CN105777586A - S(+)vigabatrin ester derivative and preparation method and application thereof - Google Patents
S(+)vigabatrin ester derivative and preparation method and application thereof Download PDFInfo
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
The invention provides a (4S)-4-(((1-(2-methyl-1-oxopropoxy)ethyoxyl) carbonyl)amino)-5-hexenoic acid derivative in the formula I or pharmaceutically acceptable salt of the derivative and a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application.The invention further provides an application method of an S(+)vigabatrin ester derivative and a method for applying a medicine composition of the derivative to treating or preventing common diseases and/or symptoms.Please see the formula I in the description.
Description
Technical field
The present invention relates to S(+) vigabatrin ester derivant and its production and use, belong to organic compound synthesis and
Medical applications technical field.
Background technology
In drug development, medicine delivers and/or a solution of bioavailability concerns is to be turned by known drug
Turn to prodrug.Generally, in prodrug, polar functional group (such as carboxylic acid, amino, hydroxyl etc.) is by presoma split screen
Covering, the latter is unstable in physiological conditions.Therefore, prodrug is generally transported through hydrophobic biological barriers, such as
Film, is generally configured with the physicochemical properties more superior than parent drug.
Pharmacologically effective prodrug is avirulent, and preferably selecting property cracks at medicine site of action.Preferable feelings
Under condition, there is rapidly and quantitatively the cracking of precursor portions, with the generation (presoma namely hydrolyzed of non-toxic by-products
Point).
Acyloxy alkyloxycarbonyl group functional group can be used for the precursor portions of regulating medicine physicochemical properties, generally,
When comparing with parent drug, the 1-(acyloxy of medicine)-alkyl derivative possesses superior bioavailability, less stimulates
Local and gastric mucosa, be generally more easy to penetrate this kind of film.
Vigabatrin (Vigabatrin, (RS) vigabactrin), trade name: Sabril.Conduct in 1974
GABA transaminase (GABA-T)) inhibitor synthesized first, the clinical observation through more than 10 years shows that it is to many
Plant intractable epilepsy pain effectively.Within 1989, formally put goods on the market in Britain, be widely used in European, Japan, the U.S..Its structure
Being similar to gamma aminobutyric acid (GABA), be the depressant of GABA primary degrading enzyme GABA medium enzyme, it can make cerebrospinal fluid GABA
Level improves.This product has safely, effectively and the feature of easily application, all effective, to part to all types of epilepsy
Outbreak effect is more preferable.Its structural formula is as follows:
GABA regulates the irritability of neuron by combining with specific memebrane protein (i.e. GABAA receptor), thus causes ion
Channel opener.Chloride ion enters into and through ion channel and causes the hyperpolarization of recipient cell, thus prevents Nerve impulse
It is delivered to other cell.Epilepsy, movement disorders (such as multiple sclerosis, kinetic tremor, tardive dyskinesia),
The individuality of fear, anxiety, depression, alcoholism and manic behavior observes low-level GABA.
Excite about the prompting of multiple common disease and/or the low GABA level of common medical condition and be better than having
Great interest prepared by the GABA analog of the pharmaceutical property (such as through the ability of blood brain barrier) of GABA.Therefore, at this
Field has synthesized the multiple GABA analog with important pharmaceutical property, such as Pregabalin etc..
One major issue of many GABA analog is that γ amino is formed with carboxyl functional group generation inner molecular reaction
Gamma-lactams, such as following vigabatrin.Owing to defining the toxicity of gamma-lactams, its formation is to vigabatrin system
Agent brings serious difficulty.The toxicity of such as vigabatrin (LD50, mouse peritoneal is injected) is more than 2500 mg/kg, and correspondence
The toxicity (LD50, mouse peritoneal is injected) of lactams (2) is 90 mg/kg.Accordingly, because the reason of safety, it is necessary to make at GABA
The synthesis of analog and/or the preparation of the compositions of GABA analog or GABA analog and/or storage byproduct in process thing are such as
The formation of lactams minimizes (particularly in the case of vigabatrin)
Extended release preparation is a conventional solution of quick system clearance rate, and it is to those skilled in the art
It is known (for example, see " Remington's Pharmaceutical Sciences, " Philadelphia College
Of Pharmacyand Science, 17TH Edition, 1985).Osmotic delivery system is also that known sustained drug delivers
Method (example is known and seen Verma et al., Drug Dev. Ind. Pharm, 2000,26:695～708).Many GABA are similar to
Thing, include vigabatrin and the obstructed excessive intestinal absorption of Pregabalin.On the contrary, these compounds typically in small intestinal by big neutrality
Amino acid transport agent (LNAA) absorbs (Jezyk et al., Pharm. RES, 1999,16,519～526).Passing through of regular dosage form
The express passway of gastrointestinal proximal absorptive region hinders and sustained release technologies is applied successfully to many GABA analog.
Hence it is highly desirable to the sustained release scheme of effective GABA analog, quick with by due to these compounds
System clearance rate and the increase of dosage frequency that causes minimize.Also need to the purest and preparation or during storing not
The spontaneously pure GABA analog of lactamize, (particularly vigabatrin and Pregabalin analog).
Summary of the invention
As it has been described above, the brand-new S(+ of the sustained release for providing a kind of orally active GABA analog) vigabatrin
Ester derivant and its preparation method and application, this is conducted in-depth research by the present inventor, is paying a large amount of creative work
After, thus complete the present invention.
Specifically, first aspect, the present invention relates to the S(+ shown in formula I) vigabatrin ester derivant:
Its chemistry is entitled: (4S)--4-(((1-(isobutyryl epoxide) and ethyoxyl) carbonyl) amino)-5-hexenoic acid.
Second aspect, the present invention relates to S(+) vigabatrin ester derivant pharmaceutically acceptable salt, such as sodium salt, calcium
Salt, magnesium salt, barium salt, mantoquita.Select and prepare suitable salt, being technology as well known to those skilled in the art.
The third aspect, the present invention relates to S(+) preparation method of vigabatrin ester derivant, concrete technology path is as follows:
Above-mentioned manufacture method, only represents one of the method for formula I compound manufacturing present invention example.The system of the compounds of this invention
The method of making is not limited in these methods, in the embodiment of this specification, owing to more specifically understanding the compounds of this invention
Manufacture method, so, those skilled in the art, according to the above description with the explanation of specific embodiment, as required, to this in addition
Suitable amendment, just can produce and be included in above-mentioned formula I compound or their salt.
Fourth aspect, the present invention relates to comprise the drug regimen of above-mentioned formula I compound or its pharmaceutically acceptable salt
Thing.Particularly relate to the drug regimen comprising formula I compound or its pharmaceutically acceptable salt with pharmaceutically acceptable carrier
Thing, described pharmaceutical composition can use method well known in the art to prepare.
5th aspect, the present invention relates to pharmaceutical composition and is applicable to oral continued administration.
6th aspect, the present invention relates to above-mentioned formula I compound or its pharmaceutically acceptable salt preparation treatment epilepsy,
Depression, anxiety, psychosis, faintness attacks, spasm, hypocinesis, cranium disease, neurodegenerative disease, fear, pain, inflammation
The purposes of the medicine of disease, gastroenteropathy or ethanol withdrawal syndrome.The especially use in treatment epilepsy, spasm and anxiety
On the way.
The present invention is characterized by: (1) greatly reduces taking dose and the side effect of vigabatrin, have employed single different
The form of structure body is administered；(2) existence of toxic impurities lactams is avoided；(3) this prodrug has slow-release function, can extend mother
The body medicine holdup time in vivo, there is fixed point Absorption simultaneously.
Detailed description of the invention
Define the present invention further with reference to following example, described embodiment describes compound and the combination describing the present invention in detail
The preparation of thing and the compound of the present invention and the application test of compositions.Those skilled in the art are not this it appears that carrying on the back
In the case of protection scope of the present invention, raw material and method can be implemented multiple remodeling.
Embodiment 1 S(+) preparation of vigabatrin ester
1) (4S)--4-(((tertbutyloxycarbonyl) amino) preparation of-5-hexenoic acid
In 500ml there-necked flask, be sequentially added into S(+) vigabatrin (19.4g, 0.15mol), dioxanes 170ml and deionization
Water 170ml, is stirred at room temperature lower addition sodium hydroxide (18g, 0.45mol), after stir 5min, add BOC anhydride (43.6g,
50ml dioxane 0.2mol), after the mixed liquor obtained is stirred at room temperature 1.5h, TLC identification, reduces pressure dense
Contracting removes major part dioxanes, and residue ether (3 × 100ml) extracts, and removes organic facies, and water layer is water-soluble with 10% citric acid
Liquid regulation pH ester, to 1～2, stands 20min, separates out a large amount of white solid, filter, and solid washing in right amount, 55 DEG C～60 DEG C true
Empty dry 4h, obtains white solid powder 27.8g, yield 81.2%, HPLC content 95.4%, is directly used in next step reaction.
2) (4S)--4-(((tertbutyloxycarbonyl) amino) preparation of-5-hexenoic acid benzyl ester
In 500ml there-necked flask, it is sequentially added into (4S)--4-(((tertbutyloxycarbonyl) amino)-5-hexenoic acid (25g,
0.11mol), DMF(160ml), benzyl bromide a-bromotoluene (18.9g, 0.11mol), be stirred at room temperature down, add cesium carbonate (35.9g,
0.11mol), stirring 4h, TLC identification [developing solvent: ethyl acetate-light petrol: methanol=10:5:1], react complete, add
160ml frozen water, stirs 10min, extracts with butyl acetate (3 × 100ml), merges organic layer, with saturated 200ml sodium chloride solution
Washing, separates organic layer, and anhydrous sodium sulfate is dried 30min, filters, and in temperature, < 45 DEG C are evaporated to do, obtain white powder
Solid 32.3g, yield 92.1%, HPLC content 94.6%, it is directly used in next step reaction.
3) (4S)--the preparation of vigabactrin benzyl ester hydrochlorate
In 250ml there-necked flask, it is sequentially added into 4S)--4-(((tertbutyloxycarbonyl) amino)-5-hexenoic acid benzyl ester (31g,
0.097mol), dioxanes 180ml and 6N hydrochloric acid solution 15ml, reactant mixture 1.5h be stirred at room temperature, TLC identification [exhibition
Open agent: ethyl acetate: methanol=10:1], react complete, add ether 250ml, stir 1h, filter, solid ether is washed in right amount
Wash, 35 DEG C～40 DEG C vacuum drying 6h, obtain white solid powder 20.6g, yield 97.1%%, HPLC content 97.6%, be directly used in
Next step reaction.
4) (4S)--4-((chloroethoxy) carbonyl) amino) preparation of-5-hexenoic acid benzyl ester
In 500ml there-necked flask, it is sequentially added into (4S)--vigabactrin benzyl ester hydrochlorate (19.2g, 0.087mol),
And N-methylmorpholine (25ml) DMF(150ml), stirring is cooled to-5 DEG C～0 DEG C, stirs 10min, instills the chlorine containing 50ml DMF
Formic acid-1-chloroethene ester (13.9g, 0.1mol), keeps-5 DEG C～0 DEG C stirring reaction 1.5h, TLC identification [developing solvents: acetic acid
Ethyl ester: methanol=10:3], react complete, add ethyl acetate 250ml, wash by 10% aqueous solution of citric acid and saturated salt respectively
Washing, the useless aqueous sodium persulfate of organic layer is dried 30min, filters, and in temperature, < 45 DEG C are evaporated to do, and obtain pale yellow powder shape solid
Body 20.1g, yield 70.9%, HPLC content 95.1%, it is directly used in next step reaction.
5) (4S)--4-((iodine ethyoxyl) carbonyl) amino) preparation of-5-hexenoic acid benzyl ester
N2Protection, in 250ml there-necked flask, is sequentially added into (4S)--4-((chloroethoxy) and carbonyl) amino)-5-hexenoic acid benzyl
Ester (18.9g, 0.058mol), acetone 180ml, the anhydrous molecular sieve of 10g and sodium iodide (26g, 0.174mol), 40 DEG C～45 DEG C,
Stirring reaction 6h, is cooled to room temperature, filters, and in temperature, < 45 DEG C are evaporated to do filtrate, and residue adds dichloromethane
230ml, washs with saturated sodium carbonate solution (3 × 50ml), then washs with water (3 × 50ml), and the useless aqueous sodium persulfate of organic layer is done
Dry 30min, filters, is evaporated to do, obtain white powdery solids 20.88g, yield 86.3%, HPLC content 93.7%, directly
React for next step.
6) (4S)--4-(((1-(isobutyryl epoxide) ethyoxyl) carbonyl) amino) preparation of-5-hexenoic acid benzyl ester
N2Protection, in 500ml there-necked flask, be sequentially added into Disilver carbonate (27.5g, 0.1mol), isopropylformic acid. (17.6g,
0.2mol), dichloromethane (280ml), after 20min is stirred at room temperature, add 4S)--4-((iodine ethyoxyl) carbonyl) amino) and-5-oneself
The dichloromethane solution 50ml of olefin(e) acid benzyl ester (20.8g, 0.05mol), is stirred at room temperature 6h, filters with kieselguhr, and filtrate is used successively
Saturated sodium bicarbonate solution (3 × 50ml) washs, and is washing with saturated aqueous common salt (3 × 50ml), and useless aqueous sodium persulfate is dried
30min, filters, is evaporated to do, obtains white paste solid 15.8g, yield 87.0%, HPLC content 94.5%, directly use
React in next step.
7) (4S)--4-(((1-(isobutyryl epoxide) ethyoxyl) carbonyl) amino)-5-hexenoic acid (S(+) vigabatrin ester)
Preparation
In 100ml autoclave, add (4S)--4-(((1-(isobutyryl epoxide) ethyoxyl) carbonyl) amino) and-5-oneself
Olefin(e) acid benzyl ester (15.0g, 0.0413mol), ethyl acetate 60ml and 10% Pd/C(1.9g), N2It is passed through H after replacing three times2, 5
Hydrogenating 3h under atmospheric pressure, filter with kieselguhr, filtrate is concentrated to dryness, solid with ethyl acetate-normal heptane recrystallization, obtains white knot
Crystalline substance solid 10.6g, Mp:71 DEG C～73 DEG C, yield 89.1%, its purity is 99.3%, (HPLC method).
1H NMR(500MHz, CDCl3/ TMS, ppm):
δ 1.14(6H, d, J=7.8Hz, 2CH 3 CH-)；δ 2.49～2.57(1H, m, CH3CH)；δ 1.46(3H, d, J=
7.8Hz, OCHOCH 3 )；δ 7.01(1H, q, OCHOCH3)；δ 7.82(1H, r, NH)；δ 5.02～5.10(2H, t, CH 2=CH-)；
δ 5.82～5.91(1H, m, CH2=CH-CH2)；δ 4.03(2H, m, CH2=CH-CH 2)；δ 1.79(2H, m, CH2=CH-
CH2—CH 2-)；δ 2.43～2.56(2H, t ,-CH2CH 2COOH)
MS:m/z (M+H+) 288.36.
Embodiment 2 S(+) preparation of vigabatrin ester sodium
S(+) vigabatrin ester (8.62g, 0.03mol) dissolves what acetonitrile (120ml), with 10% aqueous sodium carbonate regulation pH value
To 8.5～9.0, magnetic agitation 15min, it is concentrated to dryness, residue adds isopropanol (150ml) stirring 20min, filters, solid
Washing with appropriate isopropanol, 55 DEG C～60 DEG C vacuum drying, obtain white powdery solids 7.96g, its purity is 99.8%, (HPLC
Method).
Embodiment 3 S(+) preparation of vigabatrin ester calcium
S(+) vigabatrin ester sodium (1.2g, 0.0039mol) dissolves what water (4.5ml), ethanol 4.5ml, adds the water of calcium chloride
Solution (2ml, 0.0003mol), stirred overnight at room temperature, filter, solid ethanol in proper amount is washed, 55 DEG C～60 DEG C vacuum drying,
Obtaining white powdery solids 1.18g, its purity is 98.9%, (HPLC method).
Embodiment 4 S(+) preparation of vigabatrin ester barium
According to the operation of embodiment 3, replace calcium chloride water with barium chloride solution, obtain white powdery solids S(+) ammonia oneself
Olefin(e) acid ester barium 0.94g, its purity is 99.1%, (HPLC method).
Embodiment 5 S(+) preparation of vigabatrin ester magnesium
According to the operation of embodiment 3, replace calcium chloride water with magnesium chloride brine, obtain white powdery solids S(+) ammonia oneself
Olefin(e) acid ester barium 1.23g, its purity is 99.4%, (HPLC method).
Embodiment 6 S(+) preparation of vigabatrin ester copper
According to the operation of embodiment 3, replace calcium chloride water with Schweinfurt green aqueous solution, obtain white powdery solids S(+) ammonia oneself
Olefin(e) acid ester barium 1.06g, its purity is 98.2%, (HPLC method).
Embodiment 7 animal experiment
1, external test S(+) the Caco-2 cell permeability of vigabatrin ester
The method as known in the art S(+ to the present invention can be used) the passive permeability of vigabatrin ester carries out external commenting
Valency (for example, see Stewart et al., PHARM. RES., 1995,12,693).For example, it is possible to by check S(+) ammonia oneself
Olefin(e) acid ester flows through the polarization cell monolayer (such as Caco-2 cell) of cultivation evaluates being saturated property.Continuous culture will be derived from
Caco-2 cell (passing on less than 28) is inoculated into Transwell polycarbonate filter to high-density.With 10% N of fetus of DMEM/
Serum+0. 1 mM non essential amino acid+2 mM L-GLn, 5% CO2/ 95%, support cells until experimental day for 37 DEG C.?
In the presence of overflowing pump inhibitor (250uM MK-571,250 uM verapamils, 1 mM ofloxacin), pH 6. 5 times and
Top is (containing 1 mM CaC12, 1MM MgC12, 150 mM NaCl, 3 mM KCl, 1 mM NaH2P04.5 mM glucose
50 mM MES buffer in) and pH 7. 4 times in bottom side (at the Hanks average salt solution containing 10 mM HEPES
In) carry out penetration study.Insert is placed in 12 holes containing buffer or 24 hole flat boards, and at 37 DEG C, cultivates 30min.
By S(+) vigabatrin ester (100uM) is added to top and bottom side compartment (donor), and uses LC/MS/MS to survey with the interval of 1 hour
It is scheduled on the S(+ in relative compartment (receiver)) concentration of the parent drug of vigabatrin ester and/or release. use below equation
Calculate apparent osmotic value (Papp):
Papp=Vr (dC/dt)//(ACo)
Here Vr is the volume accepting compartment in units of mL, and dC/dt is S(+) vigabatrin ester and the stream of parent drug
Flux (uM/S), it measures according to the slope of a curve of the concentration vs. time accepted in compartment；Co is the S(+ in units of uM)
The initial concentration of vigabatrin ester；A is the film surface area in units of cm2, as with shown in following table:
Result shows S(+) vigabatrin ester has high cell permeability, and should be well by intestinal absorption.
2, mini pump is being used to take S(+ to hunting dog) S(+ of vigabatrin ester) sustained release of vigabatrin
By S(+) vigabatrin or S(+) dosage of vigabatrin ester (with equal to 5mgS(+) vigabatrin/kg) and be dissolved in suitable
Solvent (such as water, PEG 400 etc.), and be filled with to preweighted Alzet®Mini electro-osmotic pumping arrangement (model 2001D)
(Durect Corp., Cupertino, CA).By the Alzet that will fill at 37 DEG C®Infiltration basin water soaks 3 hours
And overnight carry out pre-equilibration sealing in container to store at 4 DEG C.Then the male hunting dog allowing four fasting is administered orally (about
5.6kg).Animal is feed in 4 hours, compartment of terrain blood sampling (1.0mL) in 48 hours after taking medicine every time, and enters blood plasma immediately
Row processes.Plasma sample is frozen in, and at one 80 DEG C store until making to be analyzed with the aforedescribed process.S(+) vigabatrin
The S(+ that what ester was provided take medicine latter 12 hours) the plasma concentration ratio of vigabatrin is at Alzet®Device is used S(+) ammonia hexene
This most seen S(+ of acid) big 3 times of the concentration of vigabatrin.These data prove that the compound of the present invention can be made further
Be suitable to sustained-release composition effectively.
Claims (10)
1. the S(+ shown in formula I) vigabatrin ester derivant or its pharmaceutically acceptable salt:
Chemistry is entitled: (4S)--4-(((1-(isobutyryl epoxide) ethyoxyl) carbonyl) amino)-5-hexenoic acid.
2. the S(+ described in claim 1) vigabatrin ester derivant or its pharmaceutically acceptable salt, it is characterised in that: described
Pharmaceutically acceptable salt be sodium salt, calcium salt, magnesium salt, barium salt, mantoquita.
3. the S(+ described in claim 1) preparation method of vigabatrin ester derivant, including following technology path:
。
4. a pharmaceutical composition, wherein contains the S(+ described in claim 1～2) vigabatrin ester derivant or its pharmaceutically
Acceptable salt and pharmaceutically acceptable carrier.
5. the pharmaceutical composition of claim 4, it is applicable to oral continued administration.
6. the S(+ described in claim 1～2) vigabatrin ester derivant or its pharmaceutically acceptable salt be used for preparing treatment
Epilepsy, depression, anxiety, psychosis, faintness attacks, spasm, hypocinesis, cranium disease, neurodegenerative disease, fear, pain
Bitterly, the purposes of the medicine of inflammation disease, gastroenteropathy or ethanol withdrawal syndrome.
7. the purposes of claim 6, is used for treating epilepsy.
8. the purposes of claim 6, is used for treating spasm.
9. the purposes of claim 6, is used for treating anxiety.
10. the purposes of claim 6, is used for treating pain.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116621720A (en) * | 2023-07-21 | 2023-08-22 | 成都硕德药业有限公司 | Preparation method of high-purity vigabatrin |
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