CN101205205A - Alanine derivatives - Google Patents
Alanine derivatives Download PDFInfo
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- CN101205205A CN101205205A CNA2007103009099A CN200710300909A CN101205205A CN 101205205 A CN101205205 A CN 101205205A CN A2007103009099 A CNA2007103009099 A CN A2007103009099A CN 200710300909 A CN200710300909 A CN 200710300909A CN 101205205 A CN101205205 A CN 101205205A
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Abstract
The invention belongs to the medical technology field, relating to a new pharmaceutically effectual lactamine derivative and to pharmaceutically-acceptable salt, easily hydrolysable ester, hydrate, and the slat or ester hydrate thereof; the invention also discloses a method for manufacturing these compounds and the application in manufacturing medicines used for curing cardio-cerebral vascular diseases, especially the application in manufacturing antithrombotic medicines. The research shows that the new pharmaceutically effectual lactamine derivative and the pharmaceutically-acceptable salt, the easily hydrolysable ester, the hydrate and the salt or ester hydrate thereof have good antithrombotic effects and can be applied to such vascular diseases as atherosclerosis, coronary heart disease, cerebrovascular disease, kidney glomerular disease, pulmonary hypertension, diabetic angiopathy, angiitis, etc. and leukothrombopenia, and can be also applied to such diseases as migraine, vascular headache, etc. The invention is worth popularizing clinically.
Description
1, technical field
The invention belongs to medical technical field, relate to hydrate new medicinal effective alanine derivatives, its pharmacy acceptable salt, its facile hydrolysis, its hydrate and salt or ester, and preparation method thereof and the application in the medicine of preparation treatment cardiovascular and cerebrovascular diseases, the particularly application in the medicine of preparation treatment thrombus.
2, background technology
Cardiovascular and cerebrovascular diseases is first killer of harm humans healthy life in the present worldwide, only just has every year 3000000 people to die from cardiovascular and cerebrovascular diseases in China, people's death was arranged, make number one in average per 10 seconds.Show that according to up-to-date medical information occurring in year by year of cardiovascular and cerebrovascular diseases rise, and the age rejuvenation, the incidence probability more than 30 years old is 17%, and 40-50 year is 37%, and 50-60 year is to be 67% more than 54%, 70 years old.As seen the growth cardiovascular and cerebrovascular diseases incidence with the age is high more.Cardiovascular and cerebrovascular diseases has the characteristics of high incidence, high mortality, high disability rate, high relapse rate, has repeated drug taking, the characteristics of SM for the patient of cardiovascular and cerebrovascular diseases.
Thrombus disease is because the lumen of vessels that causes of thrombus is narrow and inaccessible, makes main organs generation ischemic and infarct and causes the various diseases of dysfunction.It belongs to is cardiovascular and cerebrovascular diseases, and cardiovascular and cerebrovascular diseases such as global annual cerebral thrombosis, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis seize 1,200 ten thousand people's life, near 1/4 of the total death toll in the world, become the No.1 formidable enemy of human health.The number that China dies from cardiovascular and cerebrovascular diseases every year reaches more than 2,600,000 people, and the patient of survival 75% is disabled, and is wherein heavy residual more than 40%.Therefore developing more effective and safer treatment cardiovascular and cerebrovascular diseases, antithrombotic is present urgent problem.
3, summary of the invention
In order better to treat cardiovascular and cerebrovascular diseases, alleviate patient's misery, improve patient's quality of life, the invention provides new medicinal effective alanine derivatives, its pharmacy acceptable salt, its facile hydrolysis ester, its hydrate and salt or ester hydrate and preparation method thereof and in the particularly application in the thrombus medicine of preparation treatment cardiovascular and cerebrovascular diseases.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its hydrate and the salt or the ester of the compound shown in (1) that has general formula, its pharmacy acceptable salt, its facile hydrolysis:
Wherein: R
1Be hydrogen atom or C
1-C
6Alkyl;
R
2Be hydrogen atom or C
1-C
6Alkyl;
R
3Be hydrogen atom, halogen atom, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
R
4Be hydrogen atom, C
1-C
6Alkyl or by 1～5 halogen atom, C
1-C
6The phenyl of alkyl, hydroxyl, amino or carboxyl substituted.
Preferred compound is:
R
1Be hydrogen atom or C
1-C
4Alkyl;
R
2Be hydrogen atom or C
1-C
4Alkyl;
R
3Be hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
4Be C
1-C
4Alkyl or phenyl, and phenyl ring can be by 1～5 halogen, C
1-C
4Alkyl, hydroxyl, amino or carboxyl substituted.
Further preferred compound is:
R
1Be hydrogen atom or C
1-C
2Alkyl;
R
2Be hydrogen atom or methyl;
R
3Be hydrogen atom, bromine atoms, C
1-C
2Alkyl or C
1-C
2Alkoxyl group;
R
4Be C
1-C
4Alkyl or phenyl, and phenyl ring can be by 1～5 halogen atom or C
1-C
4Alkyl.
" C of the present invention
1-C
6Alkyl " be meant C
1-C
6The alkyl of straight or branched, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" C of the present invention
1-C
6Alkoxyl group " be meant C
1-C
5The alkoxyl group of straight or branched, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, hexyloxy etc.
" halogen " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom.
Best preferred compound is:
Wherein: R
1Be hydrogen atom; R
2Be methyl; R
3Be hydrogen atom; R
4For normal-butyl or
That is: L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-fourth alkylsulfonyl L-Ala (hereinafter to be referred as compd A), its structural formula is as follows:
Or L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-is to chlorobenzene alkylsulfonyl L-Ala (hereinafter to be referred as compd B), and its structural formula is as follows:
The pharmaceutical salts of the further claimed arbitrary compound mentioned above of the present invention, pharmaceutical salts wherein can be organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, especially subsalt.Wherein organic acid comprises acetate, methylsulfonic acid, Citric Acid, tartrate, toluenesulphonic acids, toxilic acid, succsinic acid, fumaric acid, fumaric acid, Aspartic Acid, salicylate, R-Glyceric acid, xitix; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises sodium, potassium, the basic cpd of barium, calcium, magnesium.
The ester of the further claimed arbitrary compound mentioned above of the present invention, ester wherein is a methyl esters; ethyl ester; n-propyl; isopropyl ester; positive butyl ester; isobutyl ester; the tert-butyl ester; secondary butyl ester; n-pentyl ester; isopentyl ester; peopentyl ester; just own ester; the acetoxyl group ethyl ester; the acetoxyl methyl ester; pivalyl oxygen methyl ester; 1-acetoxyl ethyl ester; 1-pivalyl oxygen ethyl ester; methoxycarbonyl oxygen methyl ester; 1-ethoxycarbonyl-oxygen ethyl ester; 1-sec.-propyl ketonic oxygen ethyl ester; cumarone ketone group ester; sulfo-benzo furanonyl ester; methoxymethyl ester; acetylamino methyl ester etc.It is evident that for the professional of this area the ester of The compounds of this invention can form at the free carboxy place of this compound.
The hydrate of the further claimed arbitrary compound mentioned above of the present invention, its pharmaceutical salts, ester, hydrate wherein is semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate.
The present invention also provides the preparation method of above-mentioned preferred compound, but is not limited only to following preparation method, also can make by additive method:
The preparation of step 1 intermediate 1
Bathe under the cooling at cryosel, raw material 1 is joined in the methyl alcohol, drip SOCl
2, adding the back stirring at room, the evaporated under reduced pressure solvent obtains intermediate 1.
The preparation of step 2 intermediate 2
Under nitrogen protection; in anhydrous acetonitrile, add dry pyridine, then toward the hydrochloride that wherein adds intermediate 1, room temperature reaction; toward wherein slowly adding the fourth SULPHURYL CHLORIDE; add afterreaction, the concentrating under reduced pressure acetonitrile is toward wherein adding entry; use the dilute hydrochloric acid acidifying; use ethyl acetate extraction, the organic layer drying, concentrating under reduced pressure reclaims solvent and gets intermediate 2.
The preparation of step 3 The compounds of this invention
Under nitrogen protection, intermediate 2 is dissolved in THF/H
2Among the O, add NaOH, room temperature reaction.After reaction finishes, regulate pH, use chloroform extraction, drying, activated carbon decolorizing, be evaporated to dried, must crude product.With crude product recrystallization in ethanol, get white highly finished product.
R in the above reaction equation
1, R
3, R
4, R
5The group of representative as mentioned before, i.e. the described The compounds of this invention of general formula (I).
The present invention is further claimed to comprise the hydrate of ester, its hydrate and salt or ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients.These active pharmaceutical ingredientss comprise acetylsalicylic acid, indomethacin, low molecular sodium heparin, low molecular heparin calcium, Ligustrazine, Win-35833, gemfibrozil, piracetam, aniracetam, Dihydroergotoxine, bilobalide etc.
The present invention is further claimed to comprise the hydrate of ester, its hydrate and salt or ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, wherein contains the active ingredient by the described compound 10mg～500mg of formula (1).For example: 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 80mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, 500mg, preferred dose is 50mg, 100mg.Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment, preferred oral preparation or injection in modes such as oral, administered parenterallys.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The also further claimed alanine derivatives of the present invention; its pharmacy acceptable salt; the ester of its facile hydrolysis; the hydrate of its hydrate and salt thereof or ester is used for the treatment of purposes in the medicine of cardiovascular and cerebrovascular diseases in preparation; particularly be used for the treatment of purposes in the antithrombotic medicine in preparation; alanine derivatives of the present invention; its pharmacy acceptable salt; the ester of its facile hydrolysis; the hydrate of its hydrate and salt thereof or ester has good anti thrombotic action; can be used for atherosclerosis; coronary heart disease; the cerebro-vascular diseases renal glomerular disease; pulmonary hypertension; diabetic angiopathy becomes; vascular illness and white corpuscle and thrombopenia such as vasculitis also can be used for migraine; diseases such as vascular headache.
The hydrate of the ester of alanine derivatives of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its hydrate and salt or ester has the following advantages:
(1) provides the hydrate of ester, its hydrate and the salt or the ester of new alanine derivatives, its pharmacy acceptable salt, its facile hydrolysis first, these compounds have good antithrombotic acitivity, can alleviate patient's misery, improve patient's quality of life, be worth using at clinical expansion.
(2) the present invention further carries out pharmacodynamic experiment to the part preferred compound, and The compounds of this invention can significantly shorten the dry weight of the length of thrombus, the weight in wet base that reduces thrombus, reduction thrombus, suppresses the formation of blood stasis rats in vitro thrombus; Significantly reduce the whole blood specific viscosity of stasis syndrome rat; Can obviously suppress the formation of rat carotid artery-external jugular vein blood flow bypass thrombus, show that The compounds of this invention has good anti thrombotic action, consequently those of ordinary skills are beyond thought.
(3) preparation technology of The compounds of this invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below example is further set forth the beneficial effect of alanine derivatives of the present invention by experiment, and these experimental examples comprise the pharmacodynamic experiment of new alanine derivatives of the present invention.New alanine derivatives of the present invention has following beneficial effect, but this should be interpreted as that new alanine derivatives of the present invention only has following beneficial effect.
Experimental example 1: the influence that The compounds of this invention forms stasis syndrome rat model external thrombus
Animal subject: the Wistar rat, male, body weight 200～220g, 50.
Be subjected to the reagent thing:
The blank group: 0.9% sterile saline, commercial;
Model control group: adrenalin hydrochloride injection liquid Adr (0.1%);
The acetylsalicylic acid group: aspirin tablet, Guangdong three is medical Group Co.,Ltd;
Compd A group: compd A sheet, self-control;
Compd B group: compd B sheet, self-control.
Experimental technique:
Get 50 of rats, be divided into 5 groups at random, be respectively the blank group, model control group, the acetylsalicylic acid group, the compd A group, the compd B group, compd A group and compd B group gastric infusion every day are once, successive administration 7 days, 30min after the administration in the 4th day, except that the blank group, all the other animal subcutaneous injection hydrochloric acid suprarenal gland injection liquid Adr (0.1%) 0.1ml/ only, 30min is placed on the 5min that swims in 1.5 degrees centigrade of water, and the 5th day repeats swimming once, 30min after the administration in the 6th day under identical condition, inject Adr again one time, 30min after the last administration is in animal abdominal injection vetanarcol 35mg/kg, anesthetized rat, get blood from rat aorta then, survey thrombosis.
Experimental result: see Table 1.
The influence that table 1 The compounds of this invention forms stasis syndrome rat model external thrombus (X ± SD, n=10)
| Group | Dosage (mg/kg) | Thrombus long (cm) | Weight in wet base (mg) | Dry weight (mg) |
| Blank group model control group acetylsalicylic acid group compd A group compd B group | - - 50 50 50 | 2.58±0.92 9.37±1.18 # 8.00±1.21 * 4.75±1.33 ***$$ 5.23±1.01 ***$$ | 144.0±5.27 485.0±152.4 # 367.3±85.41 * 296.1±61.32 **$ 287.2±66.15 **$ | 34.8±12.1 135.0±36.27 # 103.5±27.01 * 58.2±26.78 **$ 63.4±22.31 **$ |
Annotate: compare with the blank group,
#P＜0.001; Compare with the model group control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the acetylsalicylic acid group,
$P＜0.01,
$$P＜0.001.
Experiment conclusion:
(1) compare with the blank group, model control group extremely significantly strengthens the weight of thrombus, prolongs the length of thrombus, shows the modeling success.
(2) compare with model control group, the length of thrombus is extremely significantly shortened in acetylsalicylic acid group, compd A or compd B administration; Extremely significantly reduce the weight in wet base of thrombus, significantly reduce the dry weight of thrombus, illustrate that acetylsalicylic acid group, compd A and compd B all can obviously suppress the formation of blood stasis rats in vitro thrombus; And, to compare with the acetylsalicylic acid group, compd A or compd B group extremely significantly shorten the length of thrombus, significantly reduce the weight in wet base and the dry weight of thrombus, illustrate that compd A and compd B anti thrombotic action are better than acetylsalicylic acid.
Experimental example 2 The compounds of this invention are to the hemorheology influence of stasis syndrome rat
Animal subject: the Wistar rat, male, body weight 200～220g, 40.
Trial-product:
The blank group: 0.9% sterile saline, commercial;
Model control group: adrenalin hydrochloride injection liquid Adr (0.1%);
Compd A group: compd A capsule, self-control;
Compd B group: compd B capsule, self-control.
Experimental technique:
Get 40 of rats, be divided into 4 groups at random, be respectively the blank group, model control group, the compd A group, the compd B group, compd A group and compd B group gastric infusion every day be (dosage: 50mg/kg) once, successive administration 7 days, 30min after the administration in the 4th day, except that the blank group, all the other animal subcutaneous injection hydrochloric acid suprarenal gland injection liquid Adr (0.1%) 0.1ml/ only, 30min is placed on the 5min that swims in 1.5 degrees centigrade of water, and the 5th day repeats swimming once, 30min after the administration in the 6th day under identical condition, inject Adr again one time, 30min after the last administration is in animal abdominal injection vetanarcol 35mg/kg, anesthetized rat, get blood from rat aorta then, survey its whole blood specific viscosity, the blood plasma specific viscosity, pcv and erythrocyte sedimentation rate.
Experimental result and conclusion: experimental result sees Table 2.
The whole blood specific viscosity of the model control group utmost point significant difference (p＜0.001) of having compared with the blank group illustrates the modeling success; Compd A and the compd B whole blood specific viscosity significant difference (p＜0.05, p＜0.01) of having compared with model group illustrates that The compounds of this invention A and compd B can significantly reduce the whole blood specific viscosity of stasis syndrome rat; Other index there is not obvious influence.
Table 2 The compounds of this invention to the blood stasis rheology of stasis syndrome rat model influence (X ± SD, n=10)
| Group | The whole blood specific viscosity | The blood plasma specific viscosity | Pcv (%) | Erythrocyte sedimentation rate (nm/n) | |
| Height is cut | Low cutting | ||||
| Blank group model control group compd A group compd B group | 8.36±1.27 13.24±2.16 # 9.21±1.25 ** 9.52±1.09 ** | 9.15±1.02 11.02±1.66 # 9.31±3.52 ** 9.86±4.21 * | 1.72±0.08 1.61±0.15 1.62±0.08 1.63±0.10 | 42.0±4.1 44.0±2.2 41.0±3.8 39.0±3.9 | 1.5±1.1 1.8±0.8 2.1±1.3 1.7±0.8 |
Annotate: compare with the blank group,
#P＜0.001; Compare with the model group control group,
*P＜0.05,
*P＜0.01;
Experimental example 3 The compounds of this invention are to the thrombotic influence of rat artery-vein blood flow bypass
Animal subject: Wistar rat, body weight 200～220g, male and female half and half.
Trial-product:
The blank group: physiological saline, commercial;
The acetylsalicylic acid group: the acetylsalicylic acid tablet, Guangdong three is medical Group Co.,Ltd;
Compd A group: compd A capsule, self-control;
Compd B group: compd B capsule, self-control.
Experimental technique:
Get 40 of Wistar rats, be divided into 4 groups at random, 40 every group, be respectively blank group, acetylsalicylic acid group, compd A group, compd B group.The blank group is irritated stomach and is given physiological saline, compd A group, compd B group and acetylsalicylic acid group gastric infusion, every day 1 time, successive administration 4 days, abdominal injection 25% urethane 1g/kg anesthesia in 30 minutes after the administration in the 4th day, separate right common carotid artery and left external jugular vein, get a sleeve pipe of forming by three sections polyethylene tubes.4 trumpeter's art silk threads of a long 6cm are put in interruption, and heparin-saline solution is full of polyethylene tube, behind the open 15min of artery-vein blood flow bypass, in Herba Clinopodii, take out silk thread rapidly and weigh (weight in wet base), 60 degrees centigrade of dryings 30 minutes, weigh (dry weight), and calculate thrombus inhibiting rate (dry weight).
Inhibiting rate=(control group thrombus dry weight-administration group thrombus dry weight)/control group thrombus dry weight * 100%
Table 3 The compounds of this invention to rat artery-vein blood flow bypass thrombosis influence (X ± SD, n=10)
| Group | Dosage (mg/kg) | Weight in wet base (mg) | Dry weight (mg) | Inhibiting rate (%) |
| Blank group acetylsalicylic acid group compd A group compd B group | - 30 50 50 | 39.6±7.2 25.1±3.2 * 20.5±3.6 ** 22.3±2.9 ** | 12.5±1.8 7.6±0.8 * 7.1±1.6 ** 7.4±0.9 ** | - 39.2 43.2 40.8 |
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01.
Experimental result and conclusion: experimental result sees Table 3.
Compd A and compd B all can obviously suppress the formation of rat carotid artery-external jugular vein blood flow bypass thrombus, the significant difference of having compared with the blank group (p＜0.05, p＜0.01), and thrombus dry weight inhibiting rate is than acetylsalicylic acid group height, and effect is more excellent.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 compd A (L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-fourth alkylsulfonyl L-Ala)
1, the preparation of L-β-4-hydroxyl-3-methoxyl group-phenyl-a-alanine methyl ester hydrochloride
Bathe under the cooling at cryosel, 76g L-β-4-hydroxyl-3-methoxyl group-phenyl-a-L-Ala (0.36mol) is joined in the 500ml methyl alcohol, drip 30mlSOCl down at-10 ℃
2, add the back stirred overnight at room temperature, evaporated under reduced pressure solvent, product 87g, yield: 92.3%.mp：198～200℃。
2, the preparation of L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-fourth alkylsulfonyl alanine methyl ester
Under nitrogen protection; in the 600ml anhydrous acetonitrile, add the 60g dry pyridine; then toward wherein adding 85g (0.32mol) L-β-4-hydroxyl-3-methoxyl group-phenyl-a-alanine methyl ester hydrochloride; behind the room temperature reaction 1h; toward wherein slowly adding 50g fourth SULPHURYL CHLORIDE; add 65～70 ℃ of reactions in back 12h; the concentrating under reduced pressure acetonitrile is to the 200ml; toward wherein adding 500ml water; use the dilute hydrochloric acid acidifying, with ethyl acetate 100ml * 2 extractions, organic layer drying; concentrating under reduced pressure reclaims solvent and gets yellow oil 77.5g, yield: 70.1%.
3, the preparation of L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-fourth alkylsulfonyl L-Ala
Under nitrogen protection, 69.1g (0.2mol) L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-fourth alkylsulfonyl alanine methyl ester is dissolved in 600mlTHF/H
2In 0 (3: 1), add 25gNaOH, room temperature reaction 3 hours.After reaction finishes, regulate pH4～5, with chloroform (200ml * 3) extraction, drying, activated carbon decolorizing, concentrating under reduced pressure (t＜40 ℃=to doing, crude product.With crude product recrystallization in 300ml ethanol, get white highly finished product 49.5g, yield: 74.7%.
Results of elemental analyses (molecular formula: C
14H
21NO
6S)
Measured value: C:50.59%; H:6.51%; N:4.17%; S:9.65%
Theoretical value: C:50.74%; H:6.39%; N:4.23%; S:9.68%
The system of embodiment 2 compd Bs (L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-is to the preparation of chlorobenzene alkylsulfonyl L-Ala)
Be equipped with
1, L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-is to the preparation of chlorobenzene alkylsulfonyl alanine methyl ester
Under nitrogen protection; in the 500ml anhydrous acetonitrile, add the 60g dry pyridine; then toward wherein adding 85g (0.32mol) L-β-4-hydroxyl-3-methoxyl group-phenyl-a-alanine methyl ester hydrochloride (preparation of reference example 1 the first step); behind the room temperature reaction 1h; toward wherein slowly adding 68g (0.32mol) parachloroben-zenesulfonyl chloride/200ml acetonitrile solution; add 70～80 ℃ of reactions in back 12h; the reclaim under reduced pressure acetonitrile toward wherein adding 500ml water, is used the dilute hydrochloric acid acidifying then; with chloroform 100ml * 3 extractions; the organic layer drying, concentrating under reduced pressure reclaims solvent, solidifies; get faint yellow gluey thing 80g, yield: 62.5%.
2, L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-is to the preparation of chlorobenzene alkylsulfonyl L-Ala
Under nitrogen protection, 80g (0.2mol) L-β-4-hydroxyl-3-methoxyl group-phenyl-a-N-is dissolved in 600mlTHF/H to chlorobenzene alkylsulfonyl alanine methyl ester
2Among the O (2: 1), add 25gNaOH, room temperature reaction 5 hours.After reaction finishes, regulate pH4～5, with chloroform (200ml * 3) extraction, drying, activated carbon decolorizing, decompression and solvent recovery gets crude product.With crude product recrystallization in dehydrated alcohol, get white highly finished product 58.7g, yield: 76.1%.
Results of elemental analyses (molecular formula: C
16H
16ClNO
6S)
Measured value: C:49.68%; H:4.28%; Cl:9.11%; N:3.56%; S:8.25%
Theoretical value: C:49.81%; H:4.18%; Cl:9.19%; N:3.63%; S:8.31%
The preparation of embodiment 3 The compounds of this invention injection liquids
1, prescription:
Prescription 1:
Any one 50g in compd A, the B or derivatives thereof
Water for injection adds to 2000ml
Prepare 1000 altogether
Prescription 2:
Any one 100g in compd A, the B or derivatives thereof
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3:
Any one 200g in compd A, the B or derivatives thereof
Water for injection adds to 10000ml
Prepare 1000 altogether
Prescription 4:
Any one 300g in compd A, the B or derivatives thereof
Water for injection adds to 10000ml
Prepare 1000 altogether
2, preparation technology:
1) container of earlier dosing being used, ampoule, the plant-scale equipment, instrument etc. carry out pre-treatment.
2) take by weighing raw material by recipe quantity.
3) raw material is added stirring and dissolving in the water for injection of dosing amount 80%, add 0.1% needle-use activated carbon temperature control and stirred filtering decarbonization 10 minutes for 50 ℃.
4) the pH value of survey solution adds water and is settled to cumulative volume.
5) with the filtering with microporous membrane of 0.45 μ m.
6) clarity of inspection solution.
7) inspection of semifinished product.
8) the qualified back of inspection of semifinished product sealing by fusing is in ampoule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.05% methylene blue solution hunts leak.
11) warehouse-in is examined, packed to finished product entirely.
The preparation of embodiment 4 The compounds of this invention powder pins
1, prescription:
Prescription 1:
Any one 50g in compd A, the B or derivatives thereof
N.F,USP MANNITOL 100g
Water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 2:
Any one 100g in compd A, the B or derivatives thereof
N.F,USP MANNITOL 200g
Water for injection adds to 5000ml
Prepare 1000 altogether
2, preparation technology:
1) will produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
2) take by weighing raw material and auxiliary material by prescription;
3) N.F,USP MANNITOL is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal;
4) in solution, add raw material, stirring and dissolving;
5) the pH value of survey solution;
6) benefit adds to the full amount of water for injection constant volume;
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
8) inspection of semifinished product;
9) soup packing 2ml is in cillin bottle, half tamponade;
10) sample is put in the Freeze Drying Equipment, adopted following freeze-dry process freeze-drying :-40 ℃ of pre-freezes 4 hours ,-30～0 ℃ of low-temperature vacuum drying 18 hours, 0～30 ℃ heated up dry 2 hours, 30 ℃ of freeze-day with constant temperature 2 hours.
11) freeze-drying finishes tamponade, Zha Gai;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 The compounds of this invention sodium chloride injections
1, prescription
Prescription 1:
Any one 100g in compd A, the B or derivatives thereof
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Any one 200g in compd A, the B or derivatives thereof
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Any one 300g in compd A, the B or derivatives thereof
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection.
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention glucose injections
1, prescription
Prescription 1:
Any one 100g in compd A, the B or derivatives thereof
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Any one 300g in compd A, the B or derivatives thereof
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that glucose adds dosing amount 80%, stirring and dissolving, heated and boiled; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 10g in compd A, the B or derivatives thereof
Pregelatinized Starch 50.0g
Microcrystalline Cellulose 60.0g
10%PVP (50% ethanol) solution 50ml
Magnesium Stearate 1.5g
Silicon-dioxide 2.5g
Prepare 1000 altogether
Prescription 2:
Any one 50g in compd A, the B or derivatives thereof
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 120.0g
10%PVP (50% ethanol) solution 50ml
Magnesium Stearate 3g
Silicon-dioxide 5g
Prepare 1000 altogether
Prescription 3:
Any one 100g in compd A, the B or derivatives thereof
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 120.0g
10%PVP (50% ethanol) solution 100ml
Magnesium Stearate 3g
Silicon-dioxide 5g
Prepare 1000 altogether
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) raw material, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. the hydrate that has ester, its hydrate and the salt or the ester of the compound shown in the general formula (1), its pharmacy acceptable salt, its facile hydrolysis:
Wherein: R
1Be hydrogen atom or C
1-C
6Alkyl;
R
2Be hydrogen atom or C
1-C
6Alkyl;
R
3Be hydrogen atom, halogen atom, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
R
4Be hydrogen atom, C
1-C
6Alkyl or by 1～5 halogen atom, C
1-C
6The phenyl of alkyl, hydroxyl, amino or carboxyl substituted.
2. the hydrate of compound as claimed in claim 1, its pharmaceutical salts, ester and hydrate and medicinal salt or ester thereof, wherein:
R
1Be hydrogen atom or C
1-C
4Alkyl;
R
2Be hydrogen atom or C
1-C
4Alkyl;
R
3Be hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
4Be C
1-C
4Alkyl or phenyl, and phenyl ring can be by 1～5 halogen, C
1-C
4Alkyl, hydroxyl, amino or carboxyl substituted.
3. ester, hydrate and the salt thereof of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis or the hydrate of ester, wherein:
R
1Be hydrogen atom or C
1-C
2Alkyl;
R
2Be hydrogen atom or methyl;
R
3Be hydrogen atom, bromine atoms, C
1-C
2Alkyl or C
1-C
2Alkoxyl group;
R
4Be C
1-C
4Alkyl or phenyl, and phenyl ring can be by 1～5 halogen atom or C
1-C
4Alkyl.
4. the hydrate of the ester of compound as claimed in claim 3, its pharmacy acceptable salt, its facile hydrolysis and hydrate thereof and salt or ester,
Wherein: R
1Be hydrogen atom; R
2Be methyl; R
3Be hydrogen atom; R
4For normal-butyl or
5. as the hydrate of ester, its hydrate and the salt or the ester of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner.
6. pharmaceutical composition as claimed in claim 5 can be made into oral preparations or injection.
7. pharmaceutical composition as claimed in claim 5 contains the active ingredient by the described compound 10mg～500mg of formula (1).
8. the application of the hydrate of the described compound of the arbitrary claim of claim 1～4, its pharmaceutical salts, ester, its hydrate and medicinal salt or ester thereof in the medicine of preparation treatment cardiovascular and cerebrovascular diseases.
9. as the application of hydrate in the antithrombotic medicine of preparation treatment of ester, its hydrate and the salt or the ester of the described compound of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007103009099A CN101205205A (en) | 2006-12-15 | 2007-12-07 | Alanine derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610146234.2 | 2006-12-15 | ||
| CN200610146234 | 2006-12-15 | ||
| CNA2007103009099A CN101205205A (en) | 2006-12-15 | 2007-12-07 | Alanine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101205205A true CN101205205A (en) | 2008-06-25 |
Family
ID=39565702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007103009099A Pending CN101205205A (en) | 2006-12-15 | 2007-12-07 | Alanine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101205205A (en) |
-
2007
- 2007-12-07 CN CNA2007103009099A patent/CN101205205A/en active Pending
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| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20080523 Address after: Tianchen Avenue in Ji'nan high tech Development Zone in Shandong City, No. 2518, block A Applicant after: Shandong Xuanzhu Medical Technology Co., Ltd. Address before: Tianchen Avenue in Ji'nan high tech Development Zone in Shandong City, No. 2518, block A Applicant before: Huang Zhenhua |
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Open date: 20080625 |