CN106588773B - A kind of Brain targeting eslicarbazepine ester prodrug and its application - Google Patents

A kind of Brain targeting eslicarbazepine ester prodrug and its application Download PDF

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CN106588773B
CN106588773B CN201611039363.1A CN201611039363A CN106588773B CN 106588773 B CN106588773 B CN 106588773B CN 201611039363 A CN201611039363 A CN 201611039363A CN 106588773 B CN106588773 B CN 106588773B
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dihydro
azepine
dibenzo
carboxamide
acyloxy
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CN106588773A (en
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顾景凯
张扬
杨志超
尹磊
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Beijing Institute Of Modern Drug Metabolism
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Beijing Institute Of Modern Drug Metabolism
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention is a kind of eslicarbazepine ester prodrug and its application, which is the optical isomer, physiological acceptable salt of formula (I) compound or formula (I) compound, wherein R represents fat-soluble substituent group.Formula (Ι) compound is the eslicarbazepine prodrug containing fat-soluble substituent group, it is in vivo that eslicarbazepine plays pharmacological action through metabolic conversion, can be applied to the drug of preparation treatment, prevention and treatment or adjuvant treatment such as epilepsy central nervous system disease.

Description

A kind of Brain targeting eslicarbazepine ester prodrug and its application
Technical field
The present invention relates to field of medicaments, and in particular to a kind of eslicarbazepine ester prodrug and its application, such chemical combination Object has preferable distribution in big intracerebral, applies treating or assisting in the treatment of such as epilepsy central nervous system disease field.
Background technique
Listing the carbamazepine (CBZ) the 1960s is first generation dibenzazepine class antiepileptic (Antiepileptic drugs, AEDs) is mainly used for the uncontrollable grand mal of the other drugs such as dilantin sodium, to the greatest extent It manages curative for effect, but still there is the patient of 30-40% not to be resistant to, 33%-50% patient is subjected to unnecessary adverse reaction (Epilepsia,1996,37(s2):S1-S3.).Oxcarbazepine (OXC) is the 10- ketone group derivative of CBZ, belongs to the second generation two Benzazepine class AEDs, clinical application and CBZ are known each other, but adverse reaction is slight compared with CBZ, and patient tolerability is good.OXC with Difference of the CBZ in terms of adverse reaction and toxicity can be explained: CBZ by comparing the passway of metabolism (Fig. 1) of the two It is first epoxide M1 by 450 oxydasis of CYP in liver, though the metabolin has certain poison with antiepileptic activity Property, then M1Further it is metabolized as inactive M2And M3, into II phase metabolic response.Unlike CBZ, OXC is several in liver It is completely reduced as the metabolin M with very strong antiepileptic activity4And M5, without generating toxicity epoxide.Therefore, suffer from Person is better than CBZ to the tolerance of OXC.By OXC metabolic pathway it is found that M4Not only there is very strong antiepileptic activity, but also It is main metabolite, is the primer with potentiality to be exploited.
Bial company, Portugal takes the lead in having carried out the research of this respect, with OXC major active metabolite product M4, i.e., (S)- 10- hydroxyl -10,11- dihydro -5H- benzo [b, f] azepine-5-carboxamide (eslicarbazepine) is lead compound, and at Function has developed third generation dibenzazepine Zhuo class AEDs- eslicarbazepine acetate (Eslicarbazepine acetate), in In October, 2009 lists in states such as Germany, Denmark, Austria, for the adjuvant treatment of epilepsy, to improve the curative effect of CBZ and OXC, Improve its tolerance.2012, eslicarbazepine acetate New Drug Application was submitted to U.S. FDA by Japanese Sunovion company, and In in November, 2013 granted listing, trade nameAdjuvant treatment for epilepsy partial seizures.
It is eslicarbazepine (Eslicarbazepine), i.e. M4Pro-drug, into vivo quickly turn Eslicarbazepine is turned to, then small part is oxidized to OXC (Fig. 2), and the two plays antiepileptic action jointly.With CBZ and OXC It compares,It is mainly metabolized through esterase, largely avoids oxidation, the reduction reaction of the mediation of 450 enzyme system of CYP, into And reduce individual difference of the medicine in drug effect and medicine for aspect.In addition, S-LIC half-life period up to 9h, also has no in metabolic process Toxic epoxide.Therefore, the tolerance of eslicarbazepine acetate is more preferable.Clinical test shows to compare with placebo,Epileptic attack number can be significantly reduced, quality of making the life better, while there is good safety and response rate.
Oral absorption is good, into vivo after be quickly converted to main active metabolites eslicarbazepine, And reach C in 1-4hmax.CD-1 mouse is given in single dose stomach-fillingAfter 350mg/kg, only about 30% Ai Sili Oxcarbazepine and OXC are distributed in brain tissue, and eslicarbazepine 1.4 times of blood plasma, shows at 5 times that liver AUC value is brain tissue Eslicarbazepine is difficult to through blood-brain barrier, and brain tissue absorbs deficiency to it, and then serious liver is caused to be accumulated, this is also solved It releasesHighest oral dose the reason of being up to 1200mg/d.
Pro-drug refers to external inactive or active very little, into discharging parent medicine under enzyme or non-enzyme effect after in vivo Object and the compound for playing pharmacological action.It is to improve drug oral biology benefit using the purpose that principle of pro-drug carries out drug modification Expenditure, raising targeting, reduction toxicity, extension drug treating time etc..
Summary of the invention
The purpose of the present invention is to provide a kind of Brain targeting eslicarbazepine prodrug, further increase it is fat-soluble, to , raising brain capture amount strong through blood-brain barrier ability can be improved.
Eslicarbazepine ester prodrug of the present invention is chemical combination shown in compound shown in formula (I) or formula (I) The optical isomer or physiological acceptable salt of object,
Wherein, R represents fat-soluble substituent group；(*) represents chiral centre, can be R or S or RS.
Further, R be 4- methylcyclohexyl, 4- isopropylcyclohexyl, suberyl, 4- aminomethyl phenyl, 2- aminomethyl phenyl, 4- ethylphenyl, 3,4- methylenedioxyphenyl, 2,3- Dimethoxyphenyl, 3,4,5- trimethoxyphenyl, dihydro -1 2,3-, 4- benzdioxan base, phenylpropyl, cinnamyl, 4- methoxybenzene propyl, 3,4- dimethoxy phenylpropyl or meeting formula (II) Substituent group,
Wherein, X O, S, N；R1For the linear chain or branched chain substituent group containing 1~10 carbon atom.
Further, X is O and S, R1For methyl, ethyl, propyl, normal-butyl, isopropyl or cyclopenta.
Further, the salt of formula (I) compound include hydrochloride, hydrobromate, succinate, tartrate, sulfate, The physiological acceptable salts such as phosphate, fumarate, citrate, malate, maleate, acetate.
Representative formula (I) compound includes:
10- (4- methyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-01)
10- (4- isopropyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-02)
10- cycloheptyl acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-03)
10- (4- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-04)
10- (2- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-05)
10- (4- ethyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-06)
10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 07)
10- (2,3- dimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 08)
10- (3,4,5- trimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 09)
10- (2,3- dihydro -1,4- benzdioxan) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- Formamide (I-10)
10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-11)
10- cinnamoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-12)
10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-13)
10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 14)
10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-15)
10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-16)
10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-17)
10- (4- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-18)
10- (2- ethyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-19)
10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-20)
10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-21)
(S) -10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-22)
(S) -10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-23)
(S) -10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 24)
(S) -10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-25)
(S) -10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-26)
(S) -10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-27)
(S) -10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-28)
(S) -10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-29)
(S) -10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-30)。
The administration route of formula (I) compound or pharmaceutically acceptable salt thereof or pharmaceutical composition of the invention includes gastrointestinal tract and non-gastrointestinal Two kinds of approach of canal drug administration.Gastrointestinal administration dosage form include tablet, granule, capsule, pill, emulsion, solution, suspension or Other dosage forms.Parenteral administration mode includes drug administration by injection, such as vein, subcutaneous, muscle, abdominal cavity, dosage form include solution, Suspension, freeze-dried powder, emulsion or other dosage forms；Cutaneous penetration, such as patch, cream, gelling agent；Mucosa delivery, such as bolt Agent etc.；Nasal cavity and inhalation, such as spray, inhalant.Above-mentioned dosage form can be ordinary preparation, be also possible to sustained release, control It releases, target, the special forms such as quick-release or using the pharmaceutical carriers such as microballoon, liposome, bioabsorbable polymer material.Formula of the invention (I) compound or pharmaceutically acceptable salt thereof or pharmaceutical composition can be used for the prevention and treatment or adjuvant treatment of central nervous system disease.Such as treatment With or without secondary generalized seizure adult epilepsy partial seizures, primary generalized tonic-clonic seizure and portion Divide property breaking-out, anxiety disorder, the disturbance of emotion, bipolar disorder, attention deficit disorder, schizoaffective disorders, neuropathic pain, feeling Dyskinesia, vestibular disorder etc..
Beneficial effects of the present invention:
Brain targeting eslicarbazepine prodrug improves the energy that eslicarbazepine penetrates blood-brain barrier (BBB) in the present invention Power contains fat-soluble, the biggish fat-soluble group of steric hindrance in ester group, with the ratio of eslicarbazepine acetate in the prior art Compared with higher brain targeting, with the higher ability through blood-brain barrier, the brain for being effectively improved eslicarbazepine is taken the photograph Taken amount has better drug concentration and longer action time.
Detailed description of the invention
Fig. 1 CBZ and OXC passway of metabolism；
Fig. 2 eslicarbazepine acetate passway of metabolism；
Fig. 3 formula (I) compound structure general formula；
The synthetic route chart of Fig. 4 formula (I) compound.
Specific embodiment
A kind of brain target eslicarbazepine ester prodrug, the prodrug are the light of formula (I) compound or formula (I) compound Isomers, physiological acceptable salt are learned,
Wherein, R represents fat-soluble substituent group；(*) represents chiral centre, can be R or S or RS.
R is 4- methylcyclohexyl, 4- isopropylcyclohexyl, suberyl, 4- aminomethyl phenyl, 2- aminomethyl phenyl, 4- ethylo benzene Base, 3,4- methylenedioxyphenyl, 2,3- Dimethoxyphenyl, 3,4,5- trimethoxyphenyl, 2,3- dihydro -1,4- benzo two Oxane base, phenylpropyl, cinnamyl, 4- methoxybenzene propyl, 3,4- dimethoxy phenylpropyl or meeting formula (II) substituent group,
Wherein, X O, S, N；R1For the linear chain or branched chain substituent group containing 1~10 carbon atom, X is preferably O and S, R1It is preferred that For methyl, ethyl, propyl, normal-butyl, isopropyl or cyclopenta.
The physiological acceptable salt of formula (I) compound be hydrochloride, hydrobromate, succinate, tartrate, sulfate, Phosphate, fumarate, citrate, malate, maleate, acetate.
Formula (I) compound is preferably any one of following compounds:
10- (4- methyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-01)
10- (4- isopropyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-02)
10- cycloheptyl acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-03)
10- (4- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-04)
10- (2- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-05)
10- (4- ethyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-06)
10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 07)
10- (2,3- dimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 08)
10- (3,4,5- trimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 09)
10- (2,3- dihydro -1,4- benzdioxan) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- Formamide (I-10)
10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-11)
10- cinnamoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-12)
10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-13)
10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 14)
10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-15)
10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-16)
10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-17)
10- (4- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-18)
10- (2- ethyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-19)
10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-20)
10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-21)
(S) -10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-22)
(S) -10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-23)
(S) -10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 24)
(S) -10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-25)
(S) -10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-26)
(S) -10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-27)
(S) -10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-28)
(S) -10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-29)
(S) -10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-30)。
Embodiment 1
The synthesis of formula (I) compound
Synthetic route is illustrated in fig. 4 shown below.
With compound I-01~I-16, synthesis for, synthetic method is described further.
At room temperature, (100.0g, 0.4mol) Oxcarbazepine, 400mL methanol and 200mL water are added in 1L round-bottomed flask, (15.0g, 0.4mol) sodium borohydride is added portionwise, the 30min 1h that is placed at 45 DEG C that the reaction was continued is stirred at room temperature.End of reaction, Reaction solution is concentrated under reduced pressure to 200-300mL, filtering washes 3 times, obtains faint yellow solid powder 99.0g, is compound 1, yield 97.3%.m.p.188-192℃.
At room temperature, (9.2mmol) carboxylic acid, (18.4mmol) thionyl chloride and 1 drop pyridine are added in 5mL methylene chloride, Back flow reaction 3h.End of reaction, evaporating solvent under reduced pressure and remaining thionyl chloride obtain compound 2, the not purified direct use of crude product It is reacted in next step.
At room temperature by (3.0g, 11.8mmol) compound 1, (2.8g, 18.4mmol) pyridine, catalytic amount DMAP and 50mL without Water methylene chloride is added in 100mL round-bottomed flask (A)；(14.2mmol) compound 2 is dissolved in spare in anhydrous methylene chloride (B). At 0 DEG C, N2Protection is lower slowly to instill (B) in (A), is added dropwise, reacts at room temperature 1-3h.End of reaction adds into reaction solution Enter 20mL water, be vigorously stirred 5min, then washed three times with 10%HCl, saturated common salt washing is primary.Anhydrous sodium sulfate is dried At night, it is filtered to remove desiccant, evaporating solvent under reduced pressure obtains crude product.Column chromatographs (ethanol/methylene ethanol/methylene (v/v) =1:50~1:30) foaming solid is purified to obtain, a small amount of ether solidifies to obtain white solid powder.
10- (4- methyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-01) is white Color solid powder, yield 53.5%, m.p.154-157 DEG C；1H-NMR(CDCl3)δ0.87(s,3H,-CH3),0.92–1.97(m, 9H,4-methylcyclohexane-CH2-,4-methylcyclohexane-CH),2.23(m,1H,CHCOO-),3.07(m, 1H,C11-H),3.57(m,1H,C11-H),4.80(brs,2H,-NH2),5.99,6.39(2×brs,1H,C10-H),7.19- 7.49(m,8H,Ar-H)；13C-NMR(CDCl3)δ22.31(CH3),28.77,28.97,31.80,34.02,34.07 (cyclohexane-C),35.61(C11),43.11(tertiary C),69.36,71.42(C10),127.66,127.83, 128.07,128.46,128.78,131.12(Ar),134.34,134.60,138.96,140.76,141.80(quaternary C),156.85(NCON),175.10,175.66(CO).
10- (4- isopropyl) hexamethylene acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-02) White solid powder, yield 43.6%, m.p.171-174 DEG C；1H-NMR(CDCl3)δ0.87(m,6H,4- isopropylcyclohexane-CH3),0.95-2.01(m,9H,4-methylcyclohexane-CH2-,4- isopropylcyclohexane-CH),2.23(m,1H,CHCOO-),3.12(m,1H,C11-H),3.57(m,1H,C11-H), 4.85(brs,2H,-NH2),5.73,5.98,6.38(3×brs,1H,C10-H),7.26-7.48(m,8H,Ar-H)；13C-NMR (CDCl3)δ19.66(2C,CH3),28.74,28.79,29.07,29.28,32.68(cyclohexane-C),35.72(C11), 43.23,43.64(tertiary C),58.34,69.42,71.47(C10),127.81,127.90,128.14,128.60, 128.86,129.00,131.29(Ar),134.37,134.79,139.01,140.79,141.89(quaternary C), 156.72(NCON),175.22(2C,CO).HRMS(ESI):m/z calcd.for[M+H]+:407.2335；found: 407.2505.
10- cycloheptyl acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-03)
White solid powder, yield 62.5%, m.p.218-223 DEG C；1H-NMR(CDCl3)δ1.50-1.96(m,12H, cycloheptane-CH2-),2.48(m,1H,CHCOO-),3.09(m,1H,C11-H),3.57(m,1H,C11-H),5.27 (brs,2H,-NH2),5.72,5.98,6.38(3×brs,1H,C10-H),7.26-7.48(m,8H,Ar-H)；13C-NMR (CDCl3)δ26.20(2C),28.16,28.30,30.62,30.84(cycloheptane-C),35.67(C11),45.02 (tertiary C),58.34,69.40,71.42(C10),127.74,127.87,128.11,128.22,128.54,128.83, 131.26(Ar),134.40,134.75,138.99,140.03,140.77,141.99(quaternary C),156.82 (NCON),175.97,176.43(CO)；HRMS(ESI):m/z calcd.for[M+H]+:379.2022；found: 379.2116.
10- (4- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-04)
White solid powder, yield 57.1%, m.p.117-121 DEG C；1H-NMR(CDCl3)δ2.45(m,3H,-CH3), 3.25(m,1H,C11-H),3.81(m,1H,C11-H),4.93(brs,2H,-NH2),5.73,6.24,6.66(3×brs,1H, C10-H),7.26-7.96(m,11H,Ar-H),8.03(m,1H,Ar-H)；13C-NMR(CDCl3)δ21.60(CH3),35.91 (C11),58.36,65.76,72.49(C10),127.15,127.41,127.85,128.31,128.97,129.08,128.79, 130.57,130.93,131.74,133.06,133.86,(Ar),134.77,138.15,138.96,140.86,141.51 (quaternary C),156.82(NCON),166.28,180.27(CO).
10- (2- methyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-05)
White solid powder, yield 49.7%, m.p.124-127 DEG C；HRMS(ESI):m/z calcd.for[M+H]+: 373.1552；found:373.1675.
10- (4- ethyl) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-06)
White solid powder, yield 53.7%, m.p.166-169 DEG C；1H-NMR(CDCl3)δ2.09(m,3H,-CH3), 2.86(m,2H,-CH2-),3.27(m,1H,C11-H),3.74(m,1H,C11-H),4.88(brs,2H,-NH2),5.74,6.25, 6.68(3×brs,1H,C10-H),7.26-7.87(m,11H,Ar-H),8.02(m,1H,Ar-H).
10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 07)
White solid powder, yield 62.4%, m.p.208-212 DEG C；1H-NMR(CDCl3)δ3.21(m,1H,C11-H), 3.73(m,1H,C11-H),4.72(m,2H,-NH2),6.03(s,2H,-OCH2O),6.20,6.64(2×brs,1H,C10-H), 7.21-7.71(m,11H,Ar-H)；13C-NMR(CDCl3)δ35.91,39.32(C11),58.36,70.34,72.68(C10), 101.79(piperonylic-CH2),108.00,109.60,123.87,125.67,127.88,128.03,128.21, 128.33,128.96,129.43,131.00,131.46,131.77,133.11,133.92(Ar,piperonylic- quaternary C),134.79,139.01,140.84,141.41(quaternary C),147.74,151.86 (piperonylic-quaternary C),156.82(NCON),166.28,180.27(CO).
10- (2,3- dimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 08)
White solid powder, yield 48.2%, m.p.153-155 DEG C；1H-NMR(CDCl3)δ3.29(m,1H,C11-H), 3.80(m,7H,-OCH3×2,C11-H),4.84(m,2H,-NH2),6.25,6.67(2×brs,1H,C10-H),7.05-7.45 (m,11H,Ar-H)；13C-NMR(CDCl3)δ35.47(C11),55.71,61.04(OCH3),65.41,70.47,72.23, 72.68(C10),101.79(piperonylic-CH2),115.77,121.87,123.87,125.62,127.36,127.36, 127.87,128.34,128.49,128.90,130.26,130.80,131.49(Ar),133.01,133.98,134.44, 138.90,139.83,140.51,142.22(quaternary C),148.74,153.23(quaternary C),153.23 (NCON),156.72,165.01(CO)；HRMS(ESI):m/z calcd.for[M+H]+:419.1607；found: 419.1697.
10- (3,4,5- trimethoxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 09)
White solid powder, yield 42.9%, m.p.129-132 DEG C；1H-NMR(CDCl3)δ3.18(m,1H,C11-H), 3.84(m,1H,C11-H),3.89(s,9H,-OCH3×3),4.82(brs,2H,-NH2),5.73,6.24,6.68(3×brs, 1H,C10-H),7.17-7.54(m,10H,Ar-H)；HRMS(ESI):m/z calcd.for[M+H]+:449.1713；found: 449.1801.
10- (2,3- dihydro -1,4- benzdioxan) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- Formamide (I-10)
White solid powder, yield 27.5%, m.p.192-195 DEG C；1H-NMR(CDCl3)δ3.27(m,1H,C11-H), 3.71(m,1H,C11-H),4.29(s,2H,-OCH2 CH2O-),4.36(s,2H,-OCH2CH2 O-),4.82(brs,2H,-NH2), 6.21,6.65(2×brs,1H,C10-H),6.79(s,1H,Ar-H),7.02(m,2H,Ar-H),7.27-7.51(m,8H,Ar- H)；13C-NMR(CDCl3)δ35.68(C11),63.65,64.41(-OCH2CH2O-),65.60,70.25,72.23(C10), 119.37,120.13,121.41,123.56(Ar,quaternary C),119.37,120.13(2C),121.41(2C), 123.56,127.59,127.77,128.09,128.65,129.12,130.57,130.92,131.50(Ar),133.50, 134.24,134.71,139.05,139.97,140.69,142.01,143.95,144.40(quaternary C),156.74 (NCON),164.25(CO).
10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-11)
White solid powder, yield 56.2%, m.p.139-142 DEG C；1H-NMR(CDCl3)δ2.67(m,2H,Ar- CH2 -),2.95(m,2H,Ar-CH2 -),3.12(m,1H,C11-H),3.52(m,1H,C11-H),4.84(brs,2H,-NH2), 5.98,6.38,7.00(3×brs,1H,C10-H),6.79(s,1H,Ar-H),7.18-7.46(m,8H,Ar-H)；13C-NMR (CDCl3)δ30.47(2C,CH2),35.40(C11),69.68,71.83(C10),125.65,125.87,127.30,127.33, 127.97(2C),128.05,128.55,128.94,130.44,130.62(Ar),133.17,133.59,133.88, 138.69,139.88,140.11,140.51,140.95(quaternary C),156.72,157.03(NCON),171.47, 171.95(CO)；HRMS(ESI):m/z calcd.for[M+H]+:387.1709；found:387.1803.
10- cinnamoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-12)
White solid powder, yield 49.3%, m.p.145-148 DEG C；1H-NMR(CDCl3)δ3.22(m,1H,C11-H), 3.66(m,1H,C11-H),4.81(brs,2H,-NH2),6.61,6.44,6.55(3×brs,1H,C10-H),7.32(m,10H, Ar-H ,-COHC=CH-), 7.49 (m, 4H, Ar-H), 7.68 (m, 4H, Ar-H)；13C-NMR(CDCl3)δ35.79(C11), 69.94,70.20,72.14(C10),116.99,117.59,117.78,118.36,127.35,128.14(2C),128.83, 129.20(2C),129.97,130.40,130.90(Ar),133.65,134.22,134.54,139.02,140.41, 140.90,141.35(tertiary C,quaternary C),145.57(tertiary C),156.62,156.94 (NCON),165.98,166.41(CO).
10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-13)
White solid powder, yield 61.7%, m.p.137-141 DEG C；1H-NMR(CDCl3)δ3.02(m,1H,C11-H), 3.55(m,1H,C11-H),3.79(s,3H,-OCH3),4.67(m,2H,-NH2),5.98,6.38(2×brs,1H,C10-H), 6.83(m,2H,Ar-H),6.85-7.48(m,10H,Ar-H)；13C-NMR(CDCl3)δ30.07,35.67(CH2),36.19 (C11),55.36(CH3),69.94,70.63,72.49(C10),113.53,113.89,114.23,114.62,127.37, 127.78,128.18,128.78,129.16,129.47,129.85,130.38,130.79,131.04,132.29(Ar, quaternary C),133.66,134.34,138.93,140.29,140.71,141.57(quaternary C),156.58, 156.92,158.14(NCON),172.04,172.52(CO).
10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 14)
White solid powder, yield 57.2%, m.p.109-113 DEG C；1H-NMR(CDCl3)δ3.07(m,1H,C11-H), 3.54(m,1H,C11-H),3.83(s,6H,-OCH3×3),4.78(brs,2H,-NH2),6.00,6.39(2×brs,1H,C10- H),6.73(m,3H,Ar-H),7.21-7.47(m,8H,Ar-H)；13C-NMR(CDCl3)δ30.45,35.60(CH2),36.04 (C11),55.72,55.83(CH3),69.96,72.05(C10),111.34,111.79,120.15,127.70(2C),128.09 (2C),128.75,129.01,130.77,131.61(Ar),132.81,133.75,134.23,134.70,138.91, 140.29,140.71,141.30,147.52,148.87(quaternary C),156.75(NCON),171.88,172.36 (CO).
10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-15)
White solid powder, yield 55.2%, m.p.154-157 DEG C；1H-NMR(CDCl3)δ3.23(m,1H,C11-H), 3.71(m,1H,C11-H),4.81(brs,2H,-NH2),5.73,6.24,6.64(3×brs,1H,C10-H),7.28-7.57(m, 11H,Ar-H,furan-H).HRMS(ESI):m/z calcd.for[M+H]+:349.1188；found:349.1206.
10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-16)
White solid powder, yield 47.5%, m.p.171-174 DEG C；1H-NMR(CDCl3)δ3.25(m,1H,C11-H), 3.72(m,1H,C11-H),4.72(brs,2H,-NH2),5.74,6.23,6.63(3×brs,1H,C10-H),7.28-7.57(m, 11H,Ar-H,thiophene-H)；HRMS(ESI):m/z calcd.for[M+H]+:365.0960；found:365.1007.
By taking compound L -22~L-26 synthesis as an example, synthetic method is described further.
(36.0g, 0.24mol) L- (+)-tartaric acid is added in (95.3g, 0.933mol) acetic anhydride, is dripped at room temperature Add the 2 drop concentrated sulfuric acids, is heated to reflux 10min after stirring 5min.End of reaction, evaporated under reduced pressure solvent are removed water 2 times with 50mL toluene Compound 3,48.0g, yield 92.3%.
(48.0g, 0.22mol) compound 3 is added in 500mL methylene chloride and stirs 2min, be then added (50.8g, 0.2mol) compound 1, (17.5g, 0.22mol) pyridine, (1.0g, 8.0mmol) DMAP, are added after being stirred to react 1h at room temperature 350mL water continues to be stirred to react 12h.End of reaction filtering precipitating, 50mL are washed 3 times, are obtained compound 4,32.82g after dry, are received Rate 42.5%, m.p.226-229 DEG C, [α]D 20=-36 ° (c=1, Py).
(32.0g, 0.083mol) compound 4 is added in 200mL methanol, the sodium hydroxide for being added with stirring 1mol/L is molten Liquid 100mL filters precipitating after reacting 30min at room temperature, 300mL water is added after filtrate steaming removal solvent, in 20 DEG C of moisture-proof standing 16h After filter to obtain white solid, 50mL is washed 2 times.Under heating condition, precipitating is dissolved in 10mL methanol, stands 16h at 5 DEG C, Filtering washes precipitating with the cold ethyl alcohol of 20mL, dry 16g white solid 5, yield 76.3%, and m.p.188-192 DEG C, [α]D 20= 197 ° (c=1, Py)；1H-NMR(CDCl3)δ3.22(m,1H,C11-H),3.68(m,1H,C11-H),4.72(brs,2H,- NH2),5.52(s,1H,-OH),5.71,6.45,6.71(3×brs,1H,C10-H),7.33-7.61(m,8H,Ar-H)；HRMS (ESI):m/z calcd.for[M+H]+:254.1055；found:254.1053.
At room temperature by (3.0g, 11.8mmol) compound 5, (2.8g, 18.4mmol) pyridine, catalytic amount DMAP and 50mL without Water methylene chloride is added in 100mL round-bottomed flask (A)；(14.2mmol) compound 2 is dissolved in spare in anhydrous methylene chloride (B). At 0 DEG C, N2Protection is lower slowly to instill (B) in (A), is added dropwise, reacts at room temperature 1-3h.End of reaction adds into reaction solution Enter 20mL water, be vigorously stirred 5min, then washed three times with 10%HCl, saturated common salt washing is primary.Anhydrous sodium sulfate is dried At night, it is filtered to remove desiccant, evaporating solvent under reduced pressure obtains crude product.Column chromatographs (ethanol/methylene ethanol/methylene (v/v) =1:50~1:30) foaming solid is purified to obtain, a small amount of ether solidifies to obtain white solid powder.
(S) -10- (3,4- methylene-dioxy) benzoyloxy group -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-22)
White solid powder, yield 64.3%, m.p.178-182 DEG C；[α]D 20=-28 ° (c=1, Py)；HRMS(ESI): m/z calcd.for[M+H]+:402.1216；found:402.1219.
(S) -10- phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-23)
White solid powder, yield 62.5%, m.p.121-125 DEG C；[α]D 20=-33 ° (c=1, Py)；HRMS(ESI): m/z calcd.for[M+H]+:386.1630；found:386.1641.
(S) -10- (4- methoxyl group) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 24)
White solid powder, yield 58.3%, m.p.107-110 DEG C；[α]D 20=-38 ° (c=1, Py)；HRMS(ESI): m/z calcd.for[M+H]+:416.1736；found:416.1739.
(S) -10- (3,4- dimethoxy) phenylpropyl alcohol acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine -5- formyl Amine (I-25)
White solid powder, yield 55.7%, m.p.87-91 DEG C；[α]D 20=-41 ° (c=1, Py)；HRMS(ESI):m/ z calcd.for[M+H]+:446.1842；found:446.1839.
(S) -10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-26)
White solid powder, yield 52.1%, m.p.142-146 DEG C；[α]D 20=-24 ° (c=1, Py)；HRMS(ESI): m/z calcd.for[M+H]+:365.0960；found:365.1007.
Embodiment 2
The preliminary screening of formula (I) compound brain capture amount in rat body
Healthy Wistar rat 9 weighs a certain amount of racemic licarbazepine, racemic licarbazepine acetate, I- 03, I-04, I-07, I-11, I-13, I-14, I-16 are added 0.5%CMC-Na physiological saline (containing 0.9%NaCl) solution, press 0.13mmol/kg dosage gastric infusion.Whole blood 0.25mL is taken in 1,5,15,30,45,60,180min rear vein beard after administration, It setting in the test tube of hepari EP pipe containing esterase inhibitor DDV, 3500rpm is centrifuged 5min at 4 DEG C, and separated plasma takes 0.1mL blood plasma ,- 80 DEG C of preservations are to be measured.
Healthy Wistar rat 27.Weigh a certain amount of racemic licarbazepine, racemic licarbazepine acetate, I- 03, I-04, I-07, I-11, I-13, I-14, I-16 are added 0.5%CMC-Na physiological saline (containing 0.9%NaCl) solution, press 0.13mmol/kg dosage gastric infusion.Cervical dislocation is anaesthetized after administration after 30min and 45min to put to death, whole brain is taken out, is placed in 2mL Refrigerated methanol: water (1:1, v:v) solution.Homogenate machine homogeneous 45s is used under low temperature.After ultrasonic 1min, at 4 DEG C 3500rpm from Heart 5min.Upper liquid is pipetted to be placed in 1.5mL EP pipe, it is to be measured in -80 DEG C of freezen protectives.
Several representative formula (I) compounds are selected, I-03, I-04, I-07, I-11, I-13, I-14, I-16 are carried out preliminary Pharmacokinetic Evaluation, and be compared with racemic licarbazepine and racemic licarbazepine acetate.Firstly, preliminary visit The rope T of formula (I) compoundmax, to measure intracerebral drug concentration in range at the time point.The result shows that most formulas (I) Compound reaches peak in 45min individually in 30min.Based on this, to formula (I) compound the big intracerebral of 30min and 45min outer disappearing Rotation licarbazepine content is measured, and average value is shown in Table 1.The result shows that with racemic licarbazepine and racemic benefit cassie Flat acetate is compared, and designed formula (I) compound all has preferable brain capture characteristic, especially I-16, racemic benefit card Xiping brain content is up to 495ng/g, is 2.4 times of racemic licarbazepine acetate (210ng/g).
C of 1. formula of table (I) compound in rat serummax、TmaxAnd the highest drug concentration of big intracerebral
Embodiment 3
The further verifying of formula (I) compound brain capture amount in rat body
In order to which further verification expression (I) compound has good brain capture characteristic, select 5 intracerebrals dense from table 1 It spends higher formula (I) compound and carries out chiral resolution, formula (I) compound of corresponding S- optical isomer is prepared, by embodiment 2 Method carries out Pharmacokinetic Evaluation, and is compared with eslicarbazepine and Elixirbine Acetate.The result shows that As shown in table 2, compared with eslicarbazepine and Elixirbine Acetate, the formula (I) of designed S- optical isomer Compound brain capture amount equally with higher, especially compound I-26, i.e. (S) -10- (3- thiophene) acyloxy -10,11- Dihydro -5H- dibenzo [b, f] azepine-5-carboxamide is rapidly converted into eslicarbazepine, intracerebral content after entering brain Up to 501ng/g is 2.2 times that 3.1 times of eslicarbazepine and Elixirbine Acetate is used alone respectively.
C of formula (I) compound of table 2.S- optical isomer in rat serummax、TmaxAnd the highest drug of big intracerebral is dense Degree
Embodiment 4
Formula (I) compound or its medicinal tablets
It is illustrated by taking the preparation of compound I-26 tablet as an example:
Prescription: compound I-26 7g, lactose 1.5g, starch 0.7g, magnesium stearate 0.1g, sodium carboxymethyl starch 0.5g are sliding
Mountain flour 0.5g.
Preparation method: it is spare that sodium carboxymethyl starch (75% recipe quantity), magnesium stearate 1. are weighed by recipe quantity；2. preparing 10% starch slurry is spare；3. compound I-26, lactose, sodium carboxymethyl starch mixed 120 mesh 3 times, mixes and bonding is added Softwood is made in agent in right amount, and softwood crosses 18 meshes, and wet granular sets 60~70 DEG C of dry 1h in baking oven, with 18 mesh sieves, is added hard Fatty acid magnesium and sodium carboxymethyl starch (25% recipe quantity) mix, and receive weight according to particle, tabletting weight is answered in calculating；4. tabletting.
Embodiment 5
(I) compound or its glue,medicinal wafer
It is illustrated by taking the preparation of compound I-26 capsule as an example:
Prescription: compound I-26 7.0g, microcrystalline cellulose 3.0g, PEARLITOL 25C 5.0g, magnesium stearate 0.30g, hydroxypropyl Cellulose 1.0g, cross-linked carboxymethyl cellulose sodium 1.5g, 6% hydroxypropyl cellulose solution are appropriate.
Preparation method: it 1. weighs appropriate hydroxypropyl cellulose and pulping pan used for producing is added, purified water is added, open agitating paddle, open Steam valve heating, is made 6% slurry solution for standby；2. taking compound I-26, microcrystalline cellulose, mannitol, hydroxypropyl cellulose And 2/3 croscarmellose sodium, it sieves with 100 mesh sieve respectively；3. compound I-26 is pressed equivalent gradually-increased in V-Mixer It mixes；Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, 2/3 croscarmellose sodium are mixed in trough type mixing machine Uniformly；By the compound I-26 mixed and the mannitol mixed, microcrystalline cellulose, hydroxypropyl cellulose, 2/3 crosslinking carboxylic first Base sodium cellulosate is mixed in V-Mixer by equivalent gradually-increased, and medicinal powder enters wet granulation drying room；4. by uniformly mixed medicine Powder is set in trough type mixing machine, and 6% hydroxypropyl cellulose slurries are then added, and stirs 10min；5. softwood is transferred to swing particle In machine, pelletized with 20 mesh nylon mesh；6. wet granular is transferred in boiling drier, the dry 30min at 50~55 DEG C, until moisture content It is 5.0~7.0%；7. the particle after drying is added in oscillating granulator, with 20 mesh nylon mesh whole grains；8. after whole grain Particle is transferred in Mixers with Multi-direction Movement, and the disintegrating agent croscarmellose sodium of remaining 1/3 amount is added, after mixing 20min, Magnesium stearate lubricant is added, mixes 3min, mixed particle is enclosed into a barrel writing paper, it is to be tested to be transferred to particle intermediate station；9. particle After examining and meeting the requirements, capsule is filled by 0.130g average weight, limit test of weight variation is ± 3%, disintegration time limited≤ 20min。

Claims (4)

1. a kind of brain target eslicarbazepine ester prodrug is any one in following compounds,
10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-15)
10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-16)
10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-17)
10- (4- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-18)
10- (2- ethyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-19)
10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-20)
10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-21)
(S) -10- (3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-26)
(S) -10- (2- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-27)
(S) -10- (2- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-28)
(S) -10- (3- furans) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I-29)
(S) -10- (2- methyl -3- thiophene) acyloxy -10,11- dihydro -5H- dibenzo [b, f] azepine-5-carboxamide (I- 30).
2. the eslicarbazepine of brain target described in claim 1 ester prodrug is in preparation treatment, prevention and treatment or adjuvant treatment maincenter mind Application in drug through systemic disease.
3. the pharmaceutical composition comprising brain target eslicarbazepine ester prodrug described in claim 1.
4. pharmaceutical composition as claimed in claim 3, it is characterised in that: the administration mode of described pharmaceutical composition is to pass through mouth Clothes, injection, transdermal, mucous membrane, inhalation route are realized.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1193965A (en) * 1995-06-30 1998-09-23 波特拉和卡公司 10-acyloxy-10,11-dihydrodibenz/b, f/azepine-5-carboxamides useful for treating nervous system disorders
CN101421245A (en) * 2006-04-11 2009-04-29 拜尔坡特拉有限公司 Preparation of eslicarbazepine and related compounds by asymmetric hydrogenation
CN103570669A (en) * 2013-10-31 2014-02-12 吉林大学 Brain-targeted O-desmethylvenlafaxine phenolic ester prodrug and preparation method and applications thereof
CN104350041A (en) * 2012-05-07 2015-02-11 塞利克斯比奥私人有限公司 Compositions and methods for the treatment of neurological disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1193965A (en) * 1995-06-30 1998-09-23 波特拉和卡公司 10-acyloxy-10,11-dihydrodibenz/b, f/azepine-5-carboxamides useful for treating nervous system disorders
CN101421245A (en) * 2006-04-11 2009-04-29 拜尔坡特拉有限公司 Preparation of eslicarbazepine and related compounds by asymmetric hydrogenation
CN104350041A (en) * 2012-05-07 2015-02-11 塞利克斯比奥私人有限公司 Compositions and methods for the treatment of neurological disorders
CN103570669A (en) * 2013-10-31 2014-02-12 吉林大学 Brain-targeted O-desmethylvenlafaxine phenolic ester prodrug and preparation method and applications thereof

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