CN1147321C - Threonate possessing of partial basicity and having basic chemical structure medicine in its molecule - Google Patents
Threonate possessing of partial basicity and having basic chemical structure medicine in its moleculeInfo
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- CN1147321C CN1147321C CNB971209286A CN97120928A CN1147321C CN 1147321 C CN1147321 C CN 1147321C CN B971209286 A CNB971209286 A CN B971209286A CN 97120928 A CN97120928 A CN 97120928A CN 1147321 C CN1147321 C CN 1147321C
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Abstract
The present invention relates to alkaline threonic acid salt having an alkaline chemical structure medicine in molecules thereof, which is a batch of novel medicine with high bioavailability created by degrading primary products by the medicine provided by the present invention and vitamin C to combine threonic acid complexation salt with moderate constant by the latest enlightenment of a molecule calcium replenishing theory created in China. Compared with original medicines, the medical threonic acid salt has improved water solubility and the liposolubility, the medical threonic acid salt is mainly in a molecule state within the physiological pH range, the threonic acid is used as a carrier, the medicine is absorbed by an easily penetrating film and a film hole, and the purpose of administration in a molecule state is achieved by slowly releasing the medicine in required places. Therefore, compared with the original medicines, the medical threonic acid salt has high absorption rate and the utilization rate.
Description
The threose acid salt that basic chemical structure medicine is arranged in part alkalescence and the molecule, be on the molecule of the up-to-date foundation of China is replenished the calcium theoretical basis, the applicant enlarges range of application, with vitamin C degraded primary product L type threonic acid THREONIC ACID. or DL type threonic acid THREONIC ACID. and this patent proposition medicine complexation salify, the high novel drugs of a collection of bioavailability of initiative.
Left-handed threonic acid THREONIC ACID. has another name called the L-threonic acid THREONIC ACID., R, S-2,3,4-trihydroxy-butyric acid (R, S-2,3,4-trihydroxy-butyric acid).
The L-threonic acid THREONIC ACID. is one of ascorbic main degradation products, and it has kept the left-handed optics active structure of Vc, and objective reality is in some moving planting in the body.According to Britain's reported literature, in food processing process, 80% form that changes the L-threonic acid THREONIC ACID. into is arranged as the vitamin C of food additive.Because the L-threonic acid THREONIC ACID. is accompanied by the existence of Vc, all the toxicity of L-threonic acid THREONIC ACID. has been carried out extensive, deep research as Britain, Japan and the U.S. abroad, as long malicious test and aberration inducing is tested and shown that all it is without any side effects of the animal of 28 days and 120 days.Recently, the scientist of the U.S. proposes: ascorbic metabolic mechanism effect is (as preventing cold, enhancing human body immunity power, prophylaxis of cancer and reduction glue sterin etc.) produce by its degradation product fully, the existence of these degradation products makes a difference to ascorbic metabolic mechanism again.All these the proof L-revive smart acid have the height biological activity.It also has moderate binding constant, and under the physiological pH condition, complex mainly exists in the complex status mode in solution; The precursor medicine of complexation still has left-handed structure, and the optical characteristics that can be discerned by biomembrane is promptly arranged; Can improve the water solublity of medicine and fat-soluble; Be easier to permeates cell membranes and fenestra.So the precursor medical instrument of L-threonic acid THREONIC ACID. complexation has than former drug absorption rate utilization rate height, but also can reduce the side effect of medicine to gastrointestinal irritation.
The molecule that four post-doctors such as Yu Kai, doctor the found theory of replenishing the calcium is pointed out: when in the calcium source during with the bonded material biologically active of calcium ion, it can: (1) directly serves as the carrier of calcium ion in body, and just calcium ion arrives cell tissue smoothly; (2) make calcium preparation itself become the bioactive substance of being discerned and allowing to pass through by cell membrane; (3) very high absorbance and utilization rate are arranged.Like this, diffusion is accessory no longer just.On the contrary, the shared share of this process has taken place significantly to increase and has risen to the main path of calcium absorption.
External existing Ibuproben-Lysiante preparation oral and injection is sold trade name: Imbum.Oral absorption is very fast, oral absorption 500mg, blood peak concentration of drug 31 μ g/ml, average out to peak time 45 minutes (ibuprofen peak time 1.2-2.1 hour).The absolute bioavailability of ibuprofen is 102.7% in the Ibuproben-Lysiante, shows that it absorbs fully.Oral ibuprofen lysinate and intravenous injection Ibuproben-Lysiante have good equally toleration.Because lysine has same moderate binding constant, the precursor medicine Ibuproben-Lysiante stable in properties of its ibuprofen under the physiological pH condition, mainly exists in solution in the molecular state mode, and has than highly-water-soluble and fat-soluble.
L-Lysine mono Hydrochloride relies on the propylhomoserin racemization in dissociated chlorine ion process, its product is a DL-lysine, become DL-to rely aminoprofen with the ibuprofen complexation, molecular weight is less, and mainly exists with molecular state in the physiological pH scope, absorbs with permeable membrane and two kinds of approach of fenestra.Thereby Ibuproben-Lysiante possesses molecule administration primary condition, just be not difficult to explain that with the molecule theory of replenishing the calcium the ibuprofen absolute bioavailability is up to 102.7% in the Ibuproben-Lysiante, show that it absorbs principle completely, for this reason, the applicant thinks molecule that four post-doctors such as Yu Kai, doctor the found theoretical extensible molecular state administration theory that extends to of replenishing the calcium, for we formulate the high precursor medicine of new bioavailability, provide theoretical foundation.
For improving the dissolubility and the drug bioavailability of some drugs, also adopt the hydrotropy Technology in the pharmaceutical technology, utilize cosolvent and medicine complexation, association, formation complex salt or metathesis reaction to form soluble-salt, increase drug solubility.Be different from the basic difference of hydrotropy by the molecule theoretical molecular state administration theory of extending expansion of replenishing the calcium, emphasize that exactly carrier (similar cosolvent) should have following characteristics:
1, chelation structure has moderate binding constant, to guarantee the precursor medicine of (i) medicine and carrier complexation, mainly exists in the molecular state mode under the physiological pH condition; (ii) not being subject to material such as phosphoric acid that some and medicine form insoluble chemical compound disturbs; (iii) can slowly discharge medicine on the ground that needs medicine.
2, better water solublity is arranged, this is that the precursor medicine can be in the preceding topic of gastrointestinal absorption.
3, have moderate fat-soluble, to guarantee precursor medicine permeates cell membranes.
Moderate as the carrier molecule amount, under the little state of its precursor medicine molecular weight, still can absorb in the permeable membrane hole; Carrier has left-handed structure, the precursor medicine of complexation is as keeping its optical activity, and it is fat-soluble good, can also mainly absorb with permeable membrane, can make the administration of molecular state mode obtain more high-absorbility and utilization rate, but the carrier of the most primary is complexation medicine should have three basic characteristics of this description, just can reach the purpose of molecular state mode administration, improves the absorbance and the bioavailability of medicine.
Threonic acid THREONIC ACID. (R, S-2,3,4-trihydroxy-butyric acid) has moderate binding constant, and the l threonic acid that it and calcium network are understood has good water-solubility and fat-soluble, and aqueous solution is neutral (pH=7); In the physiological pH scope, calcium mainly exists in complex molecule attitude mode in the solution; It is slow, long half time of metabolism time in vivo, is respectively more than 240 minutes and more than 120 minutes, helps human body absorbing calcium like this.Absorbance is up to 95%.Illustrate that the L-threonic acid THREONIC ACID. is the replenish the calcium effective carrier of mode of molecule, simultaneously the also effective carrier of molecular state administering mode.
Medicine is generally the bigger Organic substance of molecular weight, and a great deal of a part of medicine is arranged is the alkalescence chemical constitution to be arranged or be the alkalescence Organic substance, have and L type or the moderate binding constant of DL type threonic acid THREONIC ACID. complexation, its precursor property of medicine matter is stable, be not subjected to interference such as phosphoric acid in the physiological pH scope, the precursor medicine becomes at high proportion that the molecular state mode exists in solution; The water solublity of precursor medicine and former medicine and fat-soluble contrast all increase, and are that carrier all can penetrate absorption at gastrointestinal tract with the threonic acid THREONIC ACID., and the place that needs at medicine slowly discharges.If complexation technology is reasonable, do not make the optical texture racemization of L-threonic acid THREONIC ACID., still keep its optical activity that has, also can improve the absorbance and the bioavailability of precursor medicine Chinese medicine; Can reduce medicine again to the gastrointestinal stimulation, must be subjected to patient and doctor's welcome, the good and business economic high efficiency of the social benefit that is produced.
The molecule that is four post-doctors such as triumphant grade, doctor is replenished the calcium before theory do not found, and the drug research worker solves the bioavailability problem of insoluble drug, has also adopted a lot of methods, as improving preparation technique, improves the dissolution and the dissolution rate of medicine; Develop new dosage form, shorten disintegration; Add cosolvent, improve drug solubility.In medicine synthesising process, the high precursor medicine of development water solublity also has the hydrotropy of employing technology etc.For being alkalescence or having the medicine of basic chemical structure, now adopt binding constant to have better water solublity and the acid of fat-soluble ore deposit or organic acid salify more greatly or not simultaneously, the precursor medicine of exploitation is more.88 kinds of the hydrochlorate medicines that 95 editions pharmacopeia of China GB are recorded, 26 kinds of sulfate medicines, 7 kinds of nitrate medicines, 13 kinds of phosphate medicines, a kind of propionate medicine, a kind of valerate medicine, 3 kinds of maleate medicines, a kind of hendecene salt medicine, a kind of undecylate medicine, 1 kind of folinate medicine, 2 kinds of benzoate medicines, 3 kinds of stearate medicines, 1 kind of Lactobionate medicine, 2 kinds of lactate medicines, 8 kinds of citrate medicines, 4 kinds of tartrate medicines, 3 kinds of gluconate medicines, a kind of palmitate medicine.Above-mentioned salt medicine and China go on the market and do not record into pharmacopeia salt medicine, and the overwhelming majority all is not possess the essential characteristic of molecular state administration.At present in new drug development, in the precursor medicine development to poorly soluble basic drugs, still adopt acid of above-mentioned ore deposit or organic salt or salt, it can only play the cosolvent effect, can not become the carrier of medicine and improve the ability that medicine penetrates molecular film, therefore can not reach the molecular state administering effect.
Before the Ibuproben-Lysiante of having set forth, moderate binding constant, good aqueous solubility (1: 1) and moderate fat-soluble, the characteristic that has possessed the theoretical defined of molecular state administration, so the absolute bioavailability of ibuprofen is up to 102.7% in the oral ibuprofen lysinate, the blood medicine reaches the peak concentration time and shortens to original 1/2nd.The theoretical practical value height of using of above-mentioned pharmacological evaluation achievement explanation molecular state administration.
Acyclovir is the eutherapeutic a kind of medicine of antiviral of generally acknowledging both at home and abroad at present.Have the herpes simplex virus I of inhibition, II type, the effect of varicella zoster virus and Epstein-Barr virus.The herpes simplex and the herpes zoster that are used for department of dermatologry, the keratitis of the herpes simplex of ophthalmology is all strong than other antiviral agents effect.But its oral administration biaavailability is very low, has report external in the derive message of medicine of development valacyclovir at present, has now entered phase ii clinical trial.
Acyclovir, chemical name: 9-(2-hydroxyl ethoxymethyl) guanine, oral absorption is very poor, and about 15～30% are absorbed by gastrointestinal.Be combined with on its guanine ring and be alkaline NH
2Group, can with L type or DL type threonic acid THREONIC ACID. complexation salify.Threonic acid THREONIC ACID. and acyclovir binding constant are all moderate, acyclovir threose acid salt stable in properties; In solution, can not disturbed in conjunction with forming insoluble drug and phosphoric acid with acyclovir, good water-solubility and fat-soluble is arranged by some; In physiology pH value scope, acyclovir is that the molecular state mode exists with complex state mainly in the solution, and higher absorbance and utilization rate are arranged.It is oral administering mode with the administering mode of injection mainly that the acyclovir threose acid salt can change present acyclovir, for patient and doctor bring facility in the medical treatment.
Atenolol, this product are used for the treatment of arrhythmia, hypertension, angina pectoris, hyperthyroidism, pheochromocytoma, myocardial infarction.Because determined curative effect, cheap, not only taken in China GB95 version pharmacopeia, its tablet but also listed national basic medicine in.But the oral absorption rate is lower, is about 50%.This product has and is alkaline NH
2Group, so it is dissolved in diluted acid, as becoming the atenolol threose acid salt with L type or the complexation of DL type threonic acid THREONIC ACID. with this product, can reach the theoretical defined basic demand of molecular state administration, the absorbance and the utilization rate of atenolol in the atenolol threose acid salt be can improve, a good effect and marketable novel drugs become.
Reserpine is used for the treatment of hypertension and hypertensive crisis.This product is almost insoluble in water, methanol, ethanol or ether, but is dissolved in diluted acid.Be that hypertensive common drug is treated by China, spread all over the rural area, city.This product absorbs fast, but bioavailability is low, is about 50%.China's Ministry of Public Health, the Ministry of Finance defend the socialized medicine medication reimbursement scope that public doctor sends out (1994) No. 1 announcements, only record its injection, and oral tablet exclude socialized medicine reimbursement scope.This product can be in gastric juice under the effect of gastric acid, improves its water solublity, absorbs very fast.As with L-threonic acid THREONIC ACID. complexation salify, stable in properties, in the physiological pH scope, the precursor medicine is that the molecular state mode exists with complex state mainly in gastric juice, not only can improve water solublity, but also have fat-soluble and optical activity.With the L-threonic acid THREONIC ACID. is carrier, makes the smooth permeates cell membranes of reserpine and absorbs, and be main path with the diffusion, makes reserpine arrive cell tissue.Can improve the utilization rate of reserpine in the reserpine threose acid salt, improve curative effect of medication.
Ciprofloxacin is one of synthetic Comprecin, is the clinical use has a broad antifungal spectrum of present China, medicine that frequency of utilization is high.Oral post-absorption is rapid on an empty stomach, and the oral absorption rate is about 70%, and the existence of food can make absorption delay.China has developed its hydrochlorate and lactate listing.As ciprofloxacin and L-threonic acid THREONIC ACID. complexation salify, make its precursor medical instrument that optical activity be arranged, have the stronger molecular film ability that penetrates than ciprofloxacin and ciprofloxacin lactate, must improve the absorbance and the bioavailability of ciprofloxacin in the ciprofloxacin threose acid salt.
Norfloxacin is one of very high antibacterials of the clinical frequency of utilization of China.At present not only in the common use of big or middle policlinic, and spread all over the rural area.Oral absorption is rapid on an empty stomach for it, but not exclusively, has only 30～40% by gastrointestinal absorption.Norfloxacin is the same with ciprofloxacin, the piperazine group that is alkalescence is arranged, with L-threonic acid THREONIC ACID. complexation salify in molecular structure, not only improve its water solublity and fat-soluble, and stable in properties, in the physiological pH scope, exist ratio higher in the molecular state mode of complex state.Also have optical characteristics, therefore have and penetrate the molecular film ability more by force.The norfloxacin threose acid salt can become China's drug market situation of selling well medicine surely than the bioavailability height of former norfloxacin.
Molecular state administration theory not only has the general guidance meaning in the precursor medicine exploitation of synthetic drug, and is applicable to the precursor medicine exploitation of antibiotics antimicrobial drug.
Tetracycline, it is hydrochlorate that China GB95 version pharmacopeia is recorded kind.Have antibiotic, parasiticide effect, be broad-spectrum antibacterial agent, have bactericidal action during high concentration.Can absorb after this product is oral but incomplete, pact can absorb 30～70%; Oral absorption is influenced by metal ion, the latter and medicine form complex reduces absorption, the blood drug level of taking medicine after feed user on an empty stomach reduces half approximately, trace it to its cause for: hydrochloric acid is a strong ore deposit acid, ionization degree is big in gastric juice, and tetracycline becomes the ratio of ionic condition big in gastric juice, is subject to the metal ion influence when oral, the latter and medicine form insoluble or the slightly solubility complex reduces absorption, so quadracycline destructible in alkaline solution lost efficacy.
The L-threonic acid THREONIC ACID., chemical name R, S-2,3, the 4-trihydroxy-butyric acid is acid than weak organic acid, littler than hydrochloric acid ionization degree, with tetracycline complexation salify, stable in properties, in the physiological pH scope, not being subject to metal ion influence, is that molecular state exists ratio to be improved largely than quadracycline with complex state in gastric juice, also has than the strong molecular film penetration capacity of quadracycline, its absorbance utilization rate must improve, and can become competitive medicine in the Tetracyclines medicine.
It is to have the tetracycline similarity that antibiotics also has quite a few.As amikacin sulfate, Micronomicin Sulfate etc., pharmacopeia is not also collected its oral formulations.But NH is arranged all in its molecular structure
2Group, can with L type or DL type threonic acid THREONIC ACID. complexation salify.Because the threonic acid THREONIC ACID. complexation constant is moderate, the threose acid salt of amikacin and micronomicin, stable in properties is under the physiological pH condition, equally mainly exist with molecular state, and be carrier with the threonic acid THREONIC ACID., amikacin and micronomicin all can reach cell tissue smoothly, and higher bioavailability is arranged, and because its stable in properties, can also change administering mode, develop the oral formulations medicine, adapt to different clinical demands.
China GB95 version pharmacopeia and local pharmacopeia, the antibiotics that records has a quite a lot of part under the physiological pH condition, the character instability, unsuitable oral or oral administration biaavailability is low, pharmacopeia is only recorded its ejection preparation medicine.As the ampicillin, the oral absorption rate only is 50%, and lenampicillin is an esters derivative, and good absorbing can strengthen 2～4 times of ampicillin curative effects.This class antibiotics, await our the further precursor medicine of developing with L-type or the complexation of DL type threonic acid THREONIC ACID., improve its stability, water solublity, fat-soluble under the physiological pH condition, develop the high oral formulations medicine of bioavailability, different clinical user demands have been adapted to, not only social benefit is good, and the business economic benefit is also high.
In sum, no matter be synthetic drug, the patent medicine that narrows, biochemical medicine, so long as medicine is in alkalescence (pH＞7) or the molecular structure basic chemical structure of being is arranged, and the binding constant of medicine chelation structure is moderate or it is high or on the low side to omit, major part can with L type or DL type threonic acid THREONIC ACID. complexation salify, reach molecular state administration purpose, improve drug absorption rate and utilization rate.Molecular state administration theory is applied to the exploitation of precursor medicine thus, and applied widely, pharmaceutical effectiveness is good, and social benefit is good, the enterprise operation high efficiency.
In L-threonic acid THREONIC ACID. and medicine salify technology, keep the optical characteristics of L-threonic acid THREONIC ACID. in the complex as far as possible.For this reason, should reach following several requirements in complexation technology:
1, do not have in the solvent of the complexation salts substances of strong acid, highly basic and strong acid and strong base exists.
2, complexation temperature should be controlled at room temperature or room temperature following (or remain on 0～5 ℃, or be controlled at below 0 ℃), decides on pharmaceutical properties.
3, the temperature that concentrates or dry should be controlled at below 80 ℃, and the time is not long as far as possible.Also can take spray drying method,, still may keep L-threonic acid THREONIC ACID. optical activity in the complex though the temperature height time is short relatively and extremely.
Be example with norfloxacin and L type or the complexation of DL type threonic acid THREONIC ACID. below, set forth technical process:
Add methanol 250ml and L type or DL type threonic acid THREONIC ACID. 0.1mol 13.8g in the 500ml three-necked bottle, stirs and add norfloxacin 0.1mol 31.9g again after miscible, after being stirred to norfloxacin and dissolving fully, stirring reaction is 1～2 hour under the room temperature, and reaction is complete.
Reaction is finished, and vacuum concentration (the control feed temperature is below 55 ℃) reaches at 30～40% o'clock to complex content, vacuum filtration, and filter cake is with an amount of methanol wash 2～3 times, merging filtrate and washing liquid to 0～5 ℃ standing over night crystallization.Vacuum filtration, filter cake with after an amount of methanol wash 2～3 times to oven dry below 50 ℃, crude product.
In the 250ml three-neck flask, add methanol 150ml, add crude product again, be controlled at 50 ℃ of following heated and stirred dissolvings, vacuum filtration, filter cake is with an amount of methanol wash 2～3 times, merging filtrate, washing liquid to 0～5 ℃ standing over night crystallization.Vacuum filtration, filter cake with after an amount of methanol wash 2～3 times to oven dry below 50 ℃, finished product.
Mother solution and washing liquid merge reclaim, refining finished product.
Medicine L type or DL type threose acid salt also can adopt the salt of medicine and the metathesis reaction of L type or DL type threose acid salt to make.
This patent proposes the medicine threonic acid THREONIC ACID. all can adopt the similar technology complexation of aforementioned norfloxacin threose acid salt salify, or adopts metathesis reaction to make.According to the physical and chemical properties of drugs difference, complexation technology can be done following adjustment:
1, can make solvent complex with deionized water by last method, freezing and crystallizing or spray drying get crude product, press again norfloxacin threose acid salt process for refining refining finished product.
2, low boiling point solvent such as, methanol water insoluble as medicine and complex, ethanol, ether, acetone can adopt in two kinds of mixed solvents that mix and carry out complexation.
3, also can the L-threonic acid THREONIC ACID. or the DL threonic acid THREONIC ACID. be raw material, make solvent again.
4, also can select complexation in big solvent of dissolving of messenger drug thing and complex and dissolubility or the mixed solvent, but feeding sequence is undertaken by the raw material elder generation throwing method that dissolubility is big in this solvent.
As the antibiotics complexation, solvent is selected, complexation, concentrate, the control temperature range of oven dry, all should select according to antibiotic physicochemical property, guaranteeing that it is tired does not reduce in the technology overall process.
According to the physicochemical property of medicine, the reaction condition of various different pharmaceuticals all should be done suitable adjustment, as mol ratio, solid-liquid ratio, temperature, solvent, response time etc.
The L-threonic acid THREONIC ACID. is ascorbic main degradation product, and l threonic acid is as far back as synthetic chemical compound of the later stage seventies, does not after this see the report of its application and research.But up to U.S. scientist Anthony in 1989 at the research large doses of vitamin C during to the drug effect of antitumor action, just chance on l threonic acid and can promote Vc absorption in vivo speed and prolong Vc metabolism time in vivo that Anthony likens l threonic acid to Vc visually and enters intravital door opener or power.But do not carry out the research of L-threonic acid THREONIC ACID. and calcium salt thereof and the correlation theory of replenishing the calcium abroad always.
The applicant is an english vocabulary of checking the L-threonic acid THREONIC ACID., Hai Shi organic compound dictionary (volumes is incomplete), chemical compound name dictionary, three English-Chinese civilian bilingual dictionaries of English-Chinese medicine vocabulary translated in the Chinese of having read, look into the english vocabulary of L-threonic acid THREONIC ACID., threonic acid THREONIC ACID., trihydroxy-butyric acid, do not find to record.Trihydroxy-butyric acid english vocabulary trihydroxy-butyric acid is found at the medication chemistry dictionary in the back.In reading, accident reads medicine and vitamin C complexation salify drug derivative vocabulary is more, and one of vitamin C degraded primary product L-threose acid salt precursor medicine english vocabulary does not all read.By the l threonic acid pharmacological research, prove the bioavailability height of l threonic acid than calcium ascorbate.But three dictionaries record L-threose acid salt and DL-threose acid salt precursor medicine vocabulary this lack, more than consult situation, illustrate that medicine and L-threonic acid THREONIC ACID. and the salifiable precursor medicine of DL-threonic acid THREONIC ACID. complexation development field remain to be developed, molecular state administration theory is applied to the research of prodrug medicine and remains to be carried out in a deep going way.
137 kinds of the ore deposit Barbiturates medicines that China GB95 version pharmacopeia is recorded, 32 kinds of organic acid salt medicines; In addition, also have quite a lot of medicine to be in alkalescence or the molecular structure basic chemical structure is arranged, but do not develop the precursor medicine with the acid complexation; The similar above-mentioned two types of character of local remedies,official are also a lot; Recently in state approval trial production and the formal production medicine also there be similar above-mentioned one, two type of character medicine.Said medicine has a common denominator, all be to be in alkalescence or the molecular structure basic chemical structure is arranged, and most medicine binding constants are moderate or on the low side, have only minority medicine binding constant higher, great majority can become the more stable complex of chemical property with the complexation of L-threonic acid THREONIC ACID., under the physiological pH condition, complex mainly exists in the molecular state mode in gastric juice, possess molecular state administration theory and point out primary condition, with the molecular state administration is that main mode absorbs, utilize local slowly release that medicine needs, improve this kinds of properties drug bioavailability.
This patent proposes with vitamin C degraded primary product L type threonic acid THREONIC ACID. or DL type threonic acid THREONIC ACID. and following medicine salify, can improve the drug absorption utilization rate, become on the market not only good effect of a new generation, and marketable new medicine, the good and economic worth height of the social benefit that produces.Thus, present patent application has originality, novelty and practicality.For this reason, the applicant to ask this patent petition to propose that the L type of basic chemical structure medicine and DL type threose acid salt are arranged in following alkalescence or the molecular structure be present patent application protection medicine.
1, threonic acid THREONIC ACID. penicillin V salt 2, threonic acid THREONIC ACID. benzylpcnicillin salt
3, threonic acid THREONIC ACID. ampicillin salt 4, threonic acid THREONIC ACID. amoxicillin salt
5, threonic acid THREONIC ACID. cefalexin salt 6, threonic acid THREONIC ACID. cefadroxil salt
7, threonic acid THREONIC ACID. cefotaxime oximate 8, threonic acid THREONIC ACID. rocephin salt
9, threonic acid THREONIC ACID. cefradine salt 10, threonic acid THREONIC ACID. tobramycin salt
11, threonic acid THREONIC ACID. norvancomycin salt 12, threonic acid THREONIC ACID. erythromycin ethylsuccinate salt
13, threonic acid THREONIC ACID. red pigment salt 14, threonic acid THREONIC ACID. Doxycycline salt
15, threonic acid THREONIC ACID. Oxytetracycline Hcl USP 16, threonic acid THREONIC ACID. neomycin salt
17, threonic acid THREONIC ACID. tetracycline salt 18, threonic acid THREONIC ACID. gentamycin salt
19, threonic acid THREONIC ACID. chloromycetin salt 20, threonic acid THREONIC ACID. lincomycin salt
21, threonic acid THREONIC ACID. clindamycin salt 22, threonic acid THREONIC ACID. sulfadiazine salt
23, threonic acid THREONIC ACID. trimethoprim salt 24, threonic acid THREONIC ACID. sulfamethoxazole salt
25, threonic acid THREONIC ACID. amikacin salt 26, threonic acid THREONIC ACID. rifamycin salt
27, threonic acid THREONIC ACID. spectinomycin salt 28, threonic acid THREONIC ACID. micronomicin salt
29, threonic acid THREONIC ACID. streptomycin salt 30, threonic acid THREONIC ACID. taurate
31, threonic acid THREONIC ACID. tinidazole salt 32, threonic acid THREONIC ACID. metronidazole salt
33, threonic acid THREONIC ACID. hydrobenzole salt 34, threonic acid THREONIC ACID. berberine salt
35, threonic acid THREONIC ACID. norfloxacin salt 36, threonic acid THREONIC ACID. ciprofloxacin salt
37, threonic acid THREONIC ACID. tamoxifen salt 38, threonic acid THREONIC ACID. acyclovir salt
39, threonic acid THREONIC ACID. ribavirin salt 40, threonic acid THREONIC ACID. procaine amine salt
41, threonic acid THREONIC ACID. form of omeprazole salts 42, threonic acid THREONIC ACID. famotidine salt
43, threonic acid THREONIC ACID. ranitidine salt 44, threonic acid THREONIC ACID. domperidone salt
45, threonic acid THREONIC ACID. fenfluramine salt 46, threonic acid THREONIC ACID. acetparaminosalol phenates
47, threonic acid THREONIC ACID. isoniazid salt 48, threonic acid THREONIC ACID. atenolol salt
49, threonic acid THREONIC ACID. diltiazem salt 50, threonic acid THREONIC ACID. flunarizine salt
51, threonic acid THREONIC ACID. albuterol salt 52, threonic acid THREONIC ACID. terbutaline salt
53, threonic acid THREONIC ACID. ephedrine salt 54, threonic acid THREONIC ACID. pseudoephedrine salt
55, threonic acid THREONIC ACID. codeine salt 56, threonic acid THREONIC ACID. dextromethorphan salt
57, threonic acid THREONIC ACID. gliclazide salt 58, threonic acid THREONIC ACID. gemfibrozil salt
59, threonic acid THREONIC ACID. miconazole salt 60, threonic acid THREONIC ACID. fluconazol salt
No matter adopt which kind of synthetic process for said medicine; complexation becomes 1～3 threonic acid THREONIC ACID. molecule of the L type of medicine or DL type and the threonic acid THREONIC ACID. salt medicine (containing the different medicine threose acid salt of water of crystallization molecule number) of 1 drug molecule complexation; or in preparation prescription and technology, adopt in L type or the DL type threonic acid THREONIC ACID. and this patent petition and list medicine hydrotropy (salify technology); make technology transfer, cooperate; or with launch products; be considered as infringement, the request Patent Law provides protection.
List of references: the molecule theory of replenishing the calcium, the biochemical industry post-doctor Yu Kai of University Of Tianjin, the doctor of Beijing Medical University Wang Zhiwen, the inorganic chemistry post-doctor of Zhejiang University are preced with that good fortune is flat, the theoretical chemistry post-doctor Zhu Shourong of Nankai University, Chinese Medicine, JIUYUE in 1997 30 days the 7th edition.
Claims (3)
1, a kind of method for preparing left-handed threose acid salt chemical compound or complex is to synthesize threose acid salt chemical compound or complex at room temperature or below the room temperature with left-handed threonic acid THREONIC ACID. and the organic drug with base; Wherein said organic drug is a penicillin V; benzylpcnicillin, ampicillin, amoxicillin, cefalexin, cefadroxil; cefotaxime, rocephin, cefradine, tobramycin; norvancomycin, erythromycin ethylsuccinate, Doxycycline, oxytetracycline; neomycin, tetracycline, gentamycin, chloromycetin; lincomycin, clindamycin, sulfadiazine, trimethoprim; sulfamethoxazole, amikacin, rifamycin, spectinomycin; micronomicin, streptomycin, taurine, tinidazole; metronidazole, hydrobenzole, berberine, norfloxacin; ciprofloxacin, tamoxifen, acyclovir, ribavirin; procainamide, omeprazole, famotidine, ranitidine; domperidone, fenfluramine, acetaminophen, isoniazid; atenolol, flunarizine, albuterol, terbutaline; ephedrine, pseudoephedrine, codeine, dextromethorphan; gliclazide, gemfibrozil, miconazole, or fluconazol.
2, according to the left-handed threose acid salt chemical compound or the complex of the preparation of the method for claim 1, described chemical compound or complex are:
The threonic acid THREONIC ACID. penicillin V salt; threonic acid THREONIC ACID. benzylpcnicillin salt; threonic acid THREONIC ACID. ampicillin salt; threonic acid THREONIC ACID. amoxicillin salt; threonic acid THREONIC ACID. cefalexin salt; threonic acid THREONIC ACID. cefadroxil salt, threonic acid THREONIC ACID. cefotaxime oximate, threonic acid THREONIC ACID. rocephin salt; threonic acid THREONIC ACID. cefradine salt; threonic acid THREONIC ACID. tobramycin salt, threonic acid THREONIC ACID. norvancomycin salt, threonic acid THREONIC ACID. erythromycin ethylsuccinate salt; threonic acid THREONIC ACID. Doxycycline salt; the threonic acid THREONIC ACID. Oxytetracycline Hcl USP, threonic acid THREONIC ACID. neomycin salt, threonic acid THREONIC ACID. tetracycline salt; threonic acid THREONIC ACID. gentamycin salt; threonic acid THREONIC ACID. chloromycetin salt, threonic acid THREONIC ACID. lincomycin salt, threonic acid THREONIC ACID. clindamycin salt; the threonic acid THREONIC ACID. sulfadiazine salt; threonic acid THREONIC ACID. trimethoprim salt, threonic acid THREONIC ACID. sulfamethoxazole salt, threonic acid THREONIC ACID. amikacin salt; threonic acid THREONIC ACID. rifamycin salt; threonic acid THREONIC ACID. spectinomycin salt, threonic acid THREONIC ACID. micronomicin salt, threonic acid THREONIC ACID. streptomycin salt; the threonic acid THREONIC ACID. taurate; threonic acid THREONIC ACID. tinidazole salt, threonic acid THREONIC ACID. metronidazole salt, threonic acid THREONIC ACID. hydrobenzole salt; the threonic acid THREONIC ACID. berberine salt; threonic acid THREONIC ACID. norfloxacin salt, threonic acid THREONIC ACID. ciprofloxacin salt, threonic acid THREONIC ACID. tamoxifen salt; threonic acid THREONIC ACID. acyclovir salt; threonic acid THREONIC ACID. ribavirin salt, threonic acid THREONIC ACID. procaine amine salt, threonic acid THREONIC ACID. form of omeprazole salts; threonic acid THREONIC ACID. famotidine salt; threonic acid THREONIC ACID. ranitidine salt, threonic acid THREONIC ACID. domperidone salt, threonic acid THREONIC ACID. fenfluramine salt; threonic acid THREONIC ACID. acetparaminosalol phenates; threonic acid THREONIC ACID. isoniazid salt, threonic acid THREONIC ACID. atenolol salt, threonic acid THREONIC ACID. flunarizine salt; threonic acid THREONIC ACID. albuterol salt; threonic acid THREONIC ACID. terbutaline salt, threonic acid THREONIC ACID. ephedrine salt, threonic acid THREONIC ACID. pseudoephedrine salt; threonic acid THREONIC ACID. codeine salt; threonic acid THREONIC ACID. dextromethorphan salt, threonic acid THREONIC ACID. gliclazide salt, threonic acid THREONIC ACID. gemfibrozil salt; threonic acid THREONIC ACID. miconazole salt, or threonic acid THREONIC ACID. fluconazol salt.
3, according to the left-handed threose acid salt chemical compound or the complex of claim 2, wherein said chemical compound or complex per molecule contain the left-handed threonic acid THREONIC ACID. of 1-3 molecule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971209286A CN1147321C (en) | 1997-11-04 | 1997-11-04 | Threonate possessing of partial basicity and having basic chemical structure medicine in its molecule |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971209286A CN1147321C (en) | 1997-11-04 | 1997-11-04 | Threonate possessing of partial basicity and having basic chemical structure medicine in its molecule |
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| Publication Number | Publication Date |
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| CN1194865A CN1194865A (en) | 1998-10-07 |
| CN1147321C true CN1147321C (en) | 2004-04-28 |
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| CN1074762C (en) | 1998-08-18 | 2001-11-14 | 北京巨能亚太生命科学研究中心 | Process for preparing chromium L-threonate, its preparing process and application |
| CN110037998A (en) * | 2018-01-16 | 2019-07-23 | 镇学初 | Purposes of the melbine salt in treatment cerebral infarction |
| CN110604730A (en) * | 2018-06-15 | 2019-12-24 | 镇学初 | Application of metformin salt in treatment of cerebral infarction |
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