CN103497186A - Alcoxyimino-contained substituted naphthyridine-carboxylic acid derivatives and preparation method thereof - Google Patents
Alcoxyimino-contained substituted naphthyridine-carboxylic acid derivatives and preparation method thereof Download PDFInfo
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Abstract
The invention relates to naphthyridine-carboxylic acid compounds as shown in the formula (I), a preparation method and medical application of the compounds and an antitumor drug composition with the compounds as effective components and particularly relates to naphthyridine-carboxylic acid derivatives, wherein the substituent group on the 1-position of a nalidixic core is 2-thiazolyl, the substituent group on the 7-position is alcoxyimino-contained pyrrolidyl, and in the formula (I), R1 is hydrogen or methyl, R2 is methyl, ethyl or benzyl, and n is 0 or 1.
Description
Technical field
The invention belongs to the medical chemistry field, relate to naphthyridon carboxylic acid derivative with anti-tumor activity and preparation method thereof, and the antineoplastic pharmaceutical compositions that contains them.Specifically, relate to the 1-(thiazol-2-yl)-7-[3-amino/aminomethyl-(3-methyl)-4-alcoxyl imido grpup pyrrolidin-1-yl)] Naphthyridinone carboxylic acid compound and preparation method thereof.
Background technology
From Nalidixic Acid (J Med Chem in 1962,1962,5:1063) since coming out, quinolone (comprising naphthyridones) class medicine has developed into a class wide spectrum that is only second at present cynnematin, efficient, hypotoxic anti-infective chemotherapeutics (Chinese Journal of Pharmaceuticals, 2011,42:840).In recent years, scientist is by the structure of modification to quinolone, successfully by it, classical anti-microbial effect is converted into mammiferous cytotoxicity, and filter out some compounds with clear and definite anti-tumor activity, wherein some candidate compound is at present in clinical study or clinical front evaluation phase (Chinese Journal of Pharmaceuticals, 2010,41:456).
Surely belong to the thiazol-2-yl to 1-(at the antitumor research field of the quinolone the maximum that makes one's way in life) structure of modification of naphthyridon carboxylic acid.Japanese scholars Tomita in 2002 etc. disclose the fluoro-1-(thiazol-2-yl of 6-that the 7-position has different azepine cyclammonium fragments) the synthetic and anti-tumor activity (J.Med.Chem.2002 of Naphthyridinone carboxylic acid compound, 45,5564), outstanding representative AT-3639(compd A wherein) mouse P388 leukemia cell is demonstrated to good inside and outside anti-tumor activity.
The further research discovery such as Japanese scholars Tsuzuki, it is AT-3639 2 times (J.Med.Chem.2004,47,2097) to mouse P388 leukemia cell's anti tumor activity in vitro that the 6-of AT-3639 removes fluorine analogue (compd B).Regrettably, water-soluble (0.0069mg/mL) of compd B is poor, causes its anti-tumor in vivo activity undesirable.
Nineteen ninety-five Japanese scholars Tomita etc. discloses the 1-(thiazol-2-yl that contains chiral carbon atom in the azepine cyclammonium substituting group of 7-position) the synthetic and inside and outside anti-tumor activity (CN:1158614A/1995) of Naphthyridinone carboxylic acid compound, outstanding representative wherein is at present in the voreloxin of III clinical trial phase (SNS-595, CN:103083316A/2005).Voreloxin on the basis that keeps the compd B anti tumor activity in vitro, its water-soluble significantly improving.Except thering is broad-spectrum anti-tumor activity, the outstanding advantages of this product be and other antitumor drugs between there is no cross resistance, its shortcoming is to have two chiral carbon atoms in its 7-position tetramethyleneimine substituent structure, to cause its production cost greatly to improve, thereby limit its range of application clinically.
In order to overcome the existing defect of above-mentioned prior art, the inventor conducts extensive research, the 1-(thiazol-2-yl that the 7-position has the tetramethyleneimine structure fragment that various alcoxyl imido grpups replace has been synthesized in design) Naphthyridinone carboxylic acid compound, and measured their anti-tumor activity.The final discovery, the 1-(thiazol-2-yl of bibliographical information different from the past)-7-[(3-aminomethyl/amino-(3-methyl)-4-alcoxyl imido grpup-1-pyrrolidyl] Naphthyridinone carboxylic acid compound has beyond thought powerful antitumor activity, compare with the antitumor candidate compound B of similar quinolone and listing antitumor drug Etoposide with same function target spot (Mammals topoisomerase II), there is more superior anti-tumor activity.
Summary of the invention
The purpose of this invention is to provide Naphthyridinone carboxylic acid compound and pharmaceutical salts thereof that a class is meaned by general formula (I),
Wherein:
R
1represent hydrogen, methyl;
R
2represent methylidene, ethyl, benzyl;
N represents 0,1.
In the pyrrolidyl part of general formula of the present invention (I) compound, the carbon atom be connected with methyl with aminomethyl (or amino) is unsymmetrical carbon, therefore can R or S or R and the S form of mixing exist, the present invention includes all these isomer and mixture.
In the pyrrolidyl part of general formula of the present invention (I) compound, owing to containing oximido, therefore general formula (I) compound can the E type or the form of Z-type or E type and Z-type mixture exist, general formula of the present invention (I) compound comprises all these isomer and mixture.
The pharmaceutically acceptable atoxic pharmaceutical salts of formula of the present invention (I) compound, comprise and mineral acid, the salt that example hydrochloric acid, sulfuric acid form, with organic acid, salt as acetic acid, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid formation, and amino acid, the salt formed as L-Ala, aspartic acid, Methionin or and sulfonic acid, the salt formed as methylsulfonic acid, tosic acid.
Formula of the present invention (I) compound also can solvate (as hydrate) form exist, therefore, within these solvates (as hydrate) are also included within compound of the present invention.
The present invention specifically comprises following compound, and their pharmaceutical salts:
7-[3-aminomethyl-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
The invention still further relates to the preparation method of formula (I) compound, as shown in reaction scheme 1.
Reaction scheme 1:
In reaction scheme 1, R, n
1and n
2definition as the aforementioned.
Can prepare like this by formula (IV) compound: add acid binding agent in protonic solvent, make formula (II) compound and formula (III) compound carry out preparation formula (IV) compound by condensation reaction.
In order to improve the reaction efficiency of more expensive initiator formula (II) compound, use excessive reactant formula (III) compound, such as to relative initiator for waiting mole to 10 times of molar weights, preferred equimolar amount to 3 times molar weight.In room temperature to 80 ℃, have or, without stirring reaction formula (II) compound under the pressure condition and formula (III) compound 3.5～30 hours, carry out preparation formula (IV) compound.Protonic solvent for this reaction is selected from water, alcohol or alcohol-water mixed solvent; Acid binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, salt of wormwood.
Then formula (IV) compound is placed in to protonic solvent and adds alkali, wherein, alkali relative type motor (IV) compound is for waiting mole to 15 times of molar weights, preferably equimolar amount to 5 times molar weight.Under 0 ℃～80 ℃, stir 2～20 hours, the reaction that is hydrolyzed, obtain formula (I) compound.Protonic solvent for this reaction is selected from water, alcohol or alcohol-water mixed solvent; Described alkali is selected from sodium hydroxide or potassium hydroxide.
Be known compound as formula (II) compound of initiator in the present invention, and can easily make by known method in existing publication, J.Med.Chem.2004 for example, 47,2097.The formula of another initiator (III) compound is also known compound, and can easily make by known method in existing publication, for example, and Chinese pharmaceutical chemistry magazine, 2009,19:109; Asian J Chem.2013,25:327; Chem.Res.Chin.Univ., 2011,27 (6): 981; J Med Chem, 1997,40:3584; Bioorg Med Chem Lett, 1998,8:221.
The present invention also provides and contains formula (I) compound as defined above and pharmaceutical salts thereof the antineoplastic pharmaceutical compositions as activeconstituents.
The weight ratio of the Naphthyridinone carboxylic acid compound that pharmaceutical composition contains in composition is 0.1～99.9%, and the weight ratio of medicine acceptable carrier in composition is 0.1～99.9%.Pharmaceutical composition exists to be applicable to medicinal dosage form.Medicinal preparation is tablet, capsule, granule, syrup, powder injection, injection.Wherein, described tablet is sugar coated tablet, film coated tablet, enteric coated tablet or slow releasing tablet; Described capsule is hard capsule, soft capsule, slow releasing capsule; Described powder injection is lyophilized injectable powder.
Above-mentioned preparation can be by conventional pharmaceutical methods preparation.The example of available medicinal adjuvant comprises vehicle, and (the carbohydrate derivative, as lactose, sucrose, glucose, seminose and Sorbitol Powder; Starch derivative, as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose, as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose and Xylo-Mucine; Gum arabic; Dextran; Silicate derivative, as Neusilin US2; Phosphate derivative, as calcium phosphate etc.), tackiness agent (gelatin, polyvinylpyrrolidone, polyoxyethylene glycol), disintegrating agent (derivatived cellulose is as Xylo-Mucine, polyvinylpyrrolidone), lubricant (talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben), correctives (sweeting agent commonly used, acidic flavoring agent, spices), thinner and solvent (distilled water, ethanol, glycerine) for injection liquid.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound contained in every dose is 0.1～1000mg, described every dose refers to, and each preparation unit, as every of tablet, every of capsule, also can refer to each taking dose, as each serving using 100mg.
For ease of administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with to dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, the activeconstituents that each unit contains the predetermined amount calculated that produces desired result for the treatment of.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis.
Although in dosage unit form, the amount of contained activeconstituents can change, generally, according to the effect of selected activeconstituents, be adjusted in 1～800mg scope.
The dosage of the formula in the present invention (I) compound or pharmaceutically acceptable salt thereof is with the difference of age of patient, sex, race, state of an illness etc. and difference.General adult's day dosage is approximately 50-1000mg, preferred 100-800mg, but single administration or minute administration for several times.
As mentioned above, the compounds of this invention has beyond thought powerful antitumor activity to leukemia and multiple solid tumor cell.Compare with the antitumor candidate compound B of similar quinolone and listing antitumor drug Etoposide with same function target spot, there is more superior anti-tumor activity, simpler preparation method, there is good water-soluble and stability simultaneously.
Embodiment
Following examples are used for the present invention is described, but are not used for limiting the scope of the invention.
Embodiment 1 7-[3-aminomethyl-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
The 1-(thiazol-2-yl)-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester (304mg, 0.6mmol), 3-aminomethyl-3-methyl-4-methoxy imino tetramethyleneimine dihydrochloride (345mg, 1mmol), the mixture of triethylamine (1.0mL, 7.5mmol) and dehydrated alcohol (15mL) is in 75 ℃ of stirring reaction 8h.Concentrating under reduced pressure, resistates is through silica gel chromatography column separating purification (eluent: V
methyl alcohol: V
methylene dichloride=1:30), obtain faint yellow solid product 325mg(yield 78%).
The mixture of above-mentioned solid (59mg, 0.13mmol), 1.0N sodium hydroxide solution (0.39mL, 0.39mmol) and dehydrated alcohol (5mL) reacts 10h in stirring at room.Adjust reaction solution pH7 with the 1N hydrochloric acid soln, fully stir 1h.Filter, filter cake is successively with distilled water, ethanol and isopropyl ether washing, and drying, use the DMF-ethyl alcohol recrystallization, obtains faint yellow solid 29mg(yield: 53%), and mp:286-288 ℃.
1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.76(s,1H),8.33(m,1H),7.85(m,2H),6.97(m,1H),4.51(m,2H),4.17(m,1H),3.88(s,3H),3.64(m,1H),2.72(d,J=29.7Hz,2H),1.26(s,3H).ESI-MS:m/z429.23(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
19H
21O
4N
6S(M+H)
+:429.13395;Found429.13251.
| C 19H 20N 6O 4S | C | H | N | S |
| Calculated value | 53.26 | 4.70 | 19.61 | 7.48 |
| Measured value | 53.29 | 4.69 | 19.59 | 7.50 |
Embodiment 2 7-[3-aminomethyls-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-aminomethyl-3-methyl-4-ethoxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 47%), mp:286-288 ℃.1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.77(s,1H),8.32(m,1H),7.85(m,2H),6.98(m,1H),4.54-4.45(m,2H),4.14(q,J=7.0Hz,3H),3.62(m,2H),2.74(m,2H),1.27(s,3H),1.24(t,J=7.0Hz,3H).ESI-MS:m/z443.23(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
20H
23O
4N
6S(M+H)
+:443.14960;Found443.14899.
Embodiment 3 7-[3-aminomethyls-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-aminomethyl-3-methyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 79%), mp:285-288 ℃.1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.62(s,1H),8.27(s,1H),7.76(s,2H),7.40-7.34(m,5H),6.82-6.77(m,1H),5.15(s,2H),4.48(s,2H),3.63(m,2H),2.74-2.61(m,2H),1.23(s,3H).ESI-MS:m/z505.27(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
25H
25O
4N
6S(M+H)
+:505.16525;Found505.16312.
Embodiment 4 7-[3-aminomethyls-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
Under return stirring, to the 6N hydrochloric acid that adds 1.5 times of molar weights in the dehydrated alcohol suspension liquid (15mL) of embodiment 3 compounds (506mg, 1mmol) (molten clear), reflux 0.5 hour, be down to room temperature, separates out solid.Filter, drying, obtain 7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-the 1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1, the yellow light solid of 8-naphthyridines-3-carboxylic acid hydrochloride 488mg(, yield: 90%).
| C 25H 24N 6O 4S.HCl | C | H | N | S | Cl |
| Calculated value | 55.50 | 4.66 | 15.53 | 5.93 | 6.55 |
| Measured value | 55.49 | 4.66 | 15.52 | 5.94 | 6.54 |
Also can prepare following salt similarly, for example:
7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid lactic acid salt;
7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate.
Embodiment 5 7-[3-aminomethyls-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid monohydrate
Embodiment 3 compounds (507mg, 1mmol) are dissolved in to 5% acetic acid (8mL), under stirring at room, with the 1N sodium hydroxide solution, adjust pH=7, place and separate out solid.Filter, drying, obtain 7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-the 1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid monohydrate 420mg(faint yellow solid, yield: 80%).
| C 25H 24N 6O 4S.H 2O | C | H | N | S |
| Calculated value | 57.46 | 5.01 | 16.08 | 6.14 |
| Measured value | 57.47 | 5.03 | 16.07 | 6.11 |
Embodiment 6 7-[3-aminomethyls-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-aminomethyl-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 77%).1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.21(s,1H),7.95(d,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H),6.80(m,1H),6.32(m,1H),4.68(m,1H),4.36(m,1H),3.95(s,3H),3.69(dd,J=12.3,8.8Hz,1H),3.64(dd,J=12.4,8.8Hz,1H),2.99–2.82(m,2H),2.79(dd,J=11.9,7.5Hz,1H).ESI-MS:m/z414.17(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
18H
18O
4N
6S(M+H)
+:414.17595;Found414.17573.
Embodiment 7 7-[3-aminomethyls-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-aminomethyl-4-ethoxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 78%), mp:275-278 ℃.1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.69(s,1H),8.23(m,1H),7.77(m,2H),7.01-6.90(m,1H),4.35(s,3H),4.17(dd,J=13.9,6.9Hz,2H),3.61(m,2H),3.17(m,2H),1.26(t,J=6.8Hz,3H).ESI-MS:m/z429.17(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
19H
21O
4N
6S(M+H)
+:429.13395;Found429.13205.
Embodiment 8 7-[3-aminomethyls-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-aminomethyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 70%), mp: > 300 ℃.1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.72(s,1H),8.35(m,1H),7.83(m,2H),7.41-7.35(m,5H),6.96(m,1H),5.16(s,2H),4.49(m,2H),4.11(m,2H),3.22–3.08(m,2H),2.81(m,1H).ESI-MS:m/z491.10(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
24H
23O
4N
6S(M+H)
+:491.14960;Found491.14841.
Embodiment 9 7-[3-amino-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-3-methyl-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 55%), mp:182-184 ℃.
1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.74(s,1H),8.29-8.31(d,J=9.2Hz1H),7.84(m,2H),6.99-6.97(d,J=8.8Hz1H),4.49-4.45(m,2H),3.91(s,3H),4.04-3.84(m,2H),1.48(s,3H).ESI-MS:m/z415.56(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
18H
19O
4N
6S(M+H)
+:415.11830;Found415.11700.
Embodiment 10 7-[3-amino-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-3-methyl-4-ethoxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 41%), mp:255-258 ℃.
1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.79(s,1H),8.36(s,1H),7.87(m,2H),7.03(s,1H),4.49(m,2H),4.16(m,2H),4.05–3.62(m,2H),1.46(s,3H),1.27(m,3H).ESI-MS:m/z429.20(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
19H
21O
4N
6S(M+H)
+:429.13395;Found429.13332.
Embodiment 11 7-[3-amino-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-3-methyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 65%), mp:175-177 ℃.1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.67(s,1H),8.24(s,1H),7.78(s,2H),7.42(m,5H),6.89(m,1H),5.16(s,2H),4.48(m,2H),3.77(m,2H),1.41(s,3H).ESI-MS:m/z491.17(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
24H
23O
4N
6S(M+H)
+:491.14960;Found491.14758.
Embodiment 12 7-[3-amino-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 45%).1H?NMR(400MHz,DMSO-d
6)δ（ppm）δ9.58(s,1H),8.23(d,J=7.8Hz,1H),7.67(d,J=7.8Hz,1H),6.93(m,1H),4.51(m,1H),4.17(d,J=12.3Hz,1H),3.88–3.72(m,2H),3.62(dd,J=12.5,3.3Hz,1H),3.55(s,3H),2.69(dd,J=12.5,3.3Hz,1H).ESI-MS:m/z400.47(M+H)
+.HRMS-ESI:m/z?Calcd.for?C
17H
16O
4N
6S(M+H)
+:400.48360;Found400.48758.
Embodiment 13 7-[3-amino-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-4-ethoxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 53%).1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.47(s,1H),8.22(m,1H),7.75(m,2H),6.98(m,1H),4.58-4.49(m,2H),4.24(q,J=7.0Hz,3H),3.72(m,2H),2.70(m,2H),1.24(t,J=7.0Hz,3H).MS-ESI(m/z):414.42。HRMS-ESI:m/z?Calcd.for?C
18H
18O
4N
6S(M+H)
+:414.45365;Found414.45758.
Embodiment 14 7-[3-amino-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 1 compound, the 1-(thiazol-2-yl)-the chloro-Isosorbide-5-Nitrae-dihydro of 7--4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester elder generation and 3-amino-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtain faint yellow solid (yield: 72%).1H?NMR(400MHz,DMSO-d
6)δ（ppm）9.42(s,1H),8.37(s,1H),7.79(s,2H),7.38-7.27(m,5H),6.92-6.87(m,1H),5.05(s,2H),4.38(s,2H),3.65(m,2H),2.75-2.68(m,2H).MS-ESI(m/z):(M+H)
+476.52。HRMS-ESI:m/z?Calcd.for?C
23H
20O
4N
6S(M+H)
+:476.49325;Found476.49259.
Embodiment 15
Coating tablet
Core formulation:
Get mentioned component and mix, the whole grain that sieves after granulation, dry, compressing tablet is made 100 labels.
Coating fluid prescription:
Opadry (Opadry) 5g, 80% appropriate amount of ethanol dressing.
Embodiment 16 capsules
Prescription:
The preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and tween 80 softwood processed, granulate with 20 mesh sieves, at room temperature 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.
The preparation of embodiment 17 injections
Formula
Preparation method: get 2 gram embodiment 3 compounds and Sorbitol Powder 50 grams, add appropriate distilled water for injection to dissolve, then add distilled water for injection to 1000 milliliter, after mixing, adjust pH value of solution to 4.0.This is film filter (0.22 μ m) filtration for solution, obtains injection.
The preparation of embodiment 18 freeze-dried preparations
Formula
Preparation method: get 1 gram embodiment 9 compounds and mannitol 5 grams, add appropriate distilled water for injection to dissolve, adding distilled water for injection to 100 milliliter, after mixing, adjust pH value of solution to 5.0.This is film filter (0.22 μ m) filtration for solution, makes it lyophilize, obtains the sterile injection powder preparation.
Anti-tumor activity (the IC of 1 pair of HL-60 cells of test example
50: μ M)
This experimental example is to study the anti-tumor activity of the compounds of this invention to HL-60 cells, and test method adopts the MTS method.
According to growth of tumour cell speed, will be inoculated in 96 well culture plates with 170 μ L/ holes in the logarithmic phase HL-60 cells, dosing after adherent growth 24h (30 μ L/ hole), each concentration is established 3 multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular zeroing hole.Tumour cell is at 37 ℃, 5%CO
2cultivate 48h under condition.After cultivation, take out culture plate, every hole adds MTS10 μ L, then puts into incubator 2-5h.Then measure the OD value at 490nm place with enzyme-linked immunosorbent assay instrument.Calculate as follows the inhibiting rate of growth of tumour cell:
according to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.Above each experiment repeats 2～3 times, obtains the average IC of 2～3 experiments
50value is as final index.
Table 1 has been listed some representation compounds in the application's formula I compound anti-tumor activity to HL-60 cells, and compares with the antitumor candidate compound B of similar quinolone and listing antitumor drug Etoposide with same function target spot.
Anti-tumor activity (the IC of table 1 embodiment 3,7 compounds to HL-60 cells
50: μ M)
| Sample | Embodiment 3 compounds | Embodiment 7 compounds | Compd B | Etoposide |
| IC 50：μM | 0.4041 | 0.5383 | 1.2938 | 2.9097 |
From table 1, the anti-tumor activity (IC of embodiment 3,7 compounds in the application's formula I compound to HL-60 cells
50: 0.4041-0.5383 μ M) be control compound B and Etoposide (IC
50: 2.4-7.2 1.2938-2.9097 μ M) is doubly.
Anti-tumor activity (the IC of 2 pairs of solid tumor cells of test example
50: μ M)
This experimental example is to study the anti-tumor activity of the compounds of this invention to solid tumor cell, and test method adopts SRB(sulphonyl rhodamine) method.
According to growth of tumour cell speed, the adherent solid tumor cell in logarithmic phase is inoculated in to 96 well culture plates with 170 μ L/ holes, dosing after adherent growth 24h (30 μ L/ hole), each concentration is established 3 multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular zeroing hole.Tumour cell is at 37 ℃, 5%CO
2cultivate 48h under condition.After cultivation, take out culture plate, every hole adds the 50uL4 ℃ of placement lh of trichoroacetic acid(TCA) (TCA) of 50% (m/v), fixed cell.Abandon stationary liquid, use distilled water wash 5 times, after air drying, every hole adds SRB solution 100uL, under room temperature, places 10-30min, is dyeed.Remove supernatant liquor, with 1% acetic acid washing 5 times, in air, after seasoning, every hole adds 10mM Tris solution 150 μ L, and 10min vibrates on oscillator plate.Measure the OD value at 570nm place with enzyme-linked immunosorbent assay instrument, return to zero with blank.Calculate as follows the inhibiting rate of growth of tumour cell:
according to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.Above each experiment repeats 2～3 times, obtains the average IC of 2～3 experiments
50value is as final index.
Table 2 has been listed some representation compounds in the application's formula I compound to multiple solid tumor cell (HCT-116/ colorectal carcinoma, MCF-7/ mammary cancer, A549/ lung cancer, the PANC-1/ carcinoma of the pancreas, the HeLa/ cervical cancer) anti-tumor activity, and compare with the antitumor candidate compound B of similar quinolone and listing antitumor drug Etoposide with same function target spot.
Anti-tumor activity (the IC of table 2 embodiment 3,9 compounds to solid tumor cell
50: μ M)
From table 2, the anti-tumor activity (IC of embodiment 3,9 compounds in the application's formula I compound to multiple solid tumor cell (HCT-116/ colorectal carcinoma, MCF-7/ mammary cancer, A549/ lung cancer, PANC-1/ carcinoma of the pancreas, HeLa/ cervical cancer)
50: 4.0537-15.7553 μ M) be control compound B and Etoposide (IC
50: 14.5900->50 μ M) 2.6-9.4 times.
The anti-tumor in vivo activity of 3 pairs of inoculation colorectal carcinoma HCT-116 nude mice models of test example
This experimental example is to study the anti-tumor in vivo activity of the compounds of this invention to inoculation solid tumor nude mice model.
The 2% soup compound 0.1ml of BALB/CA-nu mouse (20-24g, 8/group) subcutaneous vaccination colorectal carcinoma HCT-116.Experimental compound is dissolved in 0.1N NaOH, with distilled water diluting to each administration concentration.From next day (the 1st day) of inoculation to every day on the 9th, 1 time through each solution of intraperitoneal (ip) administration 0.2ml.Obtain tumor weight according to the gross tumor volume of 21-22 day after inoculation, be calculated as follows out the administration group with respect to the long inhibiting rate of the tumor proliferative of control group (%).
Inhibition rate of tumor growth (%)=[(the average knurl weight of the average knurl weight/control group of 1-(administration group)] * 100
The anti-tumor in vivo activity of table 3 embodiment 3 compounds to inoculation colorectal carcinoma HCT-116 nude mice
From table 3, embodiment 3 compounds in the application's formula I compound show good anti-tumor in vivo activity to inoculation colorectal carcinoma HCT-116 nude mice.Under the condition of identical dosage (6.25mg/kg), embodiment 3 compounds to the inhibition rate of tumor growth (97%) of inoculation colorectal carcinoma HCT-116 nude mice higher than 2 kinds of control compound B(71%) and Etoposide (34%).
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (9)
1. compound and pharmaceutical salts thereof shown in formula (I),
Wherein:
R
1represent hydrogen, methyl;
R
2represent methylidene, ethyl, benzyl;
N represents 0,1.
2. compound and pharmaceutical salts thereof shown in formula according to claim 1 (I), is characterized in that, its compound is:
7-[3-aminomethyl-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-aminomethyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(methoxy imino)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(ethoxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
7-[3-amino-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid.
3. a method for preparing the described formula of claim 1 or 2 (I) compound and pharmaceutical salts thereof, is characterized in that, it comprises the steps:
1) add acid binding agent in protonic solvent, in room temperature～80 ℃, formula II compound and formula (III) compound carries out condensation reaction 3.5～30 hours, obtains formula (IV) compound.
Wherein:
R
1, R
2with the definition of n with claim 1.
2) then formula (IV) compound is placed in to protonic solvent and adds alkali, stir 2～20 hours under 0 ℃～80 ℃, the reaction that is hydrolyzed, obtain formula (I) compound.
4. the preparation method of formula (I) compound and pharmaceutical salts thereof according to claim 3, is characterized in that, described protonic solvent is selected from water, alcohol or alcohol-water mixed solvent; Described acid binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, salt of wormwood; Described alkali is selected from sodium hydroxide or potassium hydroxide.
5. contain the application in the medicine of preparation treatment solid tumor and non-solid tumor of compound shown in the described formula of claim 1 or 2 (I) and pharmaceutical salts thereof.
6. according to the application of claim 5, it is characterized in that, described solid tumor comprises lung cancer, mammary cancer, cancer of the stomach, bladder cancer, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, head and neck cancer, esophagus cancer, colorectal carcinoma, carcinoma of the pancreas, kidney, prostate cancer, osteocarcinoma and the cancer of the brain; Described non-solid tumor refers to leukemia.
7. the antineoplastic pharmaceutical compositions for gi tract or parenteral administration that contains compound shown in the described formula of claim 1 or 2 (I) and pharmaceutical salts thereof.
8. antineoplastic pharmaceutical compositions according to claim 7, is characterized in that, said composition is tablet, capsule, granule, syrup, powder injection, injection.
9. antineoplastic pharmaceutical compositions according to claim 7, is characterized in that, described tablet is sugar coated tablet, film coated tablet, enteric coated tablet or slow releasing tablet; Described capsule is hard capsule, soft capsule, slow releasing capsule; Described powder injection is lyophilized injectable powder.
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