CN106220529B - A kind of preparation method and Pharmaceutical composition of chiral proglumide - Google Patents
A kind of preparation method and Pharmaceutical composition of chiral proglumide Download PDFInfo
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- CN106220529B CN106220529B CN201510612887.4A CN201510612887A CN106220529B CN 106220529 B CN106220529 B CN 106220529B CN 201510612887 A CN201510612887 A CN 201510612887A CN 106220529 B CN106220529 B CN 106220529B
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Abstract
The invention provides a kind of preparation method of chiral proglumide, additionally provides chiral proglumide and is preparing a kind of pharmaceutical composition for the treatment of and/or prevention of digestive tract ulcers.The present invention has obtained the low chiral proglumide of optical purity height, high income, cost, the application being especially suitable in industry using a kind of raw material are easy to get, process is few, energy consumption is low, preparation method easy to operate, Environmental Safety；And, compared with racemization proglumide, in the case of to the same or equivalent therapeutic effect of ulcer, the oxopentanoic acid of 4 benzamido of dextrorotation 5 (R) dipropylamino of the present invention 5 can significantly reduce dosage, the burden of body metabolism when alleviating administration, the security hidden trouble that may be brought because racemization proglumide is mixture has been effectively eliminated, has further ensured the drug safety of sufferer.
Description
Technical field
The present invention relates to a kind of preparation method and Pharmaceutical composition of chiral proglumide.
Background technology
According to the common knowledge of this area, for racemoid as medicine, not only dosage is bigger than normal, and can aggravate flesh
The burden of body metabolism, or even can have serious potential safety hazard；For example, there is the hand of two kinds of enantiomers each other in racemization Thalidomide
Property compound, only one of which chipal compounds are safe, and another chipal compounds then have teratogenesis, seriously
Endanger the life and health safety of people.
Proglumide, and a kind of racemoid, its entitled (±) -5- dipropylaminos -4- benzamido -5- oxygen
Generation-valeric acid, the entitled proglumide of English, is embodied in Chinese Pharmacopoeia version two page 96 in 2000, is the antagonism of gastrin-receptor
Agent, chemical constitution are similar to the whole terminal chemical structure of two kinds of enterokinins of gastrin (G-17) and CCK (CCK).Its work(
Energy group amide groups specificity and gastrin-receptor on gastrin competition parietal cell, thus can substantially suppress stomach caused by gastrin
The secretion of acid and pepsin, unobvious are acted on to gastric acid secretion caused by histamine and vagal stimulation.Gastric mucosa can be increased
The content of aminohexose, promote glycoprotein synthesis, have protection to gastric mucosa and promote Healing, peptic ulcer can be improved
Symptom and promote ulcer healing.The rebound phenomenon of gastric acid secretion does not occur for treatment peptic ulcer and gastritis, after treatment termination still
Gastric acid secretion can be made to be in normal level for half a year.
In addition, proglumide also has choleretic effect, approach has three：1. by stimulating bile acid dependent/non-dependent choleresis,
Be advantageous to arrange stone and rinse, dredging biliary tract；2. changing in bile into stone factor, heavy carbonate concentration and discharge capacity is set substantially to increase,
And the concentration of unconjugated bilirubin, cholesterol and calcium ion reduces；3. by antagonism CCK, the rush gall-bladder for suppressing endogenous CCK is received
Contracting acts on and makes gall-bladder capacity extensions, makes intracapsular bile of gallbladder component diluent, so as to prevent into stone.Proglumide is usually used in stomach and ten
Two Duodenalulcers, chronic superficial gastritis, duodenal bulbar inflammation.
At present, the proglumide product reported is mostly racemization proglumide.Racemization proglumide to be administered daily dosage bigger than normal,
And the mixing administration of its chiral isomer can also aggravate body metabolism burden.Document report is crossed prepares the paddy of optical voidness third using enzyme fractionation
Amine (Bioorganic and Medicinal Chemistry, 2002,10 (5), 1471).Although enzyme is split with many excellent
Point, but the transformation efficiency that enzyme is split in this report is relatively low, and optical purity is also not high enough, and realization of industrialization still has more bottleneck
Factor.Document also report optical voidness proglumide fully synthetic report (Chemical＆Pharmaceutical Bulletin,
19,36 (9), 3633), but the step of multiple protections are with deprotection is employed, technology path is comparatively laborious.
In order to overcome drawbacks described above, solve this area existing for above-mentioned technical problem, need badly the chiral proglumide of exploitation and
Prepare the short-cut method of chiral proglumide.Have not seen at present from commercially available racemization proglumide and carried out chemical resolution, so as to prepare hand
Property proglumide chemistry report.And so far, there is not yet the report of the Pharmaceutical composition of chiral proglumide.
The content of the invention
It is an object of the invention to provide a kind of preparation method and Pharmaceutical composition of chiral proglumide.
The invention provides a kind of chiral proglumide, described chiral proglumide is 5- (R)-dipropylamino -4- benzene first
Acylamino- -5- oxo-pentanoic acids or 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids.
Further, the ee ＞ 98.5% of 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids；5-(R)-
The fusing point of dipropylamino -4- benzamido -5- oxo-pentanoic acids is 131 DEG C~133 DEG C.
Further, 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids
Further, the ee ＞ 98.5% of 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids；5-(S)-
The fusing point of dipropylamino -4- benzamido -5- oxo-pentanoic acids is 132 DEG C~134 DEG C.
Further, 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids
Present invention also offers the preparation method of above-mentioned chiral proglumide, described preparation method comprises the following steps：
A, racemization proglumide is mixed with resolution reagent, organic solvent, after being heated to solution clarification, cools down, filtering, obtain
Filter cake and filtrate；
B, filter cake obtained by step a is recrystallized, and obtains crystallized product；
C, crystallized product obtained by step b is suspended in organic solvent, adds 5% aqueous hydrochloric acid solution, separate organic layer, wash
Wash, dry, filter, concentrate, recrystallization, produce 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids.
Further, in step a, the mol ratio of racemization proglumide and resolution reagent is 2：1；Racemization proglumide with it is organic molten
The molal volume ratio of agent is 1：2~5mmol/ml.
Further, in step a, resolution reagent is R- Alpha-Methyl benzylamines；Organic solvent be selected from methanol, ethanol, isopropanol,
In isopropyl ether any one or it is two or more.
Further, in step b, any one of the solvent of recrystallization in methanol, ethanol, isopropanol, isopropyl ether
It is or two or more.
Further, in step c, organic solvent in ethyl acetate, toluene any one or it is two or more.
Further, in step c, the w/v of crystallized product and organic solvent is 1：50g/ml；Organic solvent with
The volume ratio of 5% aqueous hydrochloric acid solution is 1：1.
Further, described preparation method is further comprising the steps of：
D, filtrate obtained by concentration step a, obtains residue；Residue is recrystallized, crystallized product is carried out at acidifying
Reason, separation, produces 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids.
Present invention also offers 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids prepare treatment and/
Or the purposes in the medicine of prevention of digestive tract ulcers.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition is with 5- (R)-dipropylamino -4-
Benzamido -5- oxo-pentanoic acids or its pharmaceutically acceptable salt, hydrate or solvate are active component, plus medicine
The preparation that the auxiliary material or complementary composition commonly used on are prepared.
In described preparation, the medicine for treating digestive tract ulcer, such as H2 acceptor inhibitors can also be used for containing other
(such as Cimetidine), nonsteroidal anti-inflammatory drug (such as Indomethacin) or Chinese medicine (such as radix glycyrrhizae, the root of herbaceous peony or borneol).
Because the stomach medicine use in conjunction with other mechanism of action can strengthen proglumide activity, combine with nonsteroidal anti-inflammatory drug
Using its gastrointestinal side effect often having can be suppressed, such as clinically there are racemization proglumide and Cimetidine Compound Tablet, racemization third
Paddy amine Chinese medicine compound prescription piece.
The present invention obtains using a kind of raw material are easy to get, process is few, energy consumption is low, preparation method easy to operate, Environmental Safety
The low chiral proglumide of optical purity height, high income, cost is arrived：5- (S)-dipropylamino -4- benzamido -5- oxygen
Generation-valeric acid, 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids, the application being especially suitable in industry；Moreover,
Compared with racemization proglumide, in the case of to the same or equivalent therapeutic effect of ulcer, 5- (R)-dipropylamino -4- of the present invention
Benzamido -5- oxo-pentanoic acids can significantly reduce dosage, and the burden of body metabolism, has when alleviating administration
Effect eliminates the security hidden trouble that may be brought because racemization proglumide is mixture, has further ensured the medication of sufferer
Safety.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
HPLC：High performance liquid chromatography.
" ee " representative " enantiomeric excess " is a kind of enantiomer of chipal compounds relative to the excessive amount of racemic sample
Degree, for given sample, as a percentage.
M.p. fusing point is referred to.
The preparation of embodiment 1, optical voidness proglumide
3.34g (10mmol) racemizations proglumide (commercially available, standards of pharmacopoeia) and R- methylbenzylamines 0.6g (5mmol), 20ml are different
Propyl alcohol Hybrid Heating adds isopropyl ether 30ml, stirred evenly, room temperature is placed, filtering, and filtrate makees lower step processing, filter cake into settled solution
Washed and dried with isopropyl ether, recrystallisation from isopropanol obtains 1.6g white solids, is suspended in 80ml ethyl acetate, adds
5% hydrochloric acid solution 80ml processing, organic layer is separated, brine It, is dried, is filtered, is concentrated, recrystallization, produces 0.98g optics
Pure (+) -5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids, HPLC measure optical purity ee ＞ 98.5%.m.p.131-133℃。
1H NMR(CDCl3, 600MHz)：δ ppm 7.84 (2H, d, J=7.32Hz), 7.57 (1H, d, J=7.92Hz),
7.50 (1H, t, J=7.38Hz), 7.43 (2H, t, J=7.92Hz), 5.23 (1H, m), 3.46-3.56 (2H, m), 3.20-
3.25(1H,m),3.06-3.11(1H,m),2.46-2.58(2H,m),2.13-2.19(1H,m),1.90-1.96(1H,m),
1.60-1.68 (2H, m), 1.53-1.59 (2H, m), 0.94 (3H, t, J=7.38Hz), 0.90 (3H, t, J=7.38Hz).
ESI-MS:m/z 335(M+H)+。
The above-mentioned filtrate concentration being filtrated to get is done, residue ethyl alcohol recrystallization, precipitation and separation.Acidification obtains precipitation can
Obtain optical voidness negative rotation proglumide, i.e. (-) -5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids, HPLC measure light
Purity ＞ 98.5% is learned,m.p.132-134℃。
1H NMR(CDCl3, 600MHz)：δ ppm 7.84 (2H, d, J=7.5Hz), 7.50 (1H, t, J=7.08Hz),
7.43 (2H, t, J=7.86Hz), 5.23 (1H, m), 3.47-3.56 (2H, m), 3.21-3.28 (1H, m), 3.07-3.12 (1H,
m),2.46-2.57(2H,m),2.13-2.19(1H,m),1.90-1.96(1H,m),1.62-1.67(2H,m),1.54-1.60
(2H, m), 0.94 (3H, t, J=7.5Hz), 0.90 (3H, t, J=7.5Hz).
ESI-MS:m/z 357(M+Na)+。
The preparation of the optical voidness proglumide of embodiment 2
3.34g (10mmol) racemizations proglumide (commercially available, standards of pharmacopoeia) and R- methylbenzylamines 0.6g (5mmol), 20ml second
Alcohol Hybrid Heating is placed into settled solution, room temperature, filtering, and filtrate makees lower step processing, and filter cake is washed and dried with cold ethanol, then is used
Ethyl alcohol recrystallization obtains 1.2g white solids, is suspended in 60ml toluene, adds 5% hydrochloric acid solution 60ml processing, separates
Organic layer, brine It, dry, filter, concentrate, recrystallization, produce 0.76g optical voidnesses (+) -5- (R)-dipropylamino -
4- benzamido -5- oxo-pentanoic acids, HPLC measure optical purities ee>98.6%. CH2Cl2),
m.p.131-133℃。
The above-mentioned filtrate concentration being filtrated to get is done, the processing of residue ethyl alcohol recrystallization.Post processing can obtain optical voidness negative rotation third
Paddy amine, i.e. (-) -5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids, HPLC measure optical purities>98.7%, m.p.132-134℃。
Embodiment 3
After 100g optical voidness dextrorotation proglumides mix with appropriate microcrystalline cellulose, 1000 capsules are distributed into, every
100mg。
Embodiment 4
100g optical voidness dextrorotation proglumides, 100g Cimetidines, after being mixed with appropriate microcrystalline cellulose, are distributed into 2000
Capsule, every capsule optical voidness containing 50mg dextrorotation proglumide and Cimetidine.
Embodiment 5
100g optical voidness dextrorotation proglumides, 100g Indomethacins, after being mixed with appropriate microcrystalline cellulose, are distributed into 2000
Capsule, every capsule optical voidness containing 50mg dextrorotation proglumide and Indomethacin.
Embodiment 6
100g optical voidness dextrorotation proglumides, 100g Chinese medical extracts, including borneol, radix glycyrrhizae, root of herbaceous peony etc., it is fine with appropriate crystallite
After dimension element mixing, 2000 capsules, every capsule optical voidness containing 50mg dextrorotation proglumide and traditional Chinese medicine ingredients are distributed into.
In order to illustrate beneficial effects of the present invention, the present invention provides tests below example.
Test example 1, optical voidness the proglumide pharmacological evaluation in gastric ulcer is treated
Pylorus ligature law causes the specific method of rat gastric ulcer model：Allow Laboratory Rats fasting 72 hours before experiment,
Can free water.Then under etherization, with the tincture of iodine, alcohol disinfecting skin of abdomen, cut from xiphoid-process by abdomen median line downwards
Skin and muscle layer, otch are about 3cm, exposure stomach, differentiate pylorus and duodenal junction along stomach to the right, avoid blood vessel in
Thread below junction, with the silk thread of sterilization in pylorus and duodenum junction by pylorus Complete Ligation.Inject each group medicine
In duodenum, stomach is then put into abdominal cavity, suturing them.Postoperative fasting, prohibit water.Big white mouse is put to death after 12 hours, is beaten rapidly
Abdominal cavity is opened, exposure body of stomach, stomach is taken out after extracting whole gastric juice out, injected with 1% formaldehyde 10m1 in stomach, then stomach is immersed into 1% first
10 minutes are fixed in aldehyde, flattening is cut off along greater curvature, damage index can be calculated by Guth etc. method, damage index is office
It is limited to the streak of glandular stomach, petechial hemorrhage stove and necrosis region, using each lesion length sum of full stomach as damage index, with mm tables
Show.If focus is wider than 2mm, its length is multiplied by 2.Its experiment the results are shown in Table 1.
Control group is exactly the group that is not administered after being modeled according to above-mentioned model.
Inhibiting rate=(control group damage index-administration group damage index)/control group damage index
Table 1, gastric ulcer experimental result
| Group | Dosage (mg/kg) | Inhibiting rate |
| Model group | — | — |
| Omeprazole | 5 | 75.3% |
| Racemization proglumide | 200 | 60.9% |
| Dextrorotation proglumide | 200 | 72.2% |
| Dextrorotation proglumide | 100 | 59.1% |
| Negative rotation proglumide | 200 | 55.1% |
| Negative rotation proglumide | 100 | 34.3% |
As a result show, dextrorotation proglumide (i.e. 5- (R)-dipropylamino -4- benzamido -5- oxos-penta of the present invention
Acid) dosage is in 100mg/Kg, you can reach suppression when racemization proglumide dosage be 200mg/Kg to ulcer and imitate
Fruit, its inhibiting rate are suitable.
To sum up, the present invention is using a kind of raw material are easy to get, process is few, energy consumption is low, preparation side easy to operate, Environmental Safety
Method, the low chiral proglumide of optical purity height, high income, cost is obtained：5- (R)-dipropylamino -4- benzamidos -
5- oxo-pentanoic acids, 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids, the application being especially suitable in industry；And
And compared with racemization proglumide, in the case of to the same or equivalent therapeutic effect of ulcer, 5- (R)-dipropyl ammonia of the present invention
Base -4- benzamido -5- oxo-pentanoic acids can significantly reduce dosage, and body metabolism is negative when alleviating administration
Load, has effectively eliminated the security hidden trouble that may be brought because racemization proglumide is mixture, has further ensured sufferer
Drug safety.
Claims (7)
- A kind of 1. preparation method of chiral proglumide, it is characterised in that：Described preparation method comprises the following steps：A, racemization proglumide is mixed with R- Alpha-Methyls benzylamine, organic solvent, after being heated to solution clarification, cools down, filtering, obtain Filter cake and filtrate；B, filter cake obtained by step a is recrystallized, and obtains crystallized product；C, crystallized product obtained by step b is suspended in organic solvent, adds 5% aqueous hydrochloric acid solution, separate organic layer, washed, Dry, filter, concentrate, recrystallization, produce 5- (R)-dipropylamino -4- benzamido -5- oxo-pentanoic acids.
- 2. preparation method according to claim 1, it is characterised in that：In step a, racemization proglumide and R- Alpha-Methyl benzylamines Mol ratio be 2：1；The molal volume of racemization proglumide and organic solvent ratio is 1：2~5mmol/ml.
- 3. preparation method according to claim 1, it is characterised in that：Organic solvent is selected from methanol, ethanol, isopropanol, different In propyl ether any one or it is two or more.
- 4. preparation method according to claim 1, it is characterised in that：In step b, the solvent of recrystallization is selected from methanol, second In alcohol, isopropanol, isopropyl ether any one or it is two or more.
- 5. preparation method according to claim 1, it is characterised in that：In step c, organic solvent is selected from ethyl acetate, first In benzene any one or it is two or more.
- 6. preparation method according to claim 1, it is characterised in that：In step c, the weight of crystallized product and organic solvent Volume ratio is 1：50g/ml；The volume ratio of organic solvent and 5% aqueous hydrochloric acid solution is 1：1.
- 7. preparation method according to claim 1, it is characterised in that：Described preparation method is further comprising the steps of：D, filtrate obtained by concentration step a, obtains residue；Residue is recrystallized, crystallized product carries out acidification, point From producing 5- (S)-dipropylamino -4- benzamido -5- oxo-pentanoic acids.
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| WO2000061288A1 (en) * | 1999-04-07 | 2000-10-19 | Merck Patent Gmbh | Functionalized supporting materials which can be obtained by means of metathesis graft polymerization |
| CN1371684A (en) * | 2001-02-28 | 2002-10-02 | 中国科学院上海药物研究所 | Novel biological activity of proglumide |
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Effective date of registration: 20230110 Address after: Room 907, 9 / F, building 12, 88 Keyuan South Road, high tech Zone, Chengdu, Sichuan 610000 Patentee after: CHENGDU BENUO KECHENG BIOTECHNOLOGY Co.,Ltd. Address before: 610000 No. 25, No. 2, No. 2, No. 4, Yuantong Second Lane, Chengdu High-tech Zone, Sichuan Province Patentee before: Zhan Wei |