CN107964020B - Fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- and its preparation method and application - Google Patents
Fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- and its preparation method and application Download PDFInfo
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Abstract
The invention discloses fluoro- 7- piperazine nalidixic acid compounds of a kind of 1- (N- lavo-ofloxacin amide groups) -6- and its preparation method and application, and structural formula is
Description
Technical field
The present invention relates to novel drugs discoveries and original new drug synthesis technical field, and in particular to a kind of 1- (N- levofloxacin
Star amide groups) the fluoro- 7- piperazine -1- base of -6--naphthyridines -4 (1H) -one -3- carboxylic acid target compound, also relate to a kind of 1- (N-
Lavo-ofloxacin amide groups) the fluoro- 7- piperazine -1- base of -6--naphthyridines -4 (1H) -one -3- carboxylic acid target compound preparation method,
And its application in antibacterial anti-tumor drug.
Background technique
Discovery of the new drug innovation originating from primer, and the split of the advantage pharmacophore skeleton based on existing drug and then structure
Building primer drug molecule is most economical and effective strategy.Fluoquinolone is clinical widely used anti-infectives, with " quinoline
Quinoline (naphthyridines) -4- ketone -3- carboxylic acid " is its advantage antibacterial activity skeleton；Meanwhile the action target spot-based on fluoroquinolones
Topoisomerase is also the important function target spot of anti-tumor drug, can convert anti-tumor activity for its antibacterial activity.Currently, anti-
Bacterium structure-effect relationship modifies N-1 the study found that fluoquinolone C-3 carboxyl is pharmacophore necessary to antibacterial activity
It can produce many outstanding antimicrobials.However, it is antitumor work that antitumor result of study, which shows that fluoquinolone C-3 carboxyl is not,
Property necessary to, anti-tumor activity can be improved with the biological isostere substitution such as amide or heterocycle or condensed hetero ring.It is as a result, abundant
Flouroquinolone drugs action target-antibacterial of topoisomerase and the advantage of anti-tumor target are played, in conjunction with fluoquinolone antibacterial
Antitumor structure activity study, existing " quinoline (the naphthyridines) -4- ketone -3- carboxylic acid " advantage of the new fluoroquinolone molecule of design construction
Antibacterial activity skeleton, and have " fluoquinolone C-3 carboxyl biology isostere " advantage anti-tumor activity skeleton, it is that discovery antibacterial is anti-swollen
One of the preferred plan of tumor economic benefits and social benefits fluoquinolone lead compound.
Summary of the invention
The invention proposes a kind of fluoro- 7- piperazine nalidixic acid compounds of 1- (N- lavo-ofloxacin amide groups) -6-, have
Antibacterial and antitumor double action and effect, while the fluoro- 7- piperazine naphthyridines of 1- (N- lavo-ofloxacin amide groups) -6- being provided
The preparation method and applications of ketone acid compound.
It realizes the technical scheme is that a kind of fluoro- 7- piperazine nalidixic acid of 1- (N- lavo-ofloxacin amide groups) -6-
Compound, shown in chemical structure such as following formula (I):
The preparation method of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6-, step
It is as follows:
(1) using fluorine chloronicotinoyl ester shown in formula (II) as raw material, through formula (III) institute is made with triethyl orthoformate condensation reaction
2- (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate shown；Concrete operation step can refer to document (Mu Yong
Fine jade etc., Enoxacin new method synthesis, medical industry, 1988,19 (10): 433-435.) method；
(2) it using lavo-ofloxacin shown in formula (IV) as raw material, is reacted shown in obtained formula (V) through carrying out hydrazinolysis with hydrazine hydrate
Lavo-ofloxacin hydrazides；Detailed operating procedures are referred to the document (synthesis of the fluoquinolone C-3 acylhydrazone such as Hu Guoqiang and anti-
Bacterium activity, Chinese Pharmaceutical Journal, 2010,45 (11): 867-870) method；
(3) with (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate of 2- shown in formula (III) and formula (V)
Shown in lavo-ofloxacin hydrazides carry out contracting cyclization reaction be made formula (VI) shown in 1- (N- lavo-ofloxacin amide groups) -6-
The fluoro- chloro- nalidixic acid ethyl ester intermediate compound of 7-；
(4) with the chloro- nalidixic acid ethyl ester intermediate of (N- lavo-ofloxacin amide groups) the fluoro- 7- of -6- of 1- shown in formula (VI)
Compound is reacted with piperazine condensation is made the fluoro- 7- piperazine -1- of 1- (N- lavo-ofloxacin amide groups) -6- shown in formula (VII)
Base-nalidixic acid ethyl ester intermediate compound；
(5) with the fluoro- 7- piperazine -1- base-nalidixic acid second of 1- shown in formula (VII) (N- lavo-ofloxacin amide groups) -6-
The fluoro- 7- piperazine of 1- (N- lavo-ofloxacin amide groups) -6- shown in formula (I) is made by hydrolysis in ester midbody compound
Nalidixic acid compound, specific name are the fluoro- 7- piperazine -1- base of 1- (N- Ofloxacin amide groups) -6--naphthyridines -4 (1H) -
Ketone -3- carboxylic acid compound.
Formula (V) lavo-ofloxacin hydrazides and 2- (2, the 6- bis- chloro- fluoro- nicotinoyl of 5- shown in formula (III) in the step (3)
Base) -3- ethyoxyl-ethyl acrylate molar ratio be 1:(1.0-1.5).
The chloro- nalidixic acid ethyl ester of (N- lavo-ofloxacin amide groups) the fluoro- 7- of -6- of 1- shown in step (4) formula (VI)
The molar ratio of midbody compound and piperazine is 1:(1.0-1.5).
In the step (5) among the fluoro- 7- piperazine -1- base-nalidixic acid ethyl ester of 1- (N- lavo-ofloxacin amide groups) -6-
In alkalinity or acid medium hydrolysis occurs for body compound.
The 1- fluoro- 7- piperazine nalidixic acid compound of (N- lavo-ofloxacin amide groups) -6- is anti-swollen in preparation antibacterial
Application in tumor medicine.
The anti-tumor drug is the drug of infection caused by treating cancer of pancreas, liver cancer or leukaemia, pathogenic microorganism.
Process flow routes of the invention are as follows:
The beneficial effects of the present invention are: the fluoro- 7- piperazine naphthalene of double effect 1- (N- lavo-ofloxacin amide groups) -6- of the invention
Structure-activity relationship of the pyridine ketone acid compound based on antibacterial fluoroquinolone and antitumor fluoquinolone, with antibacterial advantage pharmacophore skeleton
The modification group of " naphthyridines -4- ketone-carboxylic acid " as the isostere amide of antitumor fluoquinolone C-3 carboxyl, and then design construction
The new lead compounds of double fluoquinolones of double efficacy effects, achieves synergistic and detoxifying effects simultaneously, can be used as brand new
Antibacterial anti-tumor drug exploitation.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Those of ordinary skill in the art's every other embodiment obtained under that premise of not paying creative labor, belongs to this hair
The range of bright protection.
Embodiment 1
The preparation method of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- in the present embodiment,
Specific step is as follows:
(1) fluorine chloronicotinoyl ester shown in formula (II) is reacted with triethyl orthoformate and 2- (2,6- shown in formula (III) is made
The two chloro- fluoro- nicotinoyl bases of 5-) -3- ethyoxyl-ethyl acrylate；
(2) with hydrazine hydrate hydrazinolysis is occurred into for lavo-ofloxacin shown in formula (IV) and reacts left oxygen fluorine shown in obtained formula (V)
Husky star hydrazides；
(3) with (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate of 2- shown in formula (III) and (V) institute
It is fluoro- that the lavo-ofloxacin hydrazides shown carries out 1- (N- lavo-ofloxacin amide groups) -6- shown in contracting cyclization reaction obtained formula (VI)
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound of 7-, i.e. 1- (N- lavo-ofloxacin amide groups) fluoro- 7- of -6- are chloro-
Naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester；
Concrete operation step are as follows: compound (III) 5.23g (15.8mmol) is dissolved in methanol (50 milliliters), under ice bath
Compound (V) 5.8g (15.5mmol) is slowly added in the methanol solution of above compound (III), is stirred 5 hours, room temperature
Continue stirring 3 hours.The solid that filter collection generates, is washed with the methanol of freezing, dry.It is recrystallized, is obtained with dimethylamino formamide
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester of pale yellow crystals formula (VI) 1- (N- lavo-ofloxacin amide groups) fluoro- 7- of -6- is received
Rate 66.7%, mp 234-236 DEG C.1H NMR (400MHz, CDCl3): 12.95 (brs, 1H, CONH), 8.70 (s, 1H, 2-H),
The 8.33 (- H of s, 1H, 2 '), 7.71 (d, J=12.0Hz, 1H, 5-H), the 7.68 (- H of d, J=12.0Hz, 1H, 5 '), 4.54~
4.31(m,3H, OCHCH2), 4.06 (q, J=8.0Hz, 2H, OCH2), 3.48~3.37 (m, 4H, piperazine-H), 2.62
(br, 4H, piperazine-H), 2.41 (s, 3H, N-CH3), 1.63 (d, J=8.0Hz, 3H, CH3), 1.08 (t, J=8.0
Hz, 3H, OCH2CH3)。
(4) with chloro- naphthyridines -4 (1H) -one -3- carboxylic of 1- shown in formula (VI) (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-
It is fluoro- that acetoacetic ester midbody compound reacts 1- (N- lavo-ofloxacin amide groups) -6- shown in obtained formula (VII) with piperazine condensation
7- piperazine -1- base-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound, i.e. 1- (N- lavo-ofloxacin amide groups) -6-
- 1 base of fluoro- 7- piperazine-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester；
Concrete operation step are as follows: formula (VI) compound 3.0g (4.8mmol) is suspended in acetonitrile (60 milliliters), is added
Piperazine anhydrous 1.3g (15.0mmol), reaction mixture are stirred at reflux reaction 6 hours, evaporating solvent under reduced pressure.With deionized water (30
Milliliter) dispersing solid, filtering, washing neutrality.It is dry, it is recrystallized with methanol-chloroform (V/V=7:1), obtains pale yellow crystals formula
(VII) -1 base of (N- lavo-ofloxacin amide groups) the fluoro- 7- piperazine of -6- of 1- shown in-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester,
Yield 63.6%, 233~235 DEG C of mp.1H NMR (400MHz, DMSO-d6): 13.15 (brs, 1H, CONH), 8.86 (s, 1H,
2-H), the 8.45 (- H of s, 1H, 2 '), 7.82 (d, J=12.0Hz, 1H, 5-H), the 7.74 (- H of d, J=12.0Hz, 1H, 5 '), 4.66
~4.43 (m, 3H, OCHCH2), 4.16 (q, J=8.0Hz, 2H, OCH2), 3.53~3.42 (m, 8H, piperazine-H),
2.62 (br, 8H, piperazine-H), 2.46 (s, 3H, N-CH3), 1.66 (d, J=8.0Hz, 3H, CH3), 1.13 (t, J=
8.0 Hz, 3H, OCH2CH3)。
(5) with the fluoro- 7- piperazine -1- base-naphthyridines -4 of 1- shown in formula (VII) (N- lavo-ofloxacin amide groups) -6-
1- (N- lavo-ofloxacin amide shown in formula (I) is made by hydrolysis in (1H) -one -3- carboxylic acid, ethyl ester midbody compound
Base) the fluoro- 7- piperazine -1- base of -6--naphthyridines -4 (1H) -one -3- carboxylic acid compound；
Concrete operation step are as follows: formula (VII) compound 10.0g (15.0mmol) is suspended in the hydrogen that mass fraction is 3%
In lithia (200 milliliters), gentle reflux is reacted to dissolution of raw material, and proper amount of active carbon is added, and flows back 1 hour, filtering.Filtrate
With concentrated hydrochloric acid tune pH 7.0, stand overnight.Filter solid is crossed, is washed, it is dry.Crude product is suspended in the ethyl alcohol that mass fraction is 95%
(W/V=1:10) in, concentrated hydrochloric acid is added to pH 3.0~5.0, flow back dissolved solid, and heat filtering is placed and solid is precipitated.Filtering,
Solid deionized water dissolving, suitable activity carbon decoloring, filtering.Solid is precipitated with concentrated ammonia liquor tune pH 7.0, placement in filtrate.It crosses
Filter, solid are washed with dehydrated alcohol, dry, obtain 1- shown in pale yellow crystals formula (I) (N- lavo-ofloxacin amide groups) -6-
- 1 base of fluoro- 7- piperazine-naphthyridines -4 (1H) -one -3- carboxylic acid compound, yield 74.2%, 245~247 DEG C of mp.1H NMR
(400MHz, DMSO-d6): 15.58 (brs, 1H, COOH), 13.24 (brs, 1H, CONH), 8.86 (s, 1H, 2-H), 8.46
(- the H of s, 1H, 2 '), 7.83 (d, J=12.0Hz, 1H, 5-H), the 7.76 (- H of d, J=12.0Hz, 1H, 5 '), 4.67~4.47 (m,
3H,OCHCH2), 3.63~3.46 (m, 8H, piperazine-H), 2.75 (br, 8H, piperazine-H), 2.46 (s, 3H,
N-CH3), 1.66 (d, J=8.0Hz, 3H, CH3)。
Embodiment 2
The preparation method of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- in the present embodiment,
Specific step is as follows:
Step (1) and step (2) are the same as embodiment 1；
(3) with (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate of 2- shown in formula (III) and (V) institute
It is fluoro- that the lavo-ofloxacin hydrazides shown carries out 1- (N- lavo-ofloxacin amide groups) -6- shown in contracting cyclization reaction obtained formula (VI)
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound of 7-；
Concrete operation step are as follows: compound (III) 5.13g (15.5mmol) is dissolved in methanol (50 milliliters), under ice bath
Compound (V) 5.8g (15.5mmol) is slowly added in the methanol solution of above compound (III), is stirred 5 hours, room temperature
Continue stirring 3 hours.The solid that filter collection generates, is washed with the methanol of freezing, dry.It is recrystallized, is obtained with dimethylamino formamide
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester of pale yellow crystals formula (VI) 1- (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-.
(4) with chloro- naphthyridines -4 (1H) -one -3- carboxylic of 1- shown in formula (VI) (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-
It is fluoro- that acetoacetic ester midbody compound reacts 1- (N- lavo-ofloxacin amide groups) -6- shown in obtained formula (VII) with piperazine condensation
7- piperazine -1- base-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound；
Concrete operation step are as follows: formula (VI) compound 3.0g (4.8mmol) is suspended in acetonitrile (60 milliliters), is added
Piperazine anhydrous 0.416g (4.8mmol), reaction mixture are stirred at reflux reaction 6 hours, evaporating solvent under reduced pressure.Use deionized water
(30 milliliters) dispersing solid, filtering, washing are neutral.It is dry, it is recrystallized with methanol-chloroform (V/V=7:1), obtains pale yellow crystals
- 1 base of (N- lavo-ofloxacin amide groups) the fluoro- 7- piperazine of -6- of 1- shown in formula (VII)-naphthyridines -4 (1H) -one -3- carboxylic acid second
Ester.
(5) with the fluoro- 7- piperazine -1- base-naphthyridines -4 of 1- shown in formula (VII) (N- lavo-ofloxacin amide groups) -6-
1- (N- lavo-ofloxacin amide shown in formula (I) is made by hydrolysis in (1H) -one -3- carboxylic acid, ethyl ester midbody compound
Base) the fluoro- 7- piperazine -1- base of -6--naphthyridines -4 (1H) -one -3- carboxylic acid target compound；
Concrete operation step are as follows: formula (VII) compound 10.0g (15.0mmol) is suspended in the hydrogen that mass fraction is 3%
In lithia (200 milliliters), gentle reflux is reacted to dissolution of raw material, and proper amount of active carbon is added, and flows back 1 hour, filtering.Filtrate is used
Concentrated hydrochloric acid tune pH 7.0, stands overnight.Filter solid is crossed, is washed, it is dry.Crude product is suspended in the ethyl alcohol (W/V that mass fraction is 95%
=1:10) in, concentrated hydrochloric acid is added to pH 3.0~5.0, flow back dissolved solid, and heat filtering is placed and solid is precipitated.Filtering, solid
With deionized water dissolving, suitable activity carbon decoloring, filtering.Solid is precipitated with concentrated ammonia liquor tune pH 7.0, placement in filtrate.Filtering,
Solid is washed with dehydrated alcohol, dry, obtains 1- shown in pale yellow crystals formula (I) (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-
- 1 base of piperazine-naphthyridines -4 (1H) -one -3- carboxylic acid.
Embodiment 3
The preparation method of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- in the present embodiment,
Specific step is as follows:
Step (1) and step (2) are the same as embodiment 1；
(3) with (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate of 2- shown in formula (III) and (V) institute
It is fluoro- that the lavo-ofloxacin hydrazides shown carries out 1- (N- lavo-ofloxacin amide groups) -6- shown in contracting cyclization reaction obtained formula (VI)
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound of 7-；
Concrete operation step are as follows: compound (III) 6.15g (18.6mmol) is dissolved in methanol (50 milliliters), under ice bath
Compound (V) 5.8g (15.5mmol) is slowly added in the methanol solution of above compound (III), is stirred 5 hours, room temperature
Continue stirring 3 hours.The solid that filter collection generates, is washed with the methanol of freezing, dry.It is recrystallized, is obtained with dimethylamino formamide
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester of pale yellow crystals formula (VI) 1- (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-.
(4) with chloro- naphthyridines -4 (1H) -one -3- carboxylic of 1- shown in formula (VI) (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-
It is fluoro- that acetoacetic ester midbody compound reacts 1- (N- lavo-ofloxacin amide groups) -6- shown in obtained formula (VII) with piperazine condensation
7- piperazine -1- base-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound；
Concrete operation step are as follows: formula (VI) compound 3.0g (4.8mmol) is suspended in acetonitrile (60 milliliters), is added
Piperazine anhydrous 1.22g (14.4mmol), reaction mixture are stirred at reflux reaction 6 hours, evaporating solvent under reduced pressure.Use deionized water
(30 milliliters) dispersing solid, filtering, washing are neutral.It is dry, it is recrystallized with methanol-chloroform (V/V=7:1), obtains pale yellow crystals
- 1 base of (N- lavo-ofloxacin amide groups) the fluoro- 7- piperazine of -6- of 1- shown in formula (VII)-naphthyridines -4 (1H) -one -3- carboxylic acid second
Ester.
(5) with the fluoro- 7- piperazine -1- base of 1- shown in formula (VII) (N- lavo-ofloxacin amide groups) -6--naphthyridines -4 (1H) -
1- (N- lavo-ofloxacin amide groups) -6- shown in formula (I) is made by hydrolysis in ketone -3- carboxylic acid, ethyl ester midbody compound
Fluoro- 7- piperazine -1- base-naphthyridines -4 (1H) -one -3- carboxylic acid target compound；
Concrete operation step are as follows: formula (VII) compound 10.0g (15.0mmol) is suspended in the hydrogen that mass fraction is 3%
In lithia (200 milliliters), gentle reflux is reacted to dissolution of raw material, and proper amount of active carbon is added, and flows back 1 hour, filtering.Filtrate
With concentrated hydrochloric acid tune pH 7.0, stand overnight.Filter solid is crossed, is washed, it is dry.Crude product is suspended in the ethyl alcohol that mass fraction is 95%
(W/V=1:10) in, concentrated hydrochloric acid is added to pH 3.0~5.0, flow back dissolved solid, and heat filtering is placed and solid is precipitated.Filtering,
Solid deionized water dissolving, suitable activity carbon decoloring, filtering.Solid is precipitated with concentrated ammonia liquor tune pH 7.0, placement in filtrate.It crosses
Filter, solid are washed with dehydrated alcohol, dry, obtain 1- shown in pale yellow crystals formula (I) (N- lavo-ofloxacin amide groups) -6-
- 1 base of fluoro- 7- piperazine-naphthyridines -4 (1H) -one -3- carboxylic acid.
Embodiment 4
The preparation method of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- in the present embodiment,
Specific step is as follows:
Step (1) and step (2) are the same as embodiment 1；
(3) with (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate of 2- shown in formula (III) and (V) institute
It is fluoro- that the lavo-ofloxacin hydrazides shown carries out 1- (N- lavo-ofloxacin amide groups) -6- shown in contracting cyclization reaction obtained formula (VI)
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound of 7-；
Concrete operation step are as follows: compound (III) 7.70g (23.25mmol) is dissolved in methanol (50 milliliters), under ice bath
Compound (V) 5.8g (15.5mmol) is slowly added in the methanol solution of above compound (III), is stirred 5 hours, room temperature
Continue stirring 3 hours.The solid that filter collection generates, is washed with the methanol of freezing, dry.It is recrystallized, is obtained with dimethylamino formamide
Chloro- naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester of pale yellow crystals formula (VI) 1- (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-.
(4) with chloro- naphthyridines -4 (1H) -one -3- carboxylic of 1- shown in formula (VI) (N- lavo-ofloxacin amide groups) fluoro- 7- of -6-
It is fluoro- that acetoacetic ester midbody compound reacts 1- (N- lavo-ofloxacin amide groups) -6- shown in obtained formula (VII) with piperazine condensation
7- piperazine -1- base-naphthyridines -4 (1H) -one -3- carboxylic acid, ethyl ester midbody compound；
Concrete operation step are as follows: formula (VI) compound 3.0g (4.8mmol) is suspended in acetonitrile (60 milliliters), is added
Piperazine anhydrous 2.08g (24.0mmol), reaction mixture are stirred at reflux reaction 6 hours, evaporating solvent under reduced pressure.Use deionized water
(30 milliliters) dispersing solid, filtering, washing are neutral.It is dry, it is recrystallized with methanol-chloroform (V/V=7:1), obtains pale yellow crystals
- 1 base of (N- lavo-ofloxacin amide groups) the fluoro- 7- piperazine of -6- of 1- shown in formula (VII)-naphthyridines -4 (1H) -one -3- carboxylic acid second
Ester.
(5) with the fluoro- 7- piperazine -1- base-naphthyridines -4 of 1- shown in formula (VII) (N- lavo-ofloxacin amide groups) -6-
1- (N- lavo-ofloxacin amide shown in formula (I) is made by hydrolysis in (1H) -one -3- carboxylic acid, ethyl ester midbody compound
Base) the fluoro- 7- piperazine -1- base of -6--naphthyridines -4 (1H) -one -3- carboxylic acid target compound；
Concrete operation step are as follows: formula (VII) compound 10.0g (15.0mmol) is suspended in the hydrogen that mass fraction is 3%
In lithia (200 milliliters), gentle reflux is reacted to dissolution of raw material, and proper amount of active carbon is added, and flows back 1 hour, filtering.Filtrate
With concentrated hydrochloric acid tune pH 7.0, stand overnight.Filter solid is crossed, is washed, it is dry.Crude product is suspended in the ethyl alcohol that mass fraction is 95%
(W/V=1:10) in, concentrated hydrochloric acid is added to pH 3.0~5.0, flow back dissolved solid, and heat filtering is placed and solid is precipitated.Filtering,
Solid deionized water dissolving, suitable activity carbon decoloring, filtering.Solid is precipitated with concentrated ammonia liquor tune pH 7.0, placement in filtrate.It crosses
Filter, solid are washed with dehydrated alcohol, dry, obtain 1- shown in pale yellow crystals formula (I) (N- lavo-ofloxacin amide groups) -6-
- 1 base of fluoro- 7- piperazine-naphthyridines -4 (1H) -one -3- carboxylic acid.
Test example
One, the fluoro- 7- piperazine -1- base-naphthyridines -4 of a kind of 1- (N- lavo-ofloxacin amide groups) -6- provided by the invention
(1H)-ketone -3- carboxylic acid compound in vitro antitumor activity assay
1, test sample
Experimental group is the fluoro- 7- piperazine -1- base-naphthalene of 1- (N- lavo-ofloxacin amide groups) -6- shown in Formulas I of the invention
Pyridine -4 (1H) -one -3- carboxylic acid, control group are quinolinones flouroquinolone drugs lavo-ofloxacin (LOF), the similar fluorine quinoline promise of naphthyridines
Ketone drug Enoxacin (EO), classical antitumor TOPO inhibitor 10-hydroxycamptothecine (HC) and broad-spectrum anti-tumor medicine cis-platinum
(CP), totally 5 kinds of test samples；
Experimental cancer cell line is respectively human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 thin
Born of the same parents' strain is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.Normal cell uses VERO African green monkey kidney cell, and purchase is logical in Shanghai
Growth Science and Technology Ltd..
2, measuring method
The specific steps of measuring method are as follows:
(1) it uses dimethyl sulfoxide (DMSO) to dissolve respectively above-mentioned 5 kinds of test samples first, is configured to 1.0 × 10- 2mol·L-1The RPMI-1640 culture solution of the stock solution of concentration, the calf serum for being later 10% with mass percent concentration will
Stock solution is diluted to 5 concentration gradients (0.1,1.0,5.0,10.0,50.0 μm of olL-1) working solution；
Human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and the human leukemia HL60 cell of logarithmic growth phase
And VERO cell strain, with 6000, every hole cell inoculation in 96 orifice plates, be then separately added into above-mentioned 10 kinds of samples has 5
The working solution of concentration gradient.5gL is added in every hole after culture 48 hours–110 μ L of MTT (thiazolyl blue) solution continues culture 4 hours
Lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10% is added afterwards to be further cultured for 24 hours, then uses enzyme
Mark instrument measures respective absorbance (OD) value at 570nm wavelength；
(3) inhibiting rate of the test sample to cancer cell of various concentration is calculated by using the formula shown below,
Cancer inhibition rate=[(1- experimental group OD value)/control group OD value] × 100%,
Then linear regression is made to the corresponding cancer inhibition rate of each concentration with the logarithm of each concentration of test sample, obtained
To dose-effect equation, each test sample is calculated to the half-inhibitory concentration of experiment cancer cell from gained dose-effect equation
(IC50)；Each data are measured in parallel three times, are averaged, the results are shown in Table 1.
Anti-tumor activity (the IC of each test sample of table 150)
Two, the fluoro- 7- piperazine -1- base-naphthyridines -4 of a kind of 1- (N- lavo-ofloxacin amide groups) -6- provided by the invention
The measurement of (1H)-ketone -3- carboxylic acid compound antibacterial activity in vitro
1, test sample
Experimental group is the fluoro- 7- piperazine -1- base-naphthalene of 1- (N- lavo-ofloxacin amide groups) -6- shown in Formulas I of the invention
Pyridine -4 (1H) -one -3- carboxylic acid, control group are quinolinones flouroquinolone drugs lavo-ofloxacin (OF) and naphthyridones fluorine quinoline promise
Ketone drug Enoxacin (EO) and beta-lactam Amoxicillin (AC), totally 4 kinds of test samples；2, experiment bacterial strain and culture
Base
Experiment bacterial strain is respectively Gram-positive S staphylococcus S.aureus ATCC-29213, resistance to methoxy west
Woods staphylococcus aureus S.aureus ATCC-25923 (MRSA), feminine gender escherichia coli E.coli ATCC-25922 and
Pseudomonas aeruginosa p.aeruginosa ATCC27853, culture medium are beef extract-peptone, are faced by He'nan University Huaihe River
Bed clinical laboratory, medical college provides.
3, the preparation of test sample medical fluid is tested
Precision weighs above-mentioned 4 kinds of test samples, is configured to 256 μ g/ with the acetic acid distilled water solution that mass fraction is 1%
The test sample solution of mL concentration, the filter membrane degerming of 0.22 μm of state, 4 DEG C of storage are spare.
4, bacteriostatic experiment measuring method
The specific steps of measuring method are as follows:
Using the minimum inhibitory concentration (MIC) of test tube doubling dilution method measurement test sample.Each test sample takes dress
There is the pipe of 2ml culture medium 10, arranges on rack for test tube, number.It is inoculated with staphylococcus aureus S.aureus ATCC-29213, resistance to first
Oxygen XiLin staphylococcus aureus S.aureus ATCC-25923 (MRSA), feminine gender escherichia coli E.coli ATCC-
25922 or pseudomonas aeruginosa P.aeruginosa ATCC27853.Then it is added in I branch test tube with sterile working for examination
Sample solution 2ml, shakes up, and draws 2ml and is added in the second pipe, shakes up, be diluted to the 8th test tube with method, discard 2ml.It is above each
The dilution bacterium solution (10 being ready in advance is added in test tube5cfu/ml)0.1ml.The bacterium solution of 0.1ml is only added as sun in 9th test tube
Property control；10th test tube mixes after the test sample liquid of 2ml is only added, and discards 2ml, and bacterium solution is not added as negative in remaining 2ml
Control.Staphylococcus aureus S.aureus ATCC-29213, methicillin-resistant staphylococcus aureus S.aureus will be added
ATCC-25923 (MRSA), negative escherichia coli E.coli ATCC-25922, pseudomonas aeruginosa
Each pipe of P.aeruginosa ATCC27853 is placed in 37 DEG C and cultivates 24 hours, visually observes the growing state of bacterium in each pipe,
Determine minimum inhibitory concentration MIC.Each data are measured in parallel three times, are averaged, be the results are shown in Table shown in 2.
The antibacterial activity in vitro (MIC) of each test sample of table 2
As it can be seen from table 1 the compound that Formulas I provides is significantly stronger than parent to the inhibitory activity of 3 kinds of cancer cells of experiment
The activity for closing object lavo-ofloxacin (OF) and Enoxacin (EO), to the IC of three kinds of experimental cancer cell lines50Value has reached micromole
Concentration shows broad spectrum activity in the same order of magnitude with antineoplastic is compareed, while showing low toxicity to VERO cell,
There is stronger selectivity to tumour cell.Antibacterial activity in vitro (table 2) the result shows that, the antibacterial activity of compound of formula I with it is right
Quite according to the activity of lavo-ofloxacin (OF) and Enoxacin (EO), especially more sensitive to persister MRSA, to development overriding resistance
Property antimicrobial is of great significance.Therefore, show that Formula I is one by the extracorporeal anti-tumor antibacterial activity of Formula I
A rare candidate compound with double efficacy effects, the general way according to drug development are the external anti-of first progress routine
Bacterium anti-tumor i n vitro test, is then targetedly studied, thus the compound of the present invention have strong antibacterial anti-tumor activity and
Lower toxicity, can be by being mixed with economic benefits and social benefits antibacterial anti-tumor drug with acid human-acceptable at salt or with pharmaceutical carrier.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6-, it is characterised in that: chemistry knot
Structure is shown below:
。
2. the preparation side of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- described in claim 1
Method, it is characterised in that steps are as follows:
(1) using fluorine chloronicotinoyl ester as raw material, 2- (2, the 6- bis- chloro- fluoro- nicotinoyl base of 5-)-is made with triethyl orthoformate condensation reaction
3- ethyoxyl-ethyl acrylate；
(2) using lavo-ofloxacin as raw material, hydrazinolysis is carried out with hydrazine hydrate and reacts obtained lavo-ofloxacin hydrazides；
(3) 2- (2, the 6- bis- chloro- fluoro- nicotinoyl base of the 5-) -3- ethyoxyl-ethyl acrylate obtained step (1) and step (2) obtain
To lavo-ofloxacin hydrazides carry out contracting cyclization reaction, be made 1- (N- lavo-ofloxacin amide groups) chloro- naphthyridones of the fluoro- 7- of -6-
Acetoacetic ester midbody compound；
The structural formula of the chloro- nalidixic acid ethyl ester intermediate compound of 1- (N- lavo-ofloxacin amide groups) the fluoro- 7- of -6- is such as
Under:
；
(4) the chloro- nalidixic acid ethyl ester intermediate chemical combination of 1- (N- lavo-ofloxacin amide groups) the fluoro- 7- of -6- obtained with step (3)
Object is reacted with piperazine condensation, is made among the fluoro- 7- piperazine -1- base-nalidixic acid ethyl ester of 1- (N- lavo-ofloxacin amide groups) -6-
Body compound；
The fluoro- 7- piperazine -1- base of 1- (N- lavo-ofloxacin the amide groups) -6--nalidixic acid ethyl ester intermediate compound knot
Structure formula is as follows:
；
(5) in the fluoro- 7- piperazine -1- base-nalidixic acid ethyl ester of 1- (N- lavo-ofloxacin amide groups) -6- obtained step (4)
Reaction is hydrolyzed in intermediate compounds therefor, and the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- is made.
3. the system of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- according to claim 2
Preparation Method, it is characterised in that: lavo-ofloxacin hydrazides and 2- (2, the 6- bis- chloro- fluoro- nicotinoyl base of 5-) -3- second in the step (3)
Oxygroup-ethyl acrylate molar ratio is 1:(1.0-1.5).
4. the system of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- according to claim 2
Preparation Method, it is characterised in that: the chloro- nalidixic acid ethyl ester of 1- (N- lavo-ofloxacin amide groups) the fluoro- 7- of -6- in the step (4)
The molar ratio of midbody compound and piperazine is 1:(1.0-1.5).
5. the system of the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- according to claim 2
Preparation Method, it is characterised in that: the fluoro- 7- piperazine -1- base-naphthyridones of 1- (N- lavo-ofloxacin amide groups) -6- in the step (5)
In alkalinity or acid medium hydrolysis occurs for acetoacetic ester midbody compound.
6. the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- of any of claims 1 or 2 is being made
Application in standby antibacterial anti-tumor drug.
7. the fluoro- 7- piperazine nalidixic acid compound of 1- (N- lavo-ofloxacin amide groups) -6- according to claim 6 is being made
Application in standby antibacterial anti-tumor drug, it is characterised in that: the anti-tumor drug is treatment cancer of pancreas, liver cancer or leukaemia
Drug.
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| CN103764631A (en) * | 2011-08-31 | 2014-04-30 | 大塚制药株式会社 | Quinolone compound |
| CN104557973A (en) * | 2014-12-23 | 2015-04-29 | 河南大学 | 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative |
| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103764631A (en) * | 2011-08-31 | 2014-04-30 | 大塚制药株式会社 | Quinolone compound |
| CN104557973A (en) * | 2014-12-23 | 2015-04-29 | 河南大学 | 3,3'-methene-difluoroquinolone derivative of chiral oxazine quinoline ring as well as preparation method and application of 3,3'-methene-difluoroquinolone derivative |
| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
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