CN101123878A - L-threonine derivatives of high therapeutic index - Google Patents

Abstract

The present invention is directed to a prodrug comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. The prodrug has the same utility as the drug from which it is made, but it has enhanced therapeutic properties. In fact, the prodrugs of the present invention enhance at least two therapeutic qualities, as defined herein. The present invention is also directed to pharmaceutical compositions containing same.

Description

L-threonine derivatives of high therapeutic index

Invention field

The present invention relates to the amino acid derivativges of medical compounds, and the method for treatment specified disease, with the pharmaceutical composition that contains these medicines specified disease is taken a turn for the better by using these medicines.The present invention relates to use amino acid to improve many physico chemistry, biopharmaceutics and the clinical efficacy of various medicines as the covalent bond carrier of these medicines.

Background technology

The exploitation that is used for the treatment of the chemical compound of imbalance, illness and disease becomes increasingly difficult and costliness.Normally low discouraging of the probability of success of this exploitation.In addition, the time meeting that is used to develop is approaching or surpass 10 years, makes a large amount of patients can not get treatment in long-term time phase.

Even when having developed effective medical compounds, all have shortcoming to be accompanied by using of they.These shortcomings can comprise aesthetic feeling and obstacle pharmacokinetics that influences these existing drug ingedient effects, and for example, the disagreeable taste of medical compounds or composition or smell are the significant obstacle that the patient obeys dosage regimen.The dissolving characteristic that does not meet the requirements of medical compounds can cause being difficult to make the composition of homogeneous.Follow other defective of known drug compound to comprise: the absorbability of bad oral formulations; Medical compounds bioavailability in oral formulations is low; Lack proportionality; Medical compounds is in vivo with external stable low; Be difficult to pass blood/brain barrier; First-pass metabolism was too much when medical compounds passed liver; Too much intestines liver (enterohepatic) recycle; Absorption ratio is low; The ineffective treatment compound is in the release of action site; Allergy, for example, stomach-intestines inflammation and/or ulcer; Inject without the medical compounds of intestinal canal administration and the pain that has of composition; To some medical compoundss and the required excessive high dose of composition, and other disagreeable characteristic.Some medical compoundss are processed by health and are produced the toxic by-products that has harmful effect.

The new compound that is used for the treatment of large-scale various disease is sought constantly in this area, has improved characteristics to overcome the shortcoming of aforesaid existing medical compounds.

The present invention overcomes many problems that medicine is in the market followed by making prodrug.The notion of prodrug is well-known, enumerated the example of a large amount of this prodrugs in the document, and a large amount of prodrugs are provided on the market, comprise dissimilar allly reach spit of fland (statin) class medicine, ACE inhibitor like that, such as the antiviral drugs and the analog of Acyclovir (Acyclovir).Yet the present invention uses amino acid to make prodrug as a part.Prodrug of the present invention has many advantages.For example, when L-threonine derivatives of high therapeutic index by such as number of ways administrations such as oral, IV, rectum or other this methods the time, these prodrugs are changed into active drug molecule.Therefore a remarkable advantage of this L-threonine derivatives of high therapeutic index is that it is non-toxicity, can be absorbed in the body or excretes safely.This with market on the characteristic that shows of a large amount of prodrugs of providing quite different, the forward part of the prodrug on the described market itself is poisonous, reach the similar group of spit of fland (statin) class medicine, enalapril (Enalapril), Benazepril (Benazapril) and ace inhibitor like that, also have a large amount of antibiotic such as peopentyl ester (pivoxil) class, isopropyl, new ester (Axetil) class, western ester (Cilexetil) class and similar group, have height toxicity, thereby reduced the therapeutic index of active medicine.

On the other hand, L-threonine derivatives of high therapeutic index of the present invention has also been given many advantages as shown below.

Brief summary of the invention

The present invention relates to a kind of prodrug of pharmacologic activity, and it has with the covalently bound amino acid of a kind of medical compounds and forms described sour prodrug, uses it in the patient with this form, for example mammal.

Amino acid is the ideal model as prodrug, because it can form various types of connections between self and medicine.By definition, have at least two functional groups on the amino acid, amino (NH ₂) and carboxyl (COOH).For example, a-amino acid has the structure of knowing

R herein ₀Be amino acid whose pendant groups or side chain.As definition herein

It is amino acid whose main chain.Like this, for example, except amino and carboxyl on main chain, also can have functional group on the side chain.Functional group on the amino acid moiety allows to produce covalent bond between amino acid and medicine.

Be used for the present invention's medicine or medicament, contain functional group on it, allow medicine with amino acid reacts and with amino acid formation covalent bond.The example of functional group comprises NH on the medicine ₂, OH, COOH or its acid derivative, for example ester class, amide-type or analog.

Between medical compounds and the amino acid ways of connecting can be by:

1) ester bond that generates from carboxylic acid and alcohols or phenolic hydroxyl group condensation or ester exchange reaction (CO-O-), for example:

A) when medical compounds has aliphatic or aromatic hydroxyl, under the esterification condition, can form ester bond with the main chain hydroxy-acid group of amino; Or

B) when medical compounds has aliphatic or aromatic hydroxyl and amino acid and has the pendant carboxylic acid group, under the esterification condition, can form ester bond betwixt; Or

C) have hydroxy-acid group and amino acid when having side chain aliphatic or aromatic hydroxyl when medical compounds, under the esterification condition, can form ester bond betwixt; Or

D) when medical compounds have have a replacement or unsubstituted acyloxy (for example, alkoxyl-or alkoxy aryl-, aryloxycarbonyl) ester group of substituting group (compound-O-CO-substituting group), and when amino acid has the main chain hydroxy-acid group, can form ester bond betwixt by ester exchange reaction; Or

E) when medical compounds have have a replacement or unsubstituted acyloxy (for example, alkoxyl-or alkoxy aryl-, aryloxycarbonyl) ester group of substituting group (compound-O-CO-substituting group), and when amino acid has the pendant carboxylic acid group, can form ester bond betwixt by ester exchange reaction; Or

F) when medical compounds have have a replacement or unsubstituted alkoxyl-or alkoxy aryl-or the ester group of aryloxycarbonyl substituting group (compound-CO-O-substituting group), and when amino acid has side chain aliphatic or aromatic hydroxyl, can form ester bond betwixt by ester exchange reaction; Or

G) alcohols and carboxylic moiety can be on a part, and they can form lactone like this.Comprise also that within the scope of the invention for example similar Gabapentin (Gabapentin) etc. can form some compound of lactone under the ester formation condition.

2) amido link that generates from carboxylic acid and amine condensation (CO-NH-), for example:

A) have amino and amino acid when having the main chain hydroxy-acid group when medical compounds, under the acid amides formation condition, can form acid amides; Or

B) have amino and amino acid when having the pendant carboxylic acid group when medical compounds, under the acid amides formation condition, can form amido link betwixt; Or

C) have main chain when amino when medical compounds has hydroxy-acid group and amino acid, under the acid amides formation condition, can form amido link betwixt; Or

D) have side chain when amino when medical compounds has hydroxy-acid group and amino acid, under the acid amides formation condition, can form amido link betwixt.

So, the present invention relates to the prodrug that so forms.As shown below, the advantage that the prodrug that forms like this has is irrealizable for there not being key to connect described amino acid whose prodrug.For example, it can improve bioavailability, improve and render a service, and toxicity is less, shows bigger solvability and/or improve the ability that medicine enters cell membrane or passes blood-brain barrier in water, demonstrate lessly, improve therapeutic index and confers similar advantages such as side effects such as stomach-irritable bowels.

Like this, the present invention relates to improve a kind of method of the curative properties of medicine, with respect to relative medicine being used to patient with non-prodrug forms, the present invention is selected from raising effectiveness to the raising of curative properties, increase therapeutic index, be increased in the solvability in the mammalian body fluid, improve seeing through of cell membrane, improve the performance of passing blood-brain barrier, minimizing is such as side effects such as remarkable minimizing stimulation and/or ulcer, less toxicity, increase absorption ratio and similar performance, described method comprises reacts medicine and amino acid to form covalent bond betwixt and to use its product (hereinafter " prodrug ") to the patient.Prodrug of the present invention has at least a improved performance.In fact, preferably they show in the above-mentioned improvement performance at least two kinds.Other advantages of prodrug comprise, the wide in range and reaction generation easily of available amino acid.The reaction that forms acid amides normally effectively and output very high, it is about 70% that productive rate probably is higher than, and more preferably is higher than approximately 80%, and most preferably is higher than about 90%.

Description of drawings

Fig. 1 illustrates comparison after 1 hour dosed administration, based on the antagonism characteristic of seething of albinism mouse to acetylcholine-induced, to the L-serine ester (F1) of (±) brufen (Ibuprofen), the L-threonine ester (F2) of (±) brufen and the L-hydroxyproline ester (F3) of (±) brufen, the effectiveness of (±) brufen (that is raceme mixture) and brufen (S) (+).

Fig. 2 illustrates comparison after 3 hours dosed administration, based on the antagonism characteristic of seething of albinism mouse to acetylcholine-induced, to L-threonine ester (F2) of the L-serine ester (F1) of (±) brufen, (±) brufen and the L-hydroxyproline ester (F3) of (±) brufen, (±) brufen and (S) effectiveness of (+) brufen.

Fig. 3 illustrate acetysalicylic L-serine ester (preparation 1) in minute the dose-response relationship in average clotting time (MCT).

Fig. 4 illustrate acetysalicylic L-hydroxyproline ester (preparation 2) in minute the dose-response relationship in average clotting time (MCT).

Fig. 5 illustrate acetysalicylic L-threonine ester (preparation 3) in minute the dose-response relationship in average clotting time (MCT).

Fig. 6 illustrate control group (acetylsalicylic acid) in minute the dose-response relationship in average clotting time (MCT).

The relative effectivenes that Fig. 7 illustrates more acetysalicylic L-serine ester (F.1), acetysalicylic L-threonine ester (F.2), acetysalicylic L-hydroxyproline ester (F.3) and acetylsalicylic acid (PC) as in minute the function in average clotting time.

Detailed description of the present invention

As term " medicine ", " medicament " and " medicine " that uses herein use convertibly and refer to without as described in the amino acid whose patient's of being applied to reactive compound. And, as using herein, containing functional group on the medicine, it can react with described amino acid, such as NH₂, OH, COOH or its acylated derivatives (for example, ester, acid anhydride, acid amides and analog thereof) and analog thereof. When medicine is connected in amino acid, use term " L-threonine derivatives of high therapeutic index " or " prodrug of the present invention " or the word of synonym therewith.

Can be used as in the amino acid of forward part (promoieties) (that is, with drug response), is that those contain all conventional amino acid whose free amine group and/or hydroxy-acid groups. Wherein, some preferred embodiments comprise that those have the amino acid of relative high-dissolvability in water-bearing media, the 100g/L at least of the solubility in non-cushioned deionized water solution in the time of 25 ℃ for example, more preferably 250g/L at least, even more preferably 500g/L at least. For example, glycine and the solubility of proline in deionized water are respectively about 250g/L and 1620g/L in the time of 25 ℃.

Other amino acid that can be used as forward part are those amino acid that contain alkaline amino side chain, such as lysine. For example, the solubility of lysine in deionized water is about 700g/L in the time of 25 ℃.

Other amino acid that can be used as forward part are those amino acid that contain the hydroxyl side chain, such as hydroxyproline, serine and threonine. For example, threonine, hydroxyproline and the solubility of serine in deionized water are respectively about 100g/L, 369g/L and 420g/L in the time of 25 ℃.

Other preferred embodiments comprise that those have the amino acid of relative low solubility in water-bearing media, and for example, the solubility in the time of 25 ℃ in deionized water is 10g/L at the most, or 2g/L at the most for example, or 0.6g/L at the most for example. For example, the solubility of tyrosine in deionized water is about 0.5g/L in the time of 25 ℃. Because the limited solubility of these prodrugs, these prodrugs can be as producing the preparation with slow release characteristic.

Other amino acid that can be used as forward part are those amino acid that contain carboxylic acid side chain, such as glutamic acid and aspartic acid. Other can be used as amino acid right and wrong-essential amino acid and the non--amino acid that naturally exists of forward part.

Following reaction scheme represented above-mentioned discussion about containing hydroxyl, carboxyl and amino medicine and various amino acid whose reaction. In following diagram, as OH, COOH or NH₂In the time of the appearance of any functional group, R is the medicine of this functional group not, R₁Be

R wherein₀The amino acid whose side chain of hereinafter listing:

Reaction scheme A: the hydroxyl of its Chinese traditional medicine and amino acid whose carboxyl reaction are to form ester class prodrug.

R-OH  +  HOOC-R ₁-NH ₂  →  R-O-(C＝O)-R ₁-NH ₂

Medicine amino acid amino acid ester prodrugs

Reaction scheme B: the carboxyl of its Chinese traditional medicine and the hydroxyl reaction of hydroxy-amino-acid are to form ester class prodrug, and wherein hydroxyl is positioned on the side chain.

Reaction scheme C: the amino of its Chinese traditional medicine and amino acid whose carboxyl reaction are to form the amide-type prodrug.

R-NH ₂  +  HOOC-R ₁-NH ₂  →  R-NH(C＝O)-R ₁-NH ₂

Medicine amino acid amino acid acid amides prodrug

Reaction scheme D: the carboxyl of its Chinese traditional medicine and amino acid whose carboxyl reaction are to form acid anhydride class prodrug.

R-COOH  +  HOOC-R ₁-NH ₂  →   R-(C＝O)-O-(C＝O)-R ₁- NH ₂

Medicine amino amino acid anhydrides prodrug

Reaction scheme E: the amino of its Chinese traditional medicine and amino acid whose amino reaction are to form the azo prodrug derivant.

R-NH ₂  +  NH ₂-R ₁-COOH  →  R-N＝N-R ₁-COOH

Medicine amino acid amino acid azo prodrug

Reaction scheme F: the carboxyl of its Chinese traditional medicine and amino acid whose amino reaction are to form the acid amides prodrug.

R-COOH + NH ₂-R ₁-COOH → R-(C＝O)NH-R ₁-COOH

Medicine amino acid amino acid acid amides prodrug

In above-mentioned A-F diagram, used preferred amino acids is as follows:

Glycine methyl amimoacetic acid r aminobutyric acid alanine valine isoleucine leucine

Serine homoserine threonine carnitine choline aspartic acid glutamic acid

Ornithine lysine canaline canavanine arginine

Proline asparagine glutamine histidine carnosine

Phenyl alanine tyrosine tryptophan

As using herein, term " amino acid " is meant wherein have carboxyl (COOH) and amino (NH ₂) organic compound or its esters.In solution, these two end group ionizations formation dual ionization, the whole integral body that presents neutrality can be considered to amphion.Amino is contributed electronics to carboxyl, and its Ionized end is stabilized in the aqueous solution by polar water molecules.

Be that side group is distinguished from each other amino acid and comes.Some amino acid such as lysine, have amino on its side chain; Other amino acid have the side chain that contains hydroxyl, as threonine, serine, hydroxyproline and tyrosine; Some amino acid have carboxyl on side chain, as glutamic acid or aspartic acid.These functional groups on the side chain also can form covalent bond with medicine, such as ester, acid amides, and analog.When these side-chain radicals participated in forming these keys, such as hydroxyl, described combination can be described with OAA, and wherein AA is the amino acid residue that has hydroxyl on the side chain, but itself does not have hydroxyl.AA like this, wherein is meant that the amino acid that does not have pendant hydroxyl groups is because it participates in forming the reaction of ester.And when forming ester between the OH of amino acid whose hydroxyl and medicine group, hydroxyl on the carboxyl and the hydrogen on the hydroxyl form accessory substance, and therefore, resulting product does not have the OH group on carboxyl, have only acyl moiety.When in conjunction with C (=O)-when NHAA describes, mean that amino acid forms amido link between the carboxyl of medicine and amino acid whose amino.Because the NH of amido link is from amino acid, AA does not have amino amino acid yet as mentioned above.

Preferred amino acids is the amino acid that nature exists.Preferred amino acid is a-amino acid.Also preferred amino acids is the L-configuration.Preferred amino acids comprises 20 kinds of essential amino acids.Preferred amino acids is lysine (Lys); leucine (Leu); isoleucine (Ile); glycine (Gly); aspartic acid (Asp); glutamic acid (Glu); methionine (Met); alanine (Ala); valine (Val); proline (Pro); histidine (His); tyrosine (Tyr); serine (Ser); nor-leucine (Nor); arginine (Arg); phenyl alanine (Phe); tryptophan (Trp); hydroxyproline (Hyp); homoserine (Hsr); carnitine (Car); ornithine (Ort); canavanine (Cav); asparagine (Asn); glutamine (Gln); carnosine (Can); taurine (Tau); djenkollc acid (Djk); γ-An Jidingsuan (GABA); cysteine (Cys); cystine (Dcy); methyl amimoacetic acid (Sar); threonine (Thr) and analog.Preferred amino acid is 20 kinds of essential amino acids, Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser.

Prodrug from have can with the medication preparation of the group of amino acid reaction.

Preferably can be as follows according to the medicine of differential responses diagram and amino acid reaction:

Reaction scheme

Medicine A B C D E E

Cyclosporin (Cyclosporins) is

Lopinavir (Lopinavir) is

Ritonavir (Ritonavir) is

Cefdinir (Cefdinir) is

Zileuton (Zileuton) is

Viracept see nelfinaivr (Nelfinavir) is

Flavoxate (Flavoxate) is

Candesartan (Candesarten) is

Propofol (Propofol) is

Nisoldipine (Nisoldipine) is

Amlodipine (Amlodipine) is

Ciprofloxacin (Ciprofloxacin) is

Ofloxacin (Ofioxacin) is

Fosinopril (Fosinopril) is

Enalapril (Enalapril) is

Ramipril (Ramipril) is

Benazepil (Benazepril) is

Moexipril (Moexipril) is

Trandolapril (Trandolapril) is

Nasmil (Cromolyn) is

(Amoxicillin) is in the Amoxicillin

Cefuroxime (Cefuroxime) is

Cefotaxime (Ceftazimide) is

Cefpodoxime (Cefpodoxime) is

Atovaquone (Atovaquone) is

Ganciclovir (Gancyclovir) is

Penciclovir (Penciclovir) is

Famciclovir (Famciclovir) is

Aciclovir (Acyclovir) is

Nicotinic acid (Niacin) is

Bexarotene (Bexarotene) is

The third oxygen sweet smell (Propoxyphene) is

Salsalate (Salsalate) is

Paracetamol (Acetaminophen) is

Brufen (Ibuprofen) is

Lovastatin (Lovastatin) is

Simvastatin (Simavastatin) is

Atorvastatin (Atorvastatin) is

Pravastatin (Pravastatin) is

Fluvastatin (Fluvastatin) is

Nadolol (Nadolol) is

Valsartan (Valsafran) is

Methylphenidate (Methylphenidate) is

Sulfonamide (Sulfa Drugs) is

Sulfasalazine (Sulfasalazine) is

Medroxyprogesterone is

(Medroxyprogesterone)

Methylprednisolone is

(Methylprednisolone)

Estramustine (Estramustine) is

Miglitol (Miglitol) is

Mefloquine (Mefloquine) is

Capecitabine (Capacitabine) is

Reaching that azoles (Danazol) is

Eprosartan (Eprosartan) is

Divalproex sodium (Divalproex) is

Fenofibrate (Fenofibrate) is

Gabapentin (Gabapentin) ^*Be

Omeprazole (Omeprazole) is

Lansoprazole (Lansoprazole) is

Megestrol acetate (Megestrol) is

Melbine (Metformin) is

Tazarotene (Tazorotene) is

Sumatriptan (Sumitriptan) is

Naratriptan (Naratriptan) is

Zomitriptan (Zolmitriptan) is

Aspirin (Aspirin) is

Olmesartan (Olmesartan) is

Sirolimus (Sirolimus) is

Tacrolimus (Tacrolimus) is

Clopidogrel (Clopidogrel) is

Amphotericin B is

(Amphotericin B)

Tenofovir (Tenofovir) is

Unoprostone (Unoprostone) is

Fulvestrant (Fulvestrant) is

Cefditoren (Cefditoren) is

Efavirenz (Efavirenz) is

Eplerenone (Eplerenone) is

Treprostinil you (Treprostinil) are

Adefovirdipivoxil (Adefovir) is

Prodrug of the present invention contains amino and is alkaline in essence therefore.They can form acceptable salt on the various pharmacology with various inorganic acids and organic acid.Can be used to prepare the acid of the pharmaceutically-acceptable acid addition of these alkali compoundss, be those acid that form the non-toxic acid addition salts, non--toxicity acid-addition salts promptly contains acceptable anionic salt on the pharmacology, such as hydrochloride, hydrobromate, hydriodide, nitride, sulphate, disulfate, phosphate, formates, acetate, citrate, tartrate, lactate, and analog.

Point out as this paper, in one embodiment, the present invention relates to a kind of prodrug, wherein prodrug comprises as the medicine of Ciclosporin A (cyclosporine) etc. and esterification to MeBmt (x-y=CH=CH) or dihydro MeBmt part (x-y=CH ₂CH ₂) amino acid.Amino acid is connected to Ciclosporin A and is connected to other medicines by covalent bond.

Compound of the present invention is prepared by techniques well known.For example; if medicine contains the OH group; as cyclosporin; amino acid or its acylated derivatives or amino-acid alkyl ester and under the esterification condition, react so such as the carboxyl of medicines such as Ciclosporin A; described amino acid acylated derivatives is such as acyl halide; for example amino acid fluoride, amino-acid chlorides, alkyl contains 1-6 carbon atom in the described amino-acid alkyl ester.Preferably, the existence that is reflected at acid takes place down, all example hydrochloric acids of described acid, hydrobromic acid, p-methyl benzenesulfonic acid and similarly acid.Replacedly, as indicated above, if having amino on the medicine, amino acid can form acid amides as covalent bond with drug response under the acid amides formation condition so.If perhaps have carboxyl or acylated derivatives on the medicine, thus described carboxyl or acylated derivatives can and amino acid whose amino between amino acid and medicine, form amido link to form acid amides in reaction under the acid amides formation condition.As indicated above in addition, if medicine has carboxyl, the hydroxyl of amino acid side chain can react with carboxyl or acylated derivatives under the esterification condition, forms ester bond between amino acid and medicine.

If have the active group that under reaction condition, responds on the amino acid, can it be protected by blocking group well known in the art.After reaction is finished, remove blocking group.The example of the blocking group that can use is described in the W.Greene by Theodora, John Wiley﹠amp; The Sons1981 work, exercise question is that its content is introduced into as a reference in the book of " Protective Group in Organic Synthesis ".

For example, if having carboxyl on the amino acid side chain, as aspartic acid and glutamic acid, it can be used for aforesaid synthetic, and they need be protected pendant carboxylic acid usually.Suitable blocking group can be the ester class; for example 1-or 2-adamantyl of cyclohexyl ester, tertiary butyl ester, benzyl ester, allyl ester, 9-fluoro phenyl-methyl or adamantyl (adamantyl) for example, the technical protection that it can use those of ordinary skills to know after esterification is finished.

If amino acid has hydroxyl on side chain; the amino acid that for example has phenolic groups on serine, threonine, hydroxyproline etc. and the side chain, for example tyrosine etc.; when being used for aforesaid esterification, they will be expected and need protect pendant hydroxyl group or phenolic groups.The blocking group that is suitable for the hydroxyl side-chain radical can be an ethers, as benzylic ether or tertbutyl ether.Remove benzylic ether by the liquid hydrogen fluoride effect, and tertbutyl ether can be handled and be removed by trifluoroacetic acid.The blocking group that is suitable for the phenol side-chain radical can be an ethers, as mentioned above, comprises benzylic ether or tertbutyl ether or 2,6-dichloro benzyl, 2-bromo benzyloxycarbonyl, 2,4-dinitrophenyl etc.

And product can be purified to make pure basically by the technology that those of ordinary skills know, for example by chromatography such as HPLC, crystallization etc.Basically " pure " is meant and contains no more than about 10% impurity in the product.

Prodrug can be made into pharmaceutical composition, comprise described prodrug or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester class, enantiomter, diastereoisomer, N-Oization thing, allomorph (polymorph), as described herein, be accompanied by pharmaceutically acceptable carrier, and use those of ordinary skills optional but expectation know the pharmaceutically acceptable excipient of technology.

Press effective dose use on the acology with prodrug in the method.

The doctor will determine the dosage of optimal prodrug of the present invention, and dosage is along with form of medication and selected specific compound and change, further, it will depend on various factors and change, and these factors include but not limited to order of severity of the patient that receives treatment and patient's age, the disease for the treatment of etc. and to the cognition of the prodrug used.The doctor is general to be expected with abundant low dose of begin treatment less than the compound optimal dose, and with little increasing degree escalated dose, up to the optimum efficiency that reaches under this situation.Usually find, when the composition oral administration, will need relatively large active agents to produce and the effect same of ground drug administration by injection in a small amount.These compounds can use with non-accordingly-prolong medicine the same manner of form, and described compound dosage level and other healing potion that adopts usually adopt usually is the same order of magnitude.When drug administration by injection, compound usually with dosage for for example about 0.001 to about 10, used in 000mg/kg/ days, it also depends on main body and the order of severity of the disease that will treat and used compound.

In preferred embodiments, the compound that adopts be oral administration with from about 0.01mg to the about every kg body weight of the 1000mg amount of every day, depend on the disease that specific mammal main body maybe will be treated, more preferably from about 0.1 to about 500mg/kg body weight every day.This dosage can be adjusted to obtain best therapeutic response by the doctor.For example, can use the dosage that separates several times every day, or as noted, dosage correspondingly reduces along with the performance of treatment the situation is critical degree.

Prodrug can be with the administration of any mode easily, such as oral, intravenous, through intramuscular or through subcutaneous route.

Prodrug can be taken orally, and for example, with a kind of inert diluent and a kind of absorbable edible carrier administration, perhaps is sealed in the hard or soft shell capsules, perhaps is compressed to tablet, or directly adds in the food of recipe.For oral therapeutic administration, prodrug can combine with excipient, and is used for forms such as absorbable tablet, buccal tablet, lozenge, capsule, elixir, suspension, syrup, wafer.Such composition and preparation should contain at least 1% prodrug.Certainly, the percentage of composition and preparation can change, can be usually Unit Weight about 5 to about 80% between.The amount that prodrug is used in this therapeutic combination is advisable with the proper dosage that obtains.According to the present invention, preferred compositions or preparation contain the prodrug between about 200mg and the about 4000mg.Tablet, lozenge, pill, capsule etc. also can contain following composition: such as a kind of adhesive of tragacanth, gum Arabic, corn starch or gelatin etc.; Excipient such as Dicalcium Phosphate etc.; Disintegrant such as corn starch, potato starch, alginic acid etc.; Lubricant such as dolomol etc.; Can add sweetener, perhaps such as the flavor enhancement of peppermint, wintergreen or cherry flavor etc. such as sucrose, lactose or asccharin etc.When dosage unit form was capsule, except the raw material of the above-mentioned type, it can contain liquid carrier.

Other different material can be used as the bag quilt or changes the physical form of dosage unit.For example, tablet, pill or capsule can wrap quilt together with shellac, sugar or both.Syrup or elixir can contain reactive compound, and sucrose is as sweetener, and nipagin and propyl ester are as preservative, dyestuff with such as the flavor enhancement of cherry or orange taste etc.Certainly, any raw material that is used to prepare any dosage unit form all should be that pure and amount that adopt is nontoxic substantially on the medicine.In addition, reactive compound can join in sustained release formulation and the prescription.For example, can design sustained release forms, wherein active ingredient is incorporated into a kind of ion exchange resin, its can be selectively by the diffusion barrier bag by to regulate the release performance of resin, prodrug perhaps wherein of the present invention is in conjunction with a kind of lasting release polymers of knowing in this area, such as hydroxypropyl methylcellulose and similar substance.

Prodrug also can be parenterally or peritonaeum in administration.Especially advantageously preparing with the dosage unit is the injectable composition of form, conveniently using, and the dosage of preparation homogeneous.Also can prepare at glycerine, liquid macrogol, such as PEG 100, PEG 200, PEG 300, PEG 400 and similar substance, and their mixture and the dispersion in the oils.Under common storage and service condition, these goods contain preservative to stop growth of microorganism.

The medicament forms that is suitable for injecting use comprises aseptic aqueous solution (wherein water miscible) or dispersion and is used for preparing the aseptic powdery of aseptic injectable solution or dispersion temporarily.Medicament forms described in all situations all is aseptic usually and is the fluidised form that is injectable degree (syringability).It must be stable under manufacturing and holding conditions, and must keep not by the microbial contamination such as bacterium and fungi etc. usually.Carrier can be a kind of solvent or dispersion medium, and it for example contains water, ethanol, polyalcohol (for example glycerine, propane diols and one or more liquid macrogols are as disclosed herein, and analog), its mixture and vegetable oil that is fit to.For example, by using bag quilt, by in dispersion, keeping required particle size, and, can keep suitable flowability by using surfactant such as lecithin etc.Can be by various antibiotic and antifungal agents, for example metagin (parabens), anesin, phenol, sorbic acid, thimerosal and analog and stop microbial activities.Under many circumstances, preferably comprise isotonic agent, for example sugar and sodium chloride.The absorption of Injectable composition prolongs and can postpone the medicament that absorbs by using in composition, produces as aluminum monostearate and gelatin.

Sterile injectable solution is to prepare by prodrug and various required above-mentioned other composition enumerated that adds aequum in appropriate solvent, the subsequent filtration sterilization.Generally, dispersion prepares by various sterilizing activity compositions being joined in sterilization carrier (vehicle), and the sterilization carrier contains basic dispersion medium and from above-mentioned other required composition of enumerating.Under the situation of sterile powder, above-mentioned solution is vacuum drying or freeze drying as required.

Prodrug is administration partly also, as for example known the plaster (patch) of technology by use those of ordinary skills.Prodrug can be sucked administration, by preparing the appropriate formulation of prodrug of the present invention, and uses step well known to those skilled in the art.Described preparation prepares with suitable nontoxic pharmaceutically acceptable composition.Being used to prepare the composition that contains agent knows for those skilled in the art.Some these compositions see document (Remington ' s Pharmaceutical Sciences, 17 ^ThEdition, 1985), this is a canonical reference bibliography in this field.The selection that is fit to carrier quite depended on contain the needed exact nature of agent, as tablet, lozenge, gel, plaster and similar formulation.All these contain agent all considers within the scope of the invention, and they prepare with conventional method.

Drug combination preparation can use the conventional method preparation, uses on one or more physiology and/or pharmaceutically acceptable carrier or excipient.Like this, can prepare compound and its pharmaceutically acceptable salt class and solvate, by suck insufflation (through face or nose) or oral, contain clothes, inject or rectally.As for oral administration, pharmaceutical composition can take form to be, for example, by tablet or the capsule of conventional method in conjunction with pharmaceutically acceptable excipient preparation, pharmaceutically acceptable excipient such as adhesive (for example, the corn starch of pregelization, polyvinylpyrrolidone or hydroxypropyl methylcellulose), filler (for example, lactose, microcrystalline cellulose or calcium monohydrogen phosphate), lubricant (for example, dolomol, talcum or silica), disintegrant (for example, potato starch or sodium starch glycollate) or wetting agent (for example, Sodium Laurylsulfate).Tablet can be by method bag quilt well known in the art.

Being used for the form that the liquid product of oral administration can take is, for example, solution, syrup or suspension, perhaps they can be rendered as dry products, before use with water or the combination of other suitable carrier.This liquid formulation can be prepared with pharmaceutically acceptable additive by conventional method, additive such as suspending agent (for example, sorbitol syrups, corn syrup, cellulose derivatives or with hydrogenated edible oil and fat), emulsifier (for example, lecithin or gum Arabic), nonaqueous carrier (for example, the vegetable oil of apricot kernel oil, grease class, ethyl alcoh(ol) or rectifying) and preservative (for example, methyl p-hydroxybenzoate or propyl ester or sorbic acid).Prescription can also contain suitable buffer salt, flavor enhancement, pigment and sweetener.The preparation that is used for oral administration can suitably be formulated as can the active prodrug of sustained release.

Prodrug of the present invention can prepare the parenteral administration that is used for by injection, and for example group annotates or lasting infusion.Injection preparation can be unit dosage form, for example in the ampoule or in the multi-dose container, additional preservatives is arranged.Suspension in form that composition can be taked such as oiliness or the aqueous carrier, solution or emulsion, and can contain preparaton such as suspending agent, stabilizing agent and/or dispersant.Alternately, prodrug can adopt form of powder, before use with for example sterile pyrogen-free water combination of a kind of suitable carriers.

Prodrug of the present invention also can be formulated as the rectum composition, as suppository or enema,retention, for example contains conventional suppository bases, such as cocoa butter or other glyceride.

Except preparation described above, prodrug of the present invention also can prepare as a kind of storage preparation.This long-acting preparation can by implant (for example, through subcutaneous or through intramuscular) and administration, or administration by intramuscular injection.Like this, can prepare together such as sl. sol. salt with suitable polymers or hydrophobic raw material (for example, the emulsion in the acceptable oil) or ion exchange resin or sl. sol. derivative such as, prodrug.

If desired, the pharmaceutical composition that contains prodrug of the present invention may reside in packing or the dispenser device, and this device can contain one or more unit dose that contain active component.Packing can for example comprise the paper tinsel of metal or plastics, for example a blister packaging.Packing or dispenser device can provide the administration explanation.

In the form of tablet, expectation comprises lubricant, and it makes the method facility of making dosage unit; Lubricant also can be optimized erosion rate and drug flow rate.If there is lubricant to exist, the content of its existence is the extremely about 2wt.% of about 0.01wt.% of dosage unit, preferably about 0.01wt.% to 0.5wt.%.Examples of suitable lubricants includes but not limited to this: dolomol, calcium stearate, stearic acid, sodium stearyl fumarate (sodium stearylfumarate), talcum, hydrogenated vegetable oil and polyethylene glycol.Yet, as those skilled in the art will recognize that, the particle size and/or the unit intensity of regulating composition in the dosage unit can provide similar effect, and do not add lubricant, and said similar effect is and improves manufacturability and optimize erosion rate and drug flow.

Other composition also can optionally join in the dosage unit.This other optional ingredient comprises, for example, and one or more disintegrants, thinner, adhesive, hardening agent etc.Operable examples of disintegrants comprises the polyvinylpyrrolidone class that (but being not limited thereto) is crosslinked, for example Crospovidone (as, Polyplasdone_XL, can obtain from GAF), crosslinked carboxymethyl cellulose class, for example Croscarmellose (croscanmelose) (as, Ac-di-sol_, can obtain from FMC), alginic acid, sodium carboxymethyl starch (sodium carboxymethyl starches) (as, Explotab_, can be from Edward Medell Co., Inc. obtains), agar bentonite and alginic acid.The thinner that is fit to is the thinner that is generally used for using the preparation of compress technique preparation, as, dicalcium phosphate dihydrate (as, Di-Tab_, can obtain from Stauffer), with dextrin carried out crystallization processing carbohydrate (as, the sucrose of cocrystallization, dextrin, for example Di-Pak_ that can obtain from Amstar), calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dry starch, Icing Sugar etc.If the use adhesive can strengthen bonding force.The example of this adhesive comprises (but being not limited thereto) starch, gelatin and carbohydrate such as sucrose, glucose, molasses and lactose.In new dosage unit, also can there be permeation enhanced dose, to increase the speed that active agents passes oral mucosa.Permeation enhanced dose example comprises (but being not limited thereto) dimethyl sulfoxide (DMSO) (" DMSO "), dimethyl formamide (" DMF "), N,N-dimethylacetamide (" DMA "), Decylmethyl Sulphoxide (" C ₁₀MSO "), polyethylene glycol monolaurate (" PEGML "), glyceryl monolaurate, lecithin, 1-substituted azetidine heptan-2-ketone, particularly 1-n-dodecane basic ring azacyclo-heptan-(sell trade mark is that Azone.RTM. is from Nelson Research﹠amp to 2-ketone; Development Co.; Irvine; Calif.), the lower alkane alcohols (as; ethanol), SEPA_ (sells the Co. in Macrochem; Lexington, Mass.), cholic acid, taurocholate, bile salt type hardening agent and such as the surfactant of Tergitol_, Nonoxynol-9_ and TWEEN-80_.

Can optionally comprise flavor enhancement in the different pharmaceutical preparations.Can use any suitable flavor enhancement, for example mannitol, lactose or artificial sweetener such as Aspartame (Aspartam).Can add colouring agent, although these medicaments do not need.The example of colouring agent comprises any water-soluble FD﹠amp; C pigment, its mixture or corresponding color lake.

In addition, if desired, described dosage unit can add one or more preservatives or bacterial inhibitor is prepared together, as methylparoban, propylparaben, chloreresol, benzalkonium chloride or analog.

As used herein, " pharmaceutically acceptable carrier " comprises well known in the art any and all solvents, dispersion medium, bag quilt, antibacterial agent and antifungal agent, isotonic agent and the absorption delay agent that is used for pharmaceutically active substance.Except any and inconsistent conventional media of prodrug or medicament, their application in therapeutic combination are predictable.The auxiliary activity composition also can join in the composition.

The dosage unit form of Shi Yonging is meant discrete unit physically herein, is suitable for as the unit dose to the patient that will treat; Each unit contains the prodrug of a scheduled volume and required pharmaceutical carrier, and the calculating of this scheduled volume is to produce prodrug desired therapeutic effect.

As previously mentioned for convenience and administration effectively, the effective dose prodrug is blended in the dosage unit form with the pharmaceutically acceptable carrier that is fit to.For example, unit dose amount of containing main reactive compound is from about 10mg (as to the people) or be low to moderate 1mg (to meiofauna) to about 2000mg.If wiring solution-forming, the concentration preferable range of prodrug from about 10mg/mL to about 250mg/mL.To containing the composition of auxiliary activity composition, dosage is determined with reference to the mode of common dose and applying said compositions.To contain the situation of obeying administration, be present in contain the prodrug of clothes in the unit dosage forms amount from about 10 to about 50mg.

Prodrug of the present invention is effectively to treatment disease or illness, and wherein corresponding medicine (not having L-threonine derivatives of high therapeutic index of the present invention) is used always.

As used herein, when using term " treatment ", be meant reverse, relax or suppress the process of the symptom of a kind of disease, disorder or illness or one or more this diseases, disorder or illness.As used herein, " treatment " also can refer to and untreated control population relatively, perhaps with treatment before same mammal relatively, reduce the probability of happening or the incidence of disease of mammiferous a kind of disease, disorder or illness.For example, as used herein, " treatment " can refer to prevent disease, disorder or illness, and can comprise and delay or stop the outbreak of disease, disorder or illness or delay or stop the symptom of accompanying diseases, disorder or illness.As used herein, " treatment " also can refer to before mammal is tormented by disease, disorder or illness, alleviates the order of severity of this disease, disorder or illness or follow the symptom of this disease, disorder or illness.It is this before the patient is tormented by disease, disorder or illness, prevent and alleviate the order of severity of this disease, disorder or illness, as described herein relates to patient's administration composition of the present invention, and described administration time is not when the patient is tormented by this disease, disorder or illness.As used herein, " treatment " also can refer to the recurrence of prevent disease, disorder or illness, perhaps stops the recurrence of the symptom that is accompanied by this disease, disorder or illness.As above-mentioned qualification to " treatment ", term used herein " treatment " and " in treatment " are meant the behavior of treatment.

" patient " used herein or " curee " are meant a kind of warm blooded animal, mammal preferably, for example cat, dog, horse, ox, pig, mouse, rabbit and comprise human primate.Preferred patient is human.

Prodrug of the present invention does not have the corresponding medicine of amino acid key to show same effectiveness with it.Prodrug shows the treatment characteristic of enhancing.That is, with respect to the medicine that is not converted into prodrug of the present invention before administration, that prodrug of the present invention shows is at least a, the therapeutic properties of at least two kinds of enhancings more preferably.These therapeutic properties comprise (but being not limited thereto):

A. improved taste, smell

B. Qi Wang octanol/water distribution coefficient (that is the solvability in water/oil)

Each seed amino acid has different solvability in the aqueous solution.By selecting specific amino acid, can influence the octanol water partition coefficient.For example, many medicines of below listing are highly hydrophobic.Amino acid is highly-hydrophilic.For example, suppose that Propofol is a medicine, and lysine is amino acid.Propofol does not dissolve in water fully, and lysine can be dissolved into the degree of 700mg/ml.When this two kinds of different moleculars during by an ester bond esterification, the solvability of lysine ester in water of resulting Propofol surpasses 250mg/ml.

On the other hand, nasmil is highly water-soluble.In fact, it does not absorb when Orally administered.Can promote by the water solubility that influences it to absorb.In this case, will seek the situation opposite with Propofol, that is, target is to reduce water solubility.By selecting suitable low water-soluble amino acid, so can reach suitable hydrophile/lipophile balance such as tyrosine.

C. improve stability in vitro and in vivo

D. increase the permeability of blood brain barrier

E. eliminate the first pass effect of liver, that is, and medicine not metabolism in liver, and therefore more multiple medicines thing is arranged in systemic circulation

F. the minimizing (having improved bioavilability) of intestines-liver recycle

G. the painless injection of intestines external preparation

H. the bioavilability of Gai Shaning

I. improve the variation of absorption ratio (increasing ratio) with its shortage

J. reduce side effect

K. dosage proportionality

The dose ratio requirement is when medicine during with the dosed administration that increases gradually, and the active medicine amount of Zeng Jiaing is released in the blood in proportion.The measurement of dose ratio is the region area under the curve when determining to be in plasma concentration and medicine, this curve is resulting after by any administration outside the IV approach, and measurement in blood plasma/blood be in identical plasma concentration and medicine the time region area under the curve.The simple mathematical step is as follows: for example, medicine with as 3 various dose administrations, 10,100 and 1000mg, the patient is oral, measures the region area (AUC) under the curve when being in plasma concentration and medicine.Each total AUC is divided by dosage subsequently, and the gained result should be identical to 3 kinds of dosage.If like this, so just there is dose ratio.The disproportionate explanation pharmacokinetics/pharmacological Mechanism of dosage any or multiple be saturable, comprise absorption, metabolism or be used for the number of the acceptor site that pharmacology replys.

For example in above research, suppose that the AUC value that obtains is 100,1000 and 10,000, dose ratio is inappropriate so.When lacking dose ratio, have more or more a spot of medicine in the blood plasma, this depends on which kind of mechanism is saturable.Below be several possibilities:

Saturable absorption.If this is the case, along with dosage increases, proportionality reduces, and less medicine is absorbed, and therefore total AUC will reduce when dosage increases.

Saturable elimination metabolism.If this is the case, so increasing medicine will circulate in blood, and AUC will increase and increase along with dosage.

Saturable pharmacology acceptor site: in this case, because all acceptor sites will finally be occupied by medicine, any extra medicine can not increase replys.Therefore, the dosage increase can not cause replying increase.

Dose ratio is a kind of good response status, because the pharmacological reaction and the therapeutic efficiency of all dosage that can calculate to a nicety.Dose ratio all is the characteristic that is worth expectation to any medicine like this.Furtherly, dose ratio be reach and pharmaceutical formulation and feeding/fasting difference also depended on.

L. the selective hydrolysis of prodrug on action site

M. controllable release performance

N. targeted drug transmission

O. toxicity reduces, thereby increases the treatment ratio

P. reduce dosage

Q. change metabolic pathway to discharge more multiple medicines thing at action site

R. be increased in the solvability in the aqueous solution

S. strengthen usefulness

Therefore, amino acid whose prodrug has various formulations, and is prepared by conventional method:

I. oral liquid (liquid of controlled release and quick-release contains sugar or sugar-free, contains colouring agent or unassured toner, spirituosity or alcohol-free preparation, comprises masticable tablet)

Ii. oral solid formulation (tablet of controlled release and quick-release, capsule and capsule-type coating tablet)

Iii. intravenously administrable (injection, instant use and freeze-dried powder)

Iv. muscle administration (injection, instant use and freeze-dried powder)

V. subcutaneous administration (injection, instant use and freeze-dried powder)

Vi. percutaneous dosing (being mainly ointment)

Vii. nasal-cavity administration (spraying, the preparation of the treatment that is used to spray)

Viii. topical (emulsion, ointment)

Ix. rectally (emulsion, ointment and suppository)

X. vagina administration (emulsion, ointment and pessary)

Xi. dosing eyes (drops and ointment)

Xii. oral administration (masticable and instant masticable tablet)

Many medicines that this paper discusses, especially following tablet is with highly hydrophobic and be precipitated as feature easily when very a spot of water exists, as when body contact (for example gastric juice).Therefore especially difficulty provide for example peroral dosage form, its form and taste are patient's acceptables, and be stable during storage, and routinely administration so that suitable and the dosage controlled state of an illness to be provided.

Here the liquid preparation that is planned to adopt shown in the form, as be used for many medicines of oral administration, so far mainly based on using ethanol and oils or similar excipient as mounting medium.Therefore, the drinkable solutions of the many medicines that provide on the market adopts ethanol and olive oil or corn oil as mounting medium, and combines with comprising as the excipient of ethanol and LABRIFIL and the equivalence solvent system as mounting medium.For example, the cyclosporin drinkable solutions that provides on the market adopts ethanol and olive oil or corn oil as mounting medium, mating surface activating agent Labroid.See for example U.S. Patent number 4,388,307.Yet drinkable solutions of proposing in use this area and analogous composition are also with many difficulties.

In addition, the palatability of known oil base system is problematic.Especially, the taste of the known drinkable solutions of multiple medicine is beastly.The mixture that mixes mutually with a kind of suitably flavored drink has adopted so that conventional therapy is accepted fully, and wherein said drink adds pharmaceutical preparation with high dilution before in the body that is ingested, as the chocolate beverage preparation.Adopt the oil base system also to need to use high concentration of alcohol,, especially can predict when the time to children's administration to such an extent as to this itself just is out of favour inherently.In addition, the volatilization of ethanol as (adopting in a large number to solve the problem or the other problem (for example, when opening) of the palatability of being discussed), will cause the generation of drug precipitation from capsule.For example, when this composition existed with the form of soft gelatin microcapsule agent, this specific difficulty made this microcapsules product be encapsulated into necessity in airtight element, for example, and gas-Mi bubble-cap (blister) or aluminium-paper tinsel bubble-cap.This causes product heavy more expensive with production.In addition, the storage properties of previous formulations is very unfavorable.

To high amount of drug described herein, the bioavilability level that adopts existing oral administration system to reach also is low, and between individuality, between each patient's type, even same individuality different time in therapeutic process all shows very big difference.Bibliographical information shows, adopt the existing therapeutic scheme of the medicine drinkable solutions of selling on the market, the average absolute bioavilability that obtains has only about 10-30%, and between each group, significant difference is arranged, as transplanting between the recipient liver (low relatively bioavilability) and marrow (high relatively bioavilability).The difference of bioavilability report is to one of percentage of some patients or a few percent between the curee, to other patients 90% or more.As has been noted, often observe of the marked change of individual bioavilability along with the time.Like this, to many medicines as herein described, needs of patients is the bioavilability of homogeneous and Geng Gao more.

The use of this formulation, its feature are that also required patient's dosed administration can have a lot of variations.In order to reach effective treatment, medicine blood or serum levels must be in particular ranges.This required scope can change successively according to the particular disorder that will treat, whether has stoped one or more pharmacological actions of certain drug as treatment, and adopted optional treatment when being accompanied by main treatment.Because regular dosage form obtains bioavilability quite big variation is arranged, dosage every day that need reach required serum levels also will change between Different Individual even to same individual the generation significantly.Therefore, must be in the regular and frequent time interval blood/serum levels of the patient that accepts pharmacotherapy be monitored.Monitoring to blood/serum levels must be carried out as routine.This is elapsed time and bringing inconvenience inevitably, and has increased the totle drilling cost of treatment greatly.

To high amount of drug described herein, the blood/serum levels that adopts existing delivery system to reach also shows great changes between peak value and valley.To each patient, Effective Dose Level all alters a great deal between the individually dosed administration of each time in the blood in other words.

To high amount of drug described herein, especially beta-lactam antibiotic, cyclosporin, cephalosporins, steroid, quinolone antibiotic and cyclosporin also need the aqueous solution type that is provided for injecting.Well-knownly be, the high amount of drug following to this paper, the Cremaphore L_ (CreL) that uses in the preparation is the polyethoxylated derivative of castor oil at present, and is poisonous excipient.Because a large amount of allergy have appearred in this castor oil composition.Because the low aqueous solubility of medicine, prescription can allow many medicines of this situation be present in the aqueous solution with the concentration of needs at present.

Adopt existing peroral dosage form except having these difficulties of very significantly using, also inferred to have produced and do not expect the side effect that takes place.

Propose many proposals in order to solve described variety of issue in the art, comprised the peroral dosage form of solid and liquid.Yet still a main difficulty of Cun Zaiing is that the multiple medicine shown in the following table is intrinsic insoluble in water-bearing media, therefore stoped medicine that described formulation contains to remain on an abundant high concentration that can satisfy the standard of convenient use and required bioavilability, for example, can effectively absorb and reach the suitable high blood/serum levels of making peace from stomach or intestines inner chamber.

About the particular difficulty that the oral administration of these medicines runs into, will bring inevitably using the restriction of certain drug to more not serious or more not dangerous relatively disease treatment of conditions.For example, with cyclosporin as testing drug, a special dimension of this respect difficulty is, adopt cyclosporin treatment autoimmune disease and other cutaneous illness, such as treatment atopic dermatitis and psoriasis, with the stimulating hair growth of extensively proposing in this area that is used for, as be used for the treatment of the alopecia that aging or disease cause.

Like this, although this medicine of oral cyclosporin treatment expression is to have quite big potential benefit to suffering from as psoriatic patient, oral medication brings the risk of side effect to stop the common use of this medicine.Propose many proposals in order to use cyclosporin in the art, for example, described local use cyclosporin and a large amount of local delivery of drug system.Yet the trial of topical application can't provide any definite effective therapy.

Yet the present invention has overcome the problems referred to above.More specifically, with respect to the non-prodrug forms of medicine, prodrug of the present invention has increased its solvability in the aqueous solution significantly, thereby does not need employing such as ethanol or castor oil as carrier when using with solution.And according to the present invention, the prodrug of these medicines does not show the side effect of preparation in the prior art.Say further, have been found that, increased oral absorption, thereby strengthened its bioavilability and usefulness significantly when many medicines in the following form during with prodrug forms administration according to the present invention.

Combine the preferred agents that forms prodrug with amino acid and be listed in the following form, the benefit of demonstration is listed in the row second from the bottom of form.In form, key is as follows:

A) taste of Gai Shaning and smell

B) Qi Wang octanol/water distribution coefficient (that is solvability in the water)

C) stability of improving in vitro and in vivo

D) blood brain barrier permeability

E) elimination of liver first-pass effect

F) minimizing of intestines liver recycle

G) painless injection of intestines external preparation

H) bioavilability of Gai Shaning

I) increase absorption ratio

J) reduce side effect

K) dosage proportionality

L) prodrug is at the selective hydrolysis of action site

M) exhibit controlled release properties

N) targeted drug transmission

O) reduce toxicity, thereby increase the treatment ratio

P) reduce dosage

Q) change metabolic pathway on action site, to discharge more multiple medicines thing

And form has been represented the effectiveness of prodrug.The effectiveness of prodrug is identical with the effectiveness of corresponding medicine (amino acid moiety that does not have connection).Effectiveness is described in the document such as " doctor indispensable with reference to 2004 editions " (the Physicians Desk Reference, 2004 edition), and its content is hereby incorporated by.

The L-threonine derivatives of high therapeutic index of following medicine	The suitable dose scope	The preferred dose scope	The most preferred dose scope	Can form the amino acid of the prodrug of ester/acid amides/azo/acid anhydride with drug response	Preferred amino acids	Most preferred amino acid	The prodrug immune efficacy improves	Effect
									Cyclosporin preferred dosage form oral tablet/capsule oral liquid intravenous injection	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, dipeptides, especially AA-Gly that Thr and Sar or any two seed amino acids are formed, wherein Gly is the sept that is connected in cyclosporin, and AA is the above amino acid of enumerating.	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, dipeptides, especially AA-Gly that Sar or any two seed amino acids are formed, wherein Gly is the sept that is connected in cyclosporin, and AA is the above amino acid of enumerating.	Lys, Pro,, Gly and Lys-Gly, Pro-Gly, the dipeptides of Gly-Gly	B, e, f, g, h, k, l, o, and p	Prevention organ rejection phenomenon, as kidney, liver and heart allograft, treatment rheumatoid arthritis and chronic eczema disease (psoriosis)
5-1000mg 1-25mg/ml 10-250mg/5 ml	20-250mg 5-15mg/ml 25-100mg/5 ml	25-100mg 10mg/ml 50mg/5ml
			Lopinavir preferred dosage form oral tablet/capsule oral liquid	All dosage all show with medicine basis Yuan			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar		Lys, Pro, Gly, and Ala	B, h, j, k, and o	Treatment human immunodeficiency virus (HIV) infects, as acquired immunity afunction syndrome (acquired immune deficiency syndrome (AIDS), AIDS)
0.1-1mg 0.1-1mg/5ml	200-800mg 0.2-0.8g/5ml	400-500mg 400mg/5ml

Cefdinir preferred dosage form oral tablet/capsule oral liquid venous transfusion	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Lle, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Tyr, and Thr	A, b, e, f, h, i, o, and p	For by haemophilus influenzae, comprise the bacterial strain that β-lactamase produces, as, haemophilus parainfluenzae (comprising the bacterial strain that beta-lactamase produces) and Moraxella (comprising the bacterial strain that beta-lactamase produces), and micrococcus scarlatinae; The antibiotic therapy of the disease that causes such as pneumonia, bronchitis and nasosinusitis, pharyngitis and tonsillitis
									0.1-1mg 0.1-1mg/5ml 0.01-1mg/100 ml	0.2-0.5mg 0.2-0.5mg/5ml 20-500 mg/100ml	200-400mg 0.2-0.4mg/5 ml 50-150mg/l 00ml
	Zileuton preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly， Lys， Sar， Ala， Pro	b，h，i，j，k， o，p	Treatment asthma
200-1200mg 200-1200 mg/5ml					200-800mg 200-800 mg/5ml	300-400mg 200-400 mg/5ml
		Nelfinavir preferred dosage form oral tablet/capsule oral powder intravenous formulations	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly， Lys， Sar， Aia， Pro	b，h，i，j，k， o，p	Treatment human immunodeficiency virus (HIV) infects, as acquired immune deficiency syndrome (AIDS) (AIDS)
0.05-1mg 10-250mg/gm 10-250mg/100 ml	0.1-0.5mg 20-200mg/gm 20-200 mg/100ml					0.2-04mg 40-100 mg/gm 40-100 mg/100ml

Flavoxate preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Tyr, and Thr	B, h, i, j, k, l, o, and p	Treatment uropoiesis spasm
									10-1000mg 10-1000 mg/5ml	20-500mg 20-500mg/5ml	50-250mg 50-250 mg/5ml
	Candesartan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Tyr, and Thr	b，c，e，f，h， i，j，k，l，o， p，q	Treatment hypertension
1-100mg 1-100 mg/5ml					2-75mg 2-75mg/5ml	4-50 4-50 mg/5ml
		Propofol preferred dosage form venous transfusion	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Sar, Pro, Ala, and Val	b，c，d，g，h， j，k，l，m，n， o，p，q	Make central nervous system anesthesia
1-25mg/ml	2.0-20mg/ml					5-15mg/ml
			Nisoldipine preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Ser, and Hyp	b，e，h，i，j， o	Calcium ion channel blocker, treatment hypertension
2-100mg 2-100 mg/5ml	2.5-75mg 2.5-75mg/5ml	5-50mg 5-50 mg/5ml

Amlodipine preferred dosage form oral tablet/capsule oral liquid	All dosage are all with medicine basic representation IV				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Ser, and Hyp	b，e，h，i，j， o	Calcium ion channel blocker, treatment hypertension
										0.1-20mg 0.1-20mg/5ml	1-10mg 1-10mg/5ml		2.5-5 mg 2.5-5 mg/5 ml
	Ciprofloxacin preferred dosage form oral tablet/capsule oral liquid IV bulk (aseptic)	All dosage are all with the medicine basic representation												Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	a，b，c，g，h， i，j，k，o，p	Antibiotic; Suppress various bacteriums, as, Pseudomonas aeruginosa, staphylococcus aureus or proteus mirabilis; Treatment ulcer of the cornea, conjunctivitis, acute otitis externa
0.1-1.5mg 0.05-1mg/5m l 2-25mg/ml						0.1-1.0m g 0.08-1 mg/5ml 3-20mg/ml	0.2-0.8 mg 0.12-1 g/5ml 5-15 mg/ml
		Ramipril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	j，o	Treatment hypertension
0.1-20mg 0.1-20 mg/5ml	0.5-12mg 0.5-12 mg/5ml						1-10mg 1-10 mg/5ml

Trandolapril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly and Lys	j，o		Treatment hypertension
											0.1-10mg 0.1-10 mg/5ml	0.5-7.5mg 0.5-7.5 mg/5ml		1-4mg 1-4 mg/5ml
	Fosinopril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation													Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	j，o	Treatment hypertension
1-100mg 1-100 mg/5ml						2-75mg 2-75 mg/5ml		5-50mg 5-50 mg/5ml
		Enalapril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly and Lys	j，o	Treatment hypertension
0.5-100mg 0.5-100 mg/5ml							1-50mg 1-50 mg/5ml	2-25mg 2-25 mg/5ml
			Benazepil preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Orr, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	j，o	Treatment hypertension
1-100mg 1-100 mg/5ml	2-75mg 2-75 mg/5ml							2.5-50 mg 2.5-50 mg/5ml

Perindopril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	j，o	Treatment hypertension
										0.1-20mg 0.1-20mg/5ml		0.5-15 mg 0.5-15 mg/5ml	1-10mg 1-10 mg/5ml
	Moexipril preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation												Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly and Lys	j，o	Treatment hypertension
1-30mg 1-30mg/5ml						2-20mg 2-20 mg/5ml	5-15mg 5-15 mg/5ml
		Nasmil preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, and Pro	b，c，h，i， j，k，l，n， o，p，q	Suppress mast cell secretion histamine and leukotriene; Treatment mastocytosis, asthma
10-200 mg 10-200 mg/5ml	20-100mg 20-100 mg/5ml						20-50 mg 20-50 mg/5ml

Amoxicillin preferred dosage form oral tablet/capsule *The liquid oral oral powder ( *Also chewable tablets)	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly and Lys	a，b，c，h， i，j，k，l，o， p	Effectively antagonism causes the beta-lactamase negative strain that ear, nose, larynx infect, as, the antibiotic of streptococcus, staphylococcus or haemophilus influenzae; The genitourinary tract that treatment Escherichia coli, proteus mirabilis, enterococcus faecalis cause infects, the skin infection that streptococcus, staphylococcus or Escherichia coli cause, the lower respiratory infection that streptococcus, staphylococcus, haemophilus influenzae and gonorrhoea cause
									0.1-1.5 mg 0.1-1.5 mg/5ml 0.1-0.7 5mg	0.2-1.2mg 0.2-1.2 mg/5ml 0.1-0.6mg	0.25-1mg 0.25-1 mg/5ml 0.125-0.5 mg
	Cefuroxime preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	b，c，e，f， h，i，j，k，o， p	Antibiotic; Pharyngitis/tonsillitis that the treatment streptococcus causes, the acute bacterialotitis media that streptococcus, haemophilus influenzae, Moraxella (moraxella catarihalis) or streptococcus cause, Escherichia coli or bacillus canalis capsulatus belong to the urethral infection that causes, gonorrhoea that staphylococcus or streptococcus cause and skin infection
10-100 0mg 10-100 0 mg/5ml					50-750mg 50-750 mg/5ml	100-600 mg 100-600 mg/5ml

The cefotaxime preferred dosage form is used for the powder oral tablet/capsule oral liquid of intravenously administrable	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	a，b，c，g， h，i，j，k， l，o，p，q	Antibiotic, the treatment lower respiratory infection comprises pseudomonad, haemophilus influenzae, Kleb, Enterobacter (Enterbacter), Escherichia coli, proteus mirabilis, staphylococcus, the microbial pneumonia of hammer; Pseudomonas aeruginosa, Kleb, Escherichia coli, Enterobacter (Proteus enterbacter), staphylococcus, the microbial skin of hammer and skin histology infect, the urethral infection that Pseudomonas aeruginosa, Enterobacter (enterbacter proteus), Kleb, Escherichia coli cause; The bone and the infection of joint that pseudomonad, eruginosa, Kleb, Enterobacter (Enterbacter) or staphylococcus cause; Gynecological infection comprises endometritis, basin cellulits that Escherichia coli cause and the female genital tract infection that is caused by Escherichia coli, infects and central nervous system infection in the abdomen, comprises meningitis
											0.1-5mg 0.1-1mg 0.1-2.5 mg/5ml	0.25-4mg 0.25-1mg 0.25-2 mg/5ml		0.5-2mg 0.5-1mg 0.5-1mg/5ml
	Cefpodoxime Preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation														Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly and Lys	a，b，c，g， h，i，j，k， l，o，p，q	Antibiotic is especially to streptococcus, haemophilus influenzae, Moraxella catarrhalis; Treat the infection of acute otis media, pharyngitis, tonsillitis, pneumonia, bronchitis, gonorrhoea and women's rectum
10-500mg 10-500mg/5ml							25-350mg 25-350 mg/5ml		50-250 mg 50-250 mg/5ml

Atovaquone preferred dosage form oral tablet/capsule oral liquid is used for paediatrics	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Sar, Ala, Pro and Ser	a，b，h，i，j，k， o，p	The malaria that treatment plasmodium parasite cause
										More than the 50-1000 mg/5ml 10-150 mg/5ml	More than the 100-500mg/5ml 25-100mg/5ml		More than the 200-300 mg/5 ml 50-75 mg/5ml
	Acyclovir preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation												Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Sar, Hyp Pro and Ser	b，c，h，i，j，k， o，p	Treatment human cytomegalovirus (HCMV)
50-1000mg 50-1000 mg/5ml						100-750ml 100-750 mg/5ml	150-500 mg 150-500 mg/5ml
		Ganciclovir preferred dosage form oral tablet/capsule oral liquid venous transfusion	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	b，c，e，f，h，i，j， k，o，p	Treatment human cytomegalovirus (HCMV)
0.1-1mg 0.1-1mg/5ml 10-200mg/ml							0.2-0.8mg 0.2-0.8mg/5 ml 25-100 mg/ml						0.2-0.6 mg 0.2-0.6 mg/5ml 30-60 mg/ml

Penciclovir preferred dosage form liquid oral is used for the powder topical cream oral tablet/capsule of vein	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	b，c，e，f，h，i，j， k，o，p	Treatment human cytomegalovirus (HCMV)
										10-1000mg/ ml 0.1-5％ 10-500mg	25-750 mg/ml 0.25-3％ 20-300mg		50-500 mg/ml 0.5-2.5％ 25-250 mg
	Niacin sustained release agent preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation												Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Tyr, Gly and Lys	a，b，h，i，j，l， m，n，o，p，q	Lipid control
0.2-2mg 0.2-2 mg/5ml						0.25-1.5 mg 0.25-1 mg/5ml	0.5-1mg 0.5-1 mg/5ml
		Bexarotene preferred dosage form oral tablet/capsule oral liquid topical gels agent	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	b，c，h，i，j，k，l， o，p	The treatment disease of skin, especially those need retinoid X receptor activation
More than the 10-500mg/5ml 0.1-5%							More than the 25-250mg/5ml 0.25-2.5%						More than the 50-100 mg/5ml 0.5-1.5 %

The fragrant preferred dosage form oral tablet of third oxygen/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	a，b，c，h， i，j，k，l，o， p	Treatment pain
									20-400mg 20-400 mg/5ml	25-250mg 25-250 mg/5ml	30-150mg 30-150 mg/5ml
	Salsalate preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Gly, and Lys	b，c，h，i，j， k，o，p	The treatment inflammatory condition
0.2-2mg 0.2-2mg/5ml					0.25-1.5mg 0.25-1.5 mg/5ml	0.3-1mg 0.3-1mg/5ml
		Paracetamol preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Sar, Gly, and Lys	a，b，c，e， h，i，j，k，o， p	Treatment pain or heating
20-1000mg 20-1000 mg/5ml	50-800mg 50-800 mg/5ml					100-600mg 100-600 mg/5ml
			Brufen Preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Tyr, Gly and Lys	a，b，h，i，j， l，m，n，o， p，q	Treatment pain, heating or inflammation
20-1000mg 20-1000 mg/5ml	50-800mg 50-800 mg/5ml	100-600mg 100-600 mg/5ml

Lovastatin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	b，c，e，f， h，i，j，k， l，o，p	Cholesterol reducing concentration; Suppress Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase
									1-100mg 1-100mg/5ml	2-80mg 2-80 mg/5ml	5-50mg 5-50mg/5ml
	Simvastatin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	b，c，e，f， h，i，j，k， l，o，p	Cholesterol reducing concentration; Suppress Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase
1-200mg 1-200mg/5ml					2-150mg 2-150 mg/5ml	2.5-100mg 2.5-100 mg/5ml
		Atorvastatin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	b，c，e，f， h，i，j，k， l，o，p	Cholesterol reducing (chlolesterol) concentration; Suppress Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase
1-250mg 1-250mg/5ml	2-125mg 2-125 mg/5ml					5-100mg 5-100mg/5ml
			Pravastatin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Gly, and Lys	b，c，e，f， h，i，j，k， l，o，p	Cholesterol reducing (chlolesterol) concentration; Hydroxymethylglutaryl list acyl coenzyme A (suppressing HMG-CoA) reductase
1-250mg 1-250mg/5ml	2-125mg 2-125 mg/5ml	5-75mg 5-75mg/5ml

Fluvastatin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Tyr, Gly and Lys	b，c，e，f， h，i，j，k， l，o，p	Cholesterol reducing (chlolesterol) concentration; Suppress Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase
									1-250mg 1-250 mg/5ml	2-125mg 2-125 mg/5ml	5-75mg 5-75 mg/5ml
	Nadolol preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Sar, Ser, and Pro	b，h，i，j， k，l，o，p	Treatment angina pectoris and hypertension; Beta-adrenoceptor antagonists
1-250mg 1-250 mg/5ml					5-225mg 5-225 mg/5ml	10-200 mg 10-200 mg/5ml
		Valsartan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Ser, Thr, Lys, Gly and Sar	b，f，i，j， k，l，o，p	Treatment hypertension, the Angiotensin II antagonist
10-500 mg 10-500 mg/5ml	25-250 mg 25-250 mg/5ml					50-200 mg 50-200 mg/5ml
			Methylphenidate preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Hyp, Sar, and Ser	a，b，c，h， j，k，l，o， p	Treatment attention deficit disorder and hypnolepsy
1-50mg 1-50 mg/5ml	2-40mg 2-40 mg/5ml	2.5-25mg 2.5-25 mg/5ml

——————— ———— ———— ————
	Trovafloxacin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Ser, Pro, Hyp and Thr	a，b，e，h， j，k，o，p	Antibiotic; Inhibition such as Escherichia coli, Pseudomonas aeruginosa, haemophilus influenzae, streptococcus, Kleb, staphylococcus, mycoplasma pneumoniae, Peptostreptococcus, the bacterium of the fertile Pseudomonas of Prey; Treatment pneumonia and post-operative infection; The gynaecology of treatment such as Endomyometritis, parametritis, abortive infection and PNI and pelvic infection; The skin infection that treatment such as diabetic foot infects
10-500mg 10-500 mg/5ml										50-300mg 50-300 mg/5ml	80-250 mg 80-250 mg/5ml
		5-AS *Preferred dosage form oral tablet/capsule oral liquid ( *5-aminosalicylic acid)	All dosage are all with the medicine basic representation									Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Glu, Gly, Tyr and Lys	b，c，i，j，l， m，n，o，p， q	Treatment tuberculosis
1-200mg 1-200 mg/5ml	5-150mg 5-150 mg/5ml					10-125 mg 10-125 mg/5ml
			Methylprednisolone preferred dosage form intramuscular dose topical cream	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Pro, Sar and Ser	b，c，g，j，l， m，n，o，p， q	The treatment inflammation, especially those cause because of infection, tissue injury, anaphylaxis (allergy) and autoimmune disease
2-200 mg/ml 0.001-5％	5-150 mg/ml 0.01-2.5％	10-100 mg/ml 0.1-2％

The intramuscular injection of Medroxyprogesterone preferred dosage form	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Pro, Sar and Ser	b，c，g，j，l， m，n，o，p， q	Contraception is provided
											1mg-4 mg/ml	10mg-2m g/ml		40mg-1mg/ml
	Estramustine preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation														Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Orr, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Pro, Ala, Sar and Val	b，c，h，i，j， k，l，o，p	The treatment cancer is especially treated prostate cancer transfer or progression (growth)
10-500 mg 10-500 mg/5ml							25-250 mg 25-250 mg/5ml		50-200mg 50-200mg/5ml
		Miglitol preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Sar, Pro, and Ser	b，c，i，j，n， q	The treatment diabetes B
1-250mg 1-250 mg/5ml	2-150mg 2-150 mg/5ml							10-125mg 10-125mg/5ml
			Mefloquine preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys，Gly， Sar，Pro， Val，Ala	a，b，c，h， i，j，k，l，o， p，q	The treatment malaria
10-500mg 10-500 mg/5ml		100-400 mg 25-400 mg/5ml							150-300mg 150-300 mg/5ml

Reach that azoles preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Hyp, Pro, Ala, Val, Ser and Thr	a，b，c，e， f，g，h，i，j， k，l，n，o， p，q	Treatment endometriosis and fibrostatic mammary gland disease
									2-500mg 2-500 mg/5ml	10-350 mg 10-350 mg/5ml	25-250 mg 25-250 mg/5ml
	Eprosartan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly and Val	b，c，h，i，j， k，l，o，p	Angiotensin converting enzyme inhibitor, treatment hypertension
0.1-1mg 0.1-1 mg/5ml					200-800 mg 200-800 mg/5ml	300-75 0mg 300-75 0 mg/5ml
		Divalproex sodium preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly, and Val	a，b，c，f， h，i，j，k，l， o，p	The treatment epilepsy
50-800 mg 50-800 mg/5ml	75-750 mg 75-750 mg/5ml					100-60 0mg 100-60 mg/5ml
			Fenofibrate preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly, and Ala	b，c，h，i，j， k，l，o，p，q	The treatment hypercholesterolemia
10-800 mg 10-800 mg/5ml	20-750 mg 20-750 mg/5ml	100-60 0mg 100-60 0 mg/5ml

Gabapentin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Cyclic derivatives and Tyr	b，c，d，e， f，h，i，j，k， l， n，o，p，p	Treatment is twitched
									10-800 mg 10-800 mg/5ml	25-750 mg 25-750 mg/5ml	50-500 mg 50-500 mg/5ml
	Lansoprazole preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Pro, Sar, Ser and Val	b，e，f，h，i， j，k，l，o，p	The secretion of H+-K+-ATP enzyme (proton pump) system by suppressing the parietal cell surface comes the gastric acid inhibitory secretion; The treatment hyperchlorhydria
1-60mg 1-6 mg/5ml					2-50mg 2-50 mg/5ml	10-40 mg 10-40 mg/5ml
		Omeprazole preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Val, Pro and Sar	b，e，f，h，i， j，k，l，o，p	The secretion of H+-K+-ATP enzyme (proton pump) system by suppressing the parietal cell surface comes the gastric acid inhibitory secretion; The treatment hyperchlorhydria
1-200mg 1-200 mg/5ml	2-100 mg 2-100 mg/5ml					5-60 mg 5-60 mg/5ml
			Megestrol acetate preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Sar, Pro, Ser and Ala	b，c，h，i，j， k，l，n，o，p	The treatment apositia; Promote the appetite of apositia patient and aids patient
2-100 mg 2-100 mg/5ml	4-80mg 4-80 mg/5ml	20-60 mg 20-60 mg/5ml

Melbine preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Asp, Glu, the dimer of Lys and Azo	o，p	The treatment hyperglycemia; Promote insulin to cell traffic glucose
									0.2-3mg 0.2-1 mg/5ml	0.25-1.5mg 0.25-1.5 mg/5ml	0.5-1mg 0.5-1 mg/5ml
	The agent of tazarotene preferred dosage form topical gels	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, and Gly	B，c，h，l， j，k，l，o，p	Psoriasis and acne that treatment is mainly caused by pathogenic microorganism, anaphylaxis and inflammation
0.01-0.3％					0.02-0.25％	0.025-0.1 25％
		Sumatriptan preferred dosage form oral tablet/capsule oral liquid intramuscular dose	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Ala, Pro, Sar and Val	b，c，d，g， h，i，j，k，l， n，o，p，q	Serotonin subtype acceptor activator, the treatment antimigraine
5-250mg 5-250 mg/5ml 1-36mg/ml	10-200mg 10-200 mg/5ml 2-24mg/ml					20-125 mg 20-125 mg/5ml 4-20 mg/ml
			Naratriptan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Sar, Val, Ala, and Pro	b，h，i，j，k， l，o，p	Serotonin subtype acceptor activator, the treatment antimigraine
0.1-10mg 0.1-10 mg/5ml	0.25-5mg 0.25-5 mg/5ml	0.5-4mg 0.5-4 mg/5ml

Zomitriptan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation			Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Sar, Val, Ala, and Pro	b，h，i，j， k，l，o，p	Serotonin subtype acceptor activator, the treatment antimigraine
									0.1-12mg 1-12 mg/5ml	0.5-10mg 0.5-10 mg/5ml	1-7.5 mg 1-7.5 mg/5ml
	Aspirin preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly, and Ala	a，b，c，e， f，g，h，j， k，l，m， n，o，p，q	Antipyretic, antiinflammatory, anodyne, thrombolytic agent; Treatment hyperthermia, miocardial infarction and thrombolysis
10-1000 mg 10-1000 mg/ml					20-800 mg 20-800 mg/ml	25-600mg 25-600 mg/ml
		Olmesartan preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation				Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly, and Ala	b，h，i， j，k，l，o， p	Angiotensin converting enzyme inhibitor, treatment hypertension
1-100mg 1-100 mg/5ml	2-80mg 2-80 mg/5ml					4-50mg 4-50 mg/5ml
			Sirolimus preferred dosage form oral tablet/capsule oral liquid intramuscular dose	All dosage are all with the medicine basic representation								Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly, and Ala	b，h，i， j，k，l，o， p	Be used to carry out surgery transfer operation patient's immunodepressant; Antibiotic; Treatment leucoderma, trichophytosis, acne
0.1-20mg 0.1-20 mg/5ml	0.5-10gm 0.5-10 mg/5ml	1-8mg 1-8 mg/5ml

Tacrolimus preferred dosage form oral tablet/capsule oral liquid venous transfusion	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Ala, Thr, Sar and Pro	b，c，g，h，i， j，k，l，o，p	Be used to carry out surgery transfer operation patient's immunodepressant; Antibiotic; Treatment leucoderma, trichophytosis, acne
											0.1-20mg More than/5ml 1-20 mg/ml		0.2-15 more than the mg/5ml 2-15 mg/ml		0.25-10 mg More than/5ml 2.5-8 mg/ml
	Elidel preferred dosage form oral tablet/capsule oral liquid ointment creme	All dosage are all with the medicine basic representation														Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Ala, Thr, Sar and Pro	b，c，g，h，i， j，k，l，o，p	Be used to carry out surgery transfer operation patient's immunodepressant; Antibiotic; Treatment leucoderma, trichophytosis, acne
0.1-20mg More than/5ml 0.01- 10％							0.2-15 more than the mg/5ml 0.1-5%		0.25-10 mg More than/5ml 0.5-2％
		Clopidogrel preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation							20-125mg 20-125mg/5ml	25-100mg 25-100mg/5ml	Ser, Hyp, Thr, Lys, Ala, and Gly	b，c，h，i，j， k，l，m，o，p， q	The treatment cardiac muscle infects
10-250 mg 10-250 mg/5ml								20-125 mg 20-125 mg/5ml							25-100 mg 25-100 mg/5ml
			Amphotericin B preferred dosage form intravenous injection topical cream	All dosage are all with the medicine basic representation												Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Ala, and Gly	b，c，g，i，j， l，m，n，o，p， q	At fungi, especially those act on the cell membrane and change the cell permeability
0.5-20 mg/kg/ day 0.01-1 0％	1-15 mg/kg/d ay 0.1-5％								2-10 mg/kg/day 0.5-2％

Tenofovir preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Lys, Gly, Ala, Pro, Ser and Sar	b，c，h， i，j，k，l， o，p	Human immunodeficiency virus (HIV) inhibitor, the treatment HIV infection
												10-900 mg 10-900 mg/5ml		50-750 mg 50-750 mg/5ml		100-500 mg 100-500 mg/5ml
	Unoprostone preferred dosage form eye drops	All dosage are all with the medicine basic representation																Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Tyr, Pro, and Lys	b，c，h， i，j，k，l， n，o，p， q	Treatment mainly is the glaucoma that aging causes; Reduce intraocular pressure
0.01-1 ％								0.05-0.5 ％			0.01-0.2 5％
		Fulvestrant preferred dosage form intramuscular dose	All dosage are all with the medicine basic representation										Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Pro, Ala, Val and Sar	B，c，g， j，l，o，p	Treatment cancer, especially breast cancer
2-1250 mg/5m l	10-1000 mg/5ml								20-500 mg/5ml
				Cefditoren preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation						Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar						Ser, Hyp, Thr, Gly, Lys and Ala	b，c，h， i，j，k，l， o，p	Antibiotic especially suppresses haemophilus influenzae, haemophilus parainfluenzae, streptococcus, Moraxella catarrhalis; Treatment bronchitis, pharyngitis, tonsillitis, skin infection
20-500mg 20-500 mg/5m			100-400 mg 100-400 mg/5ml										150- 300 mg 150- 300 mg/ 5ml

Efavirenz preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Pro, Ala, Sar, and Val	b，c，h，i，j，k， l，o，p	Specificity, the non-nucleoside reverse transcriptase inhibitor of 1 type human immunodeficiency virus (HIV-1); The treatment HIV infection
											0.2-1.2mg 0.2-1.2 mg/5ml		300-800 mg 300-800 mg/5ml	400-750 mg 400-750 mg/5ml
	Eplerenone preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation														Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dc y, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Ser, Hyp, Thr, Lys, Gly and Val	b，c，h，i，j，k， l，o，p	Treatment hypertension checks combining of aldosterone and mineralcorticoid receptor
Treprostinil that preferred dosage form oral tablet/capsule hypodermoclysis							All dosage are all with the medicine basic representation					Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar	Gly, Lys, Val, Hyp, Thr and Ser	b，c，g，h，i，j， k，l，o，p						Suppress the vasodilation of platelet aggregation and whole body and pulmonary vascular bed, treatment and cardiovascular related diseases
	0.1-100 mg/ml 10-1000 mg	0.2-50mg/ml 20-800mg			0.5-20 mg/ml 25-50 0mg
						Adefovirdipivoxil preferred dosage form oral tablet/capsule oral liquid	All dosage are all with the medicine basic representation									Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr and Sar Lys, Leu, Ile, Gly	Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly,	Lys, Gly, Val, Ser, Hyp and Pro b, c, h, i, j, k,	B, c, h, i, j, k, l, o, p 1 type human immunodeficiency	Human immunodeficiency virus (HIV) reverse transcriptase inhibitors; Treatment HIV infects and acquired immune deficiency syndrome (AIDS) (AIDS)
1-100mg 1-100 mg/5ml Efavirenz	2-50mg 2-50mg/5ml All dosage are all with the medicine basic representation			5-20 mg 5-20 mg/5 ml Lys，Leu，Ile，Gly，Asp，Glu，Met，

Following non-restrictive example further specifies the present invention:

Synthesizing of the various amino acid derivativges of selected medicine

I. propofol derivative

Propofol (2, the 6-diisopropyl phenol) is a kind of low-molecular-weight phenol, and it is widely used as central nervous system anaesthetic, and has the activity of calm and hypnosis.It by intravenous administration to induce and to keep mammiferous anesthesia and/or calmness.The major advantage of Propofol is that induced anesthesia rapidly, side effect are little, in case and drug withdrawal, patient revives and the sedation that do not have to prolong very soon.

Propofol has shown to have a large amount of treatment and uses, and it is to have nothing in common with each other and some is surprising that described treatment is used.For example, as if it has showed is effective anti-oxidants, antemetic, antipruritic, antiepileptic, antiinflammatory agent, even has anticancer characteristic.

Mechanism of action:

The mechanism of action of Propofol is widely studied.Its central nervous system narcotic activity show as with it to the high-affinity of a special subclass of GABA acceptor relevant (Collins G.G.S., 1988, Br.J.Pharmacology.542,225-232).Yet it all is the substrate of Propofol that a large amount of not isoacceptors are arranged in the brain, so it has various active.

Propofol also has important biological effect as antioxidant.Because the activity of its broad sense, Propofol is useful to treating a large amount of inflammatory processes in theory, and oxidation is an important factor in these inflammatory processes.For example, the synthetic cyclooxygenase of mediation prostaglandin causes inflammation.By suppressing the oxidation in the respiratory tract, can use Propofol treatment mistake to suck acid, adult Respiratory Distress Syndrome(RDS), airway obstruction disease, asthma, cancer and other similar pathology disease in a large number.

Because oxidative tissue damage usually takes place, advised Propofol is used in treatment Parkinson's (Parkinson ' s disease), Alzheimer disease (Alzheimer disease), friedreich's disease (Friedrich ' s disease), Huntington (Huntington ' s disease), multiple sclerosis, amyotrophic lateral sclerosis, chorda dorsalis injury and various other neurodegenerative disease.

Propofol is on sale on American market at present, is sold with trade (brand) name Diprivan_ by Astra Zenaca as intravenous injection emulsion.It is one of the most widely used fugitive central nervous system anaesthetic on the market.The concentration that Propofol does not have in the bacterial emulsion in apyrogeneity is 10mg/mL, contains soybean oil, glycerine, lecithin, natrium adetate and sodium hydroxide in the prescription.

A remarkable shortcoming of Propofol is that it is soluble fully in water.Even when the low concentration of 10mg/mL, medicine at room temperature can precipitate from the aqueous solution.Therefore, the manufacturer of this preparation uses especially complicated and poisonous emulsifier, with special method this product is emulsified in the water.For example, the manufacturer of iv formulation uses lecithin, Cremaphor L_, castor oil and other similar emulsifier.

Yet, use this emulsifier can bring a lot of problems.Well-known is that various types of emulsifier of Cremaphor L_ can be facilitated allergy.Some patients have shown lecithin and castor oil have been produced anaphylactic shock.In addition, keeping the stability of Propofol in these emulsions is temporarily and more expensive.And the existence of lecithin and castor oil makes emulsion be easy to the microorganism that grows.Also possible is it to be dissolved in the water, but cyclodextrin also is not used for the intravenous injection treatment by the FDA approval.

So far, also nobody produces the prodrug of safety of Propofol.BP 1,102,011 and 1,160,468 and United States Patent (USP) 3,389,138 various amino acid whose phenolic ester classes have been described, wherein Propofol is connected on many side chains, these side chains can toxigenicity effects when discharging in vivo.

U.S. Pat 6,451,854 have described the Propofol that many alpha-amido acetates replace, and wherein Propofol and described side chain are replaced by many different chemical groups.The N of all these Propofols, the dibasic glycinate of N-is not expressed as nontoxic, and the chemical compound lot of wherein describing is the derivative of Propofol.Therefore, when discharging in vivo, enzyme is after the ester cracking, and many active medicines of release are not Propofols, and does not therefore have their any toxicity data, and they are new molecule fully, and the treatment in human body is renderd a service unknown.

In another open file about the water soluble salt of the amino acid esters of anaesthetic Propofol (Int.J.Pharmaceutics, 175[2]: 195-204,1998) in, the author has synthesized the many water-soluble derivative of Propofol.Yet when these prodrugs during by the esterase cracking, the alpha-non-natural amino acid with replacement of complete unknown toxicity is released in the body.

The pharmaceutical preparation that does not also have on the market up to now to discharge Propofol with no harmful side-effects is sold.Yet the present invention has generated many water-soluble, the nontoxic derivative of Propofol, and it is suitable for discharging Propofol in vivo and without any harmful side effect, and does not need poisonous and expensive additive, solubilizer and emulsifier.

Therefore, in one aspect, the present invention relates to a class prodrug of Propofol.This prodrug contains amino acid whose carboxyl, and this carboxyl is esterified to the free hydroxyl group that is present on the Propofol molecule.

More specifically, one aspect of the present invention relates to following formula: compound or its pharmaceutically acceptable salt

Wherein AA is a seed amino acid, the carboxyl of AA and the hydroxyl reaction of Propofol.

In yet another aspect, the invention still further relates to a kind of pharmaceutical composition, it comprises above-mentioned various propofol prodrugs and its pharmaceutical carrier for the treatment of effective dose.

In another embodiment, the present invention relates to a kind of methods of treatment that needs the patient of use Propofol treatment, this method comprises Propofol from effective dose to described patient that give.

In another embodiment, the present invention relates to a kind of method that increases Propofol solvability in the aqueous solution, it comprises that the hydroxy functional group that makes Propofol reacts and separates its product.

In embodiment further, the present invention relates to a kind of method, it is fully and with effective and efficient manner on the acology, when to patient's administration, alleviate or eliminate the potential toxic and side effect of the preparation that contains poisonous excipient (exepients) at present, described method comprises that the hydroxy functional group and the selected amino acid whose carboxyl functional group that make the Propofol molecule react respectively to form the ester covalent bond, separate its product and use described product to the patient.

The present invention shows, when unsubstituted amino acid that exists naturally and Propofol esterification, resulting prodrug be highly water-soluble (in the water＞200mg/L), discharge nontoxic amino acid in vivo after the cracking, and do not need poisonous emulsifier, additive and other excipient (exepients).

In addition, demonstrated the present invention and also generated medicine, described medicine is the prodrug of Propofol of the present invention, is central nervous system arcotic efficiently.Therefore present L-threonine derivatives of high therapeutic index is effective central nervous system arcotic, no matter whether discharges active parent drug.

Solvability under the amino-acid ester room temperature of the present invention in water is 10 times of Propofol at least.Especially the glycinate of Propofol, proline ester and lysine ester solubility range be greater than 100mg/mL, and the situation of lysine is higher than 250mg/mL.

Because it is blocked to be responsible for the phenolic group of antioxidation activity, prodrug of the present invention is not considered to show any antioxidation activity; Yet the inventor has been found that whether the prodrug of Propofol discharges Propofol all is effective anaesthetic.When administration in vivo, described propofol prodrugs discharges Propofol, and resulting medicine keeps the pharmacology and the anti-oxidation characteristics of described prodrug.

The prodrug of Propofol of the present invention clearly provides the many advantages that surpass Propofol, and for example, all side chains that decompose from these prodrugs all are the essential amino acids that nature exists, and are nontoxic therefore.This brings high therapeutic index.The second, all these prodrugs all are easy to cracking in vivo to discharge Propofol.And, because the highly-water-soluble of these prodrugs forms solution on the spot by using aseptic freeze-dried powder before intravenously administrable, perhaps being provided for the prefilled syringe or the bottled transfusion of injecting, they are administration easily.Amino-acid ester is more stable than Propofol, can not be oxidized because the OH group of Propofol is blocked.Propofol prodrugs of the present invention like this is more effective than Propofol itself, and toxicity and other pharmacy problem of not having present commercial preparation to have.

Propofol prodrugs of the present invention has anti-inflammatory, anti-oxidant, anticancer, anticonvulsion, town's antipruritic characteristic in Tuhe.

Propofol prodrugs of the present invention is effective to the disease or the illness for the treatment of common use Propofol treatment.Prodrug disclosed herein transforms in vivo with release of active compounds, and by alleviating or eliminating the treatment that its biopharmacy of following and pharmacokinetics barrier help Propofol.Yet should be noted that this just has enough activity when not discharging any active medicine in mammalian body these prodrugs.Because prodrug is easier to be more molten than Propofol in water, so it does not need to have vehicle excipients, such as ethanol or the castor oil possible poisonous or side effect that generation is harmful.And the oral formulations that contains propofol prodrugs is absorbed in the blood and is quite effective.

Like this, prodrug of the present invention helps treatment by biopharmacy and the pharmacokinetics barrier of eliminating existing medicine.

And, using the commercially available reagent that is easy to get, these prodrugs can be easily synthetic with high yield.

General introduction:

The step of the glycinate of synthetic Propofol, L-proline ester, L-lysine ester is as described below.Yet these are examples, and any L-threonine derivatives of high therapeutic index of Propofol can use following method preparation.Complete step and analysis data are seen experimental section.Generally speaking; shown in following diagram; when having the 4-of catalytic amount (N, N-dimethylamino) pyridine (DMAP), Propofol (10g) reacts with amino acid (1 equivalent), 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) of N-Boc protection.EDC is removed by the water extraction.Through filter after the dried over sodium sulfate, the shielded amino-acid ester of rough Propofol after concentrating by flash chromatography method purifying, the shielded ester of generation 50-60% yield.Subsequently under the room temperature, in the saturated ether of hydrochloric acid (gas), stir shielded ester class and remove blocking group.The productive rate of deprotection steps is 60-95% normally.Filter and the hydrochloride of the dry glycinate of handling Propofol and L-proline ester after, do not need to be further purified.The L-lysine propofol ester that L-lysine propofol ester hydrochloride is once protected with the list of removing trace by alcohol crystal.

Synthetic order:

1.SPI0010

2.SPI0011

3.SPI0013

Diagram

Synthesizing of the glycinate of Propofol, L-proline ester and L-lysine ester: a) EDC, DMAP, CH ₂Cl ₂B) HCl (g), Et ₂O.

Experimental section:

The synthetic of SPI0010, SPI0011 and SPI0013 carries out in batches.Usually carrying out small-scale experiment earlier carries out subsequently significantly in batches.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Aldrich, Aeros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.

1)SPI0010

Propofol (9.98g, 55.97 mMs) at room temperature is dissolved in carrene (200mL) in the argon atmospher.Add N-tert-butoxycarbonyl glycine (11.2g, 63.91 mMs) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 11.1g, 57.9 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 1.5g, 12.27 mMs).At room temperature stir after 21 hours in the argon atmosphere, add entry (200mL) and layering.Dichloromethane layer water (200mL) again washs and added sodium sulphate (5g) dry 1 hour.Filter and after concentrating under the decompression situation, go up the remaining oil of purifying at silica gel (250g), with hexane/ethyl acetate (10: 1) wash-out with the flash chromatography method.This step is generated as the glycinate (11.34g, 60% productive rate) of Propofol of the shielded N-BOC protection of white solid.

Tert-butoxy formamido group acetate-2,6-diisopropyl phenyl ester:

¹H NMR(300 MHz，CDCl ₃)：δ＝7.25-7.13(m，3H)，5.18(br s，1H)，4.22(d，2H，J＝5.7Hz)，2.89(m，2H)，1.46(s，9H)，1.18(d，12H，J＝6.9Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝169.35，155.75，145.22，140.35，126.90，124.14，80.32，42.66，28.54，27.79，23.57。

Propofol-Boc-glycinate (11.28g, 33.6 mMs) at room temperature is dissolved in absolute ether (200mL).Stir and in solution, fed hydrochloric acid (gas) in 45 minutes simultaneously.At room temperature mixture is stirred 48 hours in the argon atmospher.Add hexane (200mL) and filtering precipitate after 48 hours.White solid under 88 ℃ of high vacuum dry 5 hours.This experiment generates the SPI0010 (purity of analyzing through HPLC is 99.9% for 8.73g, 95% productive rate) as white solid.

2 of amino-acetate, 6-diisopropyl phenyl ester hydrochloride:

¹H NMR(300MHz，CDCl ₃)：δ＝8.77(br s，3H)，7.20-7.08(m，3H)，4.14(m，2H)，2.87(m，2H)，1.11(d，12H，J＝7Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝166.42，144.84，140.42，127.10，124.06，40.47，27.61，23.55。

The CHN elementary analysis:

Calculated value: C 61.87, H 8.16, and N 5.15; Measured value: C 61.14, H 8.20, N 5.14.2) SPI0011

Propofol (10.03g, 56.23 mMs) at room temperature is dissolved in carrene (100mL) in the argon atmospher.Add N-tertbutyloxycarbonyl-L-proline (14.04g, 65.22 mMs) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 11.95g, 62.33 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 1.1g, 9.0 mMs).At room temperature stir after 3 hours in the argon atmospher, add entry (100mL) and layering.Dichloromethane layer water (100mL) washing and through dry 1 hour of sodium sulphate (5g) again.Filter and behind concentrating under reduced pressure, go up purifying with the flash chromatography method at silica gel (250g) and remain grease, with hexane/ethyl acetate (10: 1) wash-out.This step generates a kind of L-proline ester (11.34g, 66% productive rate) of Propofol of protected basic N-BOC protection of transparent oily, and it leaves standstill the back and solidifies in refrigerator.

Pyrrolidines-1,2-dicarboxylic acids-1-tertiary butyl ester-2-(2,6-diisopropyl-phenyl) ester:

¹H NMR(300MHz，CDCl ₃)：δ＝7.3 1-7.20(m，3H)，4.73(m，1H)，3.70-3.50(m，2H)，3.20-2.94(m，2H)，2.46-2.20(m，2H)，2.20-2.0(m，2H)，1.55(m，9H)，1.25(m，12H)。

¹³C NMR(75MHz，CDCl ₃)：δ＝171.87，171.01，154.34，153.93，145.35145.23，140.06，140.21，126.69，126.53，123.95，80.28，79.89，59.14，46.67，46.42，31.10，30.17，28.61，28.56，28.56，27.44，27.18，23.47。

Propofol-Boc-L-proline ester (13.95g, 37.14 mMs) at room temperature is dissolved in absolute ether (100mL).Stir and in solution, fed hydrochloric acid (gas) in 60 minutes simultaneously.At room temperature in the argon atmospher mixture was stirred 22 hours.Add hexane (50mL) and filtering precipitate after 22 hours.White solid under 88 ℃ of high vacuum dry 5 hours.It is white solid (purity of analyzing through HPLC is 99.1% for 9.1g, 95% productive rate) that this experiment generates SPI0011.

Pyrrolidines-2 (S)-carboxylic acid-2, the hydrochloride of 6-diisopropyl-phenylester:

¹H NMR(300 MHz，CDCl ₃)：δ＝10.15(br s，2H)，7.27-7.14(m，3H)，4.78(t，1H，J＝7.8Hz)，3.56(m，2H)，2.85(m，2H)，2.64(m，1H)，2.40(m，1H)，2.20(m，1H)，2.05(m，1H)，1.18(m，12H)。

¹³C NMR(75 MHz，CDCl ₃)：δ＝168.30，144.23，139.74，126.98，123.96，51.58，38.21，29.32，26.64，26.18，23.71，23.02，21.67。

The CHN elementary analysis:

Calculated value: C 65.48, H 8.40, and N 4.49; Measured value: C 65.50, H 8.43, N 4.50.

3)SPI0013

Ice/water-bath cooling is added the dicyclohexyl amine salt (23.62g, 0.0447 mM) of two-N-boc-L-lysine in the water (200mL) that contains ether (200mL) and potassium acid sulfate (9.14g) to down.Stir after 20 minutes the solution layering.Ether layer extracts three times with cold water (100mL).Ether layer is through sodium sulphate (15g) dry one hour subsequently, filters and under reduced pressure concentrates.This series of steps generates N, the free acid of N '-two-boc-L-lysine (15.5 g, 100% rate of recovery).

Propofol (8.0g, 45 mMs) at room temperature is dissolved in carrene (100mL) in the argon atmospher.Add N, N-two tert-butoxycarbonyls-L-lysine (15.5g, 44.7 mMs) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 8.62g, 45 mMs) and 4-(N, N-dimethylamino) pyridine (DMAP, 0.55g, 4.5 mMs).At room temperature stir after 3 hours in the argon atmospher, add entry (100mL), the solution layering.Dichloromethane layer water (100mL) washing and through dry 1 hour of sodium sulphate (5g) again.After filtering and under reduced pressure concentrating, go up the remaining grease of purifying with the flash chromatography method at silica gel (250g), with hexane/ethyl acetate (9: 1) wash-out.This step generates a kind of L-lysine ester (12.42g, 55% productive rate) of Propofol of protected basic N-BOC protection of white foam shape.

2 (S), 6-two tert-butoxy formamido group caproic acids-2,6-diisopropyl phenyl ester:

¹H NMR(300MHz，CDCl ₃)：δ＝7.28-7.1 5(m，3H)，5.22(d，1H，J＝8.4Hz)，4.70(m，1H)，4.59(m，1H)，3.17(m，2H)，2.93(m，2H)，2.09(m，1H)，1.86(m，1H)，1.67-1.54(m，4H)，1.48(s，9H)，1.46(s，9H)，1.20(m，12H)。

¹³C NMR(75MHz，CDCl ₃)：δ＝171.82，156.10，155.65，145.25，140.30，126.80，124.03，80.14，79.28，53.76，40.29，32.09，28.66，28.54，27.48，23.91，23.10。

Propofol-two-Boc-L-lysine ester (12.34g, 24.37 mMs) at room temperature is dissolved in the absolute ether (250mL).In ice/water-bath, stirred 60 minutes under the cooling, in solution, feed hydrochloric acid (gas) simultaneously.At room temperature in the argon atmospher mixture was stirred 48 hours.Filtering precipitate is also with ethanol (100mL) crystallization after 48 hours.Gained white solid under 90 ℃ of high vacuum dry 4 hours.The SPI0013 that this experiment generates is white solid (purity of analyzing through HPLC is 98.6% for 5.5g, 60% productive rate).

2 (S), 6-diaminocaproic acid-2,6-diisopropyl phenyl ester dihydrochloride:

¹H NMR(300MHz，CDCl ₃)：δ＝9.05(br s，3H)，8.35(br s，3H)，7.26-7.13(m，3H)，4.43(t，1H，J＝6Hz)，3.0-2.6(m，4H)，2.09(m，2H)，1.80-1.50(m，4H)，1.10(d，12H，J＝7Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝168.30，144.23，139.74，126.98，123.96，51.58，38.21，29.32，26.64，23.71，23.02，21.67。

The CHN elementary analysis:

Calculated value .:C 56.99, H 8.50, and N 7.38; Measured value: C 56.48, H 8.56, and N 7.30.

II. the prodrug of NSAID (non-steroidal anti-inflammatory drug) (NSAIDs)

NSAIDs comprises the medicine in the aromatic series functional group that a class formation is special, carboxylic moiety is connected to the plane, and its example comprises: acetylsalicylic acid, salicylic acid, Diflunisal, brufen, fenoprofen, Carprofen, Flurbiprofen, Ketoprofen, naproxen, sulindac, Indomethacin, Etodolac, tolmetin, ketorolac, Diclofenac and meclofenamic acid.NSAIDs has anti-inflammatory, pain relieving, brings down a fever and the anticoagulant activity.

The example that shows the chemical constitution of this class unique compounds of pharmacological activity widely is as follows.

NSAIDs is widely used for treating edema, tissue damage acute and that chronic ache, adjusting are caused by IJD, but also is effective anticoagulant in the treatment of miocardial infarction.Except pain relieving and antiinflammatory action, many medicines also show the activity of bringing down a fever, thereby are useful to bringing down a fever.

Some medicines in above-mentioned group also are used for rheumatoid arthritis, osteoarthritis, acute gout, ankylosing spondylitis and TREATMENT OF DYSMENORRHOEA.

The mechanism of action:

The dominant mechanism that NSAIDs generates result of treatment is synthetic by suppressing prostaglandin.Especially NSAIDs suppresses cyclooxygenase, and such as COX-1 and COX-2 enzyme, wherein these two kinds of enzymes are responsible for the synthetic of prostaglandin.COX-1 is important to blood flow, the adjusting gastric acid secretion of regulating platelet aggregation, regulate in kidney and the stomach, and the COX-2 enzyme plays an important role in pain and inflammatory process.NSAIDs increases setting time significantly and can be used to prevent thromboembolism and miocardial infarction.

All NSAIDs be relatively by in to strong organic acid, the pKa value is in the scope of 3-6.Major part in them is a carboxylic acid derivates.It is necessary that acidic-group suppresses activity to COX, and in the physiological pH value, all NSAIDs are ionized.They all have significantly different hydrophilic-lipophilic balance value, and this is that aromatic radical, aromatic series and aliphatic lateral chain and other different heterocycle in its structure causes.Ability of most NSAIDs combines with the plasma protein height, and the competitive usually other medicines that plasma protein is had similar affinity that replace.Therefore must assess in earnest during the medicine co-administered of NSAIDs and other treatment type, with the prevention drug interaction.Most of described medicines are owing to its acid carboxyl and by mammal metabolism by combination.The main path of many NSAIDs metabolite clearance is glucuronidation effects, with after kidney get rid of.

It is well-known using acetylsalicylic acid (aspirin) prevention coronary heart disease, and verified this medicine is saved somebody's life to many miocardial infarction patients.Many other purposes of aspirin also are seen in report, for example, document (the medical journal Lancet (Vol 349, and p 1641)) reports that recently aspirin has reduced the danger of patient's apoplexy of the early warning sign with temporary transient ischemic heart onste.Pre-eclampsia that the placental blood pipe choking causes and growth retardation of fetus be modal two kinds of conceived complication, and there is millions of pre-eclampsia cases in the annual whole world.Comprise at one and the surpassing in 9000 women's the test of 16 countries to take the 60mg aspirin every day and to make the risk that pre-eclampsia takes place reduce by 13% (Aspirin Foundation website).Also colon cancer, lung cancer and the cancer of pancreas to the prevention postmenopausal women is effective to have shown aspirin in some researchs.Because aspirin can improve blood flow, the validity of the treatment of dementia such as the Alzheimer's disease that it causes for diabetes becomes clear day by day.

Because unique medicine potentiality, NSAIDs has attracted the enough attentions of medium.Main field to the said medicine clinical research is to be taken as NSAID (non-steroidal anti-inflammatory drug), especially about being applied in patient and the prevention coronary heart disease that suffers pain, arthritis (rheumatoid and bone), other inflammatory reactions, fever.These medicines also are used in treatment antimigraine, menstruation syndrome, backache and gout.

Although NSAIDs has made very important contribution, providing more effective and (galenic medicine (galenic) formulation for example easily on the medication, as, peroral dosage form, it is not only convenient, and suitable bioavilability is provided and allows administration under suitable controlled medicine-feeding rate to the patient) run into difficulty, and have report that the side effect of not expecting has taken place; Especially serious gastric duodenal ulcer, the erythema of mucous membrane, edema, erosion, bore a hole, have blood in stool, ulcerative colitis, these have obviously seriously hindered it and have used widely or use.Binary defect theory (The dual injury theory) relates to the coup injury of NSAID mediation, and what continue is the synthetic repressed systemic effect of prostaglandin.Local damage also can because of the hepatic metabolism product secretion of bile of activation and subsequently duodenogastric reflux take place.(Arthritisand Rheumatism 1995；38(1)：5-18)。These effects are adding up property of tool; No matter local mechanism or whole body mechanism all are enough to generate the gastro-duodenal mucosa damage.

And above-mentioned NSAIDs feature is highly hydrophobic, and exists even also be easy to precipitation during very in a small amount water, for example enter in the body body (as, gastric juice) time.Therefore providing of difficulty especially such as the acceptable peroral dosage form of patient on form and taste, stable simultaneously can the storage, and suitable controlled patient dose can be provided when administration routinely.

The liquid dosage form of proposing for example, is used for the NSAIDs of oral administration, so far mainly based on using natural gum, as: xanthans (Xanthan), cellulose, citric acid and lime spices (seeing U.S. Patent number 5,780,046) such as (limefiavor).The NSAIDs drinkable solutions of selling on the market has adopted inconsistent orange plain and berry spices, citric acid, xanthans (Xanthan gum), Tween 80, pregelatinized starch, glycerine, Sodium Benzoate and additional artificial color and spices.Yet drinkable solutions of proposing in use this area and analogous composition are with many difficulties.

In addition, the palatability of known oil base system is problematic.Especially, the taste of known drinkable solutions is offending.The mixture that mixes mutually with a kind of suitably flavored drink adopts, so that conventional therapy can be accepted, wherein said drink added pharmaceutical preparation with high dilution before being ingested, as the chocolate beverage preparation.Adopt the oil base system also to need to use high concentration of alcohol,, especially can predict when the time to children's administration to such an extent as to itself just is out of favour inherently.In addition, the volatilization of ethanol as (being adopted to solve the problem or the other problem (for example, when opening) of the palatability of being discussed by a large amount of), will cause the generation of NSAID precipitation from capsule.For example, when described composition existed with the form of soft gelatin microcapsule agent, this specific difficulty forced this microcapsules product to be encapsulated into necessity in airtight element, for example, and airtight bubble-cap (blister) or the encapsulation of aluminium foil bubble-cap.And cause product heavy more expensive with production.In addition, the storage properties of previous formulations is very unfavorable.

The stomach irritation of NSAIDs has been doctor and the theme mainly worrying of patient in the practice.The short-term of aspirin, fenoprofen, Flurbiprofen, Indomethacin, ketorolac, meclofenamic acid, mefenamic acid and piroxicam is used and is generated serious gastrointestinal side-effect.Even brufen also shows when long-term the use and causes serious gastric injury.Gastrointestinal toxicity is to be accompanied by the side effect that NSAIDs the most often runs into and to cause great concern.Only about half of among the hemorrhagic ulcer inpatient is because used NSAIDs, aspirin or used the two (Faulkner G simultaneously in the last week of being admitted to hospital, Prichard P, people such as Somerville K, Aspirin and bleeding peptic ulcers in the elderly.Br Med is J.1988; 297:1311-1313).To because the Tennessee State medical subsidy patient's that is in hospital of stomach and intestine complication an investigation expression, the patient who has used NSAJDs is than the patient who does not have to use, high 4 times of (the Griffin MR of probability of gastrointestinal bleeding or peptic ulcer take place, Piper JM, people .Nonsteroidalanti-inflammatory drug use and increased risk for peptic ulcer disease in elderlypersons.Ann Intern Med.1991 such as Daugherty JR; 114:257-263).According to the FDA report, continue to take the patient of NSAID treatment rheumatoid arthritis, have every year 2% to 4% serious gastrointestinal disease takes place.These patients compare with the patient who does not take these medicines, and stomach ulcer (4.725), duodenal ulcer (1.1 to 1.6), hemorrhage (3.8), perforation and dead respective risk all increase by using NSAID.In 1989, about 20,000 patient with rheumatoid arthritis hospitalizations are arranged every year, estimated cost is Mei Ci $10,000.(Fries JF, Miller SR, people .Toward an epidemiology ofgastropathy associated with nonsteroidal anti-inflammatory drug use.JGastroenterology.1989 such as Spitz PW; 96:647-655).

The water-soluble preparation of NSAIDs that provides some to be used to inject also is provided.As everyone knows, in present ketorolac (Ketorolac) preparation, the high concentration ethanol and the tromethamine that are used for salify are poisonous.Because the low aqueous solubility of medicine does not have preparation that the NSAIDs of desired concn is present in the aqueous solution at present.

Adopt existing peroral dosage form, except having all these tangible practical difficulties, also observed and do not expected the side effect that takes place.

In the art, in order to solve the variety of issue that runs into many proposals have been proposed, comprise the peroral dosage form of solid and liquid.Yet still a main difficulty of Cun Zaiing is that NSAIDs is intrinsic insoluble in water-bearing media, therefore hindered conveniently using and satisfying required bioavilability standard of the NSAIDs that contains abundant high concentration, for example, allow effectively absorbing the drug and reach the suitable high blood/serum levels of making peace from stomach or intestines inner chamber.

The problem of having enumerated more than NSAIDs prodrug of the present invention has overcome.More particularly, embodiment of the present invention relate to the prodrug of NSAID, and it has significantly increased the solvability of NSAID in the aqueous solution, thereby can avoid using carrier when as the solution administration, and described carrier is ethanol or castor oil for example.And according to the present invention, the prodrug of NSAID does not show the side effect of prior art preparation.In addition, prodrug of the present invention has almost completely been avoided gastric irritation when oral administration, thereby has increased therapeutic index and its usefulness of testing prodrug significantly.

Therefore, in one aspect, the present invention relates to the prodrug of NSAIDs.The preferred prodrug of NSAIDs is the compound with following general formula, or its pharmaceutically acceptable salt:

Wherein Y is NH-AA or O-AA, and AA is an amino acid, the hydroxy-acid group reaction of the amino of AA or hydroxyl and NSAIDs.

The present invention also relates to a kind of pharmaceutical composition, it comprises treatment upward above various NSAIDs and its pharmaceutical carrier of effective dose.

In another embodiment, need to the present invention relates to a kind of methods of treatment of the patient of NSAID treatment, this method comprises the NSAIDs that gives effective dose to described patient.

In another embodiment, the present invention relates to a kind of increase NSAIDs deliquescent method in the aqueous solution, it comprises that the carboxyl functional group that makes each NSAIDs molecule reacts and separates its product.

In further embodiment, the present invention relates to a kind of method, it is fully and to treat effective and efficient manner, to patient's administration the time, alleviate or eliminated the gastric mucosa injure of NSAIDs greatly, described method comprises that the carboxyl functional group that makes each NSAID molecule reacts with selected amino acid whose amino or hydroxyl respectively, to form the covalent bond of acid amides or ester respectively, separate its product again and give described product to the patient.

A. the ibuprofen amino acid derivative is synthetic

General introduction:

The overview of steps of L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic brufen is in synthetic order part.Complete step and analysis data are seen experimental section.Again explanation, these synthetic diagrams are examples.Diagram can be applied to other L-threonine derivatives of high therapeutic index of preparation NSAID of the present invention.Generally speaking; shown in following diagram; there is the 4-(N of catalytic amount; the N-dimethylamino)-during pyridine (DMAP); (4-10g reacts with the N-benzyloxy/amino acid (1 equivalent) of benzyl ester protection, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 1 equivalent) (±)-brufen in batches).Reaction one is finished, and is just extracted to remove any excessive EDC by water,, is extracted to remove brufen by sodium bicarbonate to remove DMAP by the diluted acid extraction.After dried over sodium sulfate, filter, concentrate the amino-acid ester of rough shielded (±)-brufen, products therefrom or directly use, perhaps by the flash chromatography method on silica gel purifying with the shielded ester (85-95%) of generation high yield.If used excessive slightly brufen and coupling agent, do not need to use column chromatography usually, but carry out extraction step completely.When 10% palladium-carbon catalyst and hydrochloric acid exist, by hydrogenization (25-35 psi H ₂) remove blocking group.The productive rate scope of deprotection steps is 70-90%.After filtration and drying, the hydrochloride of the serine ester of (±)-brufen and threonine ester is purifying by crystallization.The hydrochloride of L-hydroxyproline-ibuprofen ester is a kind ofly can not solidify/gel of crystallization.In this case, do not use acid, come the purifying neutral compound by repeating hydrogenization.

Because brufen is initial is mixture as enantiomter, so except the threonine ester, end-product is with the mixture release of diastereomer.To the threonine ester of brufen, water, acetone or acetonitrile washing can make it be easy to separate final diastereomer salt.Undissolved isomer (SPI0016A) compares with the trusted standard thing for preparing from S-(+)-brufen, and being defined as is active isomer.The serine ester of (±)-brufen and hydroxyproline ester be delamination by this way.

Synthetic order:

1.SPI0015

2.SPI0016A and SPI0016B

3.SPI0017

L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic (±)-brufen: a) EDC, DMAP, CH ₂Cl ₂B) HCl, 10%Pd/C, EtOH c) acetone, d) 10%Pd/C, EtOH.

Experimental section:

SPI0015, SPI0016 and SPI0017 synthetic undertaken by two batches or the three batches of forms.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Sigma-Aldrich, Acros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.

The preparation of 1) (±)-brufen-L-serine ester hydrochloride (SPI0015).

With (±)-brufen (5.04g, 24.4 N-benzyloxycarbonyl group-L-serine benzyl ester (8.11g mM),, 24.6 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC mM),, 4.87g, 25.4 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 0.40g, 3.27 mMs) at room temperature is dissolved in carrene (150mL) in the argon atmospher.At room temperature stir after 22 hours in the argon atmospher, add entry (100mL), and layering.Dichloromethane layer water (100mL) washing and through dry 1 hour of sodium sulphate (5g) once more.Behind filtration and the concentrating under reduced pressure, go up the remaining oil of purifying at silica gel (250g), with hexane/ethyl acetate (3: 1) wash-out with the flash chromatography method.Shielded L-serine-(±)-ibuprofen ester (SPI001501) that this step generates is a kind of colorless solid (11.4g, productive rate: 90%).

2 (S)-benzyloxycarbonyl amino-3-[2 (R, S)-(4-isobutyl phenenyl) propionyloxy]-the propionic acid benzyl ester:

¹H NMR(300MHz，CDCl ₃)：δ＝7.40-7.20(m，10H)，7.14-7.01(m，4H)，5.50(d，1/2H，J＝8.4Hz)，5.29(d，1/2H，J＝8.4Hz)，5.11-5.02(m，2.5H)，4.90(d，1/2H，J＝12Hz)，4.62(m，1H)，4.49-4.43(m，1H)，4.36-4.32(m，1H)，3.59(m，1H)，2.39-2.35(m，2H)，1.78(m，1H)，1.42-1.39(m，3H)，0.85(d，6H，J＝6.6Hz).

¹³C NMR(75MHz，CDCl ₃)：δ＝174.05，169.19，169.07，155.68，140.73，137.20，136.12，135.05，134.91，129.44，128.67，128.65，128.60，128.41，128.33，128.30，128.19，127.19，127.16，67.75，67.32，64.51，64.32，53.71，45.16，45.02，30.35，22.60，18.27。

Shielded brufen-L-serine ester (22.50g, 43.4 mMs) at room temperature is dissolved in ethanol (200mL), and in blanket of nitrogen, it is joined in the Parr bottle that contains 10% palladium-carbon catalyst (3.86g, 50% is wet).Add hydrochloric acid (10mL 37%HCl is dissolved in 30mL water), and replace the nitrogen atmosphere with hydrogen (25psi).Vibrate after 4 hours, remove palladium catalyst with diatomite filtration.Under reduced pressure remove ethanol/water.The washing of remaining white solid water (25mL), acetone (20mL) and dry under high vacuum (88 ℃ 4 hours).(±)-brufen-L-serine ester hydrochloride (SPI0015) that this experiment generates is colorless solid (11.3g, productive rate: 80%).

2 (S)-amino-3-[2 (R, S)-(4-isobutyl phenenyl) propionyloxy] the propionate hydrochlorate; ((R, S)-brufen-L-serine ester hydrochloride):

¹H NMR(300MHz，DMSO)：δ＝8.92(br s，3H)，7.22(t，2H，J＝7.5Hz)，7.10(d，2H，J＝7.5Hz)，4.56(m，1H)，4.37-4.20(m，2H)，3.83(q，1H，J＝6.9Hz)，2.41(d，2H，J＝6.9Hz)，1.80(m，1H)，1.41(d，3H，J＝6.9Hz)，0.85(d，6H，J＝6.9Hz)。

¹³C NMR(75MHz，DMSO)：δ＝173.36，173.32，168.08，168.04，139.70，128.96，129.92，127.20，127.05，62.47，51.59，51.49，44.28，44.00，43.90，29.68，22.28，18.70，18.42。

HPLC analyzes:

99.13% purity; Rt=3.133min; Luna C18 5u post (sn 167917-13); 4.6 * 250mm; 254nm; 50% acrylonitrile/50% trifluoroacetic acid buffer solution (0.1%); 35 C; 20ul injects; 1ml/min; The 1mg/mL sample size; Sample is dissolved in the flowing phase.

The CHN elementary analysis:

Calculated value: C 58.27, H 7.33, and N 4.25; Measured value: C 58.44, H 7.46, N 4.25.

Fusing point: 169.5-170.5 ℃

The preparation of 2a) (±)-brufen-L-threonine ester hydrochloride (SPI0016A and SPI0016B) with separate.

With (±)-brufen (4.15g, 20.11 N-benzyloxycarbonyl group-L-threonine benzyl ester (6.90g mM),, 20.11 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC mM),, 3.95g, 20.6 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 0.25g, 2.0 mMs) at room temperature is dissolved in carrene (50mL) in the argon atmospher.Stir after 19 hours, dichloromethane layer water (50mL), 5% hydrochloric acid solution (2 * 25mL), water (25mL), saturated sodium bicarbonate solution (2 * 25mL) and water (50mL) washing., filter and under reduced pressure concentrate after dry 1 hour through sodium sulphate (5g), remaining grease can use without further purifying.This step generates shielded L-threonine-(±)-ibuprofen ester (SPI001601), for a kind of light yellow oil (10.2g, productive rate: 95.3%), through leaving standstill curing.

2 (S)-benzyloxycarbonyl amino-3-[2 (R, S)-(4-isobutyl phenenyl)-propionyloxy] the butyric acid benzyl ester:

¹H NMR(300MHz，CDCl ₃)：δ＝7.40-7.15(m，10H)，7.14-7.01(m，4H)，5.48-5.25(m，2H)，5.11-5.01(m，3H)，4.90(d，1/2H，J＝12Hz)，4.68(d，1/2H，J＝12Hz)，4.48(m，1H)，3.60-3.48(m，1H)，2.39(m，2H)，1.79(m，1H)，1.42-1.35(m，3H)，1.27(d，1.5H，J＝6.6Hz)，1.17(d，1.5H，J＝6.6Hz)，0.85(m，6H)。

¹³C NMR(75MHz，CDCl ₃)：δ＝173.32，169.70，169.30，156.55，140.75，137.38，137.22，136.14，135.07，134.99，129.45，129.41，128.65，128.39，128.22，127.21，127.14，70.97，70.70，67.81，67.66，67.53，57.83，45.19，30.39，22.61，18.57，18.30，17.18，16.87。

Shielded brufen-L-threonine ester (10.15g, 19.0 mMs) is dissolved in hot ethanol (150mL), and it is added in blanket of nitrogen in the Parr bottle that contains 10% palladium-carbon catalyst (3.4g, 50% is wet).Add hydrochloric acid (6mL 37%HCl is dissolved in 20mL water), and replace blanket of nitrogen with hydrogen (30psi).Vibrate after 3 hours, (30g) removes by filter palladium catalyst with diatomite.Under reduced pressure remove ethanol/water.(±)-brufen-L-threonine ester hydrochloride (SPI0016A and SPI0016B, 6.4g, crude product productive rate: 97%), be colorless solid that this experiment generates.The crude mixture of diastereomer at room temperature stirred 2 hours in acetone (200mL) in the argon atmospher.Mistake filter solid after 2 hours (2.84g, SPI0016A).(SPI0016B 3.0g) under reduced pressure concentrates this filtrate.

1.) the purifying of SPI0016A (active isomer):

Behind synthetic 3 batches of S-brufen-L-threonine esters (SPI0016A), each batch merged (8.78g altogether), and by DIUF water (100mL) crystallization three times.The a spot of amphion of each generation.In order to reclaim salt, the solid (from each crystallization) that produces is dissolved in the ethanolic solution (3mL37% hydrochloric acid is dissolved in the 100mL ethanol) that contains 1% hydrochloric acid.Ethanolic solution is concentrating under reduced pressure at room temperature subsequently.After crystallization and recycling step for the third time, at room temperature in the argon atmospher described salt (5.6g) was stirred 44 hours in acetonitrile (100mL).Subsequent filtration is also dry under high vacuum 50-55 °, up to constant weight (5.5g).

2 (S)-amino-3 (R)-[2 (S)-(4-isobutyl phenenyl) propionyloxy] butyric acid; (S-brufen-L-threonine ester hydrochloride, active isomer):

¹H NMR(300MHz，DMSO)：δ＝8.76(br s，3H)，7.19(d，2H，J＝8.1Hz)，7.11(d，2H，J＝8.1Hz)，5.28(dq，1H，J＝6.3，3.6Hz)，4.14(q，1H，J＝3.6Hz)，3.80(q，1H，J＝7.2Hz)，2.41(d，2H，J＝7.2Hz)，1.80(m，1H)，1.37(d，3H，J＝7.2Hz)，1.21(d，3H，J＝6.3Hz)，0.85(d，6H，J＝6.6Hz)。

¹³C NMR(75 MHz，DMSO)：δ＝172.66，168.24，139.68，137.24，128.95，126.97，67.98，55.35，44.23，43.83，29.66，22.24，18.52，16.47。

The CHN elementary analysis:

Calculated value: C 59.38, H 7.62, and N 4.07; Measured value: C 59.17, H 7.63, and N 4.04.

HPLC analyzes:

98.28% purity; R.t.=6.951min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5 C; Luna C18,3u post (SN 167917-13), 4.6 * 250mm; 22ul injects.

Optical activity :+24.5 °

Fusing point: 189-190 ℃

2) purifying of SPI0016B (nonactive isomer):

After finishing 3 batches of R-brufens-L-threonine ester (SPI0016 B), each batch merged (9.02g altogether), and by DIUF water (50mL) crystallization.Crystallization process has produced amphion in a small amount.In order to reclaim salt, the solid of generation is dissolved in the ethanolic solution (hydrochloric acid of 3mL 37% is dissolved in the 100mL ethanol) that contains 1% hydrochloric acid.Ethanolic solution is concentrating under reduced pressure at room temperature subsequently.Remaining salt (5.93g) adds small amount of acetone (1mL) simultaneously by hot toluene (100mL) crystallization three times.Described salt of subsequent filtration and high vacuum dry at room temperature are up to constant weight (5.1g).

2 (S)-amino-3 (R)-[2 (R)-(4-isobutyl phenenyl) propionyloxy] butyric acid; (R-brufen-L-threonine ester hydrochloride, nonactive isomer):

¹H NMR(300MHz，DMSO)：δ＝8.82(br s，3H)，7.23(d，2H，J＝7.8Hz)，7.10(d，2H，J＝7.8Hz)，5.27(m，1H)，4.18(m，1H)，3.80(q，1H，J＝7.2Hz)，2.41(d，2H，J＝7.2Hz)，1.81(m，1H)，1.41(d，3H，J＝6.9Hz)，1.34(d，3H，J＝6.3Hz)，0.85(d，6H，J＝6.3Hz)。

¹³C NMR(75MHz，DMSO)：δ＝72.56，168.08，139.64，136.98，128.84，127.14，68.8，55.29，44.28，29.69，22.28，18.24，16.41。

The CHN elementary analysis:

Calculated value: C 59.38, H 7.62, and N 4.07; Measured value: C 59.30, H 7.60, and N 4.05.

HPLC analyzes:

98.43% purity; R.t.=6.19min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5C; Luna C18,3u post (SN 167917-13), 4.6 * 250mm; 22ul injects.

Optical activity :+10.4 °

Fusing point: 176-177 ℃

2b) S-(+)-brufen-L-threonine ester The hydrochloride standardThe preparation of (SPI0016 S).

With S-(+)-brufen (2.0g, 9.69 N-benzyloxycarbonyl group-L-threonine benzyl ester (3.25g mM),, 9.91 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC mM),, 1.90g, 9.91 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 0.12g, 1.0 mMs) at room temperature is dissolved in carrene (25mL) in the argon atmospher.Stir after 4 hours dichloromethane layer water (25mL), 5% hydrochloric acid solution (25mL), saturated sodium bicarbonate solution (2 * 25mL) and water (25mL) washing.After dry 1 hour, after filtering and under reduced pressure concentrating, remaining grease can use without being further purified through sodium sulphate (5g).This step generates shielded S-(+)-brufen-L-threonine ester (SPI001601S), for a kind of light yellow oil (5.01g, productive rate: 98%), through leaving standstill curing.

2 (S)-benzyloxycarbonyl amino-3-[2 (R, S)-(4-isobutyl phenenyl) propionyloxy] the butyric acid benzyl ester:

¹H NMR(300MHz，CDCl ₃)：δ＝7.35-7.23(m，10H)，7.10(d，2H，J＝7.8Hz)，7.05(d，2H，J＝7.8Hz)，5.48-5.25(m，2H)，5.17-5.01(m，4H)，4.50(dd，1H，J＝9.6，1.8Hz)，3.50(q，1H，J＝7.2Hz)，2.40(d，2H，J＝7.2Hz)，1.80(m，1H)，1.37(d，3H，J＝7.2Hz)，1.17(d，3H，J＝6.3Hz)，0.86(d，6H，J＝6.6Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝173.29，169.69，156.51，140.68，137.21，136.08，135.06，129.40，128.70，128.66，128.57，128.38，128.24，127.14，70.70，67.80，67.53，57.87，45.19，45.11，30.39，22.61，18.57，16.87。

Shielded S-(+)-brufen-L-threonine ester (5.0g, 9.40 mMs) is dissolved in the hot ethanol (100mL), and in blanket of nitrogen, it is joined in the Parr bottle that contains 10% palladium-carbon catalyst (1.0g, 50% is wet).Add hydrochloric acid (1mL 37%HCl is dissolved in the 10mL water), and replace blanket of nitrogen with hydrogen (32psi).Vibrate after 2 hours, (30g) removes by filter palladium catalyst with diatomite.Under reduced pressure remove ethanol/water.S-(+)-brufen-L-threonine ester hydrochloride (SPI0016S, 2.8g, crude product yield: 85%) be colorless solid that this experiment generates.This salt was stirring 3 hours in acetone (50mL) under the room temperature argon atmospher.Cross filter solid (2.24g, 69% productive rate) and dry under the room temperature high vacuum after 3 hours, up to constant weight.

2 (S)-amino-3 (R)-[2 (S)-(4-isobutyl phenenyl) propionyloxy] butyric acid; (S-brufen-L-threonine ester hydrochloride, active isomer):

¹H NMR(300MHz，DMSO)：δ＝8.76(br s，3H)，7.19(d，2H，J＝8.1Hz)，7.11(d，2H，J＝8.1Hz)，5.28(dq，1H，J＝6.3，3.6Hz)，4.14(q，1H，J＝3.6Hz)，3.80(q，1H，J＝7.2Hz)，2.41(d，2H，J＝7.2 Hz)，1.80(m，1H)，1.37(d，3H，J＝7.2Hz)，1.21(d，3H，J＝6.3Hz)，0.85(d，6H，J＝6.6Hz)。

¹³C NMR(75 MHz，DMSO)：δ＝172.66，168.24，139.68，137.24，128.95，126.97，67.98，55.35，44.23，43.83，29.66，22.24，18.52，16.47。

HPLC analyzes:

98.28% purity; R.t.=6.951min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5 C; Luna C18,3u post (SN 167917-13), 4.6 * 250mm; 22ul injects.

Optical activity :+26.5 °

Fusing point: 189-190 ℃

The preparation of 3) (±)-brufen-L-hydroxyproline ester (SPI0017).

With (±)-brufen (5.10g, 24.7 N-benzyloxycarbonyl group-L-hydroxyproline benzyl ester (8.80g mM),, 24.7 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC mM),, 5.10g, 26.0 mM) and 4-(N, the N-dimethylamino) pyridine (DMAP, 0.30g, 2.40 mMs) at room temperature is dissolved in carrene (100mL) in the argon atmospher.At room temperature stir after 24 hours in the argon atmospher, add entry (100mL) and layering.Dichloromethane layer water (100mL), 5% sodium bicarbonate solution (2 * 50mL) washings and again through dry 1 hour of sodium sulphate (5g).Filter and concentrating under reduced pressure after, can use remaining grease and without being further purified.Shielded (±)-brufen-L-hydroxyproline ester (SPI001701) that this step generates is light yellow oil (11.5g, a productive rate: 85%).

4 (R)-[2-(4-isobutyl phenenyl) propionyloxy] pyrrolidines-2 (S)-carboxylic acid; ((R, S)-brufen-L-hydroxyproline ester):

¹H NMR(300MHz，CDCl ₃)：δ＝7.33-7.02(m，14H)，5.25-4.95(m，5H)，4.5 1-4.19(m，1H)，3.75-3.50(m，3H)，2.40(d，2H，J＝6.9Hz)，2.15(m，1H)，1.81(m，1H)，1.44(d，3H，J＝7.0Hz)，0.87(d，6H，J＝6.6Hz)。

¹³C NMR(75 MHz，CDCl ₃)：δ＝173.99，171.93，171.72，154.68，154.15，140.70，137.23，137.04，136.23，135.44，135.23，129.41，128.59，128.47，128.35，128.19，128.08，127.89，127.02，72.86，72.16，67.40，67.18，67.09，58.12，57.83，52.66，52.49，52.13，45.15，36.63，35.67，32.07，30.33，29.23，22.90，22.58，18.36。

Shielded brufen-L-hydroxyproline ester (11.40g, 43.4 mMs) at room temperature is dissolved in ethanol (150mL), and in blanket of nitrogen, it is joined in the Parr bottle that contains 10% palladium-carbon catalyst (2.73g, 50% is wet).Replace blanket of nitrogen with hydrogen (34psi).Vibrate after 5 hours, remove palladium catalyst with diatomite filtration.Under reduced pressure remove ethanol.Remaining white solid (6.60g) is with DIUF water (50mL), ether (50mL) washing and dry under high vacuum, up to constant weight.(±)-brufen-L-hydroxyproline ester SPI0017 (5.64g, 84% productive rate) that this experiment generates is a colorless solid.

4 (R)-[2-(4-isobutyl phenenyl) propionyloxy] pyrrolidines-2 (S)-carboxylic acid; ((R, S)-brufen-L-hydroxyproline ester):

¹H NMR(300MHz，CDCl ₃)：δ＝7.22(d，2H，J＝7.2Hz)，7.09(d，2H，J＝7.2Hz)，5.27(m，1H)，4.40(t，0.5H，J＝7Hz)，4.24(t，0.5H，J＝9Hz)，3.75(m，1H)，3.61(m，1H)，3.28(d，0.5H，J＝13Hz)，3.15(d，0.5H，J＝13Hz)，2.42-2.10(m，4H)，1.78(m，1H)，1.40(br t，3H，J＝6Hz)，0.82(d，6H，J＝6Hz)。(mixture of diastereomer)

¹³C NMR(75MHz，CDCl ₃)：δ＝173.28，173.23，168.98，139.88，137.33，137.23，129.12，127.26，127.17，72.58，57.60，57.50，50.24，50.12，44.34，44.15，34.31，34.16，29.77，22.34，18.43，18.23。(mixture of diastereomer)

HPLC analyzes:

100% purity; R.t.=5.35,5.22min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1mL/min; 32.3 C, Luna C18, serial#188255-37; 20ul injects.

The CHN elementary analysis:

calc.：C 67.69，H 7.89，N 4.39；fbund：C 67.47，H 7.87，N 4.30。

Fusing point: 198-199 ℃

Adopt the usefulness (anti-pain potential) of L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic (±)-brufen of the abdominal constriction method of male albinism mouse acetylcholine-induced:

Carry out the effect of this research with L-serine ester, L-threonine ester and the L-hydroxyproline ester of estimating (±)-brufen, described research will be to the antagonism performance of seething of albinism mouse acetylcholine-induced as an index.Brufen (racemic mixture) and (S)-(+)-brufen contrast as a reference.

The different novel formulation of brufen and the contrast of reference be brufen (racemic mixture) and (S)-(+)-brufen by to male albinism mouse (Swiss strain system) to raise the mode administration by force, its use contains the milli Q water of 5% (v/v) Tween 80 as excipient.This research is carried out with two kinds of dosage levels, i.e. 50mg and 100mg/kg body weight and excipient control group.Use 10 animals at each dosage level.All dosage are all represented with the molar equivalent of brufen.The dosage and the molar equivalent that use are as follows.

Table 2: preparation: molar equivalent:

Preparation	Molar equivalent
		S-(+)-brufen-L-threonine ester	0.833 unit is equivalent to 1 unit brufen
(±)-brufen-L-serine ester	1.6 unit is equivalent to 1 unit brufen
		(±)-brufen-L-hydroxyproline ester	1.55 unit is equivalent to 1 unit brufen

Table 3: detection: group: dosage (mg/kg): the weight of equal value of detection:

Detection	Group	Dosage (mg/kg) [according to brufen]	The weight of equal value [mg/kg] of detection
				Excipient	The excipient control group	0.0	--
S-(+)-brufen-L-threonine ester	Experimental group 1	50.0	41.65
				Experimental group 2	100.0	83.30
	(±)-brufen-L-serine ester (brufen S)	Experimental group 3	50.0				80.0
Experimental group 4				100.0	160.0
		(±)-brufen-L-hydroxyproline ester	Experimental group 5			50.0	77.5
Experimental group 6	100.0			155.0
			Brufen (racemic mixture)		Experimental group 7	50.0	50.0
Experimental group 8	100.0	100.0
				Brufen S+	Experimental group	9	50.0	25.0
Experimental group 10	100.0	50.0

Be expressed as follows for the effectiveness aspect the single antagonism effect of seething of acetylcholine-induced at three kinds of preparations and with reference to the two kinds of dosage levels-50.0 and the 100.0mg/kg of contrast.

Table 4: detection: group: dosage (mg/kg): show the single animal number (in 10) that seethes disappearance

Detection	Group	Dosage (mg/kg) [according to brufen]	The animal number (animal number=10 of each dosage) of disappearance is singly seethed in performance
					After the administration one hour	After the administration three hours
			Excipient	The excipient contrast			0.0	0	0
S-(+)-brufen-L-threonine ester	Low dosage	50.0			1	0
			High dose	100.0			3	0
	(±)-brufen-L-serine ester	Low dosage			50.0	4			2
High dose			100.0	6			4
		(±)-brufen-L-hydroxyproline ester			Low dosage	50.0		5	4
High dose	100.0		7	7
					Brufen (racemic mixture)	Low dosage	50.0	4	2
High dose	100.0	6	6
				Brufen S+		Low dosage	50.0	5	1
High dose	100.0	6	6

Adopt Chi-square Test (Chi-square test) step to carry out statistical analysis, various preparations are compared with reference, do not show any statistically significant difference, and relatively do not show the animal number that seethes in each group, significance level separately " p " is greater than 0.05.

Based on not showing owing to using the number of animals purpose clinical observation that acetylcholine seethes, with other preparation and brufen (racemic mixture) and brufen (S)-(+) comparison, find seething of (±)-brufen-more effective antagonism acetylcholine-induced of L-hydroxyproline ester.

Table 5:(±)-effect of L-serine ester, L-threonine ester and L-hydroxyproline ester, brufen (racemic mixture) and the brufen (S)-(+) of brufen sums up--based on the characteristic of seething of resisting acetylcholine-induced in the albinism mouse

Dosage (mg/kg) [according to brufen]	Detection	The animal number (animal number=10 of each dosage) of disappearance is singly seethed in performance
				After the administration one hour	After the administration three hours
		50mg/kg	The excipient contrast			0	0
S-(+)-brufen-L-threonine ester	1			0
			(±)-brufen-L-serine ester		4	2
(±)-brufen-L-hydroxyproline ester	5			4
			Brufen (racemic mixture)		4	2
Brufen (S)-(+)	5			1

Table 6:

100mg/kg	The excipient contrast	0	0
				S-(+)-brufen-L-threonine ester	3	0
	(±)-brufen-L-serine ester	6	4
				(±)-brufen-L-hydroxyproline ester	7	7
	Brufen (racemic mixture)	6	6
				Brufen (S)-(+)	6	6

Adopt the Chi-square Test step that data are carried out statistical analysis, to estimate novel formulation with respect to usefulness with reference to contrast.Preparation is compared with reference, and check does not show any statistically significant difference, and does not relatively show the animal number that seethes in each group, and significance level separately " p " is greater than 0.05.

Data also are summarised among Fig. 1 and Fig. 2.Based on not showing owing to using the animal number that acetylcholine seethes, find from efficiency ratio clinical observation and histogram (Fig. 1 and Fig. 2), compare with brufen (racemic mixture) and brufen (S)-(+) with other preparation, what (±)-brufen-L-hydroxyproline ester can more effective antagonism acetylcholine-induced seethes.

Conclusion

Carry out the relative efficiency of this research with the novel formulation of evaluation brufen.The antagonism performance that novel formulation is seethed acetylcholine is used as an index, to determine the relative efficiency of novel formulation.Brufen (raceme mixture) and brufen (S)-(+) contrast as a reference.This research is carried out according to two kinds of dosage levels (50.0 and 100.0mg/kg) and an excipient control group.

At three kinds of preparations and as follows with reference to the usefulness of two kinds of dosage levels-50.0 of contrast and 100.0mg/kg for aspect the single antagonism effect of seething of acetylcholine-induced.

Table 7: detection: group: dosage (mg/kg): show the single animal number (in 10) that seethes disappearance

Detection	Group	Dosage (mg/kg) [according to brufen]	The animal number (animal number=10 of each dosage) of disappearance is singly seethed in performance
					After the administration one hour	After the administration three hours
			Excipient	The excipient contrast			0.0	0	0
S-(+)-brufen-L-threonine ester	Low dosage	50.0			1	0
			High dose	100.0			3	0
	(±)-brufen-L-serine ester	Low dosage			50.0	4			2
High dose			100.0	6			4
		(±)-brufen-L-hydroxyproline ester			Low dosage	50.0		5	4
High dose	100.0		7	7
					Brufen (racemic mixture)	Low dosage	50.0	4	2
High dose	100.0	6	6
				Brufen (S)-(+)		Low dosage	50.0	5	1
High dose	100.0	6	6

Adopt the Chi-square Test step to carry out statistical analysis, preparation is compared with reference, does not show any statistically significant difference, and does not relatively show the animal number that seethes in each group, and significance level separately " p " is greater than 0.05.

Yet, based on observing for not showing clinically owing to using the number of animals purpose that acetylcholine seethes, find to compare with brufen (racemic mixture) and brufen (S)-(+) with other preparation, (±)-brufen-L-hydroxyproline ester can more effectively resist seething of acetylcholine-induced.

For the male albinism mouse of fasting, the gastric stimulation potential of the L-serine ester of (±)-brufen, L-threonine ester and L-hydroxyproline ester

General introduction

Carry out this research and in the male albinism mouse of fasting, cause the relative potential of gastric stimulation/damage with the novel formulation (the L-serine ester of (±)-brufen, L-threonine ester and L-hydroxyproline ester) of estimating brufen.Brufen (racemic mixture) and brufen (S)-(+) contrast as a reference.

The different novel formulation of brufen and brufen (racemic mixture) and brufen (S)-(+) by to the male albinism mouse (Wistar strain system) of fasting to raise the mode administration by force, use and contain the milli Q water of 5% Tween 80 as excipient.This research is that 200mg and 300mg/kg body weight and an excipient control group carry out with two kinds of dosage levels.Use 5 animals at each dosage level.All dosage are all represented with the molar equivalent of brufen (racemic mixture).The dosage and the molar equivalent that use are as follows.

Table 8: preparation: molar equivalent:

Preparation	Molar equivalent
		S-(+)-brufen-L-threonine ester	0.833 unit is equivalent to 1 unit brufen
(±)-brufen-L-serine ester	1.60 unit is equivalent to 1 unit brufen
		(±)-brufen-L-hydroxyproline ester	1.55 unit is equivalent to 1 unit brufen

Each Groups List that uses is as follows:

Table 9: detection: group: dosage (mg/kg): the weight of equal value of detection:

Detection	Group	Dosage (mg/kg) [according to brufen]	The weight of equal value [mg/kg] of detection
				Excipient	The excipient control group	0.0	--
S-(+)-brufen-L-threonine ester	Experimental group 1	200.0	0.0
				Experimental group 2	300.0	166.6
	(±)-brufen-L-serine ester	Experimental group 1	200.0				249.9
Experimental group 2				300.0	320.0
		(±)-brufen-L-hydroxyproline ester	Experimental group 1			200.0	480.0
Experimental group 2	300.0			310.0
			Brufen (racemic mixture)		Experimental group 1	200.0	465.0
Experimental group 2	300.0	300.0
				Brufen (S)-(+)	Experimental group 1	200.0	100.0
Experimental group 2	300.0	150.0

Described mouse before administration 18 to 22 hours by fasting.Detection is individually dosed by raising the mode administration by force as one.After the administration three hours, animal is used CO ₂The gas inhalation is killed.Stomach is dissected, observes:

^*The amount of mucus diffusate

^*The degree of coat of the stomach hyperemia and thickening

^*Blutpunkte (part or disperse), hemorrhage character (petechia or ecchymosis) and size and

^*Perforation or any other damage

Observation to each treated animal gastric stimulation is summarized as follows

Table 10: detection: group: dosage (mg/kg): observe:

Detection	Group	Dosage (mg/kg) [according to brufen]	Observe
				Excipient	The excipient control group	0.0	No animal shows the sign of any gastric stimulation
S-(+)-brufen-L-threonine ester	Experimental group 1	200.0	No administration animal shows the sign of any gastric stimulation
				Experimental group 2	300.0	No administration animal shows the sign of any gastric stimulation
	(±)-brufen-L-serine ester	Experimental group 1	200.0				No administration animal shows the sign of any gastric stimulation
Experimental group 2				300.0	No administration animal shows the sign of any gastric stimulation
		(±)-brufen-L-hydroxyproline ester	Experimental group 1			200.0	No administration animal shows the sign of any gastric stimulation
Experimental group 2	300.0			No administration animal shows the sign of any gastric stimulation
			Brufen (racemic mixture)		Experimental group 1	200.0	In 5 animals of administration, there is 1 to observe the gastric stimulation sign
Experimental group 2	300.0	In 5 animals of administration, there are 2 to observe the gastric stimulation sign
				Brufen (S)-(+)	Experimental group 1	200.0	In all 5 animals of administration, all observe the gastric stimulation sign
Experimental group 2	300.0	In 5 animals of administration, there are 3 to observe the gastric stimulation sign

The result of this research shows that the preparation of brufen does not all have any gastric stimulation sign of the male albinism mouse that causes fasting at two kinds of dosage levels being tested (200mg and 300mg/kg body weight).Opposite, brufen (racemic mixture) and brufen (S)-(+) all cause gastric stimulation at two kinds of dosage levels being tested.And find that brufen (S)-(+) is stronger to gastric stimulation than brufen (racemic mixture).

Synthesizing of general introduction Ketoprofen S-(+)-threonine ester:

The overview of steps of the L-threonine ester of synthesizing ketoprofen is in synthetic order part.Should synthesize is demonstration example, can similarly be applied to other amino acid.Complete step and analysis data are seen experimental section.Generally speaking, when having the 4-of catalytic amount (N, N-dimethylamino) pyridine (DMAP), (±)-Ketoprofen (5g) and N-boc-L-threonine tertiary butyl ester ¹(1 equivalent), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 1 equivalent) reaction.Reaction one is finished, and just removes excessive EDC by the water extraction, removes DMAP by the diluted acid extraction, removes Ketoprofen by the sodium bicarbonate extraction.After dried over sodium sulfate, filter, concentrate rough shielded L-threonine-(±)-Ketoprofen, and by the flash chromatography method on silica gel purifying to generate the shielded L-threonine ester of high yield (98%).Fall the boc group by the diethyl ether solution cracking that contains 2M hydrochloric acid, handle to slough tertiary butyl ester with trifluoroacetic acid then.After drying, L-threonine-R, the mixture of S (±)-ketoprofen ester is by Crystallization Separation from acetonitrile.The hydrochloride of L-threonine-S (+)-ketoprofen ester preferentially is precipitated out from acetonitrile.For relatively, prepared optically pure standard sample from S (+)-Ketoprofen is initial.After drying and the analysis, the sample (1.75g) of L-threonine-S (+)-ketoprofen ester hydrochloride is separated from mixture.

Synthetic order:

Synthesizing of the L-threonine ester of (±)-Ketoprofen: a) EDC, DMAP, CH ₂Cl ₂B) HCl (2M); C) TFA; D) ACN (crystallization).

Experimental section:

SPI0018A synthetic is single batch and carries out.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Sigma-Aldrieh, Acros or Bachem, except solvent is available from FisherScientific or Mallinkrodt.

The preparation of S (+)-Ketoprofen-L-threonine ester hydrochloride (SPI0018A) with separate

(±)-Ketoprofen (5.32g, 20.92 N-tert-butyl group carbonyl-L-threonine tertiary butyl ester (Boc-Thr-OtBu mM),, 5.17g, 18.72 mM) (according to the document preparation), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 4.0g, 20.9 mM) and 4-(N, N-dimethylamino) pyridine (DMAP 0.22g) at room temperature is dissolved in carrene (50mL) in the argon atmospher.Stir after 5 hours, dichloromethane layer water (50mL), 5% hydrochloric acid solution (2 * 25mL), water (25mL), saturated sodium bicarbonate solution (2 * 25mL) and water (50mL) washing., filter and concentrating under reduced pressure after dry 1 hour through sodium sulphate (5g), go up the remaining grease of purifying (10.3g) at silica gel (150g), with hexane/ethyl acetate (2: 1) wash-out with column chromatography.After merging contained the product of each fraction, concentrated and dry under high vacuum, this step generated shielded L-threonine-(±)-ketoprofen ester (SPI001801), is a kind of limpid grease (9.42g, productive rate: 98%).

3-[2 (R, S)-(3-benzoyl phenyl) propionyloxy]-2 (S)-tert-butoxycarbonyl aminobutyric acid tertiary butyl ester: (non-enantiomer mixture)

¹H NMR(300MHz，CDCl ₃)：δ＝7.83-7.42(m，9H)，5.43(dd，1H，J＝13.2，6.9 Hz)，5.10(dd，1H，J＝20.7，9.3)，4.29(t，1H，J＝11.7Hz)，3.75(q，1H，J＝7.2Hz)，1.50-1.42(m，19.5H)，1.30-1.18(m，4.5H)。

¹³C NMR(75MHz，CDCl ₃)：δ＝196.18，172.62，172.55，168.85，168.58，155.81，140.33，140.23，137.86，137.39，132.46，132.42，131.54，131.38，130.00，129.31，129.13，129.02，128.54，128.27，82.50，82.37，80.05，71.38，71.22，57.59，57.52，45.46，45.31，28.40，27.98，27.84，18.54，18.48，17.19，16.84。

Shielded (R, S)-Ketoprofen-L-threonine ester (9.42g, 18.41 mMs) at room temperature is dissolved in carrene (25mL) in the argon atmospher.(2M, 25mL), mixture at room temperature stirred 17 hours the diethyl ether solution of adding anhydrous hydrogen chloride.Mixture under reduced pressure concentrates.Remaining foam (8.2g) is dissolved in the mixture of carrene (10mL) and trifluoroacetic acid (20mL).After at room temperature stirring 6.5 hours, solution under reduced pressure concentrates.Toluene (25mL) is added in the residue grease, and mixture concentrates once more.(2M, the 20mL) mixture of diethyl ether solution, solution concentrate for the third time to add ethanol (20mL) and anhydrous hydrogen chloride.After under room temperature and the high vacuum dry 2 hours, (±)-Ketoprofen-L-threonine ester hydrochloride (non-enantiomer mixture, 7.11g, crude product productive rate: 98%), be pale solid that this experiment generates.The crude mixture of diastereomer (7.0g) acetonitrile (200mL) crystallization 3 times.After the 3rd crystallization, remaining white solid is dry under 50 ℃ of high vacuum, up to constant weight (4 hours).This experiment generates L-threonine-S (+)-ketoprofen ester hydrochloride SPI0018A (2.2g is 30% from SPI001801 (calculating) productive rate).

2 (S)-amino-3 (R)-[2 (S)-(3-benzoyl phenyl) propionyloxy] butyrate hydrochlorate (L-threonine-S (+)-ketoprofen ester hydrochloride):

¹H NMR(300MHz，DMSO)：δ＝14.08(br s，1H)，8.72(br s，3H)，7.74-7.51(m，9H)，5.29(t，1H，J＝4.5Hz)，4.16(m，1H)，3.97(q，1H，J＝6.3Hz)，1.42(d，3H，J＝6.9Hz)，1.23(d，3H，J＝6.3Hz)。

¹³C NMR(75MHz，DMSO)：δ＝195.34，172.26，168.21，140.42，137.05，136.74，132.66，131.66，129.48，128.73，128.49，128.30，68.23，55.31，44.00，18.44，16.45。

The CHN elementary analysis:

Calculated value: C 61.30, H 5.66, and N 3.57; Measured value: C 61.02, H 5.58, N 3.58.

HPLC analyzes:

98.28% purity; R.t.=25.14min.; 55%DIUF water (0.1% trifluoroacetic acid)/45% methyl alcohol; 1mL/min; 36.4 C; Luna C18,5u post (serial# 211739-42), 4.6 * 250mm; 20ul injects.

Optical activity :+27.0 ° (20C, 174.4 mg/10mL ethanol, 589nm);

Fusing point: 166-167 ℃

The preparation of S-(+)-Ketoprofen-L-threonine ester hydrochloride reference material

(+)-Ketoprofen (1.87g, 7.74 N-tert-butyl group carbonyl-L-threonine tertiary butyl ester (Boc-Thr-OtBu mM),, 2.25g, 8.14 mM, according to literature method preparation), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC, 1.65g, 8.60 mMs) and 4-(N, the N-dimethylamino) (DMAP 0.1g) at room temperature is dissolved in carrene (25mL) in the argon atmospher to pyridine.Stir after 4 hours dichloromethane layer water (25mL) washing.Through sodium sulphate (5g) after dry 1 hour, filter and decompression concentrates down, remaining grease can be not purified and use.This step generates shielded L-threonine-(+)-ketoprofen ester, is a kind of limpid grease (4.01g, productive rate :～100%).

¹H NMR(300MHz，CDCl ₃)：δ＝7.81-7.42(m，9H)，5.43(m，1H)，5.10(d，1H，J＝9.3)，4.29(d，1H，J＝9.6Hz)，3.75(q，1H，J＝7.2Hz)，1.50-1.42(m，21H)，1.18(d，3H，J＝6.3Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝196.4，172.79，168.99，155.94，140.44，137.99，137.51，132.59，131.50，130.13，129.31，129.25，129.15，128.66，128.40，82.68，80.24，71.37，57.71，45.43，28.53，28.10，18.99，16.96。

Shielded (S)-Ketoprofen-L-threonine ester (3.92g, 7.66 mMs) at room temperature be dissolved in the argon atmospher ether that contains anhydrous hydrogen chloride (2M, 25mL) in, at room temperature stirred 17 hours.Mixture under reduced pressure concentrates.Remaining foam (3.4g) is dissolved in the mixture of carrene (20mL) and trifluoroacetic acid (20mL).After at room temperature stirring 6.5 hours, solution under reduced pressure concentrates.Toluene (25mL) adds in the residue grease, and mixture concentrates once more.Add ethanol (20mL) and contain the ether of anhydrous hydrogen chloride that (solution is concentrated through for the third time for 2M, mixture 20mL).After under room temperature and the high vacuum dry 2 hours, this experiment is generated as S (+)-Ketoprofen-L-threonine ester hydrochloride (3.05g semifinished product) of pale solid.Rough thing at room temperature stirred 2 hours with acetone (50mL) in the argon atmospher.Filter remaining white solid and dry under 50 ℃ of high vacuum, up to constant weight (4 hours).This experiment generates L-threonine-S (+)-ketoprofen ester hydrochloride (2.04g, 67% productive rate).

¹H NMR(300MHz，DMSO)：δ＝14.08(br s，1H)，8.72(br s，3H)，7.74-7.51(m，9H)，5.29(t，1H，J＝4.5Hz)，4.16(m，1H)，3.97(q，1H，J＝6.3 Hz)，1.42(d，3H，J＝6.9Hz)，1.23(d，3H，J＝6.3Hz)。

¹³C NMR(75MHz，DMSO)：δ＝195.34，172.26，168.21，140.42，137.05，136.74，132.66，131.66，129.48，128.73，128.49，128.30，68.23，55.31，44.00，18.44，16.45。

HPLC analyzes:

99.43% purity; R.t.=25.14min.; 55%DIUF water (0.1% trifluoroacetic acid)/45% methyl alcohol; 1mL/min; 36.4 C; Luna C18,5u post (serial# 211739-42), 4.6 * 250mm; 20ul injects.

Optical activity :+27.1 ° (20C, 177.8mg/10mL ethanol, 589nm);

Fusing point: 166-167 ℃

C. the amino acid derivativges of aspirin

General introduction:

The overview of steps of the salicylic L-serine ester of synthesis of acetyl, L-threonine ester and L-hydroxyproline ester is in synthesizing the order part and being other amino acid whose example.Complete step and analysis data are seen experimental section.Generally speaking, under pyridine, (10g-25g, in batches) amino acid with N-benzyloxy/benzyl ester protection reacts adjacent acetoxyl group chlorobenzoyl chloride (acetylsalicyloyl chloride).(under the room temperature 24 to 48 hours) one finished in reaction, and this mixture is poured in the ice-cold 2N hydrochloric acid.The carrene part is used sodium bicarbonate, water and salt water washing subsequently.After dried over sodium sulfate, filter, concentrate and obtain rough shielded acetylsalicylic acid amino-acid ester, by flash chromatography method purifying on silica gel.This step generates shielded acetylsalicylic acid amino-acid ester productive rate scope from 68% to 95%.In the presence of 10% palladium-carbon catalyst, by hydrogenization (20psi H ₂) slough blocking group.Water extracts the acetylsalicylic acid amino-acid ester, concentrates and drying from palladium catalyst.Final compound is washed up to purifying with solvent (water, dioxane, acetonitrile and/or carrene), and dry up to reaching constant weight under high vacuum.Synthetic order:

1.SPIB00102

2.SPIB00101

3.SPIB00103

Synthesizing of acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester: a) pyridine, CH ₂C1 ₂B) 10%Pd/C, EtOH, EtOAc.

Experimental section:

SPIB00101, SPIB00102 and SPIB00103 synthetic with a collection of or two batches carry out.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Lancaster, Sigma-Aldrich, Acros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.

1) the SPIB00102:2-O-acetylsalicylic acid-(2S, 3R)-(-)-the threonine ester

In blanket of nitrogen, N-benzyloxycarbonyl group-L-threonine benzyl ester (Z-Thr-OBzl, 21.77g, 63.40 mMs) and the mixture that contains the anhydrous methylene chloride (500mL) of pyridine (25mL) cool off in ice bath.Add adjacent acetoxyl group chlorobenzoyl chloride (17.63g, 88.76 mMs), mixture is warming up to room temperature and stirs and spend the night.After 24 hours, mixture is poured in the ice-cold 2N hydrochloric acid (400mL).Mix each layer of back and separate, carrene part water (500mL), saturated sodium bicarbonate solution (500mL), water (500mL), salt solution (500mL) washing, and through sodium sulphate (25g) drying.After the filtration, concentrating under reduced pressure, and dry under high vacuum, remaining yellow oil (35.43g) goes up purifying with the flash chromatography method at silica gel (300g, 0.035-0.070mm, 6nm aperture), with hexane/ethyl acetate (3: 1) wash-out.The product that contains cut under reduced pressure concentrates, and is dried to constant weight under the high vacuum, shielded acetylsalicylic acid-L-threonine ester SPIB0010201 (28.1g, productive rate: 88%), be colorless oil that this experiment generates.

¹H NMR(300MHz，CDCl ₃)：δ＝7.74(1H，d，J＝7.5Hz)，7.51(1H，dt，J＝7.5，1.5Hz)，7.34-7.17(11H，m)，7.06(1H，d，J＝7.2Hz)，5.62(2H，m)，5.13(4H，m)，4.65(1H，dd，J＝9.6，2.4Hz)，2.29(3H，s)，1.38(3H，d，J＝6.6Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝169.35，169.22，162.73，156.26，150.41，135.79，134.67，133.77，131.24，128.35，128.24，128.08，127.95，125.78，123.51，122.61，71.22，67.72，67.26，57.64，20.98，16.88。

Shielded acetylsalicylic acid-L-threonine ester SPIB0010201 (14.50g; 28.68 mM) at room temperature be dissolved in ethanol (100mL) and the ethyl acetate (100mL); and in blanket of nitrogen, be added in the Parr bottle that contains 10% crust C catalyst (3.0g, 50% is wet).Replace blanket of nitrogen with hydrogen (20psi).Vibrate after 20 hours, remove palladium catalyst with diatomite filtration.(600 * 4mL) washings are up to removing product for remaining solid (palladium/diatomite and product) water.Ethanol and water section be concentrating under reduced pressure at room temperature.Remaining solid water (20mL) and dioxane (20mL) washing 48 hours.After the filtration, remaining white solid is in room temperature and dry under high vacuum, until product constant weight (16 hours).Acetylsalicylic acid-L-threonine ester SPIB00102 (4.40g, 55% productive rate) that this experiment generates is white solid.

¹H NMR(300MHz，D ₂O-DCl)：δ＝8.00(1H，dd，J＝7.8，1.5Hz)，7.74(1H，dt，J＝7.8，1.5Hz)，7.47(1H，dt，J＝7.8，1.5Hz)，7.27(1H，dd，J＝7.8，1.5Hz)，5.76(1H，dq，J＝6.9，3.0Hz)，4.49(1H，d，J＝3.0Hz)，2.39(3H，s)，1.55(3H，d，J＝6.9Hz)。

¹³C NMR(75MHz，D ₂O-DCl)：δ＝173.03，168.84，163.97，149.56，135.32，131.26，126.85，123.48，121.49，69.16，56.36，20.45，15.86。

HPLC analyzes:

98.7% purity; Rt=6.233min; Luna C18 5u post (sn 167917-13); 4.6 * 250mm; 254nm; 35% methyl alcohol/65% trifluoroacetic acid (0.1%) pH=1.95; 35 C; 20ul injects; 1ml/min; Sample is dissolved in the flowing phase with 1 phosphoric acid.

The CHN elementary analysis:

Calculated value: C 55.51, H 5.38, and N 4.98; Measured value: C 55.37, H 5.40, N 5.03.

Fusing point: 153.5 ℃ (decomposition)

2) SPIB00101:2-O-acetylsalicylic acid-(2S)-(+)-serine ester

In blanket of nitrogen, N-benzyloxycarbonyl group-L-serine benzyl ester (Z-Ser-OBzl, 23.17g, 70.34 mMs) and the mixture that contains anhydrous methylene chloride (500mL) solution of pyridine (30mL) cool off in ice bath.Add adjacent acetoxyl group chlorobenzoyl chloride (21.07g, 106.1 mMs), mixture is warming up to room temperature and stirs more than two days.After 48 hours, mixture is poured in the ice-cold 2N hydrochloric acid (400mL).Mix each layer of back and separate, carrene part water (500mL), saturated sodium bicarbonate solution (500mL), water (500mL), salt solution (500mL) washing, and through sodium sulphate (25g) drying.Filter and concentrating under reduced pressure, after the drying, remaining brown oil (47.19g) goes up purifying with the flash chromatography method at silica gel (200g, 0.035-0.070mm, 6nm aperture), with hexane/ethyl acetate (3: 1) wash-out under high vacuum.The product that contains cut under reduced pressure concentrates, drying is until constant weight under high vacuum, and it is white solid that this experiment generates shielded acetylsalicylic acid-L-serine ester SPIB0010101 (32.97g, 95% productive rate).

¹H NMR(300MHz，CDCl ₃)：δ＝7.74(1H，d，J＝7.8Hz)，7.55(1H，dt，J＝7.8，1.5Hz)，7.33-7.21(11H，m)，7.08(1H，d，J＝7.5Hz)，5.68(1H，d，J＝8.4Hz)，5.20(2H，s)，5.12(2H，s)，4.77(1H，m)，4.66(1H，dd，J＝11.4，3.3Hz)，4.57(1H，dd，J＝11.4，3.3Hz)，2.30(3H，s)。

¹³C NMR(75MHz，CDCl ₃)：δ＝169.45，169.09，163.68，163.35，155.57，150.77，135.87，134.75，134.07，131.44，128.50，128.43，128.27，128.14，128.04，125.92，123.71，122.18，67.83，67.27，64.63，53.55，21.03。

Shielded acetylsalicylic acid-L-serine ester SPIB0010101 (21.0g; 42.7 mM) at room temperature be dissolved in ethanol (100mL) and ethyl acetate (100mL); and in blanket of nitrogen, join in the Parr bottle that contains 10% palladium-carbon catalyst (4.20g, 50% is wet).Replace blanket of nitrogen with hydrogen (20psi).Add 10% palladium catalyst (4.26 g) after 5 hours again and recover hydrogen-pressure (20psi).After at room temperature vibrating 20 hours, remove palladium catalyst with diatomite filtration.(1500 * 2mL) washings are removed up to product remaining solid (palladium/diatomite and product) water.Ethanol and water section be concentrating under reduced pressure at room temperature.Remaining solid (7.17g) is dissolved in the DIUF water (4.3L),, and concentrates in room temperature with under high vacuum removing insoluble matter with diatomite filtration.Use 1 subsequently, 4-dioxane (100mL) and DIUF water (50mL) washing white solid also spend the night.Cross filter solid and dry under high vacuum after 24 hours, up to product constant weight (24 hours).Acetylsalicylic acid-L-serine ester SPIB00101 (6.17g, 54% productive rate) that this experiment generates is a white solid.

¹H NMR(300MHz，D ₂O-DCl)：δ＝8.05(1H，dd，J＝7.8，1.5Hz)，7.75(1H，dt，J＝7.8，1.5Hz)，7.47(1H，dt，J＝7.8，0.9Hz)，7.27(1H，dd，J＝7.8，0.9Hz)，4.87(1H，dd，J＝12.6，4.2Hz)，4.79(1H，dd，J＝12.6，3.0Hz)，4.62(1H，dd，J＝4.2，3.0Hz)，2.39(3H，s)。

¹³C NMR(75MHz，D ₂O-DCl)：δ＝173.01，168.58，164.54，149.72，135.39，131.59，126.87，123.62，121.15，62.38，52.05，20.44。

HPLC analyzes:

98.1% purity; R.t.=5.839min.; 65% trifluoroacetic acid (0.1%)/35% methyl alcohol; 1mL/min; 35 C; Luna C18,3u post (SN 184225-37), 4.6 * 250mm; 22ul injects; DAD1B, Sig=240,4 Ref=550,100.

The CHN elementary analysis:

Calculated value: C 53.93, H 4.90, and N 5.24; Measured value: C 54.02, H 5.00, and N 5.23.

Fusing point: 147.0 ℃ (decomposition)

3) the SPIB00103:2-O-acetylsalicylic acid (2S, 4R)-the 4-Hydroxyproline ester

In blanket of nitrogen, N-benzyloxycarbonyl group-L-hydroxyproline benzyl ester (Z-Ser-OBzl, 21.5g, 60.5 mMs) 1 cools off in ice bath with the mixture that contains the anhydrous methylene chloride solution (500mL) of pyridine (25mL).Add adjacent acetoxyl group chlorobenzoyl chloride (13.2g, 66.6 mMs), mixture is warming up to room temperature and stirs and spend the night.After 24 hours, add adjacent acetoxyl group chlorobenzoyl chloride (5.0g, 25.2 mMs) again, mixture stirs and spends the night.After 48 hours, mixture is poured in the ice-cold 1N hydrochloric acid (500mL).Mix each layer of back and separate, carrene part water (500mL), saturated sodium bicarbonate solution (500mL), water (500mL), salt solution (500mL) washing, and through sodium sulphate (25g) drying.Filter the back concentrating under reduced pressure, and through high vacuum dry, remaining yellow oil (40.7g) goes up purifying with the flash chromatography method at silica gel (460g, 0.035-0.070mm, 6nm aperture), with heptane/ethyl acetate (3: 1) wash-out.The product that contains cut under reduced pressure concentrates, drying is up to constant weight under high vacuum, and it is colorless oil that this experiment generates shielded acetylsalicylic acid-L-hydroxyproline ester SPIB0010301 (21.31g, 68% productive rate).

¹H NMR(300MHz，CDCl ₃)：δ＝7.92(1H，d，J＝7.8Hz)，7.56(1H，t，J＝7.8Hz)，7.34-7.21(10H，m)，7.09(1H，d，J＝7.8Hz)，5.48(1H，s)，5.21(2H，m)，5.03(2H，d，J＝15Hz)，4.57(1H，m)，3.85(2H，m)，2.53(1H，m)，2.28(4H，m)。

¹³C NMR(75 MHz，CDCl ₃)：δ＝171.72，171.49，169.25，163.47，163.30，154.52，153.93，150.54，136.05，135.94，135.21，135.00，134.17，134.12，128.43，128.32，128.28，128.20，128.05，127.98，127.94，127.79，125.89，123.70，122.46，122.38，73.24，72.59，67.33，67.11，66.97，58.02，57.69，52.47，52.15，36.74，35.65，20.90。

Shielded acetylsalicylic acid-L-hydroxyproline ester SPIB0010301 (10.6g; 20.5 mM) at room temperature be dissolved in ethanol (75mL) and ethyl acetate (75mL); and in blanket of nitrogen, be added in the Parr bottle that contains 10% palladium-carbon catalyst (3.0g, 50% is wet).Replace blanket of nitrogen with hydrogen (20psi).After at room temperature vibrating 17 hours, reactant mixture water (500mL) washing 2 hours.Remove organic layer (top), water layer diatomite filtration with pipette.The water layer part is concentrating under reduced pressure at room temperature.Remaining solid (6.71g) is used anhydrous methylene chloride (35mL) to wash subsequently and is spent the night.Cross filter solid and dry under high vacuum after 24 hours, up to product constant weight (24 hours).Acetylsalicylic acid-L-hydroxyproline ester that this experiment generates, SPIB00301 (2.87g, 47.7% productive rate) is white solid.

¹H NMR(300MHz，D ₂O-DCl)：δ＝8.09(1H，d，J＝7.5Hz)，7.75(1H，t，J＝7.5Hz)，7.48(1H，t，J＝7.5Hz)，7.28(1H，d，J＝7.5Hz)，5.69(1H，m)，4.76(1H，t，J＝7.5Hz)，3.86(1H，dd，J＝13.5，3.9Hz)，3.74(1H，d，J＝13.5Hz)，2.81(1H，dd，J＝15.0，7.5Hz)，2.60(1H，m)，2.40(3H，s)。

¹³C NMR(75 MHz，D ₂O-DCl)：δ＝173.13，170.25，164.31，149.65，135.36，131.54，126.87，123.54，121.37，73.86，58.34，50.95，34.38，20.48。

HPLC analyzes:

98.3% purity; R.t.=7.201min.; 65% trifluoroacetic acid (0.1%)/35% methyl alcohol; 1mL/min; 35C; Luna C18,3u post (SN 184225-37), 4.6 * 250mm; 22ul injects; DAD1B, Sig=240,4 Ref=550,100.

The CHN elementary analysis:

Calculated value: C 57.34, H 5.16, and N 4.78; Measured value: C 57.09, H 5.23, and N 4.91.

Fusing point: 162 ℃ (decomposition)

Compare the gastric stimulation potential of acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester with acetylsalicylic acid

Carry out this research and in the male albinism mouse of fasting, cause the relative potential of gastric stimulation/damage with the novel formulation (acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester) of estimating aspirin.Aspirin contrast as a reference.

The different novel formulation of aspirin and aspirin by to the male albinism mouse (Wistar strain system) of fasting with the gavage administration, use and contain the phosphate buffered solution (pH 2.6) of 0.5% (w/v) carboxymethyl cellulose (CMC) as excipient.This research is carried out with two kinds of dosage levels, i.e. 100mg and 200mg/kg body weight and an excipient control group.Use 5 animals at each dosage level.All dosage are all represented with the molar equivalent of aspirin.The dosage and the molar equivalent that use are as follows.

Table 11: preparation: molar equivalent

Preparation	Molar equivalent
		Acetysalicylic L-serine ester	1.483 unit is equivalent to 1 unit aspirin
Acetysalicylic L-hydroxyproline ester	1.628 unit is equivalent to 1 unit aspirin
		Acetysalicylic L-threonine ester	1.561 unit is equivalent to 1 unit aspirin

Table 12: detection: group: dosage (mg/kg) [according to acetylsalicylic acid]: the weight of equal value [mg] of detection

Detection	Group	Dosage (mg/kg) [according to acetylsalicylic acid]	The weight of equal value [mg] of detection
				The excipient contrast	The excipient control group	0.0	--
Acetysalicylic L-serine ester	Experimental group 1	100.0	148.3
				Experimental group 2	200.0	296.6
	Acetysalicylic L-hydroxyproline ester	Experimental group 1	100.0				162.8
Experimental group 2				200.0	325.6
		Acetysalicylic L-threonine ester	Experimental group 1			100.0	156.1
Experimental group 2	200.0			312.2
			Acetylsalicylic acid with reference to contrast		Experimental group 1	100.0	100.0
Experimental group 2	200.0	200.0

Described mouse before administration during 18 to 22 hours in by fasting.Detection as single dose by raising the mode administration by force.After the administration 3 hours, animal is with CO ₂The gas inhalation is caused death by humanity.Stomach is dissected, observes:

^*The amount of mucus diffusate

^*The degree of coat of the stomach hyperemia and thickening

^*Blutpunkte (part or disperse), hemorrhage character (petechia or ecchymosis) and size and

^*Perforation

Observation to each treated animal gastric stimulation is summarized as follows

Table 13: detection: group: dosage (mg/kg) [according to acetylsalicylic acid]: observe:

Detection	Group	Dosage (mg/kg) [according to acetylsalicylic acid]	Observe
				The excipient contrast	The excipient control group	0.0	No animal shows the sign of any gastric stimulation
Acetysalicylic L-serine ester	Experimental group 1	100.0	There is not the sign that the animal of taking medicine shows any gastric stimulation
				Experimental group 2	200.0	There is not the sign that the animal of taking medicine shows any gastric stimulation
	Acetysalicylic L-hydroxyproline ester	Experimental group 1	100.0				The useless animal of taking medicine shows the sign of any gastric stimulation
Experimental group 2				200.0	There is not the sign that the animal of taking medicine shows any gastric stimulation
		Acetysalicylic L-threonine ester	Experimental group 1			100.0	There is not the sign that the animal of taking medicine shows any gastric stimulation
Experimental group 2	200.0			The useless animal of taking medicine shows the sign of any gastric stimulation
			With reference to contrast (acetylsalicylic acid)		Experimental group 1	100.0	There is not the sign that the animal of taking medicine shows any gastric stimulation
Experimental group 2	200.0	All observe gastric stimulation for 5 animals of clothes

In a word, observe acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester at two kinds of dosage levels being tested promptly: 100mg and 200mg/kg body weight are not induced the gastric stimulation of any sign.Opposite aspirin (acetylsalicylic acid) all causes gastric stimulation at the dosage level of 200mg/kg to the male albinism mouse of all fasting.Yet, aspirin at the dosage level of 100mg/kg to male mouse without any the sign that causes gastric stimulation.

And at whole 3 hours viewing duration, the animal of all different tests groups does not all show the clinical symptoms of any toxicity.

With acetylsalicylic acid relatively, acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester administration after 1 hour to the measures of effectiveness in mouse clotting time

Observe the clotting time

In the evaluation in back 1 hour of taking medicine, contrast of various different preparations, excipient and positive controls low, in and the data representation following (table 14) in average clotting time (MCT) of high dose group animal:

Table 14: the average clotting time (± S.D.) with the number of minutes summary-acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester and aspirin (positive control): low dosage: middle dosage: high dose

	Low dosage	Middle dosage	High dose
				The excipient contrast	4.9±1.10
Acetysalicylic L-serine ester	5.7±1.34	6.8±1.48	6.9±1.37
				Acetysalicylic L-hydroxyproline ester	6.1±1.10	5.7±0.82	7.5±1.18
Acetysalicylic L-threonine ester	5.2±1.14	5.6±0.84	7.4±0.97
				Positive control (acetylsalicylic acid)	6.2±1.40	8.1±1.97	9.8±1.32

Fig. 3-6 expression gives aspirin L-ester class series and animals of control group about the every class mean certificate of the number of minutes in clotting time of dose relationship+on average.

Statistical analysis shows, with the excipient control group relatively, the usefulness of high dose and middle dosage on 5% significance level, be significantly increased (Fig. 7).

Fig. 4 represents the class mean certificate of animal.It provides about the L-hydroxyproline ester of aspirin and the dose response relation of average clotting time (MCT) the number of minutes.The statistical analysis of Fig. 4 shows, compares with excipient control group (Fig. 6), and for high dose and low dosage, usefulness is significantly increased on 5% significance level.

Fig. 5 represents about the dose response relation of acetysalicylic L-threonine ester with average clotting time (MCT) the number of minutes.Statistical analysis shows, compares with the excipient control group, and for high dose group, usefulness is significantly increased on 5% significance level.

Fig. 6 represents about the dose response relation of acetylsalicylic acid with average clotting time (MCT) the number of minutes.Statistical analysis shows, with the excipient control group relatively, for high dose and middle dosage, usefulness 5% significance level on be significantly increased.The response of this dosage and usefulness is remarkable and clear significantly (Fig. 7) on the statistics.

Conclusion

This research uses the clotting time of albinism mouse as an index, estimates the usefulness of aspirin novel formulation.Aspirin is as positive control.This research is carried out on 3 dosage levels of novel formulation and a positive controls and an excipient control group.

Dosage

The dosage that is used for most of research selects to be based on acetysalicylic dosage range development test.All dosage are all represented with the aspirin molar equivalent.The dosage that is used for the major part experiment of different preparations and positive control is identical, and is expressed as follows.

Table 15: detection: low dosage (mg/kg): middle dosage (mg/kg): high dose (mg/kg)

Detection	Low dosage (mg/kg)	Middle dosage (mg/kg)	High dose (mg/kg)
				Acetysalicylic L-serine ester	1.0	4.0	10.0
Acetysalicylic L-hydroxyproline ester	1.0	4.0	10.0
				Acetysalicylic L-threonine ester	1.0	4.0	10.0
Aspirin (positive control)	1.0	4.0	10.0

Usefulness (clotting time)

Different preparations and acetysalicylic various dosage level--low, in and high dose be expressed as follows in corresponding usefulness aspect the required clotting time.

Table 16: low dosage: middle dosage: high dose

	Low dosage	Middle dosage	High dose
				The excipient contrast	4.9±1.10
Acetysalicylic L-serine ester	5.7±1.34	6.8±1.48	6.9±1.37
				Acetysalicylic L-hydroxyproline ester	6.1±1.10	5.7±0.82	7.5±1.18
Acetysalicylic L-threonine ester	5.2±1.14	5.6±0.84	7.4±0.97
				Positive control	6.2±1.40	8.1±1.97	9.8±1.32

Aspect the clotting time that acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester were observed after 1 hour, the same with acetylsalicylic acid remarkable, but to avoiding the gastric irritation aspect all to be far superior to acetylsalicylic acid at all dosage levels.

With acetylsalicylic acid relatively, acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester administration after 2 hours to the usefulness in mouse clotting time

Carry out this research to use the albinism clotting time of mouse after administration 2 hours (± 10 minutes), compare, estimate the usefulness of acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester with acetylsalicylic acid as an index.Aspirin is as positive control.Male albinism mouse is used aspirin and its 3 kinds of novel formulation with the dosage level of 20mg/kg body weight.Do not use the excipient control group.Dosage is represented with the molar equivalent of aspirin.Be used for shown in the dosage of the different preparations of most of experiment and positive control as follows.

Table 17: detection: acetysalicylic dosage (mg/kg)

Detection	According to acetysalicylic dosage (mg/kg)
		Acetysalicylic L-serine ester	20.0
Acetysalicylic L-hydroxyproline ester	20.0
		Acetysalicylic L-threonine ester	20.0
Aspirin (positive control)	20.0

Usefulness (clotting time)

Different preparations and aspirin (positive control) are at 20mg/kg body weight dosage level, and be as follows shown in the corresponding usefulness in required clotting time aspect.

The observed value in clotting time

Estimate animal at 20mg/kg body weight dosage level, after the administration 2 hours (± 10 minutes), different preparations, excipient contrast and the data representation in average clotting time of positive control (MCT) are as follows.

Table 18: acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester and acetylsalicylic acid (positive control) relatively, the (± S.D.) summary of the number of minutes of average clotting time

	Dosage (20mg/kg)
		Acetysalicylic L-serine ester	3.8±0.92
Acetysalicylic L-hydroxyproline ester	4.2±1.32
		Acetysalicylic L-threonine ester	5.3±1.06
Positive control (acetylsalicylic acid)	5.4±1.17

Find that acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester are effective to the clotting time.

In a word, observe, when estimating in 2 hours after administration, based on the needed time of blood coagulation (clotting time), L-threonine derivatives of high therapeutic index is effective.Yet, find that acetysalicylic L-threonine ester has better usefulness than other two kinds of preparations.

As shown in Figure 7, statistical analysis shows, acetysalicylic L-threonine ester is the same with acetylsalicylic acid with L-hydroxyproline ester effective, to the observed average clotting time after two hours, acetysalicylic L-hydroxyproline ester and L-threonine ester do not have significant difference with respect to positive control in 5% significance level.Yet in conjunction with potential stomach irritation, acetysalicylic L-serine ester, L-threonine ester and L-hydroxyproline ester are far superior to positive controls.

According to disclosed method, there are many screening tests to determine the purposes of the prodrug of manufacturing.These comprise the screening technique in external and the body.

External method comprises acid/basic hydrolysis, the hydrolysis in pig pancreas, the hydrolysis in mouse intestinal juice, the hydrolysis in human gastric juice, the hydrolysis in human intestinal juice and the hydrolysis in human plasma of prodrug.These determination methods are described in document (Simmons, DM, Chandran, VR and Portmann, GA, Danazol Amino Acid Prodrugs:In Vitro and In Situ BiopharmaceuticalEvaluation, Drug Development and Industrial Pharmacy, Vol 21, Issue 6, Page687,1995) in, its all the elements are incorporated by reference.

Compound of the present invention is effective to the disease or the illness of common use NSAIDs treatment.Prodrug disclosed herein transforms in vivo with release of active compounds, and by alleviating or eliminate biopharmacy and the pharmacokinetics barrier of following every kind of NSAIDs, and help treatment.Yet, it should be noted that these prodrugs itself have enough activity, even in mammalian body, do not discharge any active medicine.Because these prodrugs are more solvable in water than brufen or other NSAIDs, it does not need to have with vehicle excipients and links to each other, and such as alcohol or castor-oil plant wet goods, may be poisonous or produces unwanted side effect.And the oral formulations that contains the NSAID prodrug is absorbed into blood and quite effective.

Like this, prodrug of the present invention has the biopharmacy and the pharmacokinetics barrier of medicine now by elimination, and helps treatment.

And, by using the commercially available reagent that is easy to get, can the easily synthetic prodrug of the present invention of high yield.

IV. the proline derivative of paracetamol (paracetamol)

General introduction:

The overview of steps of the L-proline ester of synthetic paracetamol is in synthetic order part.This is synthetic to be example.Complete step and analysis data are seen experimental section.When having the DMAP of catalytic amount, paracetamol (10g) and Boc-L-proline and EDC reaction.(following 3 hours of room temperature) finished in reaction one, just washes solution with water.After dried over sodium sulfate, filter, concentrate rough shielded paracetamol amino-acid ester and by flash chromatography method purifying on silica gel.It is 72% that this step generates shielded paracetamol L-proline ester productive rate.Ester is dissolved in the carrene, and at room temperature hydrogen chloride is fed solution and sloughs blocking group.After filtration, final salt stirs up to purifying in oxolane.Under 90 ℃ and high vacuum, filter and after dry 4 hours, the productive rate of deprotection steps is 91.4%.

Synthetic order:

The L-proline ester of synthetic paracetamol: a) EDC, DMAP, CH ₂Cl ₂B) HCl (g), CH ₂Cl ₂.

Experimental section:

The synthetic of SPI0014 carries out in batches with one.The reagent of mentioning in the experimental section is the highest purity that gets, and it is available from Lancaster, Sigma-Aldrich or Acros, except solvent is available from FisherScientific or Mallinkrodt.

SPI0014: pyrrolidines-2 (S)-carboxylic acid-4-acetylamino phenyl ester hydrochloride

In argon atmospher, Boc-L-proline (14.39g, 68.80 mMs), paracetamol (10.02g, 66.28 EDC (12.9g mM),, 67.29 mM) and DMAP (1.10g, 9.0 mMs) in anhydrous methylene chloride (100mL), mix, at room temperature stirred 3 hours.After 3 hours, add entry (120mL).Mix after 5 minutes, each layer separates, carrene part water (120mL) washing and through sodium sulphate (5g) drying.Filter and concentrating under reduced pressure, after the drying, remaining grease (24.10g) is gone up purifying with the flash chromatography method at silica gel (100g, 0.035-0.070mm, 6nm aperture), in order to hexane/ethyl acetate (1: 2) wash-out under high vacuum.The product that contains each cut under reduced pressure concentrates, drying is until constant weight under high vacuum, and it is white solid (foam-like) that this experiment generates shielded paracetamol-L-proline ester SPI001401 (16.71g, 72.3% productive rate).

¹H NMR(300MHz，CDCl ₃)：δ＝8.83(1/2H，s)，8.70(1/2H，s)，7.58(1/2H，d，J＝7.5Hz)，7.46(1/2H，d，J＝7.5Hz)，6.96(2H，m)，4.47(1H，m)，3.59-3.45(2H，m)，2.36(1H，m)，2.17-1.90(6H，m)，1.46(9H，m)。

¹³C NMR(75MHz，CDCl ₃)：δ＝171.91，171.75，169.02，154.44，153.78，146.36，146.21，121.44，121.23，120.82，80.41，80.17，59.16，46.78，46.55，31.06，30.11，28.50，24.57，24.28，23.78。

Shielded paracetamol-L-proline ester SPI001401 (16.60g, 47.64 mMs) at room temperature is dissolved in carrene (400mL), and feeds hydrogen chloride gas 2 hours in solution.With remaining solid precipitation (1 hour).Carefully carrene is poured out from white depositions.Add oxolane (200mL) to sediment, mixture stirred 2 hours under argon atmospher.After the filtration, remaining white solid is dry under 90 ℃ and high vacuum, up to product constant weight (4 hours).This experiment generates the paracetamol-L-proline ester hydrochloride SPI0014 (12.4g, 91.4% productive rate) as white solid.

¹H NMR(300MHz，CDCL ₃-DMSO)：δ＝10.41(1H，br s)，10.26(1H，s)，9.55(1H，br s)，7.70(2H，d，J＝9Hz)，7.12(2H，d，J＝9Hz)，4.66(t，1H，J＝8.4Hz)，3.33(2H，m)，2.43(1H，m)，2.28(1H，m)，2.08(s，3H)，2.04(2H，m)。

¹³C NMR(75 MHz，CDCL ₃-DMSO)：δ＝168.08，167.25，144.55，137.40，121.12，119.64，58.53，45.33，27.74，23.86，23.08。

HPLC analyzes:

99.45% purity; Rt=5.733min; Luna C18 5u post (sn 167917-13); 4.6 * 250mm; 254nm; The own sulfonate buffer solution of 15%MeOH/85% (110 mMs, pH=6); 35 C; 20ul injects; 1ml/min; The 5mg/mL sample size.

The CHN elementary analysis:

Calculated value: C 54.84, H 6.02, and N 9.84; Measured value: C 54.66, H 5.98, and N 9.65.

Fusing point: 221-222 ℃

V. the amino acid derivativges of Ciclosporin A

That big ring immunodepressant comprises is unique on the class formation, ring-type, polymerization, the methylated undecapeptide of N-(undecaptide), with similar semisynthetic macrolide structure, have usually pharmacological, especially suppress immunity, anti-inflammatory and/or antiparasitic activity.First kind of isolated cyclosporin is naturally occurring fungus metabolite cyclosporine or the cyclosporin that is also referred to as Ciclosporin A, and it has following formula:

Wherein MeBmt represents the Threonyl residue of the N-methyl of this formula-(4R)-4-fourth-2E-alkene-1-base-4-methyl-(L)

Wherein-x-y-is CH=CH-(trans).Similarly other product comprises, sirolimus (b), and tacrolimus (c), and Elidel (d), it has following structure:

Therefore this classification of being made up of various cyclosporins is very huge really at present, and it comprises, for example, and [Thr] ²-, [Val] ²-, [Nva] ²-and [Nva] ²-[Nva] ⁵-cyclosporine (also being called as cyclosporin C, D, G and M respectively), [dihydro-MeBmt] ¹-[Val] ²-cyclosporin (being also referred to as dihydro cyclosporin D), [(D) Ser] ⁸-cyclosporine, [MeIle] ¹¹-cyclosporine, [(D) MeVal] ¹¹-cyclosporine (being also referred to as cyclosporin H), [MeAla] ⁶-cyclosporine, [(D) Pro] ³-cyclosporine or the like.

According to the conventional nomenclature to various cyclosporins, the structure of reference rings p0-357 (that is Ciclosporin A) defines the various cyclosporins in whole specification of the present invention and the claim.The amino acid residue of at first pointing out to exist that is different from existing ion cyclosporine (as, " [(D) Pro] ³" be meant the cyclosporin of being discussed have in the 3-site-(D) Pro-rather than-the Sar-residue), then with the term cyclosporin describe with Ciclosporin A in the identical residue residue that exists.

As used herein, term " cyclosporin " is meant all kinds of cyclosporin, wherein the x-y in the MeBmt residue has cis or trans CH=CH, perhaps x-y wherein is also included within those derivatives, and the one or more amino acid in the described derivative on the 2-11 site of Ciclosporin A are by different amino acid replacements.Yet preferably no more than two amino acid in the Ciclosporin A general formula are replaced, and a more preferably no more than described amino acid is by amino acid replacement.

In addition, amino acid residue for example is meant, be abbreviated as-Ala-,-MeVal-and-α Abu-, according to conventional convention, amino acid is interpreted as to have (L)-configuration, except as otherwise noted, as " (D) Ala-".Have before the residue abbreviation " Me " as " MeLeu-", represent the residue of alpha-n-methylation.In the art, the independent residue of cyclosporin molecule is deasil numbered, from the site 1-MeBmt-, dihydro-MeBmt-residue etc.Adopt same numerical order in specification of the present invention and the claim in the whole text.

Because its unique medicine potentiality are encircled immunodepressant greatly and have been attracted suitable attention in the report.Term " encircles immunodepressant greatly " and comprises various natural and semisynthetic derivative and other macrolides such as sirolimus, tacrolimus and the Elidel of cyclosporin.To the main field of said medicine clinical research is application as immunodepressant, especially relate to its application on the organ transplant recipient, as, the transplanting of heart, lung, the heart-lung combination, liver, kidney, pancreas, marrow, skin and cornea, especially allochthonous organ transplant.These medicines also are used for the treatment of psoriasis, atompic dermatitis, rheumatoid arthritis and nephritic syndrome.

Big ring immunodepressant is also effective for various autoimmune diseases of treatment and inflammatory symptom, especially the inflammation disease that comprises the autoimmunity part that has the cause of disease, such as arthritis (for example, rheumatoid arthritis, joint CCD (arthritis chronica progredient) and dysarthrasis deformons) and rheumatic disease.The specific autoimmune disease that has proposed or used cyclosporin treatment comprises, the autoimmunity hematologic effects (comprises, for example: hemolytic anemia, alpastic anemia, PRCA, with spontaneous thrombopenia), systemic loupus erythematosus, polychondritis, chorionitis (sclerodoma), Wegener granulation disease (Wegener granulamatosis), dermatomyositis, CAH, myasthenia gravis, psoriasis, steven-Johnson syndrome (Steven-Johnsonsyndrome), eating property of spontaneity diarrhoea, autoimmunity inflammatory bowel disease (for example comprising ulcerative colitis and Crohn disease (Crohn ' s disease)), the opthalmopathy Graves Ge Ruifuzishi illness in eye of incretion becomes, sarcoidosis, multiple sclerosis, former biliary cirrhosis, juvenile diabetes (type i diabetes), uveitis (uvetis) (front and rear), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis (interstial lung fibrosis), arthritic psoriasis, atopic dermatitis and glomerulonephritis (have or do not have nephrotic syndrome, as, comprise idiopathic nephritis syndrome or MCN).

In addition, encircling immunodepressant greatly also has as antiparasitic applicability, especially as antiprotozoan agent, and is suggested and can effectively treats malaria, ball sporozoite bacterium disease (coccidiomycosis) and schistosomiasis (schistosomiasis).Recently, also advocate they medicaments as counter-rotating or cancellation antitumor agent resistance contumors etc.

Made very important contribution although encircle immunodepressant greatly, but provide more effective and easily medication (as, galenic (galenic) system type, for example, peroral dosage form, it was both convenient, can provide suitable bioavilability to the patient again, and allow in suitable and controllable medicine-feeding rate administration) time run into difficulty, and report has the side effect of not expecting to take place; Especially the renal toxicity reaction has obviously become serious obstruction more widely-used to it or that use.

And above-mentioned big ring immunodepressant feature is highly hydrophobic and exists even also be easy to precipitation during very in a small amount water, for example enter in the body (as, gastric juice) time.Therefore especially difficulty provide such as on form and the taste concerning patient acceptable oral preparation and stable during in storage, administration clocklike so that suitable and controllable dosage to be provided to the patient.

The liquid preparation of proposing for example, is used for oral big ring immunodepressant, so far mainly based on using ethanol and oils or similar excipient as mounting medium.Like this, the big ring immunodepressant drinkable solutions of selling on the market has adopted ethanol and olive oil or corn oil as mounting medium, and comprises that together with solvent system the excipient of for example ethanol and LABRIFIL and equivalence is as mounting medium.Like this, the big ring immunodepressant drinkable solutions of selling on the market has adopted ethanol and olive oil or corn oil as mounting medium, and with Labrifil as surfactant (seeing U.S. Patent number 4,388,307).Yet drinkable solutions of proposing in use this area and analogous composition are but with many difficulties.

In addition, the palatability of known oil base system has been proved to be problematic.Especially, the taste of the known drinkable solutions of multiple medicine is offending.The mixture that mixes mutually with a kind of suitably flavored drink has adopted so that conventional therapy can be accepted, and described drink added pharmaceutical preparation, for example chocolate beverage preparation with high dilution before being ingested.Adopt the oil base system also to need to use high concentration of alcohol,, especially can predict when the time to children's administration to such an extent as to itself just is out of favour inherently.In addition, the volatilization of ethanol as (adopting to solve the problem or the other problem (for example, when opening) of palatability as discussed in a large number), will cause encircling greatly the generation of immunodepressant precipitation from capsule.When this composition exists with the form of for example soft gelatin microcapsule agent, produce a series of other problems.This specific difficulty forces this microcapsules product to be encapsulated into necessity in airtight element, for example, and airtight bubble-cap (blister) or the encapsulation of aluminium foil bubble-cap.Cause product heavy more expensive with production.In addition, the storage properties of aforementioned articles is very unfavorable.

The bioavilability level that adopts existing oral big ring immunodepressant delivery system to reach also is low, and between individuality, between different patient's type, even single individuality different time in therapeutic process all shows very big otherness.Bibliographical information shows, adopt the existing therapeutic scheme of the big ring immunodepressant drinkable solutions of selling in the market, the average absolute bioavilability that obtains has only about 30%, and between each group, significant difference is arranged, as transplanting between the recipient liver (low relatively bioavilability) and marrow (high relatively bioavilability).The difference of bioavilability report is to one of percentage of some patients or a few percent between the patient, to other patients 90% or more.As has been noted, often observe individual bioavilability along with the time marked change.Like this, needs of patients is to the big ring immunodepressant bioavilability of homogeneous and Geng Gao more.

The use characteristic of this formulation is that also required patient's dosage alters a great deal.In order to reach effective immunosuppressive therapy, cyclosporin compound blood levels or serum levels must remain in the particular range.This required scope can change successively according to the specified disease that will treat, whether in order to stop graft rejection or control autoimmune disease or illness, and be whether the selectable immunosuppressive therapy that is adopted is attended by the treatment that any general formula is the a-d immunodepressant as treatment.Because the bioavilability level difference that obtains of regular dosage form is very big, dosage every day that need reach required serum levels also will take place to change significantly between Different Individual even on the single individuality.Therefore, must be in rule and frequent time interval blood/serum levels of the patient that accepts to encircle greatly immunosuppressant treatment be monitored.To the monitoring of blood/serum levels usually by the immunoassay of radioimmunoassay (RIA) or equivalence such as carrying out based on monoclonal antibody technique, must carry out as usual.This is elapsed time and making troubles inevitably, and has increased the totle drilling cost of treatment greatly.

In fact, the big ring immunodepressant of blood/serum level also very big variation of performance between peak value and valley of adopting existing delivery system to be reached.For each patient, effectively big ring immunodepressant level all has variation greatly in the blood between each individually dosed administration.

Big ring immunodepressant also needed the aqueous solution type that is provided for injecting.As everyone knows, for big ring immunodepressant, the Cremaphore L that uses in the preparation is the polyoxy ethylization derivative of castor oil and is poisonous excipient at present.Because a large amount of allergy accidents have taken place in this castor oil composition.Because the low aqueous solubility of big ring immunodepressant does not have preparation can allow its concentration with needs be present in the aqueous solution at present.

Adopt existing peroral dosage form and undesirable side effect occurred except existing these very significantly application difficult, having observed.

Having proposed many proposals in order to solve above-mentioned variety of issue in the art, comprise the peroral dosage form of solid and liquid.Yet still the primary difficulty of Cun Zaiing is that to encircle immunodepressant greatly intrinsic insoluble in aqueous medium, therefore stoped conveniently using and satisfying the required standard in bioavilability aspect of the big ring immunodepressant formulation that contains enough high concentrations, for example, allow effectively to absorb the drug and reach the suitable high blood/serum levels of making peace from stomach or intestines inner chamber.

About the particular difficulty that the oral administration of big ring immunodepressant runs into, will cause inevitably using the restriction of the more not serious or dangerous relatively disease illness of big ring immunosuppressant treatment.Inconvenient in this respect special dimension is, adopt big ring immunosuppressant treatment autoimmune disease and other cutaneous disease, such as treatment atopic dermatitis and psoriasis, the hair growth of extensively having proposed in this area that is used for stimulates, as is used for the treatment of the alopecia that aging or disease cause.

Like this, be to have quite big potential benefit although oral big ring immunosuppressant treatment has shown medicine to suffering from as psoriatic patient, oral medication brings the risk of side effect to stop it to use widely.Propose many different proposals in order to use big ring immunodepressant in the art, for example, describing part (use) form and the many local delivery of drug system of cyclosporin.Yet the trial of topical application can't provide any definite effective treatment.

Yet the present invention has overcome the problems referred to above.Especially, embodiment of the present invention are to encircle the prodrug of immunodepressant greatly, and it has increased the solvability of described prodrug in the aqueous solution significantly, thereby does not need to adopt the excipient such as ethanol or castor oil with the solution administration time.And, according to the present invention, encircle the side effect that the prodrug of immunodepressant does not show preparation in the prior art greatly.Further, the inventor has been found that when big ring immunodepressant prodrug of the present invention, will increase its absorption, thereby strengthen described bioavailability of medicament and usefulness significantly during to patient's administration with prodrug forms.

Therefore, in one aspect, the present invention relates to encircle greatly the prodrug of immunodepressant.This prodrug comprise the trip case hydroxyl that is present on the side chain by the cyclosporin of amino acid esterification, sirolimus, tacrolimus and arbitrary hydroxyl by the Elidel molecule of amino acid esterification.

For example, one aspect of the present invention relates to the compound with following general formula, or its pharmaceutically acceptable salt:

Wherein CYCLO represents the residue in cyclosporin molecule 2-11 site, and x-y is that CH=CH is CH ₂CH ₂And AA or amino acid or formula is the dipeptides of GLY-AA.Under latter event, GLY is that glycine and AA are any a-amino acids.In the dipeptides structure, AA is connected in medicine by the OH group, and glycine is as spacer region.Glycine is esterified to cyclosporin, uses the amino of glycine and the hydroxy-acid group of AA subsequently, by amido link glycine is connected on any AA.

The present invention also relates to a kind of pharmaceutical composition, it comprises that the formula for the treatment of effective dose is compound and the pharmaceutical carrier thereof of above-mentioned formula a-d.

In another embodiment, the present invention relates to the methods of treatment that a kind of needs encircle the patient of immunosuppressant treatment greatly, this method comprises the compound that gives the above-mentioned formula a-d of effective dose to described patient.In another embodiment; the present invention relates to a kind of method that increases enlarged link immunodepressant solvability in the aqueous solution; described method is included under the ester formation condition; the particular hydroxy-functional group of the hydroxy functional group of the MeBmt part on the cyclosporin molecular locus 1 and above-mentioned formula b-d compound and amino acid or its acylated derivatives are reacted; perhaps use simple amino acid or dipeptides structure; wherein AA is connected in medicine with glycine as spacer region, and separates its product.

In further embodiment; the present invention relates to a kind of method that to patient's administration the time, increases enlarged link immunodepressant bioavilability; described method is included under the ester formation condition; the hydroxy functional group of the MeBmt part on the cyclosporin molecular locus and amino acid or its acylated derivatives are reacted; and under the ester formation condition; the particular hydroxy-functional group of above-mentioned formula b-d compound and amino acid or its acylated derivatives are reacted; perhaps by using simple amino acid or dipeptides structure; wherein AA is connected in medicine with glycine as spacer region; and separate its product and give described product to the patient.

General introduction:

N-(L-proline) glycinate of synthetic Ciclosporin A and the overview of steps of N-(L-lysine) glycinate are in synthetic order part.These embodiment are to use amino acid to synthesize graphic example.Complete step and analysis data are seen experimental section.Ciclosporin A (10g) reacts with chloroacetic anhydride (4 equivalent) in anhydrous pyridine.This experiment generates the chloracetate (SPI001201,14g, 88% productive rate) of Ciclosporin A with good productive rate.In DMF, handle chloracetate (10.1g) to generate the nitrine acetic acid esters (SPI001202,9.9g, 97% productive rate) of Ciclosporin A with sodium azide then.Use the glycinate (8.54g, 89% productive rate) of stannic chloride (9g) reduction nitrine acetic acid esters (9.8g) then with the preparation Ciclosporin A.Use EDC as coupling agent, excessive boc-L-proline or the Boc-L-lysine of the glycinate of Ciclosporin A (SPI001203) and twice combines.After with column chromatography purification, (5 ℃) handle the boc blocking group so that it is sloughed with the diethyl ether solution of 2M hydrochloric acid from the dipeptides ester of Ciclosporin A at low temperatures.The salt of the L-lysine glycinate of Ciclosporin A does not need other purifying and is dried.The salt of the L-proline glycinate of Ciclosporin A needs purifying.With sodium bicarbonate this salt is converted into free alkali, purifying by filtered through silica gel (using the acetone wash-out).Also dry with the anhydrous hydrogen chloride formation salt of dilution at low temperatures then.

Synthetic order:

N-(L-proline) glycinate and N-(L-lysine) glycinate of synthetic Ciclosporin A: a) pyridine; B) NaN ₃, DMF; C) SnCl ₂, methyl alcohol; D) boc-L-lysine, EDC; E) boc-L-proline, EDC; F) HCl, Et ₂O.

Experimental section:

SPI0022 and SPI0023's is synthetic to carry out in batches.Usually at first carry out small-scale experiment, carry out in large quantity subsequently.The reagent of mentioning in the experimental section is the highest purity that gets, available from Aldrich, Acros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.By Signature Pharmaceuticals, Inc. provides to be used in Ciclosporin A (USP level) in these steps.

1) SPI001201

Ciclosporin A (15.01g, 0.0124 mole) is dissolved in anhydrous pyridine (35mL) in room temperature and argon atmospher.This solution is cooled to 5 ℃ in ice-water bath, and adds chloroacetic anhydride (9.10g, 0.053 mole).Stir after 10 minutes, remove ice bath, solution stirred 17 hours under room temperature and argon atmospher.After 17 hours, add ether (200mL).Water (2 * 100mL) washing ether layers and dry 1 hour subsequently through sodium sulphate (10g).After under reduced pressure filtering and concentrating, remaining yellow foam dry under high vacuum (under the room temperature 1 hour), and go up by flash chromatography method purifying at silica gel (200g), with heptane/acetone (2: 1) wash-out.Merge and concentrate contain the product of each cut after, remaining light yellow foam (14.8g) is finally used (140mL) crystallization of hot ether and purifying.After drying under cooling (10 ℃, 2 hours), filtration and the high vacuum, this step generates the chloracetate SPI001201 as the Ciclosporin A of white solid (14.0g, 88.3% productive rate).

The chloracetate of Ciclosporin A:

¹H NMR(300MHz，CDCl ₃)：

δ＝8.50(d，1H，J＝9.6Hz)，7.95(d，1H，J＝6.6Hz)，7.46(d，1H，J＝9.0Hz)，7.40(d，1H，J＝7.8Hz)，5.35-4.52(m，15H)，4.37(t，1H，J＝7.2Hz)，4.12(d，1H，J＝14.7Hz)，3.89(d，1H，J＝14.7Hz)，3.45-3.0(m，15H)，2.8-2.5(m，6H)，2.5-1.5(m，16H)，1.5-0.7(m，53H)。

¹³C NMR(75MHz，CDCl ₃)：

δ＝173.78，173.37，172.86，172.61，171.28，171.18，170.91，170.79，168.78，167.64，167.18，128.77，126.68，75.46，65.95，58.89，57.47，55.80，55.31，54.86，54.34，50.19，48.91，48.35，48.02，44.80，40.96，39.44，37.07，35.93，33.85，33.25，32.40，31.74，31.50，30.38，30.12，29.82，29.53，25.13，24.92，24.78，24.40，23.99，23.75，22.85，21.94，21.41，21.25，20.84，19.85，18.79，18.32，17.89，17.82，15.46，15.24，10.08。

2)SPI001202

The chloracetate SPI001201 of Ciclosporin A (10.10g, 7.89 mMs) at room temperature is dissolved in anhydrous N, dinethylformamide (30mL).Add sodium azide (2.15g, 33.0 mMs).Lucifuge stirred the mixture 24 hours in room temperature and argon atmospher.After 24 hours, add ether (150mL) and filter this sediment.Water (filter and under reduced pressure concentrate by 2 * 100mL) washing ether layers and through sodium sulphate (15g) dry 30 minutes subsequently.Remaining white solid under room temperature and high vacuum dry 1 hour.This experiment generates the nitrine acetic acid esters SPI001202 (9.90g, 97% productive rate) of Ciclosporin A, and it is a white solid, and it can use without being further purified.

The nitrine acetic acid esters of Ciclosporin A:

¹H NMR(300MHz，CDCl ₃)：

δ＝8.48(d，1H，J＝9.3Hz)，7.95(d，1H，J＝6.9Hz)，7.45(d，1H，J＝9.0Hz)，7.39(d，1H，J＝7.8 Hz)，5.5-4.5(m，15H)，4.31(t，1H，J＝6.6 Hz)，4.04(d，1H，J＝17.3Hz)，3.53(d，1H，J＝17.3Hz)，3.45-3.0(m，15H)，2.8-2.5(m，6H)，2.5-1.5(m，16H)，1.5-0.7(m，53H)。

¹³C NMR(75MHz，CDCl ₃)：

δ＝173.76，173.32，172.82，172.53，171.13，170.89，170.76，170.69，169.70，168.20，167.49，128.63，126.61，74.96，58.91，57.39，55.56，55.21，54.80，54.23，50.14，48.99，48.23，48.24，47.93，44.71，40.89，39.33，39.22，37.02，35.83，33.81，32.96，32.31，31.67，31.42，30.31，30.09，29.76，29.47，25.08，24.92，24.84，24.67，24.51，24.40，23.94，23.82，23.71，21.85，21.33，21.25，20.82，19.79，18.71，18.25，17.92，17.81，15.17，10.03。

3)SPI001203

The nitrine acetic acid esters SPI001202 of Ciclosporin A (9.80g, 7.62 mMs) at room temperature is dissolved in methyl alcohol (250mL).Add entry (40mL), then add stannic chloride (II) (5g, 26.3 mMs).After this solution at room temperature stirs 1 hour, append additional quantity stannic chloride (II) (4g, 21.0mmol).Solution at room temperature continued to stir 2 hours.Add water (200mL) solution that contains ammoniacal liquor (40mL, 29%).After the filtration, concentrated solution (to 200mL) under reduced pressure.(2 * 200mL) extract the remaining aqueous solution with ethyl acetate.Merge the ethyl acetate part,, filtration and under reduced pressure concentrated dry through sodium sulphate (20g).Remaining transparent foaming shape thing filters purifying by silica gel (150g), with methylene chloride (20: 1) wash-out.This step generates the glycinate of Ciclosporin A, and it is transparent solid foam (8.54g, 89% productive rate).

The glycinate of Ciclosporin A:

¹H NMR(300MHz，CDCl ₃)：

δ＝8.60(d，1H，J＝9.6Hz)，8.06(d，1H，J＝6.9Hz)，7.53(d，1H，J＝8.4Hz)，7.51(d，1H，J＝6.6Hz)，5.7-4.52(m，15H)，4.41(t，1H，J＝6.9Hz)，3.5-3.0(m，17H)，2.82-2.5(m，8H)，2.5-1.5(m，16H)，1.5-0.7(m，53H)。

¹³C NMR(75MHz，CDCl ₃)：

δ＝174.10，173.67，173.23，172.72，172.55，171.18，171.10，170.73，170.61，169.68，167.77，128.82，126.42，73.83，58.57，57.32，55.99，55.20，54.74，54.31，50.08，48.82，48.28，47.90，44.70，43.81，40.74，39.33，39.24，37.02，35.84，33.72，33.07，32.39，31.72，31.41，30.25，29.98，29.74，29.51，25.05，24.81，24.73，24.54，24.31，23.91，23.78，23.68，21.86，21.33，21.25，20.68，19.76，18.74，18.24，17.94，17.79，15.18，10.03。

4)SPI0022

Glycinate of Ciclosporin A (SPI001203,2.0g, 1.59 mMs) and boc-L-lysine (1.31g, 3.78 mMs) and EDC (0.75g, 3.9 mMs) are dissolved in anhydrous methylene chloride (25mL) in room temperature and argon atmospher.Boc-L-lysine is from dicyclohexyl amine salt (2.0g the 50mL ether) preparation, and it uses cold potassium hydrogen sulfate solution (1g in the 50mL water) and cold water (2 * 50mL) extractions successively.The ether layer that contains boc-L-lysine filters, concentrates through sodium sulphate (5g) drying, and drying is 1 hour under room temperature and high vacuum.Add a small amount of DMAP crystallization in the mixture of the glycinate of EDC, boc-L-lysine and Ciclosporin A, solution at room temperature stirred 4 hours.Dichloromethane solution extracts with DIUF water (50mL), 5% sodium bicarbonate solution (50mL) and DIUF water (50mL).After sodium sulphate (10g) drying, dichloromethane solution is filtered and under reduced pressure concentrates.Remaining white foam shape thing (3.01g) is gone up by rapid column chromatography method purifying at silica gel (50g), with heptane/acetone (2: 1) wash-out.Merging the product that contains each cut also under reduced pressure concentrates and drying under high vacuum.The shielded intermediate product of purifying (2.34 g white solids, 92.8% productive rate) is placed in argon atmospher in the flask, and it cools off in ice-water bath.Add the cold anhydrous 2 M hydrochloric acid in the ether (20mL), and with this solution stirring 8 hours (at 5 ℃).Mixture slowly is warmed up to room temperature and spends the night.After stirring 20 hours altogether, flask cooled off 30 minutes in ice-water bath once more.Filter this product and under room temperature and high vacuum dry 1 hour, then 50 ℃ dry 4 hours down.This experiment generates N-(L-the lysine)-glycinate dihydrochloride trihydrate (SPI0022,1.59g, 73.9% productive rate) of Ciclosporin A, is white solid.

¹H NMR (300MHz, CDCl ₃, to the NMR data of free alkali):

δ＝8.58(d，1H，J＝9.3Hz)，8.04(d，1H，J＝6Hz)，7.80(d，1H，J＝6Hz)，7.49(d，2H，J＝8.4Hz)，5.70-4.6(m，17H)，4.41(m，1H)，4.28(dd，1H，J＝17，7.2Hz)，3.67(d，1H，J＝17Hz)，3.46(s 3H)，3.4-2.8(m，16H)，2.8-2.5(m，8H)，2.5-1.35(m，24H)，1.5-0.7(m，50H)。

¹³C NMR (75MHz, CDCl ₃, to the NMR data of free alkali):

δ＝175.23，173.77，173.34，172.75，172.63，171.34，171.22，170.94，170.84，170.91，169.89，169.70，128.74，126.67，74.41，58.82，57.43，55.91，55.21，54.81，54.42，50.17，48.89，48.31，47.98，44.78，41.92，40.82，40.69，39.44，39.32，27.19，35.91，34.88，33.71，33.25，33.12，32.44，31.83，31.50，30.38，30.06，29.81，29.55，25.14，24.90，24.52，24.43，24.00，23.76，21.93，21.42，21.29，20.81，19.84，18.82，18.32，17.96，17.86，15.21，10.10。

The CHN elementary analysis:

To C ₇₀H ₁₂₈Cl ₂N ₁₄O ₁₅-3H ₂The calculated value of O: C 55.50, H 8.92 and N 12.74; Measured value: C 58.28, H 8.98 and N 13.16.

HPLC analyzes:

99.60% purity; R.t.=14.763min.; The 20%Tris alkali (tromethamine) of 80% acetonitrile/in DIUF water; 1mL/min; 60C; Synergi Hydro RP, 4u post (serial#163383-7), 4.6 * 250mm; 20 inject; UV=210nm.

Fusing point: 196.0-198 ℃ (not revising)

5)SPI0023

Glycinate of Ciclosporin A (SPI001203,7.50g, 5.95 mMs) and boc-L-proline (2.56g, 11.90 mMs) and EDC (2.28g, 11.9 mMs) at room temperature with in the argon atmospher are dissolved in anhydrous methylene chloride (50mL).Add a small amount of DMAP crystallization in the mixture of the glycinate of EDC, boc-L-proline and Ciclosporin A, solution at room temperature stirred 3 hours.Dichloromethane solution is with DIUF water (50mL), 5% sodium bicarbonate solution (2 * 50mL) and DIUF water (50mL) extraction.After sodium sulphate (10g) drying, carrene is filtered and under reduced pressure concentrates.Remaining white foam shape thing (9.50g) is gone up by rapid column chromatography method purifying at silica gel (150g), with heptane/acetone (2: 1 succeeded by 1: 1) wash-out.Merge the product that contains each cut and under reduced pressure concentrate dry (7.94g white solid, productive rate: 91.7%) 10 minutes under room temperature and high vacuum.

The shielded intermediate product (6.46g) of purifying is placed in argon atmospher in the flask, and it cools off in ice-water bath.Add cold anhydrous 2M hydrochloric acid in the ether (150mL), with this solution stirring 8 hours (at 5 ℃).Mixture is warmed up to room temperature lentamente and spends the night.After stirring 20 hours altogether, flask cooled off 30 minutes in ice-water bath once more.Filtration product and under room temperature and high vacuum dry 30 minutes.By salt being dissolved in the DIUF water (25mL) that contains sodium bicarbonate (1g), (5.17g, productive rate: 84.6%, the HPLC purity assay is 90%) is converted into free alkali the N-of Ciclosporin A (L-proline) glycine ester hydrochloride.(3 * 25mL) extract this free alkali, and, filtration and concentrated dry through sodium sulphate (5g) with carrene.Remaining pale solid (5g) filters purifying with silica gel (100g), uses the acetone wash-out.Merge and to contain the product of each cut, under reduced pressure concentrate, and under room temperature and high vacuum dry 30 minutes.Free alkali (3.8g) is dissolved in ether (25mL), and it is added in heptane (50mL) solution that contains 2M anhydrous hydrochloric acid (5mL), in ice-water bath, cool off then, make the regenerant salt hydrochlorate.At 5 ℃ after following 20 minutes, white solid is filtered, and under room temperature and high vacuum dry 6 hours.This experiment generate as N-(L-proline) glycine ester hydrochloride of the Ciclosporin A of white solid (SPI0023,3.8g).

¹H NMR(300MHz，CDCl ₃)：

δ＝14.20(br s，2H)，8.62(d，1H，J＝10Hz)，8.06(d，1H，J＝6.9 Hz)，7.61(d，1H，J＝8.1Hz)，7.48(d，1H，J＝9Hz)，5.70-5.50(m，3H)，5.40-4.60(m，12H)，4.37(m，1H)，4.20(d，1H，J＝18Hz)，3.97(d，1H，J＝18Hz)，3.70(m，1H)，3.45(s，3H)，3.23-3.08(m，12H)，2.66(s，3H)，2.60(s，3H)，2.50-1.80(m，15H)，1.78-1.20(m，15H)，1.15-0.66(m，46H)。

¹³C NMR(75 MHz，CDCl ₃)：

δ＝174.15，173.49，172.67，172.59，171.86，171.20，171.13，171.02，170.83，169.68，168.77，167.55，128.30，127.10，80.09，75.58，62.65，59.35，57.36，55.53，55.30，54.78，54.35，53.60，50.25，50.09，48.92，48.18，48.12，44.62，40.59，40.02，39.43，39.30，37.13，35.88，33.74，33.07，32.19，32.01，31.86，31.50，31.43，30.43，29.93，29.72，29.30，29.16，27.56，26.04，25.00，24.86，24.74，24.39，20.96，19.81，18.71，18.26，18.09，17.85，17.79，15.09，14.30，10.00。

The CHN elementary analysis:

C ₆₉H ₁₂₂ClN ₁₃O ₁₄Calculated value: C 59.48, and H 8.83, and N 13.07; Measured value: C 59.84, H 9.02, and N 12.65.

HPLC analyzes:

99.59% purity; R.t.=10.613min.; The 15%Tris alkali of 85% acetonitrile/in DIUF water; 1.2mL/min; 60C; Synergi Hydro RP, 4u post (serial#1633 83-7), 4.6 * 250mm; 20ul; UV=210nm.

Fusing point: 197.0-199 ℃ (not revising)

These cyclosporin prodrugs of the present invention are effective to the disease or the illness for the treatment of common use and encircling immunodepressant greatly.These prodrugs transform in vivo with release of active compounds, and alleviate or eliminate biopharmacy and the pharmacokinetics barrier of following every kind big ring immunodepressant, thereby increase its result of treatment.Yet even it should be noted that the not any active medicine of release in mammalian body, itself also has enough activity these prodrugs.Because these prodrugs are more solvable in water than cyclosporin or other big ring immunodepressant, so it does not need to have vehicle excipients, such as may be poisonous or produce the ethanol or the castor oil of unwanted side effect.And the prodrug oral formulations that contains prodrug can be absorbed into blood and be quite effective.

Like this, the prodrug of cyclosporin of the present invention has the biopharmacy and the pharmacokinetics barrier of medicine now by elimination, and helps treatment.

And, use the commercially available reagent that is easy to get, can be with the easily synthetic described prodrug of high yield.

VI. valproic acid ester class

Valproic acid (2-Propylpentanoic) is low molecular weight carboxylic acid's derivative, is widely used as anticonvulsive drug, can effectively treat epilepsy, also has vasodilator activity and can alleviate antimigraine in brain.It with control people epileptoid seizure, is alleviated the severe pain that interrelates with antimigraine by oral administration simultaneously.

Valproic acid has shown the application that has in many treatments, and they are very inequality and somewhat astonishing.For example, except treatment epilepsy and antimigraine, to treating some mental diseases also is effective, such as the agitation of the impulsive action in bipolar disorder, being emotionally stable, control aggressiveness, the personality disorder, dementia with as the supplemental treatment for the treatment of post-traumatic stress disorder (PTSD).

The mechanism of action:

Although be used for the treatment of epilepsy for many years, it is unknown that the definite mechanism of action of valproic acid remains.Suppose that it is played a role by the concentration that increases r-aminobutyric acid (GABA) in the brain.The r-aminobutyric acid is a kind of neurotransmitter, is the chemical substance of transmitting mutually between nerve.

Valproate is the medicine of selecting for use, be used for the treatment of myoclonic epilepsy, with or without tonoclonic epileptic attack, comprise teenager's type lafora's disease of Janz, it starts from puberty or grows up early stage.Photosensitive myoclonia is normally controlled easily.Valproate also is effectively to the myoclonia for the treatment of after optimum myoclonic epilepsy, the anoxic, and, to share with Clonazepam and can treat the severe progressive myoclonic epilepsy, its feature also is a tonic clonic seizure.Valproate also can preferably be treated some stimulation-susceptibility (reflection, terrified) epilepsy.

Although valproate is effectively to infantile spasm, it is to because hyperglycinemia or other potential metabolism (mitochondrial) cause the children of spasm to avoid relatively unusually.Usually, the outbreak that Lin-Ge (Lennox-Gastaut) syndrome patient's atonia and motion can not epilepsies is unmanageable, but valproate is the medicine that is preferred for treating the epileptic attack of mixed type.Because this medicine patient that other various Anti-epilepticses are difficult to cure to some is useful, so it has reason not consider that to nearly all the non-responsiveness patient of the type of epileptic attack tries out.

Although valproate is useful, hepatotoxicity wind agitation can be fatal, but this is atopic, can not be prevented by the routine monitoring liver enzyme.Hepatotoxicity wind agitation occurs among the very little children of age, and they are the most normally with multiple anticonvulsant treatment.Blood cell that valproate is induced reduces disease may be relevant with dosage, and this need guarantee in therapeutic process the monitoring to CBC.May take place does not have the unusual situation of liver function test with the encephalopathic of hyperammonemia.The pregnant woman of conceived first month has the risk of suffering from NTD.

Valproic acid is the low-molecular-weight liquid that has characteristic odor.Orally have offending taste, and can seriously stimulate oral cavity and throat.For valproic acid being converted into convenient oral solid dosage forms, a large amount of derivatives that link to each other with ionic bond by covalent bond with carboxylic acid have been prepared.A kind of simple sodium salt of valproic acid, sodium vedproate are available solids.Yet, in two molecules of valproic acid and the atomic component of sodium and form a kind of stable co-ordination complex, be called divalproex sodium.This product is the most extensive valproic acid that provides half salt, is sold with trade (brand) name Depakote_ by the Abbott Laboratories of the U.S..Depakote_ also is used for the prolongation delivery formulations of oral administration.

A remarkable shortcoming of valproic acid is the form administration that is difficult to liquid.And the different dosing form of valproic acid can not produce the bioavilability of expectation equably.For example, all bioavilabilities from the valproic acid of valproate, its sodium salt, Divalproex_ and their prolongation delivery formulations are not interchangeable fully.Because the continuous monitoring to the blood plasma of valproic acid is necessary, because the variation of preparation and any change in plasma concentration all can influence the wholistic therapy result unfriendly.

In order to improve result of treatment, even first-class preparation on CBC, the developing drugs, and reduce first-pass metabolism, the present invention has discussed and can overcome above-mentioned some difficult valproic acid prodrug.

Up to now, also do not provide on the market and can discharge valproic acid and pharmaceutical preparation with no harmful side-effects.Yet, the present invention proposes water miscible in a large number, atoxic valproic acid derivative, it is suitable for discharging constantly in vivo valproic acid, and without any harmful side effect, does not also need expensive additive and excipient.

Therefore, on the one hand, the present invention relates to a class valproic acid prodrug.This prodrug comprises the free carboxy that is existed to the valproic acid molecule by amino acid whose hydroxy esterification.In another embodiment, amino acid whose amino and COOH radical reaction are to form amido link.

More specifically, embodiment of the present invention relate to following formula: compound or its pharmaceutically acceptable salt;

Wherein R is NH-AA or O-AA, and AA is an amino acid, the hydroxy-acid group reaction of its amino or hydroxyl and valproic acid.

The present invention also relates to a kind of pharmaceutical composition, it comprises the above-mentioned various valproic acid prodrugs and the pharmaceutical carrier thereof for the treatment of effective dose.

In another embodiment, the present invention relates to a kind of methods of treatment that needs the patient of valproic acid treatment, this method comprises the valproic acid that gives effective dose to described patient.

In a further embodiment, the present invention relates to a kind of liquid valproic acid is converted into the method for pressed powder, this method is to react by the carboxyl functional group that makes valproic acid and amino acid whose amino or hydroxy functional group, and separates its product.

In further embodiment, the present invention relates to a kind of method, by give a kind of prodrug to the patient, fully and to treat effective and efficient manner, thereby reduce or eliminate the uniformity of first-pass metabolism and raising result of treatment, described method comprises COOH functional group and the selected amino acid whose NH that makes valproic acid molecule ₂Or OH functional group reacts forming ester or acid amides covalent bond respectively, and separates its product and give described product to the patient.

Have been found that, when unsubstituted naturally occurring amino acid esterified when the valproic acid, resulting prodrug is the powder of good fluidity first-class in the pharmacy, and be absorbed in the body apace, in vivo by decomposing and discharge nontoxic amino acid, and do not need emulsifier, additive and other excipient (exepients).

And, show that the present invention also generates medicine, though they are prodrugs of valproic acid; But they self are exactly Anti-epileptics and show this effect efficiently.Thereby L-threonine derivatives of high therapeutic index of the present invention is effective Anti-epileptics, and useful to treating a large amount of mental illnesses, whether discharges active parent drug and all shows this potential.

The volume density of valproic acid prodrug is more much higher than corresponding sodium salt, and is suitable for heavy weight tablet of boil down to and capsule.And they do not show the bitter taste and the unusual odor of valproic acid.Because cause acid hydroxy-acid group blocked, prodrug of the present invention is considered to not have the activity of any acid, yet, show whether these prodrugs discharge valproic acid all is effective Anti-epileptics.Described all valproic acid prodrugs all discharge the active medicine with its all pharmacology and spiritual activity characteristic in vivo.

The valproic acid prodrug obviously provides the many advantages that surpass valproic acid, and for example, all side chains that decompose from these prodrugs all are naturally occurring essential amino acids, are nontoxic therefore.This has caused high therapeutic index.The second, all prodrugs all are easy to decompose to discharge valproic acid in vivo.And, because their highly-water-soluble forms solution on the spot by using aseptic freeze-dried powder before intravenously administrable, perhaps being contained in drug solution in syringe or the bottle in advance by what be provided for infusing, they can be easy to administration.This amino-acid ester is more stable than valproic acid, because the COOH group of valproic acid is blocked can not with alkali reaction.Therefore valproic acid prodrug of the present invention is more effective than valproic acid itself, and toxicity and other pharmacy problem of not having present commercial preparation to have.

The overview of steps of L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic valproic acid (2-Propylpentanoic) is in synthetic order part, and is the example of preparation various prodrugs of the present invention.Complete step and analysis data are seen experimental section.Generally speaking, when having the DMAP of catalytic amount, use EDC, (2-8g, in batches) amino acid with N-benzyloxy/benzyl ester protection reacts valproic acid.(following 20 hours of room temperature) finished in reaction one, just with DIUF water extraction mixture, after dried over sodium sulfate, and under reduced pressure concentrates.Rough material or be directly used in deprotection steps is perhaps used column chromatography purification.This step generates shielded valproic acid amino-acid ester, productive rate scope from 72% to 92%.In the presence of 10% palladium-carbon catalyst, by hydrogenization (30psi H ₂) slough blocking group.The amino-acid ester of valproic acid extracts from palladium catalyst with ethanol, and it is concentrated and dry.Form final salt with hydrochloric acid by acidization.The salt (productive rate from 57% to 92%) of the method purification of crude of describing with experimental section then.

Synthetic order:

1.SPIC001

2.SPIC002

3.SPIC003

L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic valproic acid: a) EDC, DMAP, CH ₂Cl ₂B) H ₂, 10%Pd/C, EtOH, EtOAc; C) HCl.

Experimental section:

SPIC001, SPIC002 and SPIC003 synthetic by a collection of or two batches carry out.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Lancaster, Sigma-Aldrich, Acros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.

1) SPIC001:2-Propylpentanoic-2 (S)-amino-2-carboxy ethyl ester hydrochloride

(L-serine valproic acid ester hydrochloride)

In argon atmospher, 2-Propylpentanoic (valproic acid, 6.48g, 44.93 N-benzyloxycarbonyl group-L-serine benzyl ester (Z-Ser-OBzl mM),, 14.80g, 44.93 mM), EDC (8.61g, 44.91 mMs) and the mixture of DMAP (549mg, 4.49 mMs) in anhydrous methylene chloride (50mL) at room temperature stirred 20 hours.After 20 hours, (3 * 50mL) wash and through magnesium sulfate (5g) drying, filter and under reduced pressure concentrate the carrene water.Remaining colorless oil (20.87g) goes up purifying with column chromatography at silica gel (150g, 0.035-0.070mm, 6nm aperture), with hexane/ethyl acetate (3: 1) wash-out.The product that contains each cut under reduced pressure concentrates, and dry after constant weight under high vacuum, and this experiment is generated as the shielded L-serine valproic acid ester SPIC00101 (18.9g, 92% productive rate) of colorless oil.

¹H NMR(300MHz，DMSO)：δ＝7.96(1H，d，J＝8.1Hz)，7.35(10H，m)，5.14(2H，s)，5.05(2H，s)，4.5 1(1H，m)，4.29(2H，m)，2.29(1H，m)，1.50-1.25(4H，m)，1.25-1.10(4H，m)，0.80(6H，t，J＝6.6 Hz)。

¹³C NMR(75MHz，DMSO)：δ＝174.88，169.15，155.85，136.58，135.45，128.26，128.18，127.47，127.71，127.57，66.32，65.66，62.47，53.09，44.20，33.86，33.79，19.95，13.85。

Shielded L-serine valproic acid ester SPIC00101 (18.9g; 41.48 mM) at room temperature be dissolved in ethanol (60mL) and the ethyl acetate (60mL); and in blanket of nitrogen, it is joined in the Parr bottle that contains 10% palladium-carbon catalyst (3.0g, 50% is wet) (500mL).Replace blanket of nitrogen with hydrogen (30psi).Vibrate after 4 hours, be added in addition ethanol/ethyl acetate (1: 1, the 100mL) palladium catalyst in (1.0g), reactant mixture is in room temperature and hydrogen (30psi) shaken overnight down.Remove catalyzer with the thin layer activated carbon filtration after 24 hours.Ethanol and ethyl acetate be concentrating under reduced pressure at room temperature.After the drying, (2M 24.6mL) carries out acidifying to remaining solid with hydrochloric ether under high vacuum.Mixture stores 2 hours in refrigerator after, filter and with other cold diethyl ether (10mL) purging compound.After the filtration, remaining white solid is dry under room temperature and high vacuum, up to product constant weight (24 hours).This experiment generates the L-serine valproic acid ester hydrochloride SPIC001 (6.34g, 57% productive rate) as white solid.

¹H NMR(300MHz，DMSO)：δ＝8.73(br s，3H)，4.47(dd，1H，J＝12.9，4.5Hz)，4.31(dd，2H，J＝12.9，3.6Hz)，2.36(m，1H)，1.50(m，2H)，1.39(m，2H)，1.20(m，4H)，0.84(t，6H，J＝7Hz)。

¹³C NMR(75MHz，DMSO)：δ＝174.67，168.19，61.84，51.16，44.12，33.76，33.58，20.07，19.92，13.97，13.89。

HPLC analyzes:

98.49% purity; Rt=4.767min; Luna C18 5u post (sn 167917-13); 4.6 * 250mm; 254nm; 33% acrylonitrile/66%DIUF water; 35C; 20ul injects; 1ml/min; The 20mg/mL sample size; Sample is dissolved in the flowing phase.

The CHN elementary analysis:

Calculated value: C 49.34, H 8.28, and N 5.23; Measured value: C 49.22, H 8.35, and N 5.24.

Fusing point: 159-160 ℃

2) SPIC002:4 (R)-(2-propyl group penta acyloxy) pyrrolidines-2 (S)-carboxylic acid

(L-hydroxyproline valproic acid ester)

In argon atmospher, 2-Propylpentanoic (valproic acid, 4.32g, 30 mMs), N-benzyloxycarbonyl group-L-hydroxyproline benzyl ester (Z-Hyp-0Bzl, 10.66g, 30 mMs) ¹, EDC (5.74g, 30 mMs) and the mixture of DMAP (366mg, 3 mMs) in anhydrous methylene chloride (30mL) at room temperature stirred 20 hours.After 20 hours, (3 * 30mL) wash carrene and through magnesium sulfate (5g) drying, filter also under reduced pressure concentrated water.Remaining colorless oil SPIC00201 (11.95g, 24.7 mMs, 82.4% productive rate) can be not purified and be used.

¹H NMR(300MHz，CDCl ₃)：δ＝7.29(10H，m)，5.28-5.00(5H，m)，4.55(1/2H，t，J＝8Hz)，4.46(1/2H，t，J＝8Hz)，3.80-3.60(2H，m)，2.43-2.16(3H，m)，1.60-1.45(2H，m)，1.40-1.32(2H，m)，1.28-1.20(4H，m)，0.86(6H，m)。

¹³C NMR(75MHz，DMSO)：δ＝174.74，171.40，171.05，153.79，153.31，136.34，136.20，135.57，135.38，128.24，128.13，127.95，127.87，127.67，127.52，127.28，127.10，72.29，71.53，66.34，66.10，57.66，57.19，52.27，51.89，44.13，40.33，35.78，34.79，34.04，33.92，33.35，20.00，19.91，13.79，13.73。

Shielded L-hydroxyproline valproic acid ester SPIC00201 (17.24g; 35.79 mM) at room temperature be dissolved in ethanol (50mL) and the ethyl acetate (100mL); and in blanket of nitrogen, it is joined in the Parr bottle (500mL) that contains 10% palladium-carbon catalyst (3.5g, 50% is wet).Replace blanket of nitrogen with hydrogen (30psi).Vibrate after 15 hours, remove catalyzer with thin layer diatomite and activated carbon filtration.Ethanol and ethyl acetate mixture be concentrating under reduced pressure at room temperature.After dried overnight under room temperature and the high vacuum, this experiment generates L-hydroxyproline valproic acid ester hydrochloride SPIC002 (9.2g, productive rate: 99.8%), be white solid.In order to remove the impurity of trace, amphion carries out purifying in two batches by reversed phase column chromatography method (50 g ODS silica gel).Amphion is placed on the post of DIUF water, with the mixture wash-out of DIUF water/methyl alcohol (2: 1,1: 1,1: 2,100% methyl alcohol).

Merge the product that contains each cut, concentrating under reduced pressure under 20 ℃ (or lower), and dry under room temperature and high vacuum, up to constant weight (24 hours, reclaim the 6.4g white solid).

¹H NMR(300MHz，CDCl ₃)：δ＝12.40(br s，1H)，8.32(br s，1H)，5.28(m，1H)，4.11(t，1H，J＝7.2Hz)，3.59(m，1H)，3.34(br d，1H，J＝10.5Hz)，2.50-2.22(m，3H)，1.62-1.50(m，2H)，1.50-1.32(m，2H)，1.32-1.19(m，4H)，0.88(t，6H，J＝7.2Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝175.99，173.35，71.83，59.56，49.77，45.08，36.19，34.51，20.87，14.31。

HPLC analyzes:

99.20% purity; R.t.=7.228min.; 70%DIUF water/30% acetonitrile; 1mL/min; 36.8C; Luna C18,5u post (serial#167917-13), 4.6 * 250mm; 22ul injects; Sample dissolution is in flowing phase.

The CHN elementary analysis:

Calculated value: C 60.68, H 9.01, and N 5.44; Measured value: C 60.58, H 9.12, N 5.48.

Fusing point: 179.0-180.0 ℃

3) SPIC003:2-propyl group valproic acid-2 (S)-amino-2-carboxyl-1 (R)-methyl carbethoxy hydrochloride (L-threonine valproic acid ester hydrochloride)

In argon atmospher, 2-Propylpentanoic (valproic acid, 4.32g, 30 mMs), N-benzyloxycarbonyl group-L-threonine benzyl ester (Z-Thr-OBzl, 10.30g, 30 mMs), EDC (5.74g, 30 mMs) and the mixture of DMAP (366mg, 3.0 mMs) in anhydrous methylene chloride (30mL) at room temperature stirred 20 hours.After 20 hours, (3 * 30mL) wash and through magnesium sulfate (5g) drying, filter and under reduced pressure concentrate the carrene water.Remaining colorless oil (13.44g) goes up purifying with column chromatography at silica gel (100g, 0.035-0.070mm, 6nm aperture), with hexane/ethyl acetate (4: 1) wash-out.

The product that contains each cut under reduced pressure concentrates, drying is until constant weight under high vacuum, and this experiment generates shielded L-threonine valproic acid ester SPIC00301 (12.65g, 89.8% productive rate), is colorless oil.

¹H NMR(300MHz，CDCl ₃)：δ＝7.40-7.05(11H，m)，5.45(1H，m)，5.17-5.02(4H，m)，4.53(1H，d，J＝9.6Hz)，2.24(1H，m)，1.58-1.40(2H，m)，1.40-1.15(9H，m)，0.86(6H，m)。

¹³C NMR(75MHz，DMSO)：δ＝174.24，169.29，156.48，136.61，135.34，128.26，128.20，127.74，127.67，127.58，69.04，66.33，65.78，57.62，44.50，33.89，33.80，20.03，19.91，16.40，13.87。

Shielded L-threonine valproic acid ester SPIC00301 (12.65 g; 26.9 mM) at room temperature be dissolved in ethanol (50mL) and the ethyl acetate (50mL); and in blanket of nitrogen, it is joined in the Parr bottle (500mL) that contains 10% palladium-carbon catalyst (2.53g, 50% is wet).Replace blanket of nitrogen with hydrogen (30psi).Remove catalyzer with the thin layer activated carbon filtration after 20 hours, and wash with ethanol (25mL).Ethanol and ethyl acetate concentrate under room temperature and decompression.After the drying, remaining solid (6.13g) is used in hydrochloric acid (3.1mL the is dense) acidifying in the DIUF water (50mL) under high vacuum.Solution for the second time with activated carbon filtration and in freeze-dryer dried overnight.This experiment generates the L-threonine valproic acid ester hydrochloride SPIC003 (6.52g, 86.0% productive rate) as white solid.

The L-threonine valproic acid ester hydrochloride SPIC003 (8.8g) that merges each batch, and by the acetonitrile crystallization purifying.After this salt is dissolved in hot acetonitrile (225mL),, filter, and place at 5 ℃ of refrigerators and to spend the night with this material of charcoal treatment.Filter white solid after 18 hours, with cold acetonitrile (10mL) washing, and dry under room temperature and high vacuum, up to product constant weight (24 hours).The L-threonine valproic acid ester hydrochloride SPIC003 (6.82g, 77.5% rate of recovery) that this step reclaims is white solid.

¹H NMR(300MHz，DMSO)：δ＝8.71(br s，3H)，5.28(m，1H)，4.16(d，1H，J＝2.7Hz)，2.33(m，1H)，1.56-1.40(m，2 H)，1.37-1.27(m，5H)，1.21-1.13(m，4H)，0.84(t，6H，J＝6.6Hz)。

¹³C NMR(75MHz，DMSO)：δ＝173.97，168.19，67.69，55.42，44.43，33.95，33.78，20.07，19.95，16.54，13.94。

HPLC analyzes:

98.88% purity; R.t.=4.864min.; 70%DIUF water/30% acetonitrile; 1mL/min; 40C; Luna C18,5u post (serial#211739-42), 4.6 * 250mm; 20ul injects; Sample is dissolved in the flowing phase.

The CHN elementary analysis:

Calculated value: C 51.15, H 8.59, and N 4.97; Measured value: C 51.29, H 8.59, and N 4.98.

Fusing point: 144 ℃

By dissolving every kind of excessive medicine and allowing it to leave standstill several hours, determine above-mentioned various ester solvability under the room temperature in water.Resulting solution centrifugal 3 minutes at 1500 rev/mins (rpm) is got the supernatant analysis.The result shows that the solvability of these esters in water surpasses 50mg/mL.

According to disclosed method, there are many screening tests to determine the application of the prodrug that generated.These tests comprise the screening technique in external and the body.

External method comprises acid/basic hydrolysis, the hydrolysis in pig pancreas, the hydrolysis in mouse intestinal juice, the hydrolysis in human gastric juice, the hydrolysis in human intestinal juice and the hydrolysis in human plasma of prodrug.These determination methods are described in document (Simmons, DM, Chandran, VR and Portmann, GA, Danazol Amino Acid Prodrugs:In Vitro and In Situ BiopharmaceuticalEvaluation, Drug Development and Industrial Pharmacy, Vol 21, Issue 6, Page687,1995) in, its all the elements are incorporated by reference.

Valproic acid prodrug of the present invention is effective to the disease or the illness for the treatment of common use valproic acid treatment.Prodrug disclosed herein transforms in vivo with release of active compounds, and by alleviating or eliminate the biopharmacy and the pharmacokinetics barrier of every kind of valproic acid prodrug, and help treatment.Yet, it should be noted that these prodrugs itself just have enough activity, even in mammalian body, do not discharge any active medicine.

Like this, prodrug of the present invention is by by biopharmacy and the pharmacokinetics barrier of removing existing medicine, and helps treatment.

And, use the commercially available reagent that is easy to get, can be with easily synthetic these prodrugs of high yield.

VII. the water-soluble prodrug of fibric acid (Fibric acid) derivative

The fibric acid derivative is useful lipidemia medicine, is used for the treatment of mammiferous hyperlipemia, and its symptom is high triglyceride, low HDL (cholesterol of high-density lipoprotein (HDL) or " good ") and high cholesterol.The fibric acid derivative also is used to reduce LDL (cholesterol of low-density lipoprotein or " bad ").The general structure of fibric acid analog is shown below, and wherein X is the aliphatic and the aromatic series functional group of various mixing.The specific derivatives that is included in this general formula is chlorine shellfish acid (clofibric acid), Fenofibric Acid (fenofibric acid), ciprofibrate (ciprfibrate) and Gemfibrozil (gemfibrozil) etc.

The fibric acid analog

The exemplary of X part chemical group is as follows in the said structure.

Fibric acid shown in the said structure (firic acid) analog has shown many treatments and has used, and they are quite different surprising with some.Put it briefly, these derivatives can be used for treating dyslipidemia and dyslipoproteinemia.The dyslipidemia and the dyslipoproteinemia of this paper definition comprise hypercholesterolemia, cholesterol levels is unusual and higher, the LDL cholesterol levels is unusual and higher, total cholesterol level is unusual and higher, blood plasma cholesterol level is unusual and higher, triglyceride levels is unusual and higher, hypertriglyceridemia, lipoprotein levels is unusual, low-density lipoprotein (LDLs) horizontal abnormality and higher, very low density lipoprotein horizontal abnormality and higher, extremely low intermediated-density lipoprotein horizontal abnormality and higher, hdl level is unusual, hyperlipidemia, hyperchylomicronemia, the chylomicron horizontal abnormality, and dysfunction that is associated and their combination, as be described in document (The ILIB Lipid Handbookfor Clinical Practice, Blood Lipids and Coronary Heart Disease, Second Edition, A.M.Gotto et al, International Lipid Information Bureau, New York, N.Y., 2000) in, the document is incorporated herein by reference.

The mechanism of action:

The mechanism of action of fibric acid derivative in clinical practice is obtained explaining in the body of trangenic mice and in the external human hepatocytes culture by peroxide activator enzyme body proliferator activated receptor α (PPAR-α).By this mechanism, the fibric acid derivative increases lipolysis by activating lipoprotein lipase, discharges the particle that is rich in triglycerides from blood plasma, and reduces the generation of apoC-III (inhibitor of lipoprotein lipase activity).

Resultant triglycerides has produced the change of LDL size and composition, becomes big lepton from intensive small-particle (owing to their easy oxidations are considered to atherogenic).These bigger particles have higher affinity to the cholesterol acceptor, and metabolism is decomposed rapidly.The synthetic increase of apolipoprotein A-1, A-II and HDL cholesterol has also been induced in the activation of PPAR-α.The fibric acid derivative also can effectively be treated gout, is because they have reduced hyperuricemia (hyperurecemic) patient's serum uric acid level.

The hyperlipidemia type comprises I type, IIa type, IIb type, III type, IV type and V-type.The level of the feature institute foundation of these types is with respect to above-mentioned normal lipid (cholesterol and triglycerides) and lipoprotein.Different classification is derived from Drug Facts and Comparisons, 52nd Edition (1998) page 1066, and the document is not hereby incorporated by reference.

When oral administration, many fibric acid derivatives do not have enough bioavilabilities, and absorb mutability, instability and depend on food.In fact, many fibric acid derivatives can not have absolute bioavailability, because fibric acid prodrug in the market can not be water-soluble, so the outer injection type of intestines is difficult to provide.And because these medicines are usually as the ester administration, they in fact are prodrugs.The necessary in vivo metabolism of these prodrugs is to discharge active medicine, i.e. fibric acid.Yet because these medicines are ester formulations, they are quite insoluble in water, therefore are difficult to preparation, also are not easy to decompose the release active medicine in vivo.

Many fibric acid derivatives are solids of molecular weight in being low to moderate, have characteristic odor.Oral with offending taste, and can seriously stimulate oral cavity and throat.Take medicine with fasting and to compare, take the haemoconcentration that can provide higher with food together.When the corresponding prodrug derivant in fibric acid derivative and they was compared, the difference on the bioavilability of feeding/fasting was more remarkable.All bioavilabilities that various places have been reported and alter a great deal between the patient between 40-60.

A prominent question of the fibric acid derivative of Chu Shouing is in the market, and when these prodrugs in vivo during cracking, the prodrug moiety that their discharge itself is highly toxic.For example, for fenofibrate and Gemfibrozil, when esterase when the forward part of Fenofibric Acid is decomposed, discharge isopropyl alcohol.Well-known is all to be highly toxic when isopropyl alcohol is discharged into any mammalian tissues.

In order to improve result of treatment, even first-class preparation on CBC, the developing drugs, and improve the solvability of medicine in water, the present invention has described the optional fibric acid derivative prodrug that can overcome above-mentioned many difficulties in detail.

Therefore, in one aspect, the present invention relates to the selectable kind of fibric acid derivative prodrug.This prodrug comprises the free carboxy that is existed to the fibric acid derivative molecular by amino acid whose hydroxy esterification.In another embodiment, the COOH of amino acid whose amino and fibric acid reaction is to form amido link.

More specifically, one aspect of the present invention relates to the compound of following formula, or its pharmaceutically acceptable salt, wherein X as hereinbefore defined,

The fibric acid analog

Wherein R is NH-AA or O-AA, and AA is an amino acid, the hydroxy-acid group of amino or hydroxyl and fibric acid derivative reaction in this amino acid.

In one embodiment, the invention still further relates to a kind of pharmaceutical composition, it comprises the treatment upward above-mentioned various fibric acid derivative prodrugs and the pharmaceutical carrier thereof of effective dose.

In another embodiment, the present invention relates to a kind of methods of treatment that needs the patient of fibric acid derivatives for treatment, this method comprises the fibric acid derivative that gives effective dose to described patient.

In a further embodiment, the present invention relates to a kind of liquid phenenyl oxygen acid derivative is converted into the method for pressed powder, carboxyl functional group and amino acid whose amino or the hydroxyl of this method by making the fibric acid derivative reacts, and separates its product.

In further embodiment, the present invention relates to a kind of method, by use a kind of prodrug to the patient, fully and to treat effective and efficient manner, thereby make derivative be easy to absorb the uniformity that also improves result of treatment when oral administration, described prodrug comprises COOH functional group and the selected amino acid whose NH that makes the fibric acid derivative molecular ₂Or OH functional group reacts forming ester or acid amides covalent bond respectively, and separates its product and give described product to the patient.

Determine, when unsubstituted naturally occurring amino acid esterified to the fibric acid derivative the time, resulting prodrug is the powder of good fluidity first-class in the pharmacy, and be absorbed in the body apace, in vivo by decomposing and discharge nontoxic amino acid, and do not need emulsifier, additive and other excipient (exepients).

And, have been found that the present invention also generates medicine, though they are prodrugs of fibric acid derivative; But they self are exactly antihyperlipidemic and show this effect efficiently.Therefore, L-threonine derivatives of high therapeutic index of the present invention is effective lipidemia medicine, and useful to treating the relevant disease of a large amount of high cholesterols, and whether discharges active parent drug and all show this potential.

Because cause acid hydroxy-acid group blocked, prodrug of the present invention is considered to not have any acidity, yet, show whether these prodrugs discharge the fibric acid derivative all is effective antihyperlipidemic.Described all fibric acid derivative prodrugs all discharge the active medicine with its all pharmacology and cholesterol reducing characteristic in vivo.

The present invention clearly provides the many advantages that surpass the fibric acid derivative, and for example, all side chains that decompose from these prodrugs all are naturally occurring essential amino acids, are nontoxic therefore.This has caused high therapeutic index.The second, all these prodrugs all are easy to decompose to discharge the fibric acid derivative in vivo.And, because its highly-water-soluble, before intravenously administrable, form solution on the spot by using aseptic freeze-dried powder, perhaps be contained in drug solution in syringe or the bottle in advance by what be provided for infusing, they are easy to administration.Amino-acid ester is more stable than fibric acid derivative, because the COOH group of fibric acid derivative is blocked can not with alkali reaction.Therefore fibric acid derivative prodrug as herein described is more effective than fibric acid derivative itself, and toxicity and other pharmacy problem of not having present commercial preparation to have.

Prodrug of the present invention is the medicine of lipidemia, and it effectively treats mammiferous hyperlipidemia, and its symptom is high triglyceride, low HDL (cholesterol of high-density lipoprotein (HDL) or " good ") and high cholesterol.The fibric acid derivative also is used to reduce LDL (cholesterol of low-density lipoprotein or " bad ").

The exemplary of L-threonine ester, L-hydroxyproline ester and the L-serine ester of synthetic fibric acid derivative is shown in the following synthetic method.These steps also can be used for all other compounds of synthetic fibric acid derivative.

Synthesizing of fibric acid derivative prodrug

The overview of steps of L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic Fenofibric Acid is in synthetic order part and as example.Complete step and analysis data see experimental section.Usually, Fenofibric Acid (100g in batches) prepares from 4-chloro-4 '-dihydroxy benaophenonel (hydroxybezophenone) according to the step in the document.Use EDC as coupling agent, and use the DMAP of catalytic amount, the tertiary butyl ester reaction of the amino acid (L-serine, L-threonine and L-hydroxyproline) of Fenofibric Acid and N-Boc protection.Blocking group is removed with the mixture of carrene with the hydrochloric acid in the acetate (1M) down at low temperature (5 ℃, 3-6 days).The amino-acid ester salt of Fenofibric Acid passes through by the ethyl acetate crystallization purifying, and dry under high vacuum.

Synthetic order:

L-serine ester, L-threonine ester and the L-hydroxyproline ester of synthetic Fenofibric Acid: a) Boc-Ser-OtBu, EDC, DMAP, CH ₂Cl ₂B) Boc-Thr-OtBu, EDC, DMAP, CH ₂Cl ₂C) Boc-Hyp-OtBu, EDC, DMAP, CH ₂Cl ₂D) HCl, AcOH, CH ₂Cl ₂

Experimental section:

SPIB00201, SPIB00202 and SPIB00203 synthetic by a collection of or two batches carry out.The reagent of mentioning in the experimental section is the highest commercially available purity that gets, available from Lancaster, Sigma-Aldrich, Acros or Bachem, except solvent is available from Fisher Scientific or Mallinkrodt.

1) Fenofibric Acid is synthetic:

The mixture of 4-chloro-4 '-dihydroxy benaophenonel (116g, 0.500 mole) and sodium hydroxide (120g, 3.00 moles) is heated to backflow in acetone (1L), continue 2 hours.Stop heating, and remove heating source.Acetone (300mL) mixed liquor that dropwise adds chloroform (179g, 1.50 moles).Do not heat, reactant mixture stirs and spends the night.Mixture is heated to reflux and continues 8 hours, then cool to room temperature.Remove by filter sediment, and wash with acetone (100mL).Filtrate under reduced pressure concentrates and obtains brown oil.Add water (200mL) in brown oil, and with 1N hcl acidifying (to pH=1).Filter the sediment that forms, and dry under high vacuum.Remaining yellow solid (268g) divides 4 batches (every batch of 400mL toluene) recrystallization from toluene.Filter and under high vacuum after the drying, this experiment generation Fenofibric Acid (116g, 73% productive rate) is light yellow solid.

¹H NMR(300MHz，DMS0-d ₆)：δ＝13.22(1H，s，br)，7.72(4H，d，J＝8.4Hz)，7.61(2H，d，J＝7.8Hz)，6.93(2H，d，J＝7.8Hz)，1.60(6H，s)。

¹³C NMR(75 MHz，DMSO-d ₆)：δ＝192.96，174.18，159.35，136.84，136.12，131.67，131.02，129.12，128.43，116.91，78.87，25.13。

2) SPIB00201:L-serine FENOBRATE acid esters

To the Fenofibric Acid (11.6g that cools off in ice-water bath, 36.3 N-benzyloxycarbonyl group-L-serine tertiary butyl ester (Boc-Ser-OtBu mM),, 8.62g, 33.0 EDC (7.59g mM),, 39.6 mM) and in the mixture of DMAP (484 mg, 3.96 mMs) drip anhydrous methylene chloride (150mL).Drip and finish, remove ice bath, reactant mixture stirred 20 hours in room temperature and argon atmospher.After 20 hours, add carrene (200mL) again, solution with water (2 * 200mL) and salt solution (200mL) washing.After dried over sodium sulfate and filtration, solution under reduced pressure concentrates.Remaining yellow oil (21.2g) goes up at silica gel (400g, 0.035-0.070mm, 6nm aperture) and uses column chromatography purification, with heptane/ethyl acetate (3: 1) wash-out.After the product that contains each cut under reduced pressure concentrated, dry up to constant weight under high vacuum, this experiment generation shielded L-serine FENOBRATE acid esters SPIB0020101 (16.2g, 87% productive rate) was a kind of light yellow oil.

¹H NMR(300MHz，CDCl ₃)：δ＝7.75(2H，d，J＝9.0Hz)，7.72(2H，d，J＝9.0Hz)，7.45(2H，d，J＝8.7Hz)，6.86(2H，d，J＝8.7Hz)，5.04(1H，d，J＝6.9Hz)，4.55-4.42(3H，m)，1.66(3H，s)，1.65(3H，s)，1.43(9H，s)，1.39(9H，s)。

¹³C NMR(75MHz，CDCl ₃)：δ＝193.92，172.99，168.07，159.24，154.87，138.24，136.19，131.94，131.06，130.40，128.41，117.26，82.88，80.13，79.24，65.44，53.44，28.27，27.92，25.70，25.30。

To being cooled to 5 ℃, the solution of the shielded L-serine FENOBRATE acid esters SPIB0020101 (16.2g, 28.8 mMs) in anhydrous methylene chloride (100mL), the acetic acid of agitation and dropping hydrochloric acid in argon atmospher (400mL, 1M, 400 mMs) solution.Reactant mixture stirred 3 days at 5 ℃.Mixture under reduced pressure concentrates after 3 days, and is dry to remove acetic acid under high vacuum.In remaining light yellow oil (24.7g), add ethyl acetate (100mL).Solution concentrates once more and is dry.In remaining light yellow oil (17.0g), add ethyl acetate (65mL).Mixture is heated to reflux and continues 5 minutes, again cool to room temperature.Remove by filter sediment and under room temperature and high vacuum dried overnight, then 43 ℃ of dryings 1 hour.It is white solid that this experiment generates L-serine Fenofibric Acid ester hydrochloride SPIB00201 (7.66g, 60% productive rate).

¹H NMR(300MHz，DMS0-d ₆)：δ＝14.12(1H，s，br)，8.77(3H，s，br)，7.72(4H，m)，7.62(2H，d，J＝8.4Hz)，6.92(2H，d，J＝9.0Hz)，4.62(1H，dd，J＝12.0，4.2Hz)，4.50(1H，dd，J＝12.0，2.4Hz)，4.41(1H，m)，1.64(3H，s)，1.63(3H，s)。

¹³C NMR(75 MHz，DMSO-d ₆)：δ＝193.06，171.70，168.06，158.72，136.93，136.06，131.73，131.09，129.62，128.49，117.64，79.02，62.99，51.11，25.04，24.94。

HPLC analyzes:

100% purity; R.t.=4.361min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1mL/min; 32.3 C, Luna C18, serial#167917-13; 20ul injects., NB275-49.

The CHN elementary analysis:

Calculated value: C 54.31, H 4.79, and N 3.17; Measured value: C 54.37, H 4.78, N 3.12.

Fusing point: 151 ℃ (decomposition)

3) SPIB00202:L-threonine FENOBRATE acid esters

To the Fenofibric Acid (25.5g that cools off in ice-water bath, 79.9 N-benzyloxycarbonyl group-L-threonine tertiary butyl ester (Boc-Thr-OtBu mM),, 20.0g, 72.6 mM, with literature method preparation), EDC (16.7g, 87.1 mM) and in the mixture of DMAP (1.06g, 8.71 mMs) dropwise add anhydrous methylene chloride (200mL).Finish after the interpolation, remove ice bath, reactant mixture stirred 20 hours in room temperature and argon atmospher.After 20 hours, add EDC (1.39g, 7.26 mMs) again, this experiment allows to stir in room temperature and argon atmospher and surpasses a weekend.After 4 days, add carrene (300mL) again, solution with water (300mL) and salt solution (300mL) washing.Through dried over sodium sulfate and after filtering, solution under reduced pressure concentrates.Remaining yellow oil (53.5g) goes up at silica gel (500g, 0.035-0.070mm, 6nm aperture) and uses column chromatography purification, with heptane/ethyl acetate (3: 1) wash-out.The product that contains each cut is behind concentrating under reduced pressure, and dry up to constant weight under high vacuum, this experiment generates shielded L-threonine FENOBRATE acid esters SPIB0020201 (34.1g, 82% productive rate), is white foam shape thing.

¹H NMR(300MHz，CDCl ₃)：δ＝7.74(2H，d，J＝8.4Hz)，7.72(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，6.87(2H，d，J＝8.4Hz)，5.47(1H，m)，4.98(1H，d，J＝9.9Hz)，4，31(1H，d，J＝9.9Hz)，1.65(3H，s)，1.64(3H，s)，1.45(9H，s)，1.42(9H，s)，1.22(3H，d，J＝6.3Hz)。

¹³C NMR(75MHz，CDCl ₃)：δ＝193.94，172.14，168.70，159.26，155.62，138.28，136.18，131.90，131.08，130.37，128.43，117.40，82.70，80.17，79.38，72.02，57.46，28.30，27.99，26.44，24.79，16.90。

To the solution that is cooled to shielded L-threonine FENOBRATE acid esters SPIB0020201 (34.1g, 59.2 mMs) 5 ℃, in anhydrous methylene chloride (100mL), the acetic acid of agitation and dropping hydrochloric acid in argon atmospher (600mL, 1M, 600 mMs) solution.Reactant mixture kept 6 days at 5 ℃.Mixture under reduced pressure concentrates, and is dry to remove acetic acid under high vacuum.Add ethyl acetate (500mL) to remaining white solid (45.8g).Mixture is heated to reflux and continues 10 minutes, and cool to room temperature.Remove by filter sediment and dried overnight under room temperature and high vacuum.The L-threonine Fenofibric Acid ester hydrochloride SPIB00202 (26.3g, 97% productive rate) that this experiment generates, it is a white solid.

¹H NMR(300MHz，DMSO-d ₆)：δ＝14.10(1H，s，br)，8.84(3H，s，br)，7.73(4H，m)，7.63(2H，d，J＝8.1Hz)，6.89(2H，d，J＝8.7Hz)，5.44(1H，m)，4.31(1H，s)，1.64(3H，s)，1.62(3H，s)，1.38(3H，d，J＝6.3Hz).

¹³C NMR(75 MHz，DMSO-d ₆)：δ＝193.04，171.00，168.13，158.76，136.90，136.08，131.70，131.06，129.49，128.48，117.41，78.99，69.40，55.21，25.59，24.22，16.06。HPLC analyzes:

98.59% purity; R.t.=4.687min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1mL/min; 32.3 C, Luna C18, serial#167917-13; 20ul injects, NB275-49, DAD1B, Sig=210.4, Ref=550,100.

The CHN elementary analysis:

Calculated value: C 55.27, H 5.08, and N 3.07; Measured value: C 54.98, H 5.13, and N 3.03.

Fusing point: 160.5 ℃ (decomposition)

4) SPIB00203:L-hydroxyproline FENOBRATE acid esters

To the Fenofibric Acid (24.9g that cools off in ice-water bath, 78.1 N-benzyloxycarbonyl group-L-hydroxyproline tertiary butyl ester (Boc-Hyp-OtBu mM),, 20.4g, 71.0 mM, according to document step preparation), EDC (16.3g, 85.2 mM) and in the mixture of DMAP (1.04g, 8.52 mMs) dropwise add anhydrous methylene chloride (200mL).Finish after the interpolation, remove ice bath, reactant mixture stirred 20 hours in room temperature and argon atmospher.After 20 hours, add EDC (1.63g, 8.52 mMs) again, this experiment allows to stir in room temperature and argon atmospher and surpasses a weekend.After 4 days, solution with water (200mL) and salt solution (200mL) washing.Through dried over sodium sulfate and after filtering, solution under reduced pressure concentrates.Remaining yellow oil (49.4g) goes up at silica gel (500g, 0.035-0.070mm, 6nm aperture) and uses column chromatography purification, with heptane/ethyl acetate (2: 1) wash-out.After the product that contains each cut under reduced pressure concentrates, dry up to constant weight under high vacuum, this experiment generation shielded L-hydroxyproline FENOBRATE acid esters SPIB0020301 (26.4g, 63% productive rate), it is a colorless oil.

¹H NMR(300MHz，CDCl ₃)：δ＝7.76(2H，d，J＝8.1Hz)，7.73(2H，d，J＝8.1Hz)，7.46(2H，d，J＝8.1Hz)，6.84(2H，d，J＝8.1Hz)，5.32(1H，m)，4.13(0.38H，t，J＝7.8Hz)，4.00(0.62H，t，J＝7.8Hz)，3.67(1.62H，m)，3.46(0.38H，d，J＝12.6Hz)，2.29(1H，m)，2.15(1H，m)，1.68(3H，s)，1.66(3H，s)，1.44-1.38(18H，m)。

¹³C NMR(75 MHz，CDCl ₃)：δ＝193.88，172.98，171.14，159.25，153.48，138.23，136.16，131.99，131.08，130.36，128.44，117.03，116.91，81.48，80.32，80.20，79.19，74.03，73.26，58.23，51.88，51.58，36.33，35.31，31.92，28.29，28.00，25.89，24.95。

To being cooled to shielded L-hydroxyproline FENOBRATE acid esters SPIB0020301 (26.0g 5 ℃, in anhydrous methylene chloride (100mL); 44.2 solution mM); the acetic acid of agitation and dropping hydrochloric acid in argon atmospher (450mL, 1M, 450 mMs) solution.Reactant mixture stirred 4 days at 5 ℃.After 4 days, mixture under reduced pressure concentrates, and is dry to remove acetic acid under high vacuum.Add ethyl acetate (200mL) to remaining yellow oil (31.5g).The ultrasonic treatment mixture, and under reduced pressure concentrate and drying under high vacuum.Add ethyl acetate (300mL) to remaining white solid (23.2g).The ethyl acetate mixture is heated to reflux and continues 10 minutes, cool to room temperature.Remove by filter sediment and dried overnight under room temperature and high vacuum.This experiment generates L-hydroxyproline Fenofibric Acid ester hydrochloride SPIB00203 (15.8g, 76% productive rate), and it is a white solid.

¹H NMR(300MHz，DMSO-d ₆)：δ＝14.07(1H，s，br)，10.75(1H，s，br)，9.40(1H，s，br)，7.71(4H，d，J＝8.1Hz)，7.60(2H，d，J＝8.1Hz)，6.96(2H，d，J＝8.1Hz)，5.42(1H，m)，4.24(1H，t，J＝9.0Hz)，3.61(1H，dd，J＝13.2，4.2Hz)，3.28(1H，d，J＝13.2Hz)，2.35(2H，m)，1.66(3H，s)，1.64(3H，s)。

¹³C NMR(75MHz，DMSO-d ₆)：δ＝193.00，171.52，169.14，158.81，136.87，136.09，131.81，131.05，129.48，128.46，117.28，78.99，73.79，57.54，50.23，34.13，25.69，24.49。

HPLC analyzes:

100% purity; R.t.=8.369min.; 60%DIUF water (0.1% trifluoroacetic acid)/40% acetonitrile; 1mL/min; 36.4 C; Luna C18,5u post (serial# 191070-3), 4.6 * 250mm; 20ul injects; DAD1A, Sig=210.4, Ref=550,100.

HPLC-MS (ESI): calculated value: M ⁺=431; Measured value: M+H=432.3

Fusing point: 187.5 ℃ (decomposition)

Leave standstill by the excessive every kind of medicine of dissolving and with it and to determine above-mentioned various ester solvability under the room temperature in water in several hours.Gained solution centrifugal 3 minutes, analytically clear liquid at 1500 rev/mins (rpm).It shows that the solvability of these esters in water surpasses 50mg/mL.

Experiment

Check triglyceride levels in the mouse blood in time zero.Then, feed mouse, fed for 1 week such as 30% sucrose water with high-carbonhydrate diet.When 1 week finished, measure the triglycerides of mouse then, and feed with normal diet.From 7-14 days, mouse is given the medicine of test group or control group.Measured triglycerides in the mouse blood once more at the 14th day.

In the comparison of the L-serine ester (detection of drugs) of fenofibrate (contrast) and Fenofibric Acid, every kind of medicine and to impinging upon same dose 50,100 and 200 mg/kg each is tested with 3 mouse.

The result is as follows.

Characteristic-fenofibrate and its preparation specimen that serum lipids reduces studied-impelled to summary-dosage range: the L-serine ester of Fenofibric Acid

Excipient: the milli Q water that contains 1% Tween 80

Test event	Dosage Mg/kg)	Number of animals	Triglycerides (mg/dl)
									Initial day	The 7th day	The 14th day
Excipient
		0	1	81	168	121
							2	88	171	222
			3	114	133	162
With reference to the contrast fenofibrate							50	4	95	157	101
	5	92	228	76
					6	80		150	73
	100	7	110	204						62
					8	115	195	69
		9	96	167					93
					200	10	144	90		48
	11	56	106	51
						12	58	125	38
	The L-serine ester of Fenofibric Acid	50	13	88						148	86
14					94	145	86
			15	100				127	73
100					16	109	-			46
		17	129	100				69
					18	71	183		47
		200	19	74				240		83
20					81	158	61
			21	42				77	46

From above result, can reach a conclusion, it is effective using high water-soluble serine ester.

According to disclosed method, there are many screening tests to determine the application of the prodrug produced.These comprise ExternalWith In the bodyScreening technique.

External method comprises acid/basic hydrolysis, the hydrolysis in pig pancreas, the hydrolysis in mouse intestinal juice, the hydrolysis in human gastric juice, the hydrolysis in human intestinal juice and the hydrolysis in human plasma of prodrug.These determination methods are described in Simmons, DM, Chandran, VR and Portmann, GA, DanazolAmino Acid Prodrugs:In Vitro and In Situ Biopharmaceutical Evaluation, DrugDevelopment and Industrial Pharmacy, Vol 21, Issue 6, Page 687,1995, and its all the elements are incorporated by reference.

These fibric acid prodrugs of the present invention are effective to the disease or the symptom for the treatment of common use fibric acid derivatives for treatment.Prodrug disclosed herein transforms in vivo with release of active compounds, and by alleviating or eliminate biopharmacy and the pharmacokinetics barrier of following various fibric acid derivatives, and help treatment.Yet, it should be noted that these prodrugs itself have enough activity, even in mammalian body, do not discharge any active medicine.

Like this, prodrug of the present invention has the biopharmacy and the pharmacokinetics barrier of medicine now by elimination, and helps treatment.

And, by using the commercially available reagent that is easy to get, can be with the easily synthetic described prodrug of high yield.

Fibric acid prodrug of the present invention is effective to the disease or the symptom for the treatment of common use fibric acid derivatives for treatment.Prodrug disclosed herein transforms in vivo with release of active compounds, and by alleviating or eliminate biopharmacy and the pharmacokinetics barrier of following various fibric acid derivatives, and help treatment.Yet, it should be noted that these prodrugs itself have enough activity, even in mammalian body, do not discharge any active medicine.

Like this, fibric acid prodrug of the present invention has the biopharmacy and the pharmacokinetics barrier of medicine now by elimination, and helps treatment.And, by using the commercially available reagent that is easy to get, can be with the easily synthetic described prodrug of high yield.

At above-mentioned general formula and in the claims, should understand AA have in the following content to give a definition

In this definition, AA is meant does not have amino amino acid residue on main chain or side chain.

In this definition, the amino acid residue of AA is meant on side chain not to be had (less) hydroxyl.

AA is meant the amino acid group that does not have carboxyl on main chain or side chain.

4) OAA-this be at the hydroxyl of medicine and the ester bond between the carboxyl on amino acid backbone or the side chain.Like this, as written upward expression, OAA is

R wherein _OIt is side chain amino acid as above definition.

In other words, OAA-can be meant the ester bond between the hydroxyl on the side chain of the carboxyl of medicine and those amino acid with hydroxyl such as threonines, serine, hydroxyproline, tyrosine etc.Hydroxyl forms the part of ester bond, is above describing with O.Like this, as written go up expression, AA is meant the amino acid that has hydroxyl on the side chain, but when representing with OAA, AA is not hydroxyl, because oxygen atom has been indicated in the general formula.

Should be understood to; although the present invention describes in detail in conjunction with its specification; above description is in order to illustrate the explanation of enumerating of the present invention, but not limiting the scope of the invention, and protection scope of the present invention is that the scope by appended claim limits.Other aspect, advantage and modification are all in the protection domain of following claim.

Claims (563)

1. method that strengthens at least two kinds of therapeutic properties of medicine, described medicine has the functional group of the acylated derivatives that is selected from hydroxyl, amino, carboxyl or described carboxyl, and the therapeutic properties of described enhancing is selected from as follows:

(a) taste of Gai Shaning or smell

(b) Qi Wang octanol/water distribution coefficient

(c) stability of Gai Shaning

(d) permeability of enhancing blood brain barrier

(e) eliminate the interior first pass effect of liver

(f) minimizing of intestines liver recycle

(g) painless injection of parenteral formulation

(h) bioavilability of Gai Shaning

(i) variation of raising absorption ratio

(j) reduce side effect (k) dosage proportionality

(1) selective hydrolysis of prodrug on site of action

(m) controllable release performance

(n) medicine of target transmits

(o) reduce toxicity (p) and reduce dosage

(q) change metabolic pathway on site of action, to discharge more multiple medicines thing

(r) be increased in solvability in the aqueous solution

(s) strengthen effectiveness,

Described method comprises that (a) effectively forming between described medicine and the described amino under the condition of covalent bond, with described medicine and amino acid reaction and (b) to its patient who needs to the product of (a).

2. according to the process of claim 1 wherein that described amino acid is naturally occurring amino acid.

3. according to the process of claim 1 wherein that described amino acid is α-L-amino acid.

4. according to the process of claim 1 wherein that described amino acid is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

5. according to the process of claim 1 wherein that AA is proline, glycine, lysine, hydroxyproline or alanine.

6. according to the method for claim 5, wherein AA is Lys or hydroxyproline.

7. according to the method for claim 6, wherein AA is Lys.

8. according to the process of claim 1 wherein that described medicine is a cyclosporin, Lopinavir, Ritonavir, Cefdinir, Zileuton, viracept see nelfinaivr, flavoxate, Candesartan, Propofol, Nisoldipine, Amlodipine, Ciprofloxacin, Ofloxacin, fosinopril, enalapril, Ramipril, benazepil, Moexipril, Trandolapril, nasmil, the Amoxicillin, cefuroxime, cefotaxime, Cefpodoxime, Atovaquone, Ganciclovir, Penciclovir, famciclovir, aciclovir, nicotinic acid, retinene, the third oxygen sweet smell, salsalate, paracetamol, brufen, Lovastatin, simvastatin, Atorvastatin, Pravastatin, Fluvastatin, Nadolol, Valsartan, methylphenidate, sulfonamide, Sulfasalazine, methylprednisolone, Medroxyprogesterone, Estramustine, Miglitol, Mefloquine, capecitabine, reach that azoles, eprosartan, divalproex sodium, fenofibrate, Gabapentin, Omeprazole, Lansoprazole, megestrol acetate, melbine, tazarotene, sumatriptan, naratriptan, Zomitriptan, aspirin, Olmesartan, sirolimus, tacrolimus, clopidogrel, anphotericin, tenofovir, Unoprostone, fulvestrant, Cefditoren, efavirenz, eplerenone, the treprostinil that, or adefovirdipivoxil.

9. the compound of a following formula, or its pharmaceutically acceptable salt:

Or

Or

Or

Or

Wherein CYCLO represents the residue on the 2-11 site of cyclosporin molecule; X-y is CH=CH or CH ₂=CH ₂, and R ²Be OAA or OGly-AA, AA is the amino acid residue that does not have the OH base on the carboxyl, and wherein Gly is a glycine residue, and is the interval group that is connected to the oxygen atom of cyclosporin, sirolimus, tacrolimus or Elidel.

10. according to the compound of claim 9, wherein AA is a kind of naturally occurring α-L-amino acid.

11. according to the compound of claim 9, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

12. according to the compound of claim 9, wherein AA is proline, glycine, lysine or ornithine.

13. according to the compound of claim 9, wherein AA is Lys or ornithine.

14. according to the compound of claim 9, wherein said compound has following formula

15. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 9-14 and its pharmaceutically acceptable carrier.

16. a treatment needs the patient's of cyclosporin treatment method, it comprise to described patient give with treatment go up effective dose according to each described compound of claim 9-14.

17. method that strengthens the cyclosporin dose ratio; it comprises the hydroxy functional group of the MeBmt part that is positioned at site 1 on the cyclosporin molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to the patient.

18. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid residue of the hydroxyl of carboxyl.

19. according to the compound of claim 18, wherein AA is naturally occurring α-L-amino acid.

20. according to the compound of claim 18, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

21. according to the compound of claim 18, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

22. according to the compound of claim 18, wherein AA is Lys or hydroxyproline.

23. according to the compound of claim 18, wherein AA is Lys.

24. a pharmaceutical composition, it comprise treatment go up effective dose according to each described compound of claim 18-23 or its pharmaceutically acceptable carrier.

25. a treatment needs a kind of method of the patient of Lopinavir treatment, it comprise to described patient give with treatment go up effective dose according to each described compound of claim 18-23.

26. a method that increases Lopinavir solvability in the aqueous solution, it comprises the hydroxy functional group of Lopinavir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

27. a method that increases the bioavilability of Lopinavir when patient's administration comprises the hydroxy functional group of Lopinavir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separate its product, to the described product of described patient's administration.

28. a method for the treatment of mammal AIDS, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 18-23, to suppress hiv protease.

29. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁AA ₁Be not have the OH group and the amino acid that on its side chain, has OH; And AA removes NH ₂The amino acid of group.

30. according to the compound of claim 29, wherein AA and AA ₁Be L-α-naturally occurring amino acid.

31. compound according to claim 29, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, and AA ₁Be Ser, Thr, Tyr or hydroxyproline.

32. according to the compound of claim 29, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, perhaps AA ₁Be Tyr, hydroxyproline or serine.

33. according to the compound of claim 29, wherein AA or AA ₁Be serine or hydroxyproline.

34. according to the compound of claim 29, wherein AA or AA ₁It is hydroxyproline.

35. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 29-34, or its pharmaceutically acceptable carrier.

36. a treatment needs the patient's of Cefdinir treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 29-34.

37. a method that increases Cefdinir solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the Cefdinir molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

38. method that to patient's administration the time, increases the bioavilability of Cefdinir; it comprises that the carboxylic acid functional that makes the Cefdinir molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product and give and described product to described patient.

39. a method for the treatment of the infectious disease that mammal causes by pathogenic microorganisms, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 29-34.

40. a following formula: compound, or its pharmaceutically acceptable salt:

Zileuton

Wherein AA is the amino acid that does not have OH on carboxyl.

41. according to the compound of claim 40, wherein AA is L-α-naturally occurring amino acid.

42. according to the compound of claim 40, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

43. according to the compound of claim 40, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

44. according to the compound of claim 40, wherein AA is Lys or hydroxyproline.

45. according to the compound of claim 40, wherein AA is Lys.

46. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 40-45, or its pharmaceutically acceptable carrier.

47. a treatment needs the patient's of Zileuton treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 40-45.

48. a method that increases Zileuton solvability in the aqueous solution comprises that the hydroxy functional group that makes the Zileuton molecule and an amino acid or its acylated derivatives react, and separates its product under the ester formation condition.

49. a method for the treatment of mammal asthma, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 40-45.

50. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid that does not have hydroxyl on its carboxyl.

51. according to the compound of claim 50, wherein AA is the naturally occurring a-amino acid of L-.

52. according to the compound of claim 50, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

53. according to the compound of claim 50, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

54. according to the compound of claim 50, wherein AA is Lys or hydroxyproline.

55. according to the compound of claim 50, wherein AA is Lys.

56. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 50-55 and its pharmaceutically acceptable carrier.

57. a treatment needs the patient's of viracept see nelfinaivr treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 50-55.

58. a method that increases viracept see nelfinaivr solvability in the aqueous solution, it comprises that the hydroxy functional group that makes the viracept see nelfinaivr molecule and amino acid or its acylated derivatives react under the ester formation condition, and separates its product.

59. method that to patient's administration the time, increases the bioavilability of viracept see nelfinaivr; it comprises that the hydroxy functional group that makes the viracept see nelfinaivr molecule and amino acid or its acylated derivatives react under the ester formation condition; and separate its product, give and described product to described patient.

60. a method for the treatment of the AIDS that mammal causes by HIV, it comprise to the described mammal of this treatment of needs give with treatment go up effective dose according to each described compound of claim 50-55.

61. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA ₁Connect by ester bond, and do not have the amino acid residue of hydroxyl, and have only hydroxyl on its side chain, be connected by amido link with AA, and be not have amino amino acid residue.

62. according to the compound of claim 61, wherein AA and AA ₁It is naturally occurring L-a-amino acid alone.

63. compound according to claim 61, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

64. according to the compound of claim 61, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, and AA ₁Be Thr, Ser or hydroxyproline.

65. according to the compound of claim 61, wherein AA or AA ₁Be serine or hydroxyproline.

66. according to the compound of claim 61, wherein AA or AA ₁It is hydroxyproline.

67. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 61-66 and its a kind of pharmaceutically acceptable carrier.

68. a treatment needs a kind of method of the patient of flavoxate treatment, it comprise to described patient give with the treatment effective dose according to each described compound of claim 61-66.

69. a method that increases flavoxate solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the flavoxate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

70. method that to patient's administration the time, increases the bioavilability of flavoxate; it comprises that the carboxylic acid functional that makes the flavoxate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product and give and described product to described patient.

71. a method for the treatment of mammal uropoiesis spasm, it comprise to the described mammal of needs treatments give with the treatment effective dose according to each described compound of claim 61-66.

72. a following formula: compound, or its pharmaceutically acceptable salt:

Candesartan Cilexetil

Wherein R is NH-AA ₁Or O-AA, be connected by amido link with AA, and be not have amino amino acid residue on main chain or the side chain, and AA ₁Be the amino acid residue that does not have hydroxyl, and on its side chain, have hydroxyl.

73. according to the compound of claim 72, wherein AA ₁Be Ser, Try or Tyr or hydroxyproline.

74. according to the compound of claim 72, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

75. according to the compound of claim 72, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, or AA ₁Be serine, threonine or hydroxyproline.

76. according to the compound of claim 72, wherein AA or AA ₁Or serine or hydroxyproline.

77. according to the compound of claim 72, wherein AA or AA ₁It is hydroxyproline.

78. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 72-77 and its pharmaceutically acceptable carrier.

79. a treatment needs a kind of method of the patient of Candesartan treatment, the method comprise on described patient's drug treatment effective dose according to each described compound of claim 72-77.

80. a method that increases Candesartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Candesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

81. method that to patient's administration the time, increases the bioavilability of Candesartan; it comprises the carboxylic acid functional of Candesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

82. a treatment mammal hypertensive method, it comprise to the described mammal of needs treatment give with the treatment effective dose according to each described compound of claim 72-77.

83. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid that does not have hydroxyl on its carboxyl.

84. 3 compound according to Claim 8, wherein AA is a kind of naturally occurring L-amino acid.

85. 3 compound according to Claim 8, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

86. 3 compound according to Claim 8, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

87. 3 compound according to Claim 8, wherein AA is Lys, Gly or proline.

88. 3 compound according to Claim 8, wherein AA is a proline.

89. a pharmaceutical composition, it comprises each described compound of 3-88 according to Claim 8 and its pharmaceutically acceptable carrier for the treatment of effective dose.

90. a treatment needs the patient's of Propofol treatment method, the method comprises each described compound of 3-88 according to Claim 8 of effective dose on described patient's drug treatment.

91. the method that the safety that increases the long anaesthetic effect of Propofol in the aqueous solution distributes, it comprises the hydroxy functional group of Propofol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

92. a method that increases the bioavilability of Propofol to patient's administration the time, it comprises the hydroxy functional group of Propofol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product, to described patient to and described product.

93. a method that provides central nervous system to anaesthetize to the patient, it comprises each described compound of 3-88 according to Claim 8 of giving and treating effective dose to the patient of this anesthesia of needs.

94. a following formula: compound, or its pharmaceutically acceptable salt:

The Amlodipine Nisoldipine

R ₂Be

R ₄Be NH-AA ₁Or O-AA,

R ₅Be AA ₂,

Wherein AA is the amino acid residue that does not have hydroxyl that is connected by ester bond, and it has hydroxyl on side chain,

AA ₁Be not have amino amino acid residue,

AA ₂Be the amino acid residue that on carboxyl, does not have hydroxyl,

AA ₃It is the amino acid residue that on amino, does not have hydrogen atom.

95. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is naturally occurring L-a-amino acid alone.

96. according to the compound of claim 94, wherein AA ₁, AA ₂And AA ₃Be alone the residue of Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, and AA is Ser, Thr, hydroxyproline or Tyr.

97. according to the compound of claim 94, wherein AA ₁, AA ₂And AA ₃It is alone the residue of proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

98. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is alone the amino acid residue of serine or hydroxyproline.

99. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is alone the amino acid residue of hydroxyproline.

100. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 94-99 and its pharmaceutically acceptable carrier.

101. a treatment needs the patient's of calcium channel blocker treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 94-100.

102. method that increases calcium channel blocker solvability in the aqueous solution; described calcium channel blocker is selected from Amlodipine or Nisoldipine; described method comprises reacts the carboxylic acid functional of calcium channel blocking agent molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

103. method that to patient's administration the time, increases the bioavilability of calcium channel blocker; described calcium channel blocker is selected from Amlodipine or Nisoldipine; described method comprises reacts the carboxylic acid functional of calcium ion channel blocker molecule and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product and give and described product to described patient.

104. a treatment mammal hypertensive method, comprise to the mammal of the described treatment of needs give with the treatment effective dose according to each described compound of claim 94-100.

105. a following formula: compound, or its pharmaceutically acceptable salt:

The Ofloxacin Ciprofloxacin

Wherein R is NH-AA or O-AA ₁, wherein AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have hydroxyl, but have hydroxyl on its side chain.

106. according to the compound of claim 105, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

107. compound according to claim 105, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

108. according to the compound of claim 105, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

109. according to the compound of claim 105, wherein AA or AA ₁Be serine or hydroxyproline.

110. according to the compound of claim 105, wherein AA or AA ₁It is hydroxyproline.

111. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 105-109 and its pharmaceutically acceptable carrier.

112. a treatment is by the patient's of infected by microbes infectious disease method, and xacin-series (oxacin) and Ciprofloxacin are poisonous treatments to this microorganism, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 105-109.

113. method that increases quinolone antibiotic solvability in the aqueous solution; described quinolone antibiotic has carboxylic group or acidylate group; described method comprises reacts the carboxylic acid functional of quinolone antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

114. method that to patient's administration the time, increases the antibiotic bioavilability of quinolone; described quinolone antibiotic has carboxylic group or acidylate group; described method comprises reacts the carboxylic acid functional of quinolone antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product, give and described product to described patient.

115. method for the treatment of the infectious disease that mammal causes by pathogenic microorganisms, and Ofloxacin and Ciprofloxacin are poisonous to described pathogenic microorganisms, and described method comprises to described mammal gives various preparations according to each described use quinolone Antibiotique composition of claim 105-109 with antimicrobial effective amount.

116. a following formula: compound, perhaps pharmaceutically acceptable salt:

Enalapril

Ramipril

Fosinopril Na

Benazepil

Perindopril

Moexipril

Trandolapril

Wherein R is NH-AA or O-AA ₁, and AA do not have amino amino acid residue, and AA ₁Be not have the amino acid residue of OH group and on its side chain, have the OH group.

117. according to the compound of claim 116, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

118. compound according to claim 116, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be hydroxyproline, Tyr or Ser or Thr.

119. according to the compound of claim 116, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, or AA ₁Be serine, hydroxyproline or Thr.

120. according to the compound of claim 116, wherein AA or AA ₁Be alone serine or hydroxyproline.

121. according to the compound of claim 116, wherein AA or AA ₁It is hydroxyproline.

122. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 116-121 and its pharmaceutically acceptable carrier.

123. a method for the treatment of the hyperpietic, it comprise to described patient give with the treatment effective dose according to each described compound of claim 116-121.

124. method that increases ace inhibitor solvability in the aqueous solution; described ace inhibitor has carboxyl or acidylate group; described method comprises reacts the carboxylic acid functional of ace inhibitor molecules and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

125. method that to patient's administration the time, increases the bioavilability of ace inhibitor; described ace inhibitor has carboxyl or acidylate group; described method comprises reacts the carboxylic acid functional of ace inhibitor molecules and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product and give and described product to described patient.

126. a following formula: compound, or its pharmaceutically acceptable salt:

Nasmil

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on its carboxyl, and R is an ethyl.

127. according to the compound of claim 126, wherein AA is naturally occurring L-a-amino acid.

128. according to the compound of claim 126, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

129. according to the compound of claim 126, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

130. according to the compound of claim 126, wherein AA is Lys or hydroxyproline.

131. according to the compound of claim 126, wherein AA is Lys.

132. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 126-131 and its pharmaceutically acceptable carrier.

133. a treatment needs the patient's of nasmil treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 126-131.

134. a method that increases nasmil solvability in the aqueous solution, it comprises the hydroxy functional group of nasmil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

135. method that to patient's administration the time, increases the bioavilability of nasmil; it comprises the hydroxy functional group of nasmil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product, to the described product of described patient's administration.

136. a following formula: compound, or its pharmaceutically acceptable salt:

The Amoxicillin

Cefuroxime

Cefotaxime

Cefpodoxime

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

137. according to the compound of claim 136, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

138. compound according to claim 136, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Ser, Thr, Tyr or hydroxyproline.

139. according to the compound of claim 136, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

140. according to the compound of claim 136, wherein AA or AA ₁Be serine or hydroxyproline.

141. according to the compound of claim 136, wherein AA or AA ₁It is hydroxyproline.

142. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 136-141 and its pharmaceutically acceptable carrier.

143. a treatment is by the patient's of infected by microbes method, and Amoxicillin, cefuroxime, cefotaxime and Cefpodoxime (ceftazidime) are poisonous to this microorganism, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 136-141.

144. method that increases cephalosporin antibiotics solvability in the aqueous solution; described cephalosporin antibiotics has carboxylic acid functional; described method comprises reacts the carboxylic acid functional of cynnematin antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

145. method that to patient's administration the time, increases the bioavilability of cephalosporin antibiotics; described cephalosporin antibiotics has a carboxylic acid functional; described method comprises that the carboxylic acid functional that makes the cephalosporin antibiotics molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product, give and described product to described patient.

146. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

147. according to the compound of claim 146, wherein AA is naturally occurring L-a-amino acid.

148. according to the compound of claim 146, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

149. according to the compound of claim 146, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

150. according to the compound of claim 146, wherein AA is Lys or hydroxyproline.

151. according to the compound of claim 146, wherein AA is Lys.

152. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 146-151 and its pharmaceutically acceptable carrier.

153. the method for the mammiferous malaria that causes by the plasmodium parasite of treatment, it comprise to described patient give with the treatment effective dose according to each described compound of claim 146-151.

154. a method that increases Atovaquone solvability in the aqueous solution, it comprises the hydroxy functional group of Atovaquone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

155. method that to patient's administration the time, increases the bioavilability of Atovaquone; it comprises the hydroxy functional group of Atovaquone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product, give and described product to described patient.

156. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

157. according to the compound of claim 156, wherein AA is the naturally occurring a-amino acid of L-.

158. compound according to claim 156, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, condition is for when described medicine is aciclovir, and AA is not Ala or Gly so.

159. according to the compound of claim 156, wherein AA is proline, lysine, hydroxyproline or alanine.

160. according to the compound of claim 156, wherein AA is Lys or proline.

161. according to the compound of claim 156, wherein AA is Lys.

162. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 156-161 and its pharmaceutically acceptable carrier.

163. a treatment suffers from the patient's of human cytomegalovirus method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 156-161.

164. an increase has the method for nucleoside analog solvability in the aqueous solution of OH functional group, it comprises the hydroxy functional group of nucleoside analog molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

165. method that to patient's administration the time, increases the bioavilability of nucleoside analog with OH functional group; it comprises the hydroxy functional group of nucleoside analog molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

166. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

167. according to the compound of claim 166, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

168. compound according to claim 166, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Thr, Ser or hydroxyproline.

169. according to the compound of claim 166, wherein AA is alanine, proline, glycine, lysine, serine, threonine or hydroxyproline.

170. according to the compound of claim 166, wherein AA or AA ₁Or serine or hydroxyproline.

171. according to the compound of claim 166, wherein AA or AA ₁It is hydroxyproline.

172. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 166-171, and pharmaceutically acceptable carrier.

173. a method that reduces mammal body lipid concentration, it comprise to described patient give with the treatment effective dose according to each described compound of claim 166-171.

174. a method that increases nicotinic acid solvability in the aqueous solution, it comprises the carboxylic acid functional of nicotinic acid molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

175. method that to patient's administration the time, increases the bioavilability of nicotinic acid; it comprises the carboxylic acid functional of nicotinic acid molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

176. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

177. according to the compound of claim 176, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

178. compound according to claim 176, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

179. according to the compound of claim 176, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

180. according to the compound of claim 176, wherein AA or AA ₁Be serine or hydroxyproline.

181. according to the compound of claim 176, wherein AA or AA ₁It is hydroxyproline.

182. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 176-181 and its pharmaceutically acceptable carrier.

183. an a kind of method for the treatment of the dermatosis patient that need to activate retinoid X acceptor, the method comprise to described patient give with the treatment effective dose according to each described compound of claim 176-181.

184. a method that increases retinene solvability in the aqueous solution, it comprises the carboxylic acid functional of retinene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

185. method that to patient's administration the time, increases the bioavilability of retinene; it comprises the carboxylic acid functional of retinene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

186. a following formula: compound, or its pharmaceutically acceptable salt:

The third oxygen sweet smell

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

187. according to the compound of claim 186, wherein AA is naturally occurring L-a-amino acid.

188. according to the compound of claim 186, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

189. according to the compound of claim 186, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

190. according to the compound of claim 186, wherein AA is Lys or hydroxyproline.

191. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 186-190 and its pharmaceutically acceptable carrier.

192. a method for the treatment of mammal pain, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 186-190.

193. a method that increases by third oxygen sweet smell solvability in the aqueous solution, it comprises the hydroxy functional group of the fragrant molecule of third oxygen and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

194. method that to patient's administration the time, increases the bioavilability of the third oxygen sweet smell; it comprises the hydroxy functional group of the fragrant molecule of third oxygen and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

195. a following formula: compound, or its pharmaceutically acceptable salt:

Salsalate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have hydroxyl, and on its side chain, have hydroxyl.

196. according to the compound of claim 195, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

197. compound according to claim 195, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

198. according to the compound of claim 195, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

199. according to the compound of claim 195, wherein AA is Lys or hydroxyproline.

200. according to the compound of claim 195, wherein AA is Lys.

201. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 195-200 and its pharmaceutically acceptable carrier.

202. a method for the treatment of patient's inflammation, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 195-200.

203. a method that increases salsalate solvability in the aqueous solution, it comprises the hydroxy functional group of salsalate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

204. method that to patient's administration the time, increases the bioavilability of salsalate; it comprises the hydroxy functional group of salsalate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

205. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid residue that does not have hydroxyl on carboxyl.

206. according to the compound of claim 205, wherein AA is naturally occurring L-a-amino acid.

207. according to the compound of claim 205, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

208. according to the compound of claim 205, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

209. according to the compound of claim 205, wherein AA is Lys or proline.

210. according to the compound of claim 205, wherein AA is a proline.

211. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 205-209 and its pharmaceutically acceptable carrier.

212. a treatment suffers from the method for pain or fever, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 205-209.

213. a method that increases paracetamol solvability in the aqueous solution, it comprises the hydroxy functional group of paracetamol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

214. method that to patient's administration the time, increases the bioavilability of paracetamol; it comprises the hydroxy functional group of paracetamol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

215. a following formula: compound, or its pharmaceutically acceptable salt:

Brufen

Wherein R is NH-AA or O-AA ₁, AA does not have an amino amino acid residue on it, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

216. according to the compound of claim 215, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

217. compound according to claim 215, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA1 is Thr, Ser, Tyr or hydroxyproline.

218. according to the compound of claim 215, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

219. according to the compound of claim 215, wherein AA or AA ₁Be serine or hydroxyproline.

220. according to the compound of claim 215, wherein AA or AA ₁It is hydroxyproline.

221. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 215-220 and its pharmaceutically acceptable carrier.

222. a method for the treatment of patient's pain, fever or inflammation, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 215-220.

223. a method that increases brufen solvability in the aqueous solution, it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

224. method that to patient's administration the time, increases the bioavilability of brufen; it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

225. method that reduces the brufen gastric irritation; it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product; with give and described product to patient that it is needed, described product to the stimulation of stomach less than brufen.

226. a following formula: compound, or its pharmaceutically acceptable salt:

Simvastatin

Pravastatin

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

227. according to the compound of claim 226, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

228. compound according to claim 226, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA1 is Tyr, Ser, Thr or hydroxyproline.

229. according to the compound of claim 226, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

230. according to the compound of claim 226, wherein AA or AA ₁Be serine or hydroxyproline.

231. according to the compound of claim 226, wherein AA or AA ₁It is hydroxyproline.

232. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 226-231 and its pharmaceutically acceptable carrier.

233. one kind is reduced the method for cholesterol concentration that the mammal that needs treatment needs the patient of Si Dating class pharmacotherapy, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 226-231.

234. a following formula: compound, or its pharmaceutically acceptable salt:

Nadolol

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

235. according to the compound of claim 234, wherein AA is naturally occurring L-a-amino acid.

236. according to the compound of claim 234, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

237. according to the compound of claim 234, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

238. according to the compound of claim 234, wherein AA is Lys or hydroxyproline.

239. according to the compound of claim 234, wherein AA is Lys.

240. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 234-239 and pharmaceutically acceptable carrier thereof.

241. a treatment suffers from the patient's of angina pectoris of being selected from and high blood pressure disease method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 234-239.

242. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

243. according to the compound of claim 242, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

244. compound according to claim 242, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Ser, Thr, Tyr or hydroxyproline.

245. according to the compound of claim 242, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

246. according to the compound of claim 242, wherein AA or AA ₁Be serine or hydroxyproline.

247. according to the compound of claim 242, wherein AA or AA ₁It is hydroxyproline.

248. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 242-247 and its pharmaceutically acceptable carrier.

249. a method for the treatment of the hyperpietic, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 242-247.

250. a method that increases Valsartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Valsartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

251. method that to patient's administration the time, increases the bioavilability of Valsartan; it comprises the carboxylic acid functional of Valsartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

252. a following formula: compound, or its pharmaceutically acceptable salt:

Methylphenidate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have a hydroxyl.

253. according to the compound of claim 252, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

254. compound according to claim 252, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

255. according to the compound of claim 252, wherein AA is proline, glycine, bad ammonia, serine, threonine, hydroxyproline or alanine.

256. according to the compound of claim 252, wherein AA or AA ₁Be serine or hydroxyproline.

257. according to the compound of claim 252, wherein AA or AA ₁It is hydroxyproline.

258. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 252-257 and its pharmaceutically acceptable carrier.

259. a treatment suffers from the method for attention deficit disorder and hypnolepsy disease, described method comprise to the described patient of this treatment of needs give with the treatment effective dose according to each described compound of claim 252-257.

260. a method that increases methylphenidate solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the methylphenidate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

261. method that to patient's administration the time, increases the bioavilability of methylphenidate; it comprises the carboxylic acid functional of methylphenidate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

262. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

263. according to the compound of claim 262, wherein AA is naturally occurring L-a-amino acid.

264. according to the compound of claim 262, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

265. according to the compound of claim 262, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

266. according to the compound of claim 262, wherein AA is Lys or hydroxyproline.

267. according to the compound of claim 262, wherein AA is Lys.

268. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 262-267 and its pharmaceutically acceptable carrier.

269. a treatment is by the method for tissue damage, infection, allergy or self-inflammation that immunological diseases cause, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 262-267.

270. a method that increases methylprednisolone solvability in the aqueous solution, it comprises that the hydroxy functional group that makes the methylprednisolone molecule and amino acid or its acylated derivatives react under the ester formation condition, and separates its product.

271. method that to patient's administration the time, increases the bioavilability of methylprednisolone; it comprises that the hydroxy functional group that makes the methylprednisolone molecule and amino acid or its acylated derivatives react under the ester formation condition; and separate its product, give and described product to described patient.

272. a compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

273. according to the compound of claim 272, wherein AA is naturally occurring L-a-amino acid.

274. according to the compound of claim 272, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

275. according to the compound of claim 272, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

276. according to the compound of claim 272, wherein AA is Lys or hydroxyproline.

277. according to the compound of claim 272, wherein AA is Lys.

278. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 272-277 and its pharmaceutically acceptable carrier.

279. one kind makes patient's method of contraception, this method comprise to described patient give with treatment go up effective dose according to each described compound of claim 272-277.

280. a method that increases Medroxyprogesterone solvability in the aqueous solution, it comprises the hydroxy functional group of Medroxyprogesterone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

281. method that to patient's administration the time, increases the bioavilability of Medroxyprogesterone; it comprises the hydroxy functional group of Medroxyprogesterone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

282. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that removes the OH group on carboxyl.

283. according to the compound of claim 282, wherein AA is a kind of a-amino acid.

284. according to the compound of claim 282, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

285. according to the compound of claim 282, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

286. according to the compound of claim 282, wherein AA is Lys or hydroxyproline.

287. according to the compound of claim 282, wherein AA is Lys.

288. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 282-287 and its pharmaceutically acceptable carrier.

289. a treatment needs the patient's of Estramustine treatment method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 282-287.

290. a method that increases Estramustine solvability in the aqueous solution, it comprises the hydroxy functional group of Estramustine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

291. a following formula: compound, or its pharmaceutically acceptable salt:

Miglitol

Wherein AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

292. according to the compound of claim 291, wherein AA is naturally occurring L-a-amino acid.

293. according to the compound of claim 291, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

294. according to the compound of claim 291, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

295. according to the compound of claim 291, wherein AA is Lys or hydroxyproline.

296. according to the compound of claim 291, wherein AA is Lys.

297. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 291-296 and its pharmaceutically acceptable carrier.

298. a method for the treatment of the type ii diabetes patient, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 291-296.

299. a method that increases Miglitol solvability in the aqueous solution, it comprises the hydroxy functional group of Miglitol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

300. method that to patient's administration the time, increases the bioavilability of Miglitol; it comprises the hydroxy functional group of Miglitol molecule and amino acid or its acylated derivatives is reacted in the ester formation condition; and separate its product and give and described product to described patient.

301. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

302. according to the compound of claim 301, wherein AA is a kind of naturally occurring L-a-amino acid.

303. according to the compound of claim 301, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

304. according to the compound of claim 301, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

305. according to the compound of claim 301, wherein AA is Lys or hydroxyproline.

306. according to the compound of claim 301, wherein AA is Lys.

307. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 301-306 and its pharmaceutically acceptable carrier.

308. a method for the treatment of malaria patients, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 301-306.

309. a method that increases Mefloquine solvability in the aqueous solution, it comprises the hydroxy functional group of Mefloquine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

310. method that to patient's administration the time, increases the bioavilability of Mefloquine; it comprises the hydroxy functional group of Mefloquine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

311. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA forms ester bond and is the amino acid residue that does not have the OH group on carboxyl.

312. according to the compound of claim 311, wherein AA is a kind of naturally occurring L-a-amino acid.

313. according to the compound of claim 311, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

314. according to the compound of claim 311, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

315. according to the compound of claim 311, wherein AA is Lys or hydroxyproline.

316. according to the compound of claim 311, wherein AA is Lys.

317. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 311-315 and its pharmaceutically acceptable carrier.

318. a treatment suffers from endometriosis patient's method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 311-315.

319. an increase reaches the method for that azoles solvability in the aqueous solution, it comprises and reacting under the ester formation condition reaching the hydroxy functional group of that azoles molecule and amino acid or its acylated derivatives, and separates its product.

320. method that to patient's administration the time, increases the bioavilability that reaches that azoles; it comprises and reacting under the ester formation condition reaching the hydroxy functional group of that azoles molecule and amino acid or its acylated derivatives; and separate its product and give and described product to described patient.

321. a following formula: compound, or its pharmaceutically acceptable salt:

Eprosartan

Wherein R or NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

322. according to the compound of claim 321, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

323. compound according to claim 321, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

324. according to the compound of claim 321, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

325. according to the compound of claim 321, wherein AA or AA ₁Be serine or hydroxyproline.

326. according to the compound of claim 321, wherein AA or AA ₁It is hydroxyproline.

327. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 321-326 and its pharmaceutically acceptable carrier.

328. a treatment needs the patient's of Eprosartan treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 321-326.

329. a method that increases Eprosartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Eprosartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

330. method that to patient's administration the time, increases the bioavilability of Eprosartan; it comprises the carboxylic acid functional of Eprosartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

331. a following formula: compound, or its pharmaceutically acceptable salt:

Valproic acid

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

332. according to the compound of claim 331, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

333. compound according to claim 331, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

334. according to the compound of claim 331, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

335. according to the compound of claim 331, wherein AA or AA ₁Be serine or hydroxyproline.

336. according to the compound of claim 331, wherein AA or AA ₁It is hydroxyproline.

337. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 331-336 and its pharmaceutically acceptable carrier.

338. a treatment suffers from the patient's of epilepsy method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 331-336.

339. a method that increases divalproex sodium solvability in the aqueous solution, it comprises the carboxylic acid functional of divalproex sodium molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

340. method that to patient's administration the time, increases the bioavilability of divalproex sodium; it comprises the carboxylic acid functional of divalproex sodium molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

341. a following formula: compound, or its pharmaceutically acceptable salt:

Fenofibrate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

342. according to the compound of claim 341, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

343. compound according to claim 341, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

344. according to the compound of claim 341, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

345. according to the compound of claim 341, wherein AA or AA ₁Be serine or hydroxyproline.

346. according to the compound of claim 341, wherein AA or AA ₁It is hydroxyproline.

347. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 341-346 and its pharmaceutically acceptable carrier.

348. a treatment needs the patient's of fenofibrate treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 341-346.

349. a method that increases fenofibrate solvability in the aqueous solution, it comprises the carboxylic acid functional of fenofibrate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

350. method that to patient's administration the time, increases the bioavilability of fenofibrate; it comprises the carboxylic acid functional of fenofibrate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

351. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

352. according to the compound of claim 351, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

353. compound according to claim 351, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

354. according to the compound of claim 351, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

355. according to the compound of claim 351, wherein AA or AA ₁Be serine or hydroxyproline.

356. according to the compound of claim 351, wherein AA or AA ₁Be hydroxyproline or tyrosine.

357. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 351-356 and its pharmaceutically acceptable carrier.

358. a treatment needs the patient's of Gabapentin treatment method, described method comprise to described patient treat effective dose according to each described compound of claim 351-356.

359. a method that increases Gabapentin solvability in the aqueous solution, it comprises the carboxylic acid functional of Gabapentin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

360. method that to patient's administration the time, increases the bioavilability of Gabapentin; it comprises the carboxylic acid functional of Gabapentin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give described product to described patient.

361. a following formula: compound, or its pharmaceutically acceptable salt:

Omeprazole

Lansoprazole

Wherein AA is connected by amino key and is the amino acid residue that does not have hydroxyl on carboxyl.

362. according to the compound of claim 361, wherein AA is naturally occurring L-a-amino acid.

363. according to the compound of claim 361, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

364. according to the compound of claim 361, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

365. according to the compound of claim 361, wherein AA is serine or hydroxyproline.

366. according to the compound of claim 361, wherein AA is a hydroxyproline.

367. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 361-366 and pharmaceutically acceptable carrier.

368. a method for the treatment of the hyperhydrochloria patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 361-366.

369. a method that increases proton pump inhibitor solvability in the aqueous solution, it comprises the amido functional group of proton pump inhibitor molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

370. method that to patient's administration the time, increases the bioavilability of proton pump inhibitor, it comprises the amido functional group of proton pump inhibitor molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

371. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

372. according to the compound of claim 371, wherein AA is a kind of naturally occurring L-a-amino acid.

373. according to the compound of claim 371, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

374. according to the compound of claim 371, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

375. according to the compound of claim 371, wherein AA is Lys or hydroxyproline.

376. according to the compound of claim 371, wherein AA is Lys.

377. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 371-376 and its pharmaceutically acceptable carrier.

378. a method that needs the treatment apositia patient of megestrol acetate treatment, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 371-376.

379. a method that increases megestrol acetate solvability in the aqueous solution, it comprises the hydroxy functional group of megestrol acetate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

380. method that to patient's administration the time, increases the bioavilability of megestrol acetate; it comprises the hydroxy functional group of megestrol acetate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

381. a following formula: compound, or its pharmaceutically acceptable salt:

Melbine

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have carboxyl.

382. according to the compound of claim 381, wherein AA is naturally occurring L-a-amino acid.

383. according to the compound of claim 381, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

384. according to the compound of claim 381, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

385. according to the compound of claim 381, wherein AA is serine or hydroxyproline.

386. according to the compound of claim 381, wherein AA is a hydroxyproline.

387. a pharmaceutical composition, comprise the treatment effective dose according to each described compound of claim 381-386 and its pharmaceutically acceptable carrier.

388. a method for the treatment of the hyperglycemia patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 381-386.

389. a method that increases melbine solvability in the aqueous solution, it comprises the amido functional group of melbine molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

390. method that to patient's administration the time, increases the bioavilability of melbine, it comprises the amido functional group of melbine molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

391. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

392. according to the compound of claim 391, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

393. compound according to claim 391, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

394. according to the compound of claim 391, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

395. according to the compound of claim 391, wherein AA or AA ₁Be serine or hydroxyproline.

396. according to the compound of claim 391, wherein AA or AA ₁It is hydroxyproline.

397. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 391-396 and its pharmaceutically acceptable carrier.

398. a method for the treatment of psoriasis and patients with acne, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 391-396.

399. a method that increases tazarotene solvability in the aqueous solution, it comprises the carboxylic acid functional of tazarotene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

400. method that to patient's administration the time, increases the bioavilability of tazarotene; it comprises the carboxylic acid functional of tazarotene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

401. a following formula: compound, or its pharmaceutically acceptable salt:

Sumatriptan

Zomitriptan

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have carboxyl.

402. according to the compound of claim 401, wherein AA is naturally occurring L-a-amino acid.

403. according to the compound of claim 401, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

404. according to the compound of claim 401, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

405. according to the compound of claim 401, wherein AA is serine or hydroxyproline.

406. according to the compound of claim 401, wherein AA is a hydroxyproline.

407. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 401-406 and its pharmaceutically acceptable carrier.

408. the treatment migraineur's of needs treatment method, described method comprise to described patient treatment treatment effective dose according to each described compound of claim 401-406.

409. one kind increases the optionally method of 5-HT receptor potentiators solvability in the aqueous solution, it comprises the amido functional group carboxylic moiety amino acid whose with it of 5-HT receptor potentiators molecule is optionally reacted under the acid amides formation condition, and separates its product.

410. one kind increases the optionally method of the bioavilability of 5-HT receptor potentiators to patient's administration the time, it comprises the amido functional group carboxylic moiety amino acid whose with it of 5-HT receptor potentiators molecule is optionally reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

411. a following formula: compound, or its pharmaceutically acceptable salt:

Aspirin

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be not have described hydroxyl and the amino acid residue that on side chain, has hydroxyl.

412. according to the compound of claim 411, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

413. compound according to claim 411, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

414. according to the compound of claim 411, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

415. according to the compound of claim 411, wherein AA or AA ₁Be serine or hydroxyproline.

416. according to the compound of claim 411, wherein AA or AA ₁It is hydroxyproline.

417. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 411-416 and its pharmaceutically acceptable carrier.

418. a method that increases aspirin solvability in the aqueous solution, it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

419. method that to patient's administration the time, increases the bioavilability of aspirin; it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

420. a minimizing is by the method for the gastrointestinal stimulation that causes to the administration aspirin; it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; give and formed product to described mammal, wherein said product is littler to gastric irritation with respect to aspirin.

421. a following formula: compound, or its pharmaceutically acceptable salt:

Olmesartan

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

422. according to the compound of claim 421, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

423. compound according to claim 421, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

424. according to the compound of claim 421, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

425. according to the compound of claim 421, wherein AA or AA ₁Be serine or hydroxyproline.

426. according to the compound of claim 421, wherein AA or AA ₁It is hydroxyproline.

427. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 421-426 and its pharmaceutically acceptable carrier.

428. the treatment hyperpietic's of the described treatment of needs method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 421-426.

429. a method that increases Olmesartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Olmesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

430. method that to patient's administration the time, increases the bioavilability of Olmesartan; it comprises the carboxylic acid functional of Olmesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

431. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

432. according to the compound of claim 431, wherein AA is a kind of naturally occurring L-a-amino acid.

433. according to the compound of claim 431, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

434. according to the compound of claim 431, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

435. according to the compound of claim 431, wherein AA is Lys or hydroxyproline.

436. according to the compound of claim 431, wherein AA is Lys.

437. a pharmaceutical composition, it comprise the treatment effective dose according to the described compound of claim 431 and its pharmaceutically acceptable carrier.

438. a treatment needs the patient's of immunosuppressant treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 431-436.

439. a method that increases immunodepressant solvability in the aqueous solution, it comprises the hydroxy functional group of immunosupress agent molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

440. method that to patient's administration the time, increases the bioavilability of immunodepressant; it comprises the hydroxy functional group of immunosupress agent molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

441. a following formula: compound, or its pharmaceutically acceptable salt:

Clopidogrel

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

442. according to the compound of claim 441, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

443. compound according to claim 441, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

444. according to the compound of claim 441, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

445. according to the compound of claim 441, wherein AA or AA ₁Be serine or hydroxyproline.

446. according to the compound of claim 441, wherein AA or AA ₁It is hydroxyproline.

447. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 441-446 and its pharmaceutically acceptable carrier.

448. a method for the treatment of cardiac muscle of mammal infraction, it comprise to the mammal of its needs is given with treatment on effective dose according to each described compound of claim 441-446.

449. a method that increases clopidogrel solvability in the aqueous solution, it comprises the carboxylic acid functional of clopidogrel molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

450. method that to patient's administration the time, increases the bioavilability of clopidogrel; it comprises the carboxylic acid functional of clopidogrel molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

451. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

452. according to the compound of claim 451, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

453. compound according to claim 451, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

454. according to the compound of claim 451, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

455. according to the compound of claim 451, wherein AA or AA ₁Be serine or hydroxyproline.

456. according to the compound of claim 451, wherein AA or AA ₁It is hydroxyproline.

457. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 451-456 and its pharmaceutically acceptable carrier.

458. a treatment needs the patient's of amphotericin B treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 451-456.

459. a method that increases amphotericin B solvability in the aqueous solution, it comprises the carboxylic acid functional of amphotericin B molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

460. method that to patient's administration the time, increases the bioavilability of amphotericin B; it comprises the carboxylic acid functional of amphotericin B molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

461. a following formula: compound and its pharmaceutically acceptable salt

Wherein R is O-AA, and AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

462. according to the compound of claim 461, wherein AA is naturally occurring L-a-amino acid.

463. according to the compound of claim 461, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

464. according to the compound of claim 461, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

465. according to the compound of claim 461, wherein AA is serine or hydroxyproline.

466. according to the compound of claim 461, wherein AA is a hydroxyproline.

467. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 461-466 and its pharmaceutically acceptable carrier.

468. a treatment needs the patient's of tenofovir treatment method, described method comprise to described patient's administering therapeutic effective dose according to each described compound of claim 461-466.

469. a method that increases tenofovir solvability in the aqueous solution, it comprises the phosphoric acid functional group of tenofovir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

470. method that to patient's administration the time, increases the bioavilability of tenofovir; comprise the phosphoric acid functional group of tenofovir molecule and amino acid or its acylated derivatives are reacted under the ester formation condition; and separate its product and give and described product to described patient.

471. a following formula: compound, or its pharmaceutically acceptable salt:

Unoprostone

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

472. according to the compound of claim 471, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

473. compound according to claim 471, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

474. according to the compound of claim 471, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

475. according to the compound of claim 471, wherein AA or AA ₁Be serine or hydroxyproline.

476. according to the compound of claim 471, wherein AA or AA ₁It is hydroxyproline.

477. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 471-476 and its pharmaceutically acceptable carrier.

478. a method for the treatment of glaucoma patient, it comprise to described patient give with the treatment effective dose according to each described compound of claim 471-476.

479. a method that increases Unoprostone solvability in the aqueous solution, it comprises the carboxylic acid functional of Unoprostone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

480. method that to patient's administration the time, increases the bioavilability of Unoprostone; it comprises the carboxylic acid functional of Unoprostone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

481. a following formula: compound, or its pharmaceutically acceptable salt

Wherein AA is connected by ester bond and is the amino acid that does not have OH on carboxyl.

482. according to the compound of claim 481, wherein AA is naturally occurring L-a-amino acid.

483. according to the compound of claim 481, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

484. according to the compound of claim 481, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

485. according to the compound of claim 481, wherein AA is Lys or hydroxyproline.

486. according to the compound of claim 481, wherein AA is Lys.

487. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 481-486 and its pharmaceutically acceptable carrier.

488. a method for the treatment of breast cancer, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 481-486.

489. a method that increases fulvestrant solvability in the aqueous solution, it comprises the hydroxy functional group of fulvestrant molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

490. method that to patient's administration the time, increases the bioavilability of fulvestrant; it comprises the hydroxy functional group of fulvestrant molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

491. a following formula: compound and its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

492. according to the compound of claim 491, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

493. compound according to claim 491, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

494. according to the compound of claim 491, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

495. according to the compound of claim 491, wherein AA or AA ₁Be serine or hydroxyproline.

496. according to the compound of claim 491, wherein AA or AA ₁It is hydroxyproline.

497. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 491-496 and its pharmaceutically acceptable carrier.

498. a treatment is subjected to the patient's of infected by microbes method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 491-496.

499. a method that increases Cefditoren solvability in the aqueous solution, it comprises the carboxylic acid functional of Cefditoren molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

500. method that to patient's administration the time, increases the bioavilability of Cefditoren; it comprises the carboxylic acid functional of Cefditoren molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

501. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have the OH group on carboxyl.

502. according to the compound of claim 501, wherein AA is naturally occurring L-a-amino acid.

503. according to the compound of claim 501, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

504. according to the compound of claim 501, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

505. according to the compound of claim 501, wherein AA is serine or hydroxyproline.

506. according to the compound of claim 501, wherein AA is a hydroxyproline.

507. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 501-505 and its pharmaceutically acceptable carrier.

508. a method for the treatment of the patient who infects AIDS, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 501-505.

509. a method that increases efavirenz solvability in the aqueous solution, it comprises the amine functional group of efavirenz molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

510. method that to patient's administration the time, increases the bioavilability of efavirenz, it comprises the amido functional group of efavirenz molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

511. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁It is the amino acid residue that does not have described hydroxyl and on its side chain, have hydroxyl.

512. according to the compound of claim 511, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

513. compound according to claim 511, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Thr, Ser or hydroxyproline.

514. according to the compound of claim 511, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

515. according to the compound of claim 511, wherein AA or AA ₁Be serine or hydroxyproline.

516. according to the compound of claim 511, wherein AA or AA ₁It is hydroxyproline.

517. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 511-516 and its pharmaceutically acceptable carrier.

518. the hypertensive method of treatment, it comprise to the patient of required treatment give with the treatment effective dose according to each described compound of claim 511-516.

519. a method that increases eplerenone solvability in the aqueous solution, it comprises the carboxylic acid functional of eplerenone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

520. method that to patient's administration the time, increases the bioavilability of eplerenone; it comprises the carboxylic acid functional of eplerenone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

521. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is an amino acid residue that is connected by ester bond.

522. according to the compound of claim 521, wherein AA is naturally occurring L-a-amino acid.

523. according to the compound of claim 521, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

524. according to the compound of claim 521, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

525. according to the compound of claim 521, wherein AA is Lys or hydroxyproline.

526. according to the compound of claim 521, wherein AA is Lys.

527. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 521-526 and its pharmaceutically acceptable carrier.

528. a treatment needs the cardiovascular related diseases patient's of your treatment of treprostinil method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 521-526.

529. one kind increases your method of solvability in the aqueous solution of treprostinil, it comprises the hydroxy functional group of your molecule of treprostinil and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

530. method that to patient's administration the time, increases your bioavilability of treprostinil; it comprises the hydroxy functional group of your molecule of treprostinil and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

531. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is O-AA, and AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

532. according to the compound of claim 531, wherein AA is naturally occurring L-a-amino acid.

533. according to the compound of claim 531, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

534. according to the compound of claim 531, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

535. according to the compound of claim 531, wherein AA is serine or hydroxyproline.

536. according to the compound of claim 531, wherein AA is a hydroxyproline.

537. a pharmaceutical composition, it comprise the treatment effective dose according to each described a kind of compound of claim 531-536 and its pharmaceutically acceptable carrier.

538. a method for the treatment of AIDS patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 531-536.

539. a method that increases adefovirdipivoxil solvability in the aqueous solution, it comprises the phosphoric acid functional group of adefovirdipivoxil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

540. method that to patient's administration the time, increases the bioavilability of adefovirdipivoxil; it comprises the phosphoric acid functional group of adefovirdipivoxil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

541. a following formula: compound, or its pharmaceutically acceptable salt:

R-N＝N-AA ₁-COOH

Sulfo-medicine azo derivative or

R-NH CO-AA-NH ₂

The sulfa drugs amide derivatives

Wherein R is the sulfanilamide (SN) part of general category sulfonamide, AA ₁Be not have amino, also do not have an amino acid residue of carboxyl.

542. according to the compound of claim 541, wherein AA is naturally occurring L-a-amino acid.

543. according to the compound of claim 541, wherein AA is the L-isomer.

544. according to the compound of claim 541, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

545. according to the compound of claim 541, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

546. according to the compound of claim 541, wherein AA is serine or hydroxyproline.

547. according to the compound of claim 541, wherein AA is a hydroxyproline.

548. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 541-547 and its pharmaceutically acceptable carrier.

549. a method that increases sulfa drugs solvability in the aqueous solution, it comprises the amine of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition, and separates its product.

550. method that to patient's administration the time, increases the bioavilability of sulfa drugs; it comprises the amido functional group of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and give and described product to described patient.

551. method that the limpid water-soluble intravenous formulations of sulfa drugs is provided to patient's administration the time; it comprises the amine of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and to described patient to give and described product without the enteron aisle mode.

552. method that the appropriate formulation of sulfa drugs is provided to patient's administration the time; it comprises the amido functional group of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and to described patient with per rectum, through skin, contain clothes, transvaginal or give and described product through the mode of nose.

553. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein the chemical constitution of salazine is a 5-aminosalicylic acid, and R ₁Be not have carboxyl and amino amino acid residue.

554. according to the compound of claim 553, wherein AA is an a-amino acid.

555. according to the compound of claim 553, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

556. according to the compound of claim 553, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

557. according to the compound of claim 553, wherein AA is serine or hydroxyproline.

558. according to the compound of claim 553, wherein AA is a hydroxyproline.

559. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 553-558 and its pharmaceutically acceptable carrier.

560. a method that increases salazine solvability in the aqueous solution, it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition, and separates its product.

561. a kind of method that to patient's administration the time, increases the bioavilability of salazine; it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition; and separate its product and to the described product of described patient's administration.

562. method that the limpid water-soluble intravenous formulations of salazine is provided to patient's administration the time; it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition; and separate its product and give and described product in the parenteral mode to described patient.

563. a method for the treatment of other inflammation communicate illness of mammal ulcerative colitis, Crohn's disease and colon and rectum, this method comprise to the described mammal of its needs is given with medicine treatment effective dose according to each described compound of claim 553-558.

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