CN106432076B - A kind of Ciprofloxacin C3 amide derivatives and its preparation method and application - Google Patents
A kind of Ciprofloxacin C3 amide derivatives and its preparation method and application Download PDFInfo
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- CN106432076B CN106432076B CN201610819187.7A CN201610819187A CN106432076B CN 106432076 B CN106432076 B CN 106432076B CN 201610819187 A CN201610819187 A CN 201610819187A CN 106432076 B CN106432076 B CN 106432076B
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- ciprofloxacin
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960003405 ciprofloxacin Drugs 0.000 title claims abstract description 35
- 150000001408 amides Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 claims abstract description 10
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 13
- -1 m-methoxyphenyl Chemical group 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 7
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 231100000489 sensitizer Toxicity 0.000 claims description 5
- 238000007445 Chromatographic isolation Methods 0.000 claims description 4
- 238000011097 chromatography purification Methods 0.000 claims description 4
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 claims description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 230000002195 synergetic effect Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 3
- 230000001408 fungistatic effect Effects 0.000 abstract description 3
- 238000005292 vacuum distillation Methods 0.000 abstract 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 26
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 17
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- 239000007788 liquid Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ANFBUVUHZHKENQ-UHFFFAOYSA-N benzene;chloroamine Chemical compound ClN.C1=CC=CC=C1 ANFBUVUHZHKENQ-UHFFFAOYSA-N 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of Ciprofloxacin C3 amide derivatives and its preparation method and application.Ciprofloxacin C3 amide derivatives have the structure of general formula (I).Ciprofloxacin Hydrochloride is added in excessive methylene chloride, it is 7.5-8.5 that triethylamine, which is added dropwise, and adjusts the pH of reaction solution, then plus suitable ethyl chloroformate, return stirring becomes to reaction solution and clarifies at 20 DEG C, then triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, add arylamine, continue reflux 1-2 hours, cooling, vacuum distillation, concentration, obtains target product.Ciprofloxacin C3 amide derivatives provided by the invention have preferable sound photodynamic activity, are substantially better than Ciprofloxacin with supersonic synergic fungistatic effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is specifically related to a kind of Ciprofloxacin C3 amide derivatives and preparation method thereof
With the application in field of medicaments.
Background technique
Sound motivation therapy is the feature strong using ultrasonic penetration power, in conjunction with the new method of sound sensitiser treatment tumour, ultrasonic wave
It penetrates tissue and excites the sound sensitiser being gathered in tumor tissues, generating has the active active oxygen of Strong oxdiative, such as singlet oxygen, certainly
By base etc., the substrate of Oxidative demage tumor cell proliferation leads to death of neoplastic cells.In recent years, result of study discovery cyclopropyl is husky
Star not only shows certain anti-tumor activity, also has certain quick property of sound, certain structural modification is carried out to Ciprofloxacin
It is possible that obtaining antitumor action preferably has the sound sensitiser of potential applicability in clinical practice.Currently, there has been no Ciprofloxacin C3 amides
The research of derivative and its sound photodynamic activity is reported.
Summary of the invention
The object of the present invention is to provide a kind of Ciprofloxacin C3 amide derivatives.
The object of the invention is also to provide a kind of preparation methods of Ciprofloxacin C3 amide derivatives.
The object of the invention is also to provide a kind of application of Ciprofloxacin C3 amide derivatives in supersonic synergic is antibacterial.
In order to achieve the goal above, the technical solution adopted by the present invention is that: a kind of Ciprofloxacin C3 amide derivatives have
The structure of general formula (I):
Wherein, Ar is phenyl, substituted-phenyl, heterocyclic arene or substituted heterocycle aromatic hydrocarbons.Preferably, the Ar is selected to first
Phenyl, rubigan, m-methoxyphenyl, benzyl or naphthylamine base.
A kind of preparation method of Ciprofloxacin C3 amide derivatives, comprising the following steps: be added to Ciprofloxacin Hydrochloride
Then plus suitable ethyl chloroformate in excessive methylene chloride, it is 7.5-8.5,20 that triethylamine, which is added dropwise, and adjusts the pH of reaction solution
Return stirring becomes to reaction solution and clarifies at DEG C, and triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, and arylamine is added, continues back
Stream 0.5-1 hours, it is cooling, it is evaporated under reduced pressure, concentration obtains target product.
A kind of preparation method of above-mentioned Ciprofloxacin C3 amide derivatives, including purification step: target product is used
Column chromatographic isolation and purification, eluant, eluent are the mixed liquor of ethyl acetate and petroleum ether.Preferably, by volume, ethyl acetate: petroleum
Ether=1:1
A kind of preparation method of above-mentioned Ciprofloxacin C3 amide derivatives, the arylamine is para-aminotoluene, to ammonia
Base chlorobenzene, m-anisidine, benzylamine or naphthalidine.
A kind of preparation method of above-mentioned Ciprofloxacin C3 amide derivatives, in molar ratio, Ciprofloxacin Hydrochloride: chloro-carbonic acid
Ethyl ester: arylamine=1:1-2:1-1.5.
Ciprofloxacin C3 amide derivatives of the invention are preparing the application in sound power anti-tumor drug and antibacterial medicines.
It is used to prepare sound sensitiser drug.
Reaction equation of the invention is as follows:
The beneficial effects of the present invention are: simple synthetic method of the present invention, safety, easy post-processing.And target product and super
Bacteriostasis under sound synergistic effect is higher than Ciprofloxacin parent nucleus, has better sound photodynamic activity compared with Ciprofloxacin.So this
Invent the target compound provided and supersonic synergetic effect has higher bacteriostatic activity when bacterium.It can be by that can be connect with human body
The acid received is mixed for the high efficiency antibacterial medicines under sound dynamic therapy method at salt or with pharmaceutical carrier.
Specific embodiment
Technical solution of the present invention is described in detail below by specific example.
Embodiment 1
(1) the fluoro- 1,4- dihydro -4- oxo -7- of 1- cyclopropyl -6- [1- (4- carbethoxyl group) piperazine provided in this embodiment
Base] quinoline -3- (N- p-methylphenyl) formamide, structural formula is as follows:
(2) preparation method
The Ciprofloxacin Hydrochloride for weighing 3.8582g is added in round-bottomed flask, after the drying of 50mL anhydrous sodium sulfate is added
Triethylamine of the 20mmol anhydrous sodium sulfate after dry is gradually added dropwise to reaction solution, adjusted anti-by methylene chloride, 38 DEG C of heating stirrings
Answering liquid pH is 7.5-8.5.Then, 15mmol ethyl chloroformate is slowly added dropwise to reaction solution in half an hour, reflux is stirred at 20 DEG C
It mixes to reaction solution to become and clarify.Appropriate triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, add 10mmol to amino first
Benzene continues half an hour of flowing back.It after reaction solution is cooling, is evaporated under reduced pressure, concentration obtains canescence crude product.It is pure using column chromatography for separation
Change (eluant, eluent is ethyl acetate: petroleum ether 1:1) and obtains final product 0.8g, yield 13.33%.
Fusing point is 202 DEG C.
1H NMR(600MHz,CDCl3) δ 12.11 (t, 1H ,-CONH-), 8.89 (s, 1H, quinoline ring 2-H), 8.06-8.09
(d, 1H, J=13.0Hz, quinoline ring 5-H), 7.64-7.65 (d, 2H, J=8.3Hz, phenyl ring-H), 7.33-7.34 (d, 1H, J=
7.0Hz, quinoline ring 8-H), 7.15-7.16 (d, 2H, J=8.2Hz, phenyl ring-H), 4.18-4.22 (dd, 2H, J=7.1Hz ,-
OCH2), 3.71 (t, 4H, piperazine ring-H), 3.48-3.52 (dt, 1H, J=10.8Hz, cyclopropyl ring 1'-H), 3.25-3.26 (t,
4H, piperazine ring-H), 2.33 (s, 3H ,-CH3), 1.34-1.37 (q, 2H, J=6.7Hz, cyclopropyl ring 3'-H), 1.29-1.32 (t,
3H,-CH3), 1.18-1.21 (q, 2H, J=6.5Hz, cyclopropyl ring 2'-H).
MS(m/z):493.28[M+H]+, calculate 492.22.
Embodiment 2
(1) the fluoro- 1,4- dihydro -4- oxo -7- of 1- cyclopropyl -6- [1- (4- carbethoxyl group) piperazine provided in this embodiment
Base] quinoline -3- (N- rubigan) formamide, structural formula are as follows:
(2) preparation method
The Ciprofloxacin Hydrochloride for weighing 3.8582g is added in round-bottomed flask, after the drying of 50mL anhydrous sodium sulfate is added
Triethylamine of the 20mmol anhydrous sodium sulfate after dry is gradually added dropwise to reaction solution, adjusted anti-by methylene chloride, 38 DEG C of heating stirrings
Answering liquid pH is 7.5-8.5.Then, 15mmol ethyl chloroformate is slowly added dropwise to reaction solution in half an hour, reflux is stirred at 20 DEG C
It mixes to reaction solution to become and clarify.Appropriate triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, add 10mmol to amino chlorine
Benzene continues half an hour of flowing back.Liquid is evaporated under reduced pressure after reaction solution is cooling, and concentration obtains canescence crude product.It is pure using column chromatography for separation
Change (eluant, eluent is ethyl acetate: petroleum ether 1:1) and obtains final product 0.8g, yield 15.68%.
Fusing point is 243 DEG C.
1H NMR(600MHz,CDCl3) δ 12.28 (t, 1H ,-CONH-), 8.87 (s, 1H, quinoline ring 2-H), 8.06-8.08
(d, 1H, J=13.0Hz, quinoline ring 5-H), 7.70-7.71 (d, 2H, J=8.8Hz, phenyl ring-H), 7.34-7.35 (d, 1H, J=
7.0Hz, quinoline ring 8-H), 7.29-7.30 (d, 2H, J=8.8Hz, phenyl ring-H), 4.18-4.22 (dd, 2H, J=7.1Hz ,-
OCH2), 3.71-3.72 (t, 4H, piperazine ring-H), 3.49-3.52 (dt, 1H, J=10.8Hz, cyclopropyl ring 1'-H), 3.26-
3.27 (t, 4H, piperazine ring-H), 1.35-1.38 (q, 2H, J=6.7Hz, cyclopropyl ring 3'-H), 1.29-1.32 (t, 3H ,-CH3),
1.19-1.21 (q, 2H, J=6.5Hz, cyclopropyl ring 2'-H).
MS(m/z):513.16[M+H]+, calculate 512.16.
Embodiment 3
(1) the fluoro- 1,4- dihydro -4- oxo -7- of 1- cyclopropyl -6- [1- (4- carbethoxyl group) piperazine provided in this embodiment
Base] quinoline -3- (N- methoxyphenyl) formamide, structural formula are as follows:
(2) preparation method
The Ciprofloxacin Hydrochloride for weighing 3.8582g is added in round-bottomed flask, after the drying of 50mL anhydrous sodium sulfate is added
Triethylamine of the 20mmol anhydrous sodium sulfate after dry is gradually added dropwise to reaction solution, adjusted anti-by methylene chloride, 38 DEG C of heating stirrings
Answering liquid pH is 7.5-8.5.Then, 15mmol ethyl chloroformate is slowly added dropwise to reaction solution in half an hour, reflux is stirred at 20 DEG C
It mixes to reaction solution to become and clarify.Appropriate triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, adds the meta-methoxy of 10mmol
Aniline continues half an hour of flowing back.Liquid is evaporated under reduced pressure after reaction solution is cooling, and concentration obtains canescence crude product.Using column chromatography for separation
It purifies (eluant, eluent: ethyl acetate: petroleum ether 1:1) and obtains final product 0.8g, yield 12.61%.
Fusing point is 211 DEG C.
1H NMR(600MHz,CDCl3) δ 12.20 (t, 1H ,-CONH-), 8.86 (s, 1H, quinoline ring 2-H), 8.05-8.07
(d, 1H, J=13.0Hz, quinoline ring 5-H), 7.51 (s, 1H, phenyl ring-H), 7.31-7.33 (d, 1H, J=7.0Hz, phenyl ring-H),
7.27 (s, 1H, quinoline ring 8-H), 7.21-7.22 (d, 1H, J=7.9Hz, phenyl ring-H), 6.65-6.66 (d, 1H, J=7.1Hz,
Phenyl ring-H), 4.18-4.21 (dd, 2H, J=7.1Hz ,-OCH2-),3.83(s,3H,-OCH3), 3.71 (t, 4H, piperazine ring-H),
3.48-3.52 (dt, 1H, J=10.8Hz, cyclopropyl ring 1'-H), 3.23-3.25 (t, 4H, piperazine ring H), 1.33-1.37 (q, 2H,
J=6.6Hz, cyclopropyl ring 3'-H), 1.29-1.31 (t, 3H ,-CH3), 1.19-1.21 (q, 2H, J=6.5Hz, cyclopropyl ring 2'-
H)。
MS(m/z):509.19[M+H]+.Calculate 508.21
Embodiment 4
(1) the fluoro- 1,4- dihydro -4- oxo -7- of 1- cyclopropyl -6- [1- (4- carbethoxyl group) piperazine provided in this embodiment
Base] quinoline -3- formyl benzylamine, structural formula are as follows:
(2) preparation method
The Ciprofloxacin Hydrochloride for weighing 3.8582g is added in round-bottomed flask, after the drying of 50mL anhydrous sodium sulfate is added
Triethylamine of the 20mmol anhydrous sodium sulfate after dry is gradually added dropwise to reaction solution, adjusted anti-by methylene chloride, 38 DEG C of heating stirrings
Answering liquid pH is 7.5-8.5.Then, 15mmol ethyl chloroformate is slowly added dropwise to reaction solution in half an hour, reflux is stirred at 20 DEG C
It mixes to reaction solution to become and clarify.Appropriate triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, adds the benzylamine of 10mmol, after
Continuous reflux half an hour.Liquid is evaporated under reduced pressure after reaction solution is cooling, and concentration obtains canescence crude product.It (is washed using column chromatographic isolation and purification
De- agent: ethyl acetate: petroleum ether 1:1) obtain final product 0.8g, yield 19.29%.
Fusing point is 140-142 DEG C.
1H NMR(600MHz,CDCl3) δ 10.36 (t, 1H ,-CONH-), 8.86 (s, 1H, quinoline ring 2-H), 8.02-8.05
(d, 1H, J=13.1Hz, quinoline ring 5-H), 7.37-7.38 (d, 1H, J=7.5Hz, phenyl ring-H), 7.33 (dd, 2H, J=
7.3Hz, phenyl ring-H), 7.31 (s, 1H, quinoline ring 8-H), 7.23-7.25 (d, 1H, phenyl ring-H), 4.18-4.21 (dd, 2H, J=
7.1Hz,-OCH2-),3.71(t,2H,-CH2), 3.44-3.47 (dt, 1H, J=10.8Hz, cyclopropyl ring 1'-H), 3.24-3.26
(t, 4H, piperazine ring-H), 1.33-1.35 (q, 2H, J=6.7Hz, cyclopropyl ring 3'-H), 1.29-131 (t, 3H ,-CH3),1.17
(q, 2H, J=2.9Hz, cyclopropyl ring 2'-H).
MS(m/z):493.31[M+H]+, calculate 492.22.
Embodiment 5
(1) the fluoro- 1,4- dihydro -4- oxo -7- of 1- cyclopropyl -6- [1- (4- carbethoxyl group) piperazine provided in this embodiment
Base] quinoline -3- formyl alpha naphthylamine, structural formula are as follows:
(2) preparation method
The Ciprofloxacin Hydrochloride for weighing 3.8582g is added in round-bottomed flask, after the drying of 50mL anhydrous sodium sulfate is added
Triethylamine of the 20mmol anhydrous sodium sulfate after dry is gradually added dropwise to reaction solution, adjusted anti-by methylene chloride, 38 DEG C of heating stirrings
Answering liquid pH is 7.5-8.5.Then, 15mmol ethyl chloroformate is slowly added dropwise to reaction solution in half an hour, reflux is stirred at 20 DEG C
It mixes to reaction solution to become and clarify.Appropriate triethylamine is added dropwise into reaction solution makes pH 7.5-8.5, adds the naphthalidine of 10mmol,
Continue half an hour of flowing back.Liquid is evaporated under reduced pressure after reaction solution is cooling, and concentration obtains canescence crude product.Using column chromatographic isolation and purification
(eluant, eluent: ethyl acetate: petroleum ether 1:1) obtains final product 0.8g, yield 9.21%.
Fusing point is 236-238 DEG C.
1H NMR(600MHz,CDCl3) δ 12.84 (t, 1H-CONH-), 8.97 (s, 1H, quinoline ring 2-H), 8.51-8.52
(d, 1H, J=7.5Hz, naphthalene nucleus-H), 8.39-8.40 (d, 1H, J=8.5Hz, naphthalene nucleus-H), 8.18-8.20 (d, 1H, J=
13.0Hz, quinoline ring 5-H), 7.86-7.87 (d, 1H, J=8.1Hz, naphthalene nucleus-H), 7.62-7.65 (dd, 2H, J=11.7Hz,
Naphthalene nucleus-H), 7.35-7.36 (d, 1H, J=7.0Hz, quinoline ring 8-H), 4.18-4.22 (dd, 2H, J=7.1Hz ,-OCH2-),
3.71-3.72 (t, 4H, piperazine ring-H), 3.49-3.52 (dt, 1H, J=10.8Hz, cyclopropyl ring 1'-H), 3.26-3.27 (t,
4H, piperazine ring-H), 1.35-1.38 (q, 2H, J=6.6Hz, cyclopropyl ring 3'-H), 1.30-1.32 (t, 3H ,-CH3),1.19-
1.21 (q, 2H, J=6.5Hz, cyclopropyl ring 2'-H)；
MS(m/z):529.22[M+H]+, calculate 528.22.
Bacteriostatic activity under 6 Ciprofloxacin C3 amide derivatives of embodiment and supersonic synergetic effect
Ciprofloxacin is compareed similar in the Ciprofloxacin C3 amide derivatives and its structure provided with embodiment 1,2,4 and 5
For test sample, the medicine storage liquid of 0.5g/L concentration is made into dimethyl sulfoxide (DMSO) respectively.
Take respectively 60 μ l of medicine storage liquid move into 10ml sterile saline in be diluted, then by the drug solution with
Cfu value is 107The Escherichia coli of the order of magnitude mix and carry out ultrasonic irradiation 45min.Bacterium solution after ultrasonic irradiation is classified
After being diluted in denumerable range, coated plate culture is carried out, in cultivating 24 hours in 37 DEG C of incubators.And cultured bacterium is carried out
It counts.Each drug is calculated according to the following formula to the bacteriostasis rate of bacterium.
Bacterium bacteriostasis rate (%)=[(non-dosing group bacterial population-dosing group bacterial population)/non-dosing group bacterial population] × 100%
Then it is calculated according to bacterial population after various derivatives ultrasonic treatment, show that different derivatives and supersonic synergic are made
Bacteriostasis rate under the conditions of.It the results are shown in Table 1, the Ciprofloxacin C3 amide derivatives and supersonic synergic condition provided for each embodiment
Under bacteriostasis rate data.
Table 1 is at ultrasound environments and 20 DEG C to antibacterial situation after Escherichia coli ultrasonic irradiation 45min
| Medicine name | Embodiment 1 | Embodiment 2 | Embodiment 4 | Embodiment 5 | Ciprofloxacin |
| Bacteriostasis rate | 94.97% | 88.67% | 98.05% | 93.33% | 75% |
From table 1 it follows that after each Ciprofloxacin C3 derivative and supersonic synergetic effect that embodiment 1,2,4,5 provides
Antibacterial situation be better than the fungistatic effect of control drug Ciprofloxacin, this shows that each cyclopropyl that embodiment 1,2,4,5 provides is husky
Star C3 derivative and combination of ultrasound can produce apparent collaboration bacteriostasis.So compound provided by the invention and ultrasound are tied
Conjunction can produce apparent collaboration fungistatic effect, therefore, can be by mixing system with acid human-acceptable at salt or with pharmaceutical carrier
For at for the high efficiency antibacterial medicines under sound dynamic therapy method.
Claims (8)
1. a kind of Ciprofloxacin C3 amide derivatives, which is characterized in that the structure with general formula (I):
Wherein, Ar is p-methylphenyl, rubigan, m-methoxyphenyl or benzyl.
2. a kind of preparation method of Ciprofloxacin C3 amide derivatives according to claim 1, which is characterized in that including with
Lower step: Ciprofloxacin Hydrochloride is added in excessive methylene chloride, and it is 7.5- that triethylamine, which is added dropwise, and adjusts the pH of reaction solution
Then plus suitable ethyl chloroformate 8.5, return stirring becomes to reaction solution and clarifies at 20 DEG C, and triethylamine is added dropwise into reaction solution
Make pH 7.5-8.5, arylamine is added, continues reflux 0.5-1 hours, it is cooling, it is evaporated under reduced pressure, concentration obtains target product.
3. a kind of preparation method of Ciprofloxacin C3 amide derivatives according to claim 2, which is characterized in that including pure
Change step, target product is used into column chromatographic isolation and purification, eluant, eluent is the mixed liquor of ethyl acetate and petroleum ether.
4. a kind of preparation method of Ciprofloxacin C3 amide derivatives according to claim 3, which is characterized in that press volume
Than ethyl acetate: petroleum ether=1:1.
5. a kind of preparation method of Ciprofloxacin C3 amide derivatives according to claim 2,3 or 4, which is characterized in that
The arylamine is para-aminotoluene, to amino-chloro-benzene, m-anisidine or benzylamine.
6. a kind of preparation method of Ciprofloxacin C3 amide derivatives according to claim 2,3 or 4, which is characterized in that
In molar ratio, Ciprofloxacin Hydrochloride: ethyl chloroformate: arylamine=1:1-2:1-1.5.
7. Ciprofloxacin C3 amide derivatives according to claim 1 are preparing sound power anti-tumor drug and antibacterial medicines
In application.
8. application according to claim 7, which is characterized in that Ciprofloxacin C3 amide derivatives are preparing sound sensitiser drug
In application.
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