CN103351308A - Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof - Google Patents
Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof Download PDFInfo
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Abstract
The invention discloses a prodrug compound represented by a structure formula 1, a composition or a preparation thereof, and a use of the prodrug compound in preparation of drugs for treatment of treatable conditions of non-steroidal anti-inflammation drugs in human or animals. The prodrug compound has a more rapid skin penetration speed compared with the corresponding parent drug. The invention further discloses a transdermal treatment application system, which at least contains one of the prodrug compound represented by the structure formula 1, or the composition, or the preparation.
Description
The division statement
The application is that the application number submitted on September 3rd, 2006 is 200680055747.0, denomination of invention is divided an application for the Chinese patent application of " having the positively charged water miscible paracetamol of rapid skin penetration speed and the prodrug of related compound thereof ".
Technical field
The present invention relates to paracetamol, acetaminosalol and related compound thereof with positive charge, but and water miscible prodrug and in treatment any paracetamol of human or animal and the application on the acetaminosalol therapeutic state.Specifically, the present invention is the side effect of using paracetamol and related compound thereof to bring in order to overcome.These prodrugs can oral or transdermal administration.
Background technology
APAP (paracetamol), 4-acetamidophenyl salicylate (acetaminosalol) and related compound thereof belong to 4-aminophenols non-steroidal anti-inflammatory drugs.APAP (paracetamol) is a kind of main antipyretic and analgesic.The better tolerance of paracetamol does not have many side effects of acetylsalicylic acid, and need not to write out a prescription and can obtain.They can be used for sign and the symptom of rheumatoid arthritis and osteoarthritis, and are used for bringing down a fever.
Yet, take paracetamol and related compound thereof and can bring a lot of side effects, liver toxicity most importantly, a few cases causes renal toxicity in human body and laboratory animal.The acute excessive use of paracetamol can cause dose-dependently and hepatic necrosis may be fatal, can cause renal tubular necrosis and hypoglycemia under a few cases.Fishman (Fishman; Robert, U.S. Patent number 7,052,715) point out that another problem of following oral medication to produce is, the pain or the inflammation that produce in order effectively to treat remote location, the concentration of medicine in blood circulation must be very high.These concentration are often far above direct actual required in pain or injury of targeting of hypothesis medicine.Fishman and other many people (Van Engelen et al. U.S. Patent number 6,416,772; Macrides et al. U.S. Patent number 6,346,278; Kirby et al. U.S. Patent number 6,444,234, Pearson et al. U.S. Patent number 6,528,040, and Botknecht et al. U.S. Patent number 5,885,597) attempted being used for transdermal administration by the mode developing drugs transfer system of preparation.Yet because the skin penetration speed of these medicines is very slow, the mode by preparation is difficult to make its plasma concentration to reach effective treatment level.Susan Milosovich etc. has designed and synthesized 4-dimethylaminobutyricacid acid testosterone hydrochloride (TSBH), and it has a fat-soluble part and a tertiary amine structure that exists with protonated form under physiological pH.They find that this prodrug (TSBH) is 60 times [Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993)] of female medicine (TS) through the speed of human body skin.
Summary of the invention
Technical problem
APAP (paracetamol), 4-acetamidophenyl salicylate (acetaminosalol) and related compound thereof belong to 4-aminophenols non-steroidal anti-inflammatory drugs.APAP (paracetamol) is a kind of main antipyretic and analgesic.They can be used for sign and the symptom of rheumatoid arthritis and osteoarthritis, and are used for bringing down a fever.
Yet, take paracetamol and related compound thereof and can produce a lot of side effects, liver toxicity most importantly, a few cases causes renal toxicity in human body and laboratory animal.The acute excessive use of paracetamol can cause dose-dependently and hepatic necrosis may be fatal, and can cause renal tubular necrosis and hypoglycemia under a few cases.
Solution
The present invention relates to the novel prodrugs with positive charge of paracetamol and related compound thereof, and in the application of field of medicaments.The prodrug of these paracetamol has the structure of general formula (1) " structural formula 1 ".
In the structural formula 1, R
1Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
2Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
3Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; X represents O, or 2-OCO-C
6H
4-O; A
-Represent Cl
-, Br
-, F
-, I
-, AcO
-, citrate, or other any negative ion; N=0,1,2,3,4,5,6,7,8,9,10 All R groups can comprise C, H, and O, S, or N atom can contain singly-bound, two key and triple bond; Arbitrary CH
2Group can be by O, S, or NH replaces.
No matter medicine is to absorb or other approach absorption through intestines and stomach, all need to pass barrier membranes with the form of molecule.Medicine needs at first dissolving, and if medicine have desirable biopharmacy characteristic, the zone that its can be from the regional diffusion of high density to lower concentration strides across cytolemma and enters blood or systemic circulation system.All microbial films contain lipid as major ingredient.In the biofilm structure active molecule all have phosphatic high polarity head construction and, in most of the cases, two highly hydrophobic hydrocarbon tail chains.Microbial film has bilayer structure, and the hydrophilic head structural plane is to the water zone of both sides.Very hydrophilic medicine can't be by passing biomembranous lipid layer very hydrophobic medicine stop wherein as a biomembranous part because of the reason of similar compatibility, thereby can not effectively enter inner tenuigenin.
The objective of the invention is by improve paracetamol and related compound thereof in gastric juice solubleness and improve penetrating velocity to microbial film and skin barrier, make it can pass through transdermal administration (external application), thereby avoid the side effect of paracetamol and related compound thereof.These novel prodrugs have two identical constructional features: they have a lipophilic part (oil soluble part) and an one-level that exists with protonated form under the physiological pH condition, secondary, or tertiary amine group (water-soluble portion).Like this water-soluble-oil molten balance be that medicine effectively passes microbial film necessary [Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993)].Greatly increased the solubleness of medicine with the amino of positive charge.N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride, 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, N-acetyl-4-amino phenol (paracetamol), the solubleness of 4-acetamidophenyl salicylate (acetaminosalol) in water is respectively〉400mg, 400mg,＜0.2mg,＜0.1mg/ml.In most cases, the dissolving of medicine is the step of the slowest in the absorption process and maximum speed limit.Paracetamol, acetaminosalol and related compound thereof the solubleness in gastric juice is very little.When these novel prodrugs when oral such as the formulation of tablet, capsule, solution and suspension, they can be dissolved in the gastric juice rapidly.Positive charge in these prodrugs on the amino can with the negative charge bonding of the phosphoric acid salt end group of cytolemma.Therefore, thus very high these prodrugs that promote of the partial concn of medicine in the microbial film outside by the zone of area with high mercury to lower concentration.After these prodrugs entered into microbial film, hydrophilic parts can promote prodrug and enter tenuigenin, a kind of concentrated aqueous solution of semi liquid state or suspension.PH value in the stomach is 1-3, thus the phosphoric acid salt end group negative charge on the cytolemma of stomach mucous membrane can with proton (H
+) bonding.Positive charge in these prodrugs then not can with the phosphoric acid salt end group bonding of stomach mucous membrane.So these prodrugs can be to the stomach injury.
N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride, 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, APAP (paracetamol), the speed that 4-acetamidophenyl salicylate (acetaminosalol) and related compound thereof see through in the human body skin is measured by improved Franz pond external.Wherein human body skin separates from the front or the skin histology at the thigh position of back (360-400 μ m is thick).Accept solution contains 2% bovine serum globulin by 10ml physiological saline and form, and stir with 600 rev/mins speed.The accumulation total amount that these prodrugs and female medicine thereof pass skin is to measure with specific high performance liquid chromatography to the relation of time.With 2ml30%N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride solution, 2ml30%4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride solution, 2ml30% paracetamol suspension liquid, or 2ml30% acetaminosalol suspension liquid is as donor solution, solvent is pH=7.4 phosphate buffer soln (0.2M), and the result as shown in Figure 1.Calculate, N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride, 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, paracetamol, the apparent penetrating value of acetaminosalol is 1.5mg, 1.8mg, 0.01mg and 0.01mg/cm
2/ h.Medicine is passed microbial film to positive charge on the presentation of results dialkyl amido ethyl and skin barrier is extremely important.The transdermal speed of other prodrug in the general formula " structural formula 1 " is very high, and very approaching with N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride.
N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride has been compared in experiment in the body, and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, paracetamol, acetaminosalol see through nothing hair alive without the speed of hindering the skin of mouse.Donor is by 20% solution composition of these compounds that are dissolved in the 1ml Virahol.It is applied to hairless mouse back 10cm
2The position.Plasma concentration with specific high-performance liquid chromatography method paracetamol and 4-acetamidophenyl salicylate.Result (Fig. 2) shows, uses for system after about 50 minutes, and the plasma concentration of N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride reaches peak value.About 1-2 hour plasma drug level just can reach peak value behind oral paracetamol, acetaminosalol and the related compound thereof.The peak value of the plasma drug level of paracetamol and acetaminosalol is about 0.01mg/ml, and the peak value of the plasma drug level of N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride is about the about 120 times difference of 1.2mg/ml().The paracetamol of about 1.2mg/ml and acetaminosalol have exceeded 50 times more than than the plasma concentration of effective analgesia and effective antiinflammatory in the blood plasma.This is stem-winding result.Can easily send rapidly paracetamol and acetaminosalol in the host by transdermal administration and reach the effective plasma concentration for the treatment of with prodrug forms.These results show that prodrug not only can be oral, and can be used for various treatments by transdermal administration.Other prodrug in the general formula (1) " structural formula 1 " transdermal speed in vivo is close with N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride.
Measuring the acute toxicity of these prodrugs.Oral mld (the LD of mouse
50) as follows: N-acetyl-p-aminophenyl dimethylamino butyric ester hydrochloride, 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, paracetamol and and the LD of acetaminosalol
50Be respectively 550mg/kg, 670mg/kg, 338mg/kg, 550mg/kg.
Paracetamol and acetaminosalol have been proved to be analgesia and antipyretic effect.A good prodrug should be able to be got back to female medicine very soon in blood plasma.Vitro test proves, the N in people's blood plasma in these prodrugs, and N-lignocaine ethyl ester base can be sheared rapidly by the enzyme in the blood plasma.Prodrug above 90% can be got back to female medicine.Because the specific absorption of prodrug is better, the prodrug curative effect of same dose is stronger than its female medicine.Analgesia and the antipyretic effect of these prodrugs tested respectively in experiment, and makes comparisons with paracetamol and acetaminosalol.
Analgesic activity: the time expand of measuring the mouse tail threshold of pain according to the method (J.Pharmacol.Exp.Ther., 72,74 (1941)) of D'Amour-Smith.With these prodrugs respectively with the dosage of 50mg/kg to the mouse transdermal administration, the tail of mouse is exposed in the thermal stimulus, measure threshold of pain time expand.The result as shown in Figure 3.N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride all have good analgesic activities.
The writhing number of times that occurs behind the mouse peritoneal administration acetum is counted, and calculated the inhibiting rate of writhing based on control group.At the administration acetum before 60 minutes, respectively to the mouse transdermal administration: N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride (100mg/kg, B) and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride (100mg/kg, C).A is the blank group.Measurement result sees Table 1.
Table 1. paracetamol and acetaminosalol prodrug are to the inhibiting rate of mouse writhing
| Group | Dosage (mg/kg) | The writhing number of times | Inhibiting rate % |
| |
0 | 35.0 | - |
| B | 100 | 15.6 | 55 |
| C | 100 | 15.7 | 55 |
The result shows that prodrug has good analgesic activities.Other compound in the general formula " structural formula 1 " has also shown close analgesic activities.
Antipyretic effect: rat is accepted colibacillus deactivating suspension as pyrogeneous substance.The A group is blank group.After 2 hours, respectively to the rat transdermal administration: N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride (100mg/kg, B); 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride (100mg/kg, C).Survey a body temperature every 90 minutes to rat before and after the administration, the results are shown in Table 2.
The antipyretic effect of table 2. paracetamol and acetaminosalol prodrug
| Compound | T=0 minute | T=90 minute | T=180 minute | T=270 minute |
| A (control group) | 37.34±0.05 | 37.36±0.07 | 37.37±0.05 | 37.44±0.08 |
| B(100mg/kg) | 37.32±0.06 | 36.61±0.05 | 36.50±0.08 | 36.50±0.07 |
| C(100mg/kg) | 37.27±0.06 | 36.63±0.05 | 36.52±0.08 | 36.50±0.07 |
The result demonstrates stronger antipyretic activity when showing prodrug with the dosed administration of 100mg/kg.Other compound exhibits in the general formula " structural formula 1 " goes out close antipyretic activity.
When some non-steroidal anti-inflammatory drugs of oral high dosage, it can show anti-reactivity-antasthmatic effect by the activity that suppresses cyclooxygenase.Because these prodrug microbial film seepage velocities are fast, thereby can treat asthma by the mode that sprays into mouth or nasal cavity.
Because these prodrugs can suppress the cyclooxygenase activity and transdermal speed is fast, therefore can be used for treating psoriasis, acne, sunburn or other dermatosis.They also can be used for treating skin carcinoma, lung cancer, mammary cancer and other cancer.
The present invention relates to contain the pharmaceutical preparation of the represented prodrug of general formula " structural formula 1 " and its common additives, auxiliary, for example, be used for oral tablet, capsule or solution etc., or be used for solution, emulsion, ointment, latex or the gel etc. of transdermal administration.The represented novel active compound of general formula " structural formula 1 " can with VITAMIN such as vitamin A, B, C, E or β-carotene, or other drug, such as β-carotene, the couplings such as N-acetylcystein, caffeine, pseudoephedrine, azaperone, folic acid are used for the treatment of human or animal's any paracetamol and the medicable state of acetaminosalol.
The skin-penetrating therapeutic application system, contain the compound of general formula " structural formula 1 " expression or contain the compound of at least a general formula " structural formula 1 " expression as the composition of activeconstituents, can be used for treating any paracetamol and the medicable state of acetaminosalol among the human or animal.These systems can be bandage or paster, and it contains one and comprises the hypothallus of active substance and the protective layer of a non-infiltration.Most preferred system is an active substance reservoir, contains a permeable bottom towards skin.By the control release rate, improve curative effect and reduce paracetamol and the side effect of acetaminosalol thereby this system can make non-steroidal anti-inflammatory drugs be stabilized in the optimal treatment plasma drug level.These systems can be worn over any position of wrist, ankle joint, arm, leg or health.
The represented compound of above-mentioned general formula (1) " structural formula 1 " can be by paracetamol, acetaminosalol and related compound thereof, under the effect of coupler, makes with compound reaction in the general formula (2) " structural formula 2 ".Coupler has: N, N'-dicyclohexylcarbodiimide, N, N'-DIC, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-benzotriazole-N, N, N', N'-tetramethyl-urea hexafluoro boric acid ester (HBTU), benzotriazole--1-base-oxygen base-three (dimethyl amido) phosphorus hexafluorophosphate (BOP) etc.
In the structural formula 2, R
1Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
2Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; N=0,1,2,3,4,5,6,7,8,9,10
The represented compound of above-mentioned general formula (1) " structural formula 1 " can be by paracetamol, acetaminosalol and related compound thereof, and the compound reaction represented with general formula (3) " structural formula 3 " makes.
In the structural formula 3, R
1Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
2Represent H, or the alkyl of arbitrary 1-12 carbon atom, the alkoxyl group of a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, the alkynyl of a 1-12 carbon atom, or aryl; R
3Represent H, or the alkyl of arbitrary 1-12 carbon atom, the alkoxyl group of a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, the alkynyl of a 1-12 carbon atom, or aryl; X represents halogen, or p-toluenesulfonyl; A
-Represent Cl
-, Br
-, F
-, I
-, AcO
-, citrate, or other any negative ion; N=0,1,2,3,4,5,6,7,8,9,10
Advantage
A fatty contents and a water-soluble portion (amido that exists with protonated form under the physiological pH value) are arranged in the prodrug structure of these paracetamol, acetaminosalol and related compound thereof.The amino of these prodrug positively chargeds has two large advantages: at first, it has greatly improved the solubleness of prodrug, and when these prodrugs were oral with tablet, capsule, solution or suspension, it can very fast being dissolved in the gastric juice.The second, in these prodrugs the amino of positively charged can with electronegative phosphoric acid salt end group bonding on the cytolemma.Therefore, the partial concn of prodrug outside film can be very high, thereby promote these prodrugs to see through to low concentration region from area with high mercury.After these prodrugs enter into microbial film, hydrophilic parts will promote medicine and enter tenuigenin, in a kind of concentrated the semi liquid state aqueous solution or suspension.Experimental results show that and surpass female medicine of getting back to that 90% prodrug can be very fast.These prodrugs have better specific absorption, so under the same dose, the curative effect of prodrug is better than paracetamol, and acetaminosalol and related compound thereof.Experimental result shows prodrug, N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride and 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, and the speed that sees through human body skin is faster nearly 150 times than paracetamol and acetaminosalol.Plasma drug level reaches peak value after the about 1-2 of oral paracetamol, acetaminosalol and related compound thereof hour, and its plasma drug level just can reach peak value about 50 minutes and prodrug only needs.The most exciting result is that prodrug not only can be oral, and can be used for any treatment with transdermal means, thereby avoided most of side effects of acetyl aminophenol, acetaminosalol and related compound thereof, most importantly liver toxicity and renal toxicity.The large benefit of another of transdermal administration is that medication is convenient, particularly more is easy to the administration to children.
Description of drawings
Fig. 1: the N-acetyl by the human skin tissue that separates in Franz pond (n=5)-4-aminophenyl dimethylamino butyric ester hydrochloride (A, 30% solution), 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride (A, 30% solution), N-paracetamol (A, and 4-acetamidophenyl salicylate (D, 30% suspension liquid) 30% suspension liquid).Carrier soln under the various conditions is the phosphate buffer soln (0.2M) of pH7.4.
Fig. 2: to the local N-acetyl that the is dissolved in the 1ml Virahol-4-aminophenyl dimethylamino butyric ester hydrochloride that uses in hairless mouse (n=5) back, 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, behind paracetamol and the acetaminosalol, the total amount of paracetamol and acetaminosalol in the blood plasma.
Fig. 3: at the N-of transdermal administration 50mg/kg acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride, behind the 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride, the threshold of pain time expand of mouse tail.A is control group.
Fig. 4: in structural formula 1, R
1Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
2Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R
3Represent H, the alkynyl of the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; X represents O, or 2-OCO-C
6H
4-O; A
-Represent Cl
-, Br
-, F
-, I
-, AcO
-, citrate, or other any negative ion; N=0,1,2,3,4,5,6,7,8,9,10 All R groups can comprise C, H, and O, S, or N atom can contain singly-bound, two key and triple bond.Arbitrary CH
2Group can be by O, S, or NH replaces.
Preferred forms
The preparation of N-acetyl-4-aminophenyl dimethylamino butyric ester hydrochloride
15.1g(0.1mol) paracetamol is dissolved in 200ml acetone and the 200ml10% sodium hydrogen carbonate solution.Add 18.6g(0.1mol) dimethylamino butyryl chloride hydrochloride, stirring at room 3 hours.Boil off solvent.Add the 500ml ethyl acetate, mixed solution is washed 1 time with the 200ml5% sodium hydrogen carbonate solution, again with 100ml washing 3 times.The organic solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Pass into hydrogen chloride gas in the filtrate.The solid collected by filtration product.Get the target product of the easy moisture absorption of 26g after the drying, productive rate is 86.4%.Solubleness in the water: 400mg/ml; Ultimate analysis: C
14H
21ClN
2O
3Molecular weight: 300.78.Theoretical value (%) C:55.90; H:7.04; Cl:11.79; N:9.31; O:15.96; Measured value (%) C:55.96; H:7.06; Cl:11.76; N:9.29; O:15.93.
1H-NMR（400MHz，D
2O）：δ：1.98（s，3H），2.01（m，2H），2.21（m，2H），2.90（s，6H），3.24（m，2H），7.05（m，2H），7.60（m，2H），7.80（b，1H）。
Embodiment
The preparation of N-acetyl-4-aminophenyl diethylin butyric ester hydrochloride
15.1g(0.1mol) paracetamol and 16g(0.1mol) the diethylin butyric acid is dissolved in the 300ml methylene dichloride.Reaction is cooled to 0 ° of C with ice bath.Add 20.6g(0.1mol) N, the N'-dicyclohexylcarbodiimide.Mixture stirred 1 hour at 0 ° of C, again stirring at room 2 hours.Solids removed by filtration.Dichloromethane solution is washed 2 times with the sodium hydrogen carbonate solution of 100ml5%, again with 100ml washing 3 times.The organic solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Stir in the reaction mixture and add 6g acetic acid.The solid collected by filtration product.Obtain the target product of the easy moisture absorption of 27g after the drying, productive rate 82.1%.Solubleness in the water: 400mg/ml; Ultimate analysis: C
16H
25ClN
2O
3Molecular weight: 328.83.Theoretical value (%) C:58.44; H:7.66; Cl:10.78; N:8.52; O:14.60; Measured value (%) C:58.40; H:7.68; Cl:10.76; N:8.55; O:14.61.
1H-NMR（400MHz，D
2O）：δ：1.50（t，6H），2.00（m，2H），2.02（s，3H），2.21（m，2H），3.24（m，2H），3.27（m，4H），7.05（m，2H），7.60（m，2H），7.80（b，1H）。
The preparation of 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride
27.1g(0.1mol) acetaminosalol is dissolved in 200ml acetone and the 200ml10% sodium hydrogen carbonate solution.Add 18.6g(0.1mol) dimethylamino butyryl chloride hydrochloride, stirring at room 3 hours.Solvent evaporated.Add the 500ml ethyl acetate in the reaction mixture, mixed solution is washed 1 time with the 200ml5% sodium hydrogen carbonate solution, again with 100ml washing 3 times.The organic layer anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Pass into hydrogen chloride gas in the filtrate.The solid collected by filtration product.Get the target product of the easy moisture absorption of 36g after the drying, productive rate is 85.5%.Solubleness in the water: 400mg/ml; Ultimate analysis: C
21H
25ClN
2O
5Molecular weight: 420.89.Theoretical value (%) C:59.93; H:5.99; Cl:8.42; N:6.66; O:19.01; Measured value (%) C:59.96; H:6.02; Cl:8.40; N:6.64; O:18.98.
1H-NMR（400MHz，D
2O）：δ：1.99（s，3H），2.01（m，2H），2.21（m，2H），2.90（s，6H），3.24（m，2H），7.13（m，2H），7.22（m，2H），7.47（m，1H），7.60（m，2H），7.80（b，1H），8.10（m，1H）。
The preparation of 4-acetamidophenyl salicylyl dimethy butyric ester hydrochloride
27.1g(0.1mol) acetaminosalol and 16g(0.1mol) the diethylin butyric acid is dissolved in the 300ml methylene dichloride.Reaction mixture is cooled to 0 ° of C with ice bath.Add 20.6g(0.1mol) N, the N'-dicyclohexylcarbodiimide.Mixture stirred 1 hour at 0 ° of C, and stirring at room is 2 hours again.Solids removed by filtration.Dichloromethane solution is washed 2 times with the 100ml5% sodium hydrogen carbonate solution, again with 100ml washing 3 times.The organic solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Stir in the reaction mixture and add 6g acetic acid.The solid collected by filtration product.Get the target product of the easy moisture absorption of 39g after the drying, productive rate is 86.9%.Solubleness in the water: 400mg/ml; Ultimate analysis: C
23H
29ClN
2O
5Molecular weight: 448.94.Theoretical value (%) C:61.53; H:6.51; Cl:7.90; N:6.24; O:17.82; Measured value (%) C:61.50; H:6.56; Cl:7.85; N:6.22; O:17.87.
1H-NMR（400MHz，D
2O）：δ：1.50（t，6H），2.00（m，2H），2.02（s，3H），2.21（m，2H），3.24（m，2H），3.27（m，4H），7.11（m，2H），7.21（m，2H），7.47（m，1H），7.65（m，2H），7.80（b，1H），8.10（m，1H）。
Industrial applicibility
These prodrugs in the general formula (1) " structural formula 1 " are better than paracetamol, acetaminosalol and related compound thereof.They can be used for the treatment of human or animal's the treatable state of any paracetamol, acetaminosalol and related compound thereof.They can be used for sign and the symptom of rheumatoid arthritis and osteoarthritis, bring down a fever and treat dysmenorrhoea.Because it is very fast that these prodrugs see through biomembranous speed, thereby can treat asthma in the mode that sucks.Because the anti-inflammatory action of these prodrugs can be used for treating psoriasis, acne, sunburn or other dermatosis.They also can be used for treating skin carcinoma, lung cancer, mammary cancer and other cancers.
Claims (26)
1. " structural formula 1 " represented compound,
Structural formula 1
Wherein,
R
1Represent H, the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, or the alkynyl of 1-12 carbon atom;
R
2Represent H, the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, or the alkynyl of 1-12 carbon atom;
R
3Represent H, the alkoxyl group of the alkyl of arbitrary 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, or the alkynyl of 1-12 carbon atom;
X represents 2-OCO-C
6H
4-O; A
-Represent Cl
-, Br
-, F
-, I
-, AcO
-, citrate, or other can make the negative ion of protonated amido positive charge balance; With
N=0,1,2,3,4,5,6,7,8,9 or 10.
2. compound as claimed in claim 1, wherein R
3Represent H.
3. compound as claimed in claim 1 or 2, wherein A
-Represent Cl
-, Br
-, F
-, I
-, AcO
-, or citrate.
4. composition, its contain at least a such as claim 1,2 or 3 described compounds as its activeconstituents.
5. composition as claimed in claim 4, it also comprises water.
6. preparation, it comprises such as claim 4 or 5 described compositions and/or additive and/or auxiliary.
7. preparation as claimed in claim 6, it is the oral administered dosage form that is selected from tablet, capsule, solution and the suspendible.
8. preparation as claimed in claim 6, it is the transdermal administration formulation that is selected from solution, spray, emulsion, ointment, latex and the gel formulation.
9. skin-penetrating therapeutic application system, it contains an active substance at least, and wherein said active substance is such as claim 1,2 or 3 described compounds, such as claim 4 or 5 described compositions or such as claim 6,7 or 8 described preparations.
10. skin-penetrating therapeutic application system as claimed in claim 9, wherein said system is bandage or paster, it contains one and comprises the hypothallus of active substance and the protective layer of a non-infiltration.
11. such as claim 9 or 10 described skin-penetrating therapeutic application systems, it is characterized in that containing an active substance reservoir, it contains a permeable bottom towards skin.
12. such as claim 9,10 or 11 described skin-penetrating therapeutic application systems, it is characterized in that to pass through the control release rate, thereby this system can make nonsteroidal anti-inflammatory drug be stabilized in the side effect that the optimal treatment Plasma Concentration improves curative effect and reduces nonsteroidal anti-inflammatory drug.
13. such as claim 9,10 or 11 described skin-penetrating therapeutic application systems, it is characterized in that and by the control release rate, to improve curative effect and to reduce side effect thereby this system can make described active substance or its meta-bolites be stabilized in the optimal treatment Plasma Concentration.
14. such as claim 1,2 or 3 described compounds, such as claim 4 or 5 described compositions or such as claim 6, the 7 or 8 described preparations purposes for the preparation of the medicine of asthma among the treatment human or animal, wherein said medicine can be treated by the mode of lip-syncing or nose or other position spray deliveries of health.
15. such as claim 1,2 or 3 described compounds, such as claim 4 or 5 described compositions or such as claim 6, the 7 or 8 described preparations purposes for the preparation of the medicine of the medicable state of non-steroidal anti-inflammatory drugs among the treatment human or animal.
16. purposes as claimed in claim 15, the medicable state of wherein said non-steroidal anti-inflammatory drugs is selected from: the vomiting that pain, fever, cancer, radiotherapy cause, diabetic neuropathy, hemophilic arthritis, bone loss, glaucoma, tetter and sunburn.
17. purposes as claimed in claim 16, wherein said pain are selected from ocular pain, ear's pain behind headache, toothache, myalgia, dysmenorrhoea, acute migraine, the operation on cornea, and arthritis pain.
18. purposes as claimed in claim 15, the treatable state of wherein said NSAID (non-steroidal anti-inflammatory drug) is selected from psoriasis and acne.
19. purposes as claimed in claim 15, the treatable state of wherein said NSAID (non-steroidal anti-inflammatory drug) is selected from eye inflammation and ear's inflammation.
20. purposes as claimed in claim 15, wherein said pain status are inflammatory pain.
21. purposes as claimed in claim 15, wherein said cancer is selected from mammary cancer, colorectal carcinoma, carcinoma of the pancreas and skin carcinoma.
22. such as each the described purposes in the claim 15 to 21, wherein said medicine can be treated by the mode of oral or transdermal administration.
23. such as each the described purposes in the claim 15 to 21, wherein said medicine can be treated to reach treatment effective plasma level concentration at the region transdermal administration by solution, spray, emulsion, ointment, latex or gel formulation.
24. such as each the described purposes in the claim 15 to 21, wherein said medicine is oral dosage form or transdermal administration formulation.
25. such as each the described purposes in the claim 15 to 21, wherein said medicine is the transdermal administration formulation.
26. such as each the described purposes in the claim 15 to 21, wherein said medicine is by treating such as each the described skin-penetrating therapeutic application system administration in the claim 9 to 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310140739 CN103351308A (en) | 2006-09-03 | 2006-09-03 | Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310140739 CN103351308A (en) | 2006-09-03 | 2006-09-03 | Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800557470A Division CN101506143B (en) | 2006-09-03 | 2006-09-03 | Positively charged water-soluble prodrugs of acetaminophen and related compounds with fast skin penetration rate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103351308A true CN103351308A (en) | 2013-10-16 |
Family
ID=49307746
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201310140739 Pending CN103351308A (en) | 2006-09-03 | 2006-09-03 | Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103351308A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919776A (en) * | 2014-04-29 | 2014-07-16 | 杨献华 | Pharmaceutical composition for treating arthritis |
| WO2021185382A1 (en) * | 2020-03-20 | 2021-09-23 | Techfields Pharma Co. Ltd. | Method for improving the stability of a pharmaceutical composition comprising a high penetration drug, and the pharmaceutical composition obtained therefrom |
-
2006
- 2006-09-03 CN CN 201310140739 patent/CN103351308A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919776A (en) * | 2014-04-29 | 2014-07-16 | 杨献华 | Pharmaceutical composition for treating arthritis |
| CN103919776B (en) * | 2014-04-29 | 2016-03-02 | 临沂草之美医药科技有限公司 | A kind of pharmaceutical composition for the treatment of of arthritis |
| WO2021185382A1 (en) * | 2020-03-20 | 2021-09-23 | Techfields Pharma Co. Ltd. | Method for improving the stability of a pharmaceutical composition comprising a high penetration drug, and the pharmaceutical composition obtained therefrom |
| JP7485407B2 (en) | 2020-03-20 | 2024-05-16 | テックフィールズ インコーポレイテッド | Method for improving the stability of a pharmaceutical composition containing a highly permeable drug, and pharmaceutical composition obtained thereby |
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