is used for clinical purpose, but through type (I) compound combines with the inert support of pharmaceutically accepting and it is mixed with oral, non-stomach and intestine are used or solid, semisolid or the liquid pharmaceutical formulation of topical application.The pharmaceutically acceptable inert support that can be used for this purpose can be divided into solid-state or liquid.
Pharmaceutical composition of the present invention, the The compounds of this invention and/or the medicine acceptable carrier that contain the physiology significant quantity, when adding the medicine acceptable carrier, the weight ratio of compound of the present invention in composition that pharmaceutical composition of the present invention contains is 0.1-99.9%, and the weight ratio of medicine acceptable carrier in composition is 0.1-99.9%.
Pharmaceutical composition of the present invention exists to be fit to medicinal dosage form, and these dosage forms are: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, suppository, ointment, plaster, creme, sprays, aerosol, drops, patch.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the The compounds of this invention that contains in every dose is 0.1mg-1000mg, described every dose refers to, and each preparation unit is as every of tablet, capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when solid that is prepared into pulvis, tablet dispersion powder, capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation.Spendable solid-state carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5% or 10% to 70% micronize activeconstituents.The specific examples of suitable solid-state carrier comprises that magnesiumcarbonate, Magnesium Stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, Huang have a liking for glue, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet and capsule are represented best oral solid formulation.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injectable formulation of parenteral administration can be water or water-propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. make the physiological condition that is suitable for live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can add appropriate colouring agent, seasonings, stablizer and thickening material again by activeconstituents is dissolved in the water, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to prepare in viscous substance such as natural or synthetical glue, methylcellulose gum, Xylo-Mucine and other the known suspension agent and be suitable for oral aqueous suspensions.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in the 1-500mg scope according to the effectiveness of selected activeconstituents.
When formula of the present invention (I) active compound during as the medicine of treatment infectation of bacteria, the preferred amount of the 6-14mg/kg body weight of giving in the fs.But dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can determine to be suitable for the preferred dose of certain situation according to a conventional method.Generally, the amount of begin treatment is lower than the optimal dose of activeconstituents, increases dosage then gradually, up to reaching optimum therapeuticing effect.For simplicity, total per daily dose can be divided into several parts, divides administration for several times.
As mentioned above, The compounds of this invention has stronger anti-microbial activity and wide antimicrobial spectrum to the various pathogenic organisms that comprise Gram-negative bacteria and gram positive bacterial strain.The compounds of this invention is higher to the activity of the anti-microbial activity of gram negative strain and known antimicrobial agents such as Gatifloxacin, and particularly, The compounds of this invention is to the anti-microbial activity of the gram positive bacterial strain activity far above known antimicrobial agents.
For example with the compound (it is the representative of substituted piperazinyl type compound embodiment 1,2,3 compounds as the 7-position) of embodiment 2 methods preparations to the antibacterial activity in vitro of various bacteriums with the structurally similar compounds Gatifloxacin that has gone on the market of explaining among mouse peritoneal pneumonia infection suis and enterococcal endogenous protective curative effect and the CN 87100580 listed in table 1 and table 2 more respectively.
The vitro antibacterial activity of table 1. embodiment 2 compounds and Gatifloxacin
MIC(g/mL)
Experimental bacteria embodiment 2 compound Gatifloxacins
Form staph 26,069 0.01 0.06
Micrococcus scarlatinae A12 0.06 0.25
Streptococcus pneumoniae 70 0.06 0.06
Faecalis 27 0.12 0.12
Colon bacillus ATTC 25 922 0.005 0.01
Shigella flexneri 958 0.12 0.5
Table 2 embodiment 2 compounds and Gatifloxacin activity in vivo
ED50
Bacterial infection drug administration approach
(mg/Kg)
Streptococcus pneumoniae embodiment 2 compound p.o 4.31
03-18-3 i.v 2.82
Gatifloxacin p.o 7.44
i.v 4.49
Faecalis embodiment 2 compound p.o 7.35
0217-7 i.v 3.57
Gatifloxacin p.o 8.60
i.v 7.58
By table 1,2 as seen, embodiment 2 compounds are 2～6 times of Gatifloxacin to the external activity of form staph, micrococcus scarlatinae, colon bacillus, shigella flexneri.Though suitable with the two external activity of faecalis to streptococcus pneumoniae, activity in vivo, embodiment 2 compounds but are 2 times of Gatifloxacin, this shows that absorption is better in the former body.
With the compound (it is the representative of substituted-amino volution pyrrolidyl type compound embodiment 4,5,6 compounds as the 7-position) of embodiment 6 methods preparations to the antibacterial activity in vitro of various bacteriums with the structurally similar compounds A that explained among mouse peritoneal pneumonia infection suis and enterococcal endogenous protective curative effect and the CN 1400209 listed in table 3 and table 4 more respectively.
The vitro antibacterial activity of table 3. embodiment 6 compounds and compd A
MIC(g/mL)
Experimental bacteria embodiment 6 compound compd As
*
Form staph 26,069 0.002 0.005
Micrococcus scarlatinae A12 0.001 0.005
Streptococcus pneumoniae 70 0.002 0.005
Faecalis 27 0.001 0.03
Colon bacillus ATTC 25 922 0.005 0.01
Shigella flexneri 958 0.03 0.25
*Compd A is compound 7-(aminomethyl-5-azaspiro [2.4] heptane-5-yl)-1-cyclopropyl-6-fluoro-8-methoxyl group-1 that CN 1400209 describes, 4-dihydro-4-oxo-quinoline-3-carboxylic acid
The activity in vivo of table 4 embodiment 6 compounds and compd A
ED50
Bacterial infection drug administration approach
(mg/Kg)
Streptococcus pneumoniae embodiment 6 compound p.o 1.29
03-18-3 i.v 0.81
Compd A p.o 3.52
i.v 2.34
Faecalis embodiment 6 compound p.o 2.51
0217-7 i.v 1.98
Compd A p.o 5.64
i.v 4.04
By table 3,4 as seen, embodiment 6 compounds are 2～30 times of compd A to the 4 strain gram-positive microorganisms of test and the external activity of 2 strain Gram-negative bacterias, to mouse peritoneal pneumonia infection suis and faecalis, the activity in vivo of embodiment 6 compounds is 2～3 times of contrast drug compound A.
With the compound of embodiment 7,9 methods preparations to the external activities of various bacteriums respectively with CN 1114959 and CN 1074218 in the structurally similar compounds gemifloxacin described and Moxifloxacin relatively list in table 5.
Table 5. embodiment 7,9 compounds and the vitro antibacterial activity that contrasts medicine
MIC(g/mL)
Experimental bacteria embodiment 7 embodiment 9
The gemifloxacin Moxifloxacin
The compound compound
Form staph 26,069 0.005 0.03 0.002 0.01
Micrococcus scarlatinae A12 0.002 0.03 0.005 0.01
Streptococcus pneumoniae 70 0.005 0.01 0.002 0.005
Faecalis 27 0.01 0.01 0.03 0.12
Colon bacillus ATTC 25 922 0.03 0.03 0.005 0.005
Shigella flexneri 958 0.01 0.005 0.002 0.002
By table 5 as seen, embodiment 7 compounds are 2～16 times of gemifloxacin to the external activity of form staph, micrococcus scarlatinae, streptococcus pneumoniae, and to faecalis, colon bacillus, shigella flexneri, embodiment 7 compounds and gemifloxacin are quite or slightly.Embodiment 9 compounds are 2～4 times of Moxifloxacin to form staph, micrococcus scarlatinae, streptococcus pneumoniae, enterococcal activity, and the two is suitable to colon bacillus, shigella flexneri.
The pharmacokinetics aspect of performance is compared with known quinolone compounds, and The compounds of this invention has suitable water-soluble, therefore can be absorbed well in vivo, show very high bioavailability, the suitable antiseptic-germicide that is used as.
In addition, because the toxicity of The compounds of this invention is low, it can be used for prevention effectively and the treatment warm blooded animal comprises that the mankind are by the caused disease of infectation of bacteria.
Oral acute toxicity test
For measuring the oral acute toxicity of The compounds of this invention, compound with embodiment 2,5 and the preparation of 6 methods has been carried out toxicity test, the oral male mice that awards of solution that will contain these three compounds of different concns, dosage is the 0.1ml/10g body weight, the dead mouse that counts respectively after 7 days is measured, and calculates the medium lethal dose (LD50) of each compound with the Bliss program.The results are shown in Table 3.
The oral acute toxicity of the mouse of table 3 test compound
Test compound LDS0 (mg/Kg)
Embodiment 2＞4000
Embodiment 5＞4000
Embodiment 6＞4000
Experimental result shows that these toxicity of compound are low, is fit to very much medicinal.
Embodiment:
In the following example, will more specifically explain the present invention.But should be understood that following preparation example and embodiment to be intended to the present invention is described and scope of the present invention is not constituted any restriction.
Preparation example 1
1-cyclopropyl-6,7-two fluoro-8-methoxyl group-5-nitros-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
Under the ice bath, 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1, (10.0g 30.9mmol) is dissolved in dense H to 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
2SO
4(85.0mL), add KNO in batches
3(4.7g 46.4mmol) and under equality of temperature reacts 3h.After reaction finishes, in the frozen water (500mL) that the reaction solution impouring is stirred fast, continue to stir 0.5h, filter, get VII-1 (9.5g, 83.3%) with recrystallizing methanol behind the filtration cakes torrefaction, be white solid, mp＞270 ℃.
1H?NMR(CDCl
3)δ，ppm：1.07-1.24(4H，m)，1.36(3H，t，J＝7.8Hz)，4.02-4.04(1H，m)，4.17(3H，s)，4.35(2H，q，J＝7.8Hz)，8.60(1H，s)
Preparation example 2
5-amino-1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
Reduced iron powder (2.4g, 42.8mmol), H
2The mixture of O (4.5mL) and Glacial acetic acid (0.3mL) refluxes and reacts 15min down, drip compound (4.0g, chloroform 10.8mmol) (100mL) solution, the continuation back flow reaction 6h of preparation in the preparation example 1, filtered while hot then, filtrate are put cold back and are washed 2 times with 6M HCl.Drying is filtered, and filtrate gets crude product after dividing exactly solvent, to get yellow solid (3.2g, 87.2%), mp 209-210 ℃ behind the mixed solvent recrystallization of ethanol and chloroform.
Preparation example 3
5-amino-1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
The compound of preparation in the preparation example 2 (3.2g 9.5mmol) is dissolved among dense HCl (4.0mL) and the HOAc (16.0mL), in 100 ℃ of following reaction 1h, concentration of reaction solution to the 5.0mL, in raffinate impouring 100mL frozen water, stirring 0.5h after-filtration, filter cake H
2O washes after drying and gets yellow solid (2.8g, 93.1%), mp＞270 ℃
Embodiment 1
5-amino-1-cyclopropyl-6,7-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
The compound of preparation in the preparation example 3 (0.50g, 1.6mmol) and the 2-methylpiperazine (0.30g 3.2mmol) is dissolved in the pyridine (10.00mL), in 100 ℃ of following reaction 6h.Reaction finishes, and steaming desolventizes, resistates after with ethyl alcohol recrystallization yellow solid product (0.35g, 55.6%).
1H?NMR(CF
3COOD)δ，ppm：1.00-1.46(7H，m)，3.80-3.97(10H，m)，4.26(1H，m)，9.12(1H，s)。EI(M/Z)：390(M
+)。
Embodiment 2
5-amino-1-cyclopropyl-6,7-two fluoro-7-(4-methyl isophthalic acid-piperazinyl)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, react and get by compound and the 1-methylpiperazine of preparation in the preparation example 3, product is a yellow solid, yield is 51.1%.
1H?NMR(CF
3COOD)δ，ppm：1.00-1.31(4H，m)，3.09(3H，s)，3.33-3.97(11H，m)，4.24(1H，m)，9.11(1H，s)。EI(M/Z)：390(M
+)。
Embodiment 3
5-amino-1-cyclopropyl-6,7-two fluoro-7-(5-methyl-2,5-diazabicyclo [2,2,1] heptane-2-yl)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, by the compound and the 5-methyl-2 of preparation in the preparation example 3,5-diazabicyclo [2,2,1] heptane reacts and gets, and product is a yellow solid, and yield is 23.3%.
1H?NMR(CF
3COOD)δ，ppm：0.93-1.42(4H，m)，2.43-2.57(2H，s)，3.08(3H，s)，3.64(3H，s)，3.26-5.04(7H，m)，9.10(1H，s，C2-H)。EI(M/Z)：402(M
+)。
Embodiment 4
5-amino-1-cyclopropyl-6-fluoro-7-(7-amino-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, react and get by compound and 7-amino-5-azaspiro [2, the 4] heptane of preparation in the preparation example 3, yield is 30.7%.
1H?NMR(CF
3COOD)δ，ppm：0.76-1.49(8H，m)，3.64(3H，s)，3.06-4.31(6H，m)，8.95(1H，s)。EI(M/Z)：402(M
+)。
Embodiment 5
5-amino-1-cyclopropyl-6-fluoro-7-(7-aminomethyl-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
Method one: with embodiment 1 method, carrying out condensation reaction products by the compound for preparing in the preparation example 3 and 7-aminomethyl-5-azaspiro [2,4] heptane is yellow solid, yield 23.6%.
1H?NMR(CF
3COOD)δ，ppm：0.78-1.39(8H，m)，2.38(1H，m)，3.63(3H，s)，3.17-4.37(7H，m)，8.78(1H，s)。EI(M/Z)：416(M
+)。
Method two: with embodiment 1 method, compound and 7-acetyl aminomethyl-5-azaspiro [2 by preparation in the preparation example 3,4] heptane carries out condensation reaction and gets 5-amino-1-cyclopropyl-6-fluoro-7-(7-acetyl aminomethyl-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (
1H NMR (CF
3COOD) δ, ppm:0.71-1.65 (8H, m), 2.44 (1H, m), 2.48 (3H, s), 3.53 (3H, s), 3.17-4.37 (7H, m), 8.85 (1H, s); EI (M/Z): 458 (M
+).), obtaining title embodiment product with the 14%NaOH aqueous hydrolysis then, product is a yellow solid, yield 21.7%.
Embodiment 6
5-amino-1-cyclopropyl-6-fluoro-7-(7-methyl aminomethyl-5-azaspiro [2,4] heptane-5-yl)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
Method one: with embodiment 1 method, carry out condensation reaction by the compound and 7-methyl aminomethyl-5-azaspiro [2, the 4] heptane that prepare in the preparation example 3, product is a yellow solid, two step yields 24.8%.
1H?NMR(CF
3COOD)δ，ppm：0.75-1.44(8H，m)，2.40(1H，m)，2.96(3H，s)，3.62(3H，s)，3.22-4.42(7H，m)，8.89(1H，s)。EI(M/Z)：430(M
+)。
Method two: with embodiment 1 method, compound and 7-(N-methyl-N-tertbutyloxycarbonyl) aminomethyl-5-azaspiro [2 by preparation in the preparation example 3,4] heptane carries out condensation reaction and gets 5-amino-1-cyclopropyl-6-fluoro-7-[7-(N-methyl-N-tertbutyloxycarbonyl) aminomethyl-5-azaspiro [2,4] heptane-5-yl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (
1H NMR (DMSO) δ, ppm:0.78-1.45 (17H, m), 2.44 (1H, m), 2.92 (3H, s), 3.68 (3H, s), 3.24-4.46 (7H, m), 6.36 (2H, br), 8.85 (1H, s).EI(M/Z)：530(M
+)。), then with CF
3COOH removes the tertbutyloxycarbonyl protection and obtains title embodiment product, and product is a yellow solid, two step yields 25.5%.
Embodiment 7
5-amino-7-(3-aminomethyl-4-methoxy imino-1-pyrrolidyl)-1-cyclopropyl-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, by the compound of preparation in the preparation example 3 and two CF of 3-aminomethyl-4-methoxy imino tetramethyleneimine
3COOH reactant salt and getting, yield is 28.5%.
1H?NMR(CF
3COOD)δ，ppm：0.85-1.18(4H，m)，2.72-3.12(3H，m)，3.23(3H，s)，3.96(3H，s)，3.35-4.17(5H，m)，8.82(1H，s)。EI(M/Z)：433(M
+)。
Embodiment 8
5-amino-1-cyclopropyl-7-[(R, R)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, by the compound and [R, the R]-2 of preparation in the preparation example 3,8-diazabicyclo [4,3,0] nonane reacts and gets, and product is a yellow solid, and yield is 52.6%.
1HNMR(CDCl
3)，δ，ppm：0.72-1.00(4H，m)，1.65-1.80(4H，m)，2.31(1H，br)，2.44-3.20(2H，m)，3.21(3H，s)，3.46-4.02(6H，m)，6.34(2H，br)，8.62(1H，s)。EI(M/Z)：416(M
+)。
Embodiment 9
5-amino-1-cyclopropyl-7-[(S, S)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, by the compound and [S, the S]-2 of preparation in the preparation example 3,8-diazabicyclo [4,3,0] nonane reacts and gets, and product is a yellow solid, and yield is 55.6%.
1HNMR(CDCl
3)，δ，ppm：0.72-1.02(4H，m)，1.55-1.81(4H，m)，2.34(1H，br)，2.69-3.10(2H，m)，3.44(3H，s)，3.46-4.05(6H，m)，6.34(2H，br)，8.62(1H，s)。EI(M/7)：416(M
+)。
Embodiment 10
5-amino-1-cyclopropyl-7-(2,8-diazabicyclo [4,3,0] nonane-8-yl)-6-fluoro-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid
With embodiment 1 method, by the compound and 2 of preparation in the preparation example 3,8-diazabicyclo [4,3,0] nonane reacts and gets, and product is a yellow solid, and yield is 50.2%.
1HNMR(CDCl
3)，δ，ppm：0.72-1.24(4H，m)，1.63-1.82(4H，m)，2.42(1H，br)，2.76-3.19(2H，m)，3.46(3H，s)，3.57-4.04(6H，m)，6.34(2H，br)，8.61(1H，s)。EI(M/Z)：416(M
+)。
Embodiment 11
The preparation of coating tablet:
The label prescription:
Embodiment 2 compound 10.0g
Lactose 50.0g
Starch 40.0g
Hydroxypropylcellulose 4.0g
10% pregnant dimension ketone is an amount of
Magnesium Stearate 0.5g
Get mentioned component and mix, the whole grain that sieves after the granulation, drying, compressing tablet is made 100 labels.
Coating fluid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
Embodiment 12
The preparation of capsule:
Prescription:
Embodiment 5 compound 100g
Starch 10g
Sodium starch glycolate 20g
Low-substituted hydroxypropyl cellulose 10g
Tween 80 is an amount of
Polyvinylpyrrolidone 5% ethanol liquid is an amount of
Sodium lauryl sulphate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules
The preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and tween 80 system softwood, get the granulation of 20 mesh sieves, under 15 ℃ of room temperatures, dry, add sodium lauryl sulphate, mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
Embodiment 13
The preparation of injection:
Get 1 gram embodiment, 6 compounds, add an amount of water for injection and make dissolving, add poloxamer 10 grams, add sodium-chlor 4 grams, dextran 10 grams add glucose 4 grams, N.F,USP MANNITOL 5 grams, mix, add water for injection to 1000 milliliter, make 10 bottles of intravenous injections.
Claims (9)
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| CN1861599A (en) * | 2005-05-11 | 2006-11-15 | 孙飘扬 | Quinone carboxylic acid kind derivant, it preparation process and medicine application |
| MX2008011633A (en) * | 2006-03-13 | 2008-12-16 | Activx Biosciences Inc | Aminoquinolones as gsk-3 inhibitors. |
| CN100441580C (en) * | 2006-07-14 | 2008-12-10 | 中山大学 | Quinolinedione derivatives and their application in the preparation of antibacterial drugs |
| JP5373799B2 (en) | 2007-09-12 | 2013-12-18 | 杏林製薬株式会社 | Spirocyclic aminoquinolones as GSK-3 inhibitors |
| US8071591B2 (en) | 2009-03-11 | 2011-12-06 | Kyorin Pharmaceutical Co., Ltd. | 7-cycloalkylaminoquinolones as GSK-3 inhibitors |
| CN102675306A (en) * | 2011-03-17 | 2012-09-19 | 苏州中科天马肽工程中心有限公司 | Preparing method of moxifloxacin or slat thereof |
| CN109096276B (en) * | 2018-08-01 | 2021-05-28 | 上海博志研新药物技术有限公司 | Preparation method of moxifloxacin hydrochloride and intermediate thereof |
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