CN103497186B - 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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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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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 medicinal chemistry arts, relate to naphthyridon carboxylic acid derivative with anti-tumor activity and preparation method thereof, and contain their antineoplastic pharmaceutical compositions.Specifically, 1-(thiazol-2-yl is related to)-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, since 5:1063) coming out, quinolone (comprising naphthyridones) class medicine has developed into the class wide spectrum being only second to cynnematin at present, 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 the anti-microbial effect of its classics is converted into mammiferous cytotoxicity, and filter out some compounds with clear and definite anti-tumor activity, wherein some candidate compound has been in clinical study or pre-clinical assessment stage (Chinese Journal of Pharmaceuticals at present, 2010,41:456).
Surely belong to 1-(thiazol-2-yl 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 7-position has different azepine cyclammonium fragment) synthesis of Naphthyridinone carboxylic acid compound and anti-tumor activity (J.Med.Chem.2002 thereof, 45,5564), wherein outstanding representative AT-3639(compd A) good inside and outside anti-tumor activity is demonstrated to mouse P388 leukemia cell.
Japanese scholars Tsuzuki etc. studies discovery further, and the 6-of AT-3639 goes fluorine analogue (compd B) anti tumor activity in vitro to mouse P388 leukemia cell to be 2 times (J.Med.Chem.2004,47,2097) of AT-3639.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 in the azepine cyclammonium substituting group of 7-position containing the 1-(thiazol-2-yl of chiral carbon atom) synthesis of Naphthyridinone carboxylic acid compound and inside and outside anti-tumor activity (CN:1158614A/1995) thereof, outstanding representative is wherein the voreloxin (SNS-595, CN:103083316A/2005) being in III clinical trial phase at present.Voreloxin is on the basis keeping compd B anti tumor activity in vitro, and it is water-soluble significantly improves.Except there is broad-spectrum anti-tumor activity, the outstanding advantages of this product does not have cross resistance between other antitumor drugs, its shortcoming there are two chiral carbon atoms in its 7-position tetramethyleneimine substituent structure, its production cost will be caused greatly to improve, thus limit its range of application clinically.
In order to overcome the defect existing for above-mentioned prior art, present inventor has performed and study widely, design and synthesis 7-position has the 1-(thiazol-2-yl of the pyrrolidine scaffold fragment that various alcoxyl imido grpup replaces) Naphthyridinone carboxylic acid compound, and determine their anti-tumor activity.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, with similar quinolone antitumor candidate compound B and there is identical action target spot (mammalian topoisomerase II) listing antitumor drug Etoposide compared with, there is more superior anti-tumor activity.
Summary of the invention
The object of this invention is to provide Naphthyridinone carboxylic acid compound and pharmaceutical salts thereof that a class represents by general formula (I),
Wherein:
R
1represent hydrogen, methyl;
R
2represent methyl, ethyl, benzyl;
N represents 0,1.
In the pyrrolidinyl moiety 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 S mixing form exist, the present invention includes all these isomer and mixture.
In the pyrrolidinyl moiety of general formula of the present invention (I) compound, due to containing oximido, therefore general formula (I) compound can the form of E type or Z-type or E type and Z-type mixture exist, and 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 are formed, with organic acid, as the salt that acetic acid, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid are formed, and amino acid, as L-Ala, aspartic acid, Methionin formed salt or and sulfonic acid, as methylsulfonic acid, tosic acid formed salt.
Formula of the present invention (I) compound also can solvate (as hydrate) form exist, therefore, 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-(ethoxyimino)-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-(ethoxyimino)-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-(ethoxyimino)-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-(ethoxyimino)-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.
Formula (IV) compound can be prepared like this: in protonic solvent, add acid binding agent, makes 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 starting materials of 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 is to 3 times of molar weights.In room temperature to 80 DEG C, have or without stirring reaction formula (II) compound under 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 protonic solvent and adds alkali, wherein, alkali relative type motor (IV) compound is for waiting mole to 15 times of molar weights, and preferred equimolar amount is to 5 times of molar weights.Stir 2 ~ 20 hours at 0 DEG C ~ 80 DEG C, be hydrolyzed reaction, obtains 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.
Formula (II) compound being used as initiator is in the present invention known compound, and can easily obtain by method known in existing publication, such as J.Med.Chem.2004,47,2097.Formula (III) compound of another initiator is also known compound, and can easily obtain by method known in existing publication, such as, 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 containing formula as defined above (I) compound and pharmaceutical salts thereof the antineoplastic pharmaceutical compositions as activeconstituents.
The Naphthyridinone carboxylic acid compound that pharmaceutical composition contains weight ratio is in the composition 0.1 ~ 99.9%, and medicine acceptable carrier weight ratio is in the composition 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 is prepared by conventional pharmaceutical method.The example of available medicinal adjuvant comprises vehicle, and (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 (conventional sweeting agent, acidic flavoring agent, spices), thinner and injection liquid solvent (distilled water, ethanol, glycerine).
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound contained in every agent is 0.1 ~ 1000mg, described every agent refers to each preparation unit, as every sheet of tablet, every of capsule, also can refer to each taking dose, as each serving with 100mg.
For ease of administration and dosage homogeneous, become dosage unit form to be particularly advantageous said medicine Formulation.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 predetermined amount calculated of the result for the treatment of desired by generation.This dosage unit form can be packaged form, as tablet, capsule or the pulvis that is contained in tubule or bottle.
Although the amount of contained activeconstituents can change in dosage unit form, generally according to the effect of selected activeconstituents, regulate within the scope of 1 ~ 800mg.
The dosage of formula (I) compound or pharmaceutically acceptable salt thereof in the present invention is different with the difference at the age, sex, race, the state of an illness etc. of patient.The day dosage of general adult is approximately 50-1000mg, preferred 100-800mg, can single administration or point 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.With similar quinolone antitumor candidate compound B and there is identical action target spot listing antitumor drug Etoposide compared with, there is more superior anti-tumor activity, simpler preparation method, there is good water-soluble and stability simultaneously.
Embodiment
Following examples for illustration of the present invention, 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
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 DEG C of stirring reaction 8h.Concentrating under reduced pressure, residue over silica gel chromatographic column separation and 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 temperature.Adjust reaction solution pH7 with 1N hydrochloric acid soln, fully stir 1h.Filter, filter cake is successively with the washing of distilled water, ethanol and isopropyl ether, dry, uses DMF-ethyl alcohol recrystallization, obtains faint yellow solid 29mg(yield: 53%), mp:286-288 DEG C.
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-aminomethyl-3-methyl-4-(ethoxyimino)-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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-aminomethyl-3-methyl-4-ethoxyimino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 47%), mp:286-288 DEG C.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-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
With the preparation method of embodiment 1 compound, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-aminomethyl-3-methyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 79%), mp:285-288 DEG C.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-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 hydrochloride
Under return stirring, in the dehydrated alcohol suspension liquid (15mL) of embodiment 3 compound (506mg, 1mmol), add the 6N hydrochloric acid (molten clear) of 1.5 times of molar weights, reflux 0.5 hour, is down to room temperature, separates out solid.Filter, dry, obtain 7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl) and the yellow light solid of-Isosorbide-5-Nitrae-dihydro-4-oxo-1,8-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 following salt can be prepared similarly, such as:
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-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 monohydrate
Embodiment 3 compound (507mg, 1mmol) is dissolved in 5% acetic acid (8mL), under stirring at room temperature, adjusts pH=7 with 1N sodium hydroxide solution, place and separate out solid.Filter, dry, obtain 7-[3-aminomethyl-3-methyl-4-(benzyloxy imido grpup)-pyrrolidin-1-yl)]-1-(thiazol-2-yl) and-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-aminomethyl-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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-aminomethyl-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains 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.forC
18H
18O
4N
6S(M+H)
+:414.17595;Found414.17573.
Embodiment 7 7-[3-aminomethyl-4-(ethoxyimino)-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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-aminomethyl-4-ethoxyimino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 78%), mp:275-278 DEG C.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/zCalcd.for C
19H
21O
4N
6S(M+H)
+:429.13395;Found429.13205.
Embodiment 8 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
With the preparation method of embodiment 1 compound, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-aminomethyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 70%), mp:>300 DEG C.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.forC
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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-3-methyl-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 55%), mp:182-184 DEG C.
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/zCalcd.for C
18H
19O
4N
6S(M+H)
+:415.11830;Found415.11700.
Embodiment 10 7-[3-amino-3-methyl-4-(ethoxyimino)-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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-3-methyl-4-ethoxyimino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 41%), mp:255-258 DEG C.
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.forC
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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-3-methyl-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains faint yellow solid (yield: 65%), mp:175-177 DEG C.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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-4-methoxy imino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains 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-(ethoxyimino)-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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-4-ethoxyimino tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains 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, 1-(thiazol-2-yl) the chloro-Isosorbide-5-Nitrae of-7--dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid, ethyl ester first with 3-amino-4-benzyloxy imido grpup tetramethyleneimine dihydrochloride generation condensation reaction, then alkaline hydrolysis.Crude product DMF-ethyl alcohol recrystallization, obtains 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 to mix, sieve after granulation whole grain, and 100 labels made by dry, compressing tablet.
Coating fluid prescription:
Opadry (Opadry) 5g, 80% appropriate amount of ethanol dressing.
Embodiment 16 capsule
Prescription:
Preparation method:
Get recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and tween 80 softwood, granulate with 20 mesh sieves, at room temperature dry, add sodium lauryl sulphate, mix, load No. 0 gastric-dissolved capsule by 0.27g/S, sample examination, stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
The preparation of embodiment 17 injection
Formula
Preparation method: get 2 grams of embodiment 3 compounds and Sorbitol Powder 50 grams, adds appropriate distilled water for injection and dissolves, then add distilled water for injection to 1000 milliliter, after mixing, adjusts pH value of solution to 4.0.This solution film filter (0.22 μm) filters, and obtains injection.
The preparation of embodiment 18 freeze-dried preparation
Formula
Preparation method: get 1 gram of embodiment 9 compound and mannitol 5 grams, adds appropriate distilled water for injection and dissolves, adding distilled water for injection to 100 milliliter, after mixing, adjusts pH value of solution to 5.0.This solution film filter (0.22 μm) filters, and makes it lyophilize, obtains sterile injection powder preparation.
Anti-tumor activity (the IC of test example 1 pair of HL-60 cells
50: μM)
This experimental example is that research the compounds of this invention is to the anti-tumor activity of HL-60 cells, and test method adopts MTS method.
According to tumor cell growth rates, will be in logarithmic phase HL-60 cells and be inoculated in 96 well culture plates with 170 μ L/ holes, dosing after adherent growth 24h (30 μ L/ hole), each concentration establishes 3 multiple holes.And establish the physiological saline Vehicle controls of respective concentration and acellular zeroing hole.Tumour cell is at 37 DEG C, 5%CO
248h is cultivated under condition.After cultivation, take out culture plate, every hole adds MTS10 μ L, then puts into incubator 2-5h.Then the OD value at 490nm place is measured with enzyme-linked immunosorbent assay instrument.Calculate the inhibiting rate of growth of tumour cell as follows:
according to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.Each experiment repetition 2 ~ 3 times above, obtains the average IC of 2 ~ 3 experiments
50value is as final index.
Table 1 lists some representation compounds in the formula I compound of the application to the anti-tumor activity of HL-60 cells, and compares with similar quinolone antitumor candidate compound B and the listing antitumor drug Etoposide with identical action target spot.
Table 1 embodiment 3,7 compound is to the anti-tumor activity (IC of HL-60 cells
50: μM)
| Sample | Embodiment 3 compound | Embodiment 7 compound | Compd B | Etoposide |
| IC 50：μM | 0.4041 | 0.5383 | 1.2938 | 2.9097 |
From table 1, embodiment 3,7 compound in the formula I compound of the application is to the anti-tumor activity (IC of HL-60 cells
50: 0.4041-0.5383 μM) be control compound B and Etoposide (IC
50: 1.2938-2.9097 μM) 2.4-7.2 doubly.
Anti-tumor activity (the IC of test example 2 pairs of solid tumor cells
50: μM)
This experimental example is that research the compounds of this invention is to the anti-tumor activity of solid tumor cell, and test method adopts SRB(Sulforhodamine) method.
According to tumor cell growth rates, the adherent solid tumor cell being in logarithmic phase is inoculated in 96 well culture plates with 170 μ L/ holes, dosing after adherent growth 24h (30 μ L/ hole), each concentration establishes 3 multiple holes.And establish the physiological saline Vehicle controls of respective concentration and acellular zeroing hole.Tumour cell is at 37 DEG C, 5%CO
248h is cultivated under condition.After cultivation, take out culture plate, the trichoroacetic acid(TCA) (TCA) 50uL4 DEG C that every hole adds 50% (m/v) places lh, fixed cell.Abandon stationary liquid, with distilled water wash 5 times, in atmosphere after drying, every hole adds SRB solution 100uL, and ambient temperatare puts 10-30min, dyes.Remove supernatant liquor, wash 5 times, in air after seasoning with 1% acetic acid, every hole adds 10mM Tris solution 150 μ L, and oscillator plate vibrates 10min.Measure the OD value at 570nm place with enzyme-linked immunosorbent assay instrument, return to zero with blank.Calculate the inhibiting rate of growth of tumour cell as follows:
according to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.Each experiment repetition 2 ~ 3 times above, obtains the average IC of 2 ~ 3 experiments
50value is as final index.
Table 2 lists some representation compounds in the formula I compound of the application 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) anti-tumor activity, and to compare with similar quinolone antitumor candidate compound B and the listing antitumor drug Etoposide with identical action target spot.
Table 2 embodiment 3,9 compound is to the anti-tumor activity (IC of solid tumor cell
50: μM)
From table 2, embodiment 3,9 compound in the formula I compound of the application is to the anti-tumor activity (IC of 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 μM) be control compound B and Etoposide (IC
50: 14.5900->50 μM) 2.6->9.4 doubly.
The anti-tumor in vivo of test example 3 to inoculation colorectal carcinoma HCT-116 nude mice model is active
It is active that this experimental example is to study the anti-tumor in vivo 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 administration group relative to the long inhibiting rate of the tumor proliferative of control group (%).
Inhibition rate of tumor growth (%)=[(the average knurl weight of 1-(administration group average knurl weight/control group)] × 100
The anti-tumor in vivo of table 3 embodiment 3 compound to inoculation colorectal carcinoma HCT-116 nude mice is active
From table 3, it is active that embodiment 3 compound in the formula I compound of the application shows good anti-tumor in vivo to inoculation colorectal carcinoma HCT-116 nude mice.Under the condition of identical dosage (6.25mg/kg), embodiment 3 compound is to inoculating the inhibition rate of tumor growth (97%) of 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 without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (9)
1. compound shown in formula (I) and pharmaceutical salts thereof,
Wherein:
R
1represent hydrogen, methyl;
R
2represent methyl, ethyl, benzyl;
N represents 0,1.
2. compound shown in formula according to claim 1 (I) and pharmaceutical salts thereof, it 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-(ethoxyimino)-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-(ethoxyimino)-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-(ethoxyimino)-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-(ethoxyimino)-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. prepare a method for formula described in claim 1 (I) compound, it is characterized in that, it comprises the steps:
1) in protonic solvent, add acid binding agent, in room temperature ~ 80 DEG C, formula II compound and formula (III) compound carry out condensation reaction 3.5 ~ 30 hours, obtain formula (IV) compound;
Wherein:
R
1, R
2with the definition of n with claim 1;
2) then formula (IV) compound is placed in protonic solvent and adds alkali, stir 2 ~ 20 hours at 0 DEG C ~ 80 DEG C, be hydrolyzed reaction, obtains formula (I) compound.
4. the preparation method of formula (I) compound and pharmaceutical salts thereof according to claim 3, it 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. compound shown in formula described in claim 1 or 2 (I) and the application of pharmaceutical salts in the medicine preparing treatment solid tumor and non-physical knurl thereof.
6. application according to claim 5, 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-physical knurl refers to leukemia.
7. the antineoplastic pharmaceutical compositions for gi tract or parenteral administration containing compound shown in formula (I) described in claim 1 or 2 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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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4195087A (en) * | 1976-12-10 | 1980-03-25 | Abic, Ltd. | Derivatives of naphthyridine |
| CN1158614A (en) * | 1994-06-14 | 1997-09-03 | 大日本制药株式会社 | Novel compound, process for producing the same, and antitumor agent |
| WO2010113151A1 (en) * | 2009-03-31 | 2010-10-07 | Technion Research & Development Foundation Ltd. | Conjugated antimicrobial agents |
| CN102321082A (en) * | 2011-07-12 | 2012-01-18 | 中国医学科学院医药生物技术研究所 | Naphthyridinone carboxylic acid compound and preparation method thereof |
| CN102329315A (en) * | 2011-07-22 | 2012-01-25 | 中国医学科学院医药生物技术研究所 | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof |
| WO2013033228A1 (en) * | 2011-08-29 | 2013-03-07 | Ptc Therapeutics, Inc. | Antibacterial compounds and methods for use |
-
2013
- 2013-09-24 CN CN201310438031.0A patent/CN103497186B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4195087A (en) * | 1976-12-10 | 1980-03-25 | Abic, Ltd. | Derivatives of naphthyridine |
| CN1158614A (en) * | 1994-06-14 | 1997-09-03 | 大日本制药株式会社 | Novel compound, process for producing the same, and antitumor agent |
| WO2010113151A1 (en) * | 2009-03-31 | 2010-10-07 | Technion Research & Development Foundation Ltd. | Conjugated antimicrobial agents |
| CN102321082A (en) * | 2011-07-12 | 2012-01-18 | 中国医学科学院医药生物技术研究所 | Naphthyridinone carboxylic acid compound and preparation method thereof |
| CN102329315A (en) * | 2011-07-22 | 2012-01-25 | 中国医学科学院医药生物技术研究所 | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof |
| WO2013033228A1 (en) * | 2011-08-29 | 2013-03-07 | Ptc Therapeutics, Inc. | Antibacterial compounds and methods for use |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and Structure-Activity Relationships of Potent Antitumor Active Quinoline and Naphthyridine Derivatives;Sanjay K. Srivastava et al.，;《Anti-Cancer Agents in Medicinal Chemistry》;20071231;第7卷(第6期);第685-709页 * |
| 喹诺酮对专性厌氧菌的体内外活性;郭强 等;《国外医药抗生素分册》;20100115;第31卷(第1期);第7-12页 * |
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