CN1197839C - Stibene derivative organic amine salt, its preparation method, use and medicinal composition - Google Patents
Stibene derivative organic amine salt, its preparation method, use and medicinal composition Download PDFInfo
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- CN1197839C CN1197839C CN 03105355 CN03105355A CN1197839C CN 1197839 C CN1197839 C CN 1197839C CN 03105355 CN03105355 CN 03105355 CN 03105355 A CN03105355 A CN 03105355A CN 1197839 C CN1197839 C CN 1197839C
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Abstract
The present invention relates to an organic amine salt of a stilbene derivative, a preparation method thereof, an application thereof and a medicine composition thereof. The present invention provides various organic amine salts of a stilbene derivative. The preparation method comprises the step that a stilbene derivative reacts with amine or an organic amine compound to generate the corresponding organic amine salt. The organic amine salt of a stilbene derivative of the present invention can be used for preparing a medicine for preventing and treating tumors and precancerosis and for preparing a medicine for treating connective tissue disease dermatosis, and can be prepared into various oral preparations, injection preparations and external preparations. Compared with the water solubility of the stilbene derivative as a parent compound, the water solubility of the organic amine salt of a stilbene derivative of the present invention is greatly enhanced; thus, the dosage is low, and the curative effect is favorable.
Description
Technical field:
The present invention relates to multiple organic amine salt, its preparation method of diphenyl ethylene derivatives and be used to prepare prevention and the purposes of treatment tumour and precancerous lesion medicine, preparation treatment connective tissue disease (CTD) or dermatosis treating medicine.The invention still further relates to the pharmaceutical composition that contains the diphenyl ethylene derivatives organic amine salt.
Background technology:
The diphenyl ethylene derivatives compounds is a kind of known antitumor drug.Relevant diphenyl ethylene derivatives compounds and preparation method thereof, GB2010836 have at first carried out reporting (on December 21st, 1978), and April 20 nineteen eighty-two, US4326055 further reported its preparation method and potential applicability in clinical practice thereof again.Prevention is all arranged for diphenyl ethylene derivatives local topical or whole body administration and treatment is good, the effect of malignant tumour and precancerous lesion, and antitumor action is remarkable.This compounds can be made into polytype preparation, adapt to the medication of different approaches, thereby indication is extensive.
But,, its pharmacological action intensity and scope all are restricted because diphenyl ethylene derivatives is water-soluble extremely low.
Summary of the invention:
The technical problem to be solved in the present invention is that diphenyl ethylene derivatives is transformed, and improves that it is water-soluble, to increase curative effect.The objective of the invention is to develop the organic amine salt compounds and the pharmaceutical composition thereof of diphenyl ethylene derivatives.
The present invention generates corresponding organic amine salt (formula I) with diphenyl ethylene derivatives (formula II) and ammonia or organic amine compound (formula III) reaction, confirms that through test formula I compound can improve the water-soluble several times of diphenyl ethylene derivatives; And show through pharmacodynamic study, when not changing original pharmacological action feature of diphenyl ethylene derivatives, its organic amine salt, promptly formula I compound can heighten the effect of a treatment.
NR
10R
11R
12
(II) (III)
In formula I and the formula III compound, R
10, R
11, R
12Expression:
(1) R
10, R
11, R
12All be hydrogen, promptly the formula III compound is an ammonia;
(2) R
10And R
11Be hydrogen, R
12Be chain alkylene, replacement chain alkylene, aryl, the substituted arene base that is no more than 12 carbon atoms; Described substituting group can be any known functional group, as the alkyl of hydroxyalkyl, aminoalkyl group, carboxyl substituted, amino acids chain alkylene etc.Be that the formula III compound is a primary amine;
(3) R
10Be hydrogen, R
11And R
12Be chain alkylene, cyclic hydrocarbon radical, replacement chain alkylene, substituted ring alkyl, aryl, the substituted arene base that is no more than 12 carbon atoms, described substituting group can be any known functional group, and promptly the formula III compound is a secondary amine, as the glucose methylamine;
(4) R
10, R
11And R
12Be the chain alkylene, cyclic hydrocarbon radical, replacement chain alkylene, substituted ring alkyl, aryl, the substituted arene base that are no more than 12 carbon atoms, described substituting group can be any known functional group, and promptly the formula III compound is a tertiary amine;
(5) R
10Be hydrogen, R
11And R
12The nitrogen-atoms that links to each other jointly with them constitutes cyclic secondary amine and the cyclic tertiary amine that is no more than 6 yuan of rings, carbon atom on these cyclic secondary amines or the cyclic tertiary amine ring can be replaced by heteroatoms, as being replaced by nitrogen-atoms, promptly the formula III compound is a cyclammonium, as hexahydropyridine, piperidines etc.
Above-mentioned chain alkylene, alkyl, amino acids chain alkylene that comprises hydroxyalkyl, aminoalkyl group, carboxyl substituted etc. can be straight or branched, for example chain alkylene can be methyl, ethyl, sec.-propyl and 2-methyl-propyl; Hydroxyalkyl can be methylol, hydroxyethyl, hydroxyl sec.-propyl etc.
In formula I and the formula II compound:
N is 1 or 2, preferred 2;
R
1And R
2Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, preferred hydrogen;
R
3And R
4Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, preferable methyl;
R
5And R
6Be hydrogen, methyl, preferred hydrogen;
R
7Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, preferable methyl;
R
8And R
9Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, preferred hydrogen.
Formula I compound is made by neutralization reaction by formula II compound and formula III compound, and reaction formula is:
Temperature of reaction: the solvent refluxing state is reaction down, usually at 60 ℃～80 ℃;
Reaction times: 0.5～4 hour, use 2 hours usually;
Reaction solvent: methyl alcohol, ethanol, chloroform, water or their mixture.
Diphenyl ethylene derivatives of the present invention is 4-[(E preferably)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid;
Described organic amine is primary amine, secondary amine or tertiary amine; Can be chain or cyclic amine; Described chain is a straight or branched;
Described organic amine can be by hydroxyl, amino, carboxyl, aminoacid replacement;
Described cyclic amine is to contain heteroatomic hexa-atomic cyclammonium, and described heteroatoms is nitrogen or oxygen;
Preferably, described organic amine is 2-methylol-2-amino-1, ammediol, meglumine, Methionin, piperazine, hexahydropyridine, dimethylethanolamine, quadrol.
4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] preparation method of phenylformic acid organic amine salt, be with 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid and ammonia or organic amine compound neutralization reaction, generate corresponding organic amine salt.Temperature of reaction is the solvent refluxing temperature, usually at 60 ℃～80 ℃; Reaction times: 0.5～4 hour, use 2 hours usually; Reaction solvent: methyl alcohol, ethanol, chloroform, water or their mixture.
Formula I compound of the present invention can be used for preparation prevention and treatment tumour and precancerous lesion medicine, also can be used for preparing the medicine of treatment connective tissue disease (CTD) such as rheumatic arthritis etc. and treatment tetter such as psoriatic etc.
This compounds can be made into several formulations forms such as oral preparations, injection and external preparation.
Suitable oral preparations formulation has tablet, capsule, suspension etc.; Suitable injection formulation has injection liquid, lyophilisate etc.; The suitable external preparations formulation has emulsifiable paste, ointment, lotion etc.
Can comprise various medicine acceptable carriers, assistant agent in the various preparations, as comprise various non-activities but can influence the activeconstituents of its pharmacokinetics feature.For example, can comprise weighting agent, fixing agent, carrier substance etc. in the solid formulation; Can comprise sterilant etc. in the liquid formulation.Precondition is that all auxiliary materials all must nontoxic, parmacodynamics-less activity and suitable mutually with corresponding dosage forms.
The dosage of new compound of the present invention is decided because of formulation in clinical application, also answers individuation simultaneously.Tablet and capsular common dose were respectively 0.01-5.0mg/ days and 0.1-1.0mg/ days.
The parent diphenyl ethylene derivatives of formula I compound (formula II compound) water-soluble extremely low, the corresponding amines class formula I compound (a class new compound provided by the invention) that itself and the reaction of formula III compound are generated can improve water-soluble.
With HPLC method susceptible of proof: become the water-soluble of formula I compound behind the amine salt to increase its corresponding water-soluble seeing table greatly than former formula II compound.
Diphenyl ethylene derivatives and the water-soluble contrast of its organic amine salt (HPLC method mensuration)
| Compound | Formula II | Formula I | ||||||
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | ||
| Concentration (μ g/ml) | 0.04 | 14.4 | 117.5 | 8.8 | 24 | 82.9 | 20.9 | 8.0 |
The inventor has also compared the curative effect and and the water miscible relation of formula I compound and its parent formula II compound.The result shows that the pharmacologically active of formula I compound is the several times of its parent formula II compound, and is proportionate with water-soluble.
Confirm that through pharmacodynamics test the organic amine new compound of diphenyl ethylene derivatives provided by the invention has sure antitumor action.In addition, the oral connective tissue disease (CTD)s such as rheumatic arthritis for the treatment of of new compound of the present invention, external application has good efficacy to the various skin disease, and it is definite to treat these two kinds of curative effect of disease.Compare with its parent, can reach identical curative effect with small amount of drug.Therefore, compound of the present invention is a kind of high-quality, efficient, a pharmacological action medicine widely.
Pharmacological testing confirms; New compound of the present invention has extremely strong anti-tumor activity, in the pathological model test of mouse, produce papilloma with dimethylbenzanthracene and Oleum Tiglii induced animal, press the dosage in 0.2mg/kg/ week, 0.1mg/kg/ week and 0.05mg/kg/ week again and give animal abdominal injection new compound of the present invention, to observe its curative effect to this tumour, as a result, the diameter of tumour has dwindled 75%, 56% and 48% respectively after 2 weeks.And allowing animal mix the medicine in food 0.4mg/kg/ week, diameter of tumor has dwindled 63% after 2 weeks.The above results is compared with blank and with the positive control that formula II compound carries out all significant difference.
The side effect that new compound of the present invention is excessive when using mainly shows as vitamin A and too much levies, and symptom mainly shows on the appendicle and mucosal tissue of skin, skin, as furfur, alopecia etc.
By embodiment and test example the present invention is elaborated below, but be it should be understood that embodiment and test example do not limit the present invention.
Embodiment:
The preparation of embodiment 1～7 Chinese style I compound
Formula I compound is made by neutralization reaction by formula II compound and formula III compound.
Used formula II compound is 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid, its structural formula is:
Formula II
Used formula III compound sees the following form
The formula III compound
Embodiment 1 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid 2-methylol-2-amino-1, ammediol salt
In the 250ml there-necked flask, add 3.5g (10mmol) 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid, 130ml methyl alcohol, 20ml chloroform, temperature rising reflux, dissolving back fully adds 1.21g (10mmol) Pehanorm, there is insolubles to separate out, temperature rising reflux 2 hours, freezing 30 minutes of cooling back, suction filtration, freezing methyl alcohol is washed, dry behind the recrystallization 4.4g white solid title compound.Yield 93.8%, 190.5～192.6 ℃ of fusing points.
13CNMR(DMSO)：170.196、144.335、143.774、140.561、139.975、137.826、129.262、128.525、126.464、126.364、123.723、123.414、60.955、60.054、34.942、34.747、34.104、33.865、31.785、31.697、17.504。
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 73.24 | 8.44 | 3.12 |
| 73.15 | 8.37 | 3.20 |
Embodiment 2 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid meglumine salt
With 2g 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid dissolves with the 110ml trichloromethane, reflux and drip the 20ml DMF solution of 1.15g meglumine down, finish and refluxed 1.5 hours, the oily matter of evaporated under reduced pressure solvent adds the 10ml dehydrated alcohol, molten clear, refrigerator-freezer is separated out solid.
Suction filtration gets white solid thing title compound, dry 2.6g, 212～214 ℃ of fusing points, yield 85.8%.
13CNMR(DMSO)：170.817、144.418、143.836、140.665、138.749、137.765、135.826、129.336、128.545、126.572、126.510、123.802、123.497、71.638、70.954、70.615、69.010、63.713、51.769、35.003、74.810、34.194、33.962、33.476、31.865、31.786.17.598。
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 68.62 | 8.07 | 2.98 |
| 69.60 | 7.95 | 2.51 |
Embodiment 3 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid lysine salt
In the 250ml there-necked flask, add 3.5g (10mmol) 4-[(E)-2 (5,6,7,8-tetrahydrochysene 5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid, 150ml methyl alcohol, reflux molten back drips the 10ml aqueous solution of 1.46g (10mmol) Methionin, drips off in 1 hour, drips off the back and continues to reflux 2 hours.Cooling back suction filtration, freezing methanol wash, recrystallization, dry title compound white powder 4.5g, yield 91.0%, 187～195 ℃ of fusing points.
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 72.01 | 8.52 | 6.21 |
| 71.86 | 8.46 | 5.89 |
Embodiment 4 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid piperazine salt
With 1g 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid is with 25ml trichloromethane, 50ml dissolve with ethanol, and temperature rising reflux drips the 0.5g piperazine, drips the 5ml ethanolic soln, finish and refluxed 3 hours, crystal, suction filtration are separated out in cooling, freezing methyl alcohol is washed, and gets crystalline compounds, behind the recrystallization, dry title compound solid 0.75g, 258～262 ℃ of fusing points, yield 60.1%.
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 76.15 | 8.51 | 6.04 |
| 78.16 | 8.79 | 6.22 |
Embodiment 5 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid hexahydropyridine salt
With 1g 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid is with 25ml trichloromethane, 50ml dissolve with ethanol, and temperature rising reflux drips the 0.3g hexahydropyridine, drips the 5ml ethanolic soln, finish and refluxed 3 hours, crystal, suction filtration are separated out in cooling, freezing methyl alcohol is washed, and gets crystalline compounds, behind the recrystallization, dry title compound solid 0.8g, 181.0～185.5 ℃ of fusing points, yield 64.5%.
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 81.00 | 9.64 | 3.12 |
| 80.92 | 9.03 | 3.02 |
Embodiment 6 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid dimethyl ethanol amine salt
With 1g 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid is with 25ml trichloromethane, 50ml dissolve with ethanol, and temperature rising reflux drips the 0.3g dimethylethanolamine, drips the 5ml ethanolic soln, finish and refluxed 3 hours, crystal, suction filtration are separated out in cooling, freezing methyl alcohol is washed, and gets crystalline compounds, behind the recrystallization, dry title compound solid 0.85g, 168～170 ℃ of fusing points, yield 67.7%.
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 77.63 | 8.68 | 3.10 |
| 76.60 | 8.69 | 3.08 |
Embodiment 7 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid diethyl amine salt
With 1g 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid is with 25ml trichloromethane, 50ml dissolve with ethanol, and temperature rising reflux drips the 0.3g dimethylethanolamine, drips the 5ml ethanolic soln, finish and refluxed 3 hours, crystal, suction filtration are separated out in cooling, freezing methyl alcohol is washed, and gets crystalline compounds, behind the recrystallization, dry title compound solid 0.8,169～172 ℃ of fusing points, yield 68.4%.
Results of elemental analyses
| C(％) | H(％) | N(％) |
| 77.85 | 8.09 | 6.95 |
| 78.03 | 8.69 | 6.57 |
Embodiment 8 formula I compound capsule formulas
| Composition | Content in each capsule |
| Embodiment 1 formula I compound * | 0.2mg |
| Honeybee is cured | 50mg |
| Vegetables oil | 96.8mg |
| Trisodium EDTA | 1mg |
| Propylene glycol | 2mg |
* be 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid 2-methylol-2-amino-1, ammediol salt
Embodiment 9 formula I compound ointment prescription
| Composition | Content |
| Embodiment 1 formula I compound | 0.05％ |
| Hexadecanol | 2.5g |
| Lanolin | 6.0g |
| Vaseline | 15.0g |
| Stearyl alcohol | 2.0g |
| Distilled water adds to | 100.0g |
It below is test example of the present invention.
The antitumor curative effect of test example 1 The compounds of this invention and its parent compound relatively
1, be subjected to the reagent thing:
New compound of the present invention (5) (being 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid hexahydropyridine salt) tablet and injection liquid
2, experimental animal: the purebred mouse of C57BL/6 that grows up, body weight 20 ± 2g, male and female dual-purpose, 10 every group.
3, dosage:
Be by reagent thing and control drug:
Abdominal injection: totally three groups of 0.2mg/kg/ week, 0.1mg/kg/ week and 0.05mg/kg/ weeks.The administration capacity is 5mL/.
Oral (to mix the administration of food method): 0.4mg/kg/ week.
Above-mentioned dosage is all in bulk drug.
4, experimental control:
Positive control: the tablet and the injection liquid of formula II compound (parent compound of The compounds of this invention).
Blank: intraperitoneal injection gives the solvent of same capability, and oral medication gives blank.
5, medication: abdominal injection and oral.
6, test method:
The pathological model test of mouse.Produce papilloma with dimethylbenzanthracene and Oleum Tiglii induced animal, modeling success back is with abdominal injection and oral two kinds of administrations, and in two weeks of successive administration, total dose weekly is divided into 7 times to be finished, and be administered once every day.Put to death animal in 24 hours after the drug withdrawal, calculate the percentage that diameter of tumor dwindles, will be subjected to reagent thing group and blank group, positive controls and blank group at last, compared by the result of reagent thing group and positive controls.
7, test-results:
After 2 weeks of medication, the animal of intraperitoneal injection, be subjected to reagent thing group diameter of tumor to dwindle 75%, 56% and 48% respectively, positive controls has been dwindled 49%, 41% and 34% blank group respectively and has been dwindled-30%, is subjected to reagent thing group and blank group, positive controls and blank group, is subjected to the minification of reagent thing group and positive controls that significant difference (p＜0.01) is all arranged; The animal of oral administration, be subjected to that reagent thing group diameter of tumor has dwindled 63%, positive controls has dwindled 41%, the blank group has dwindled-29%, be subjected to reagent thing group and blank group, positive controls and blank group, be subjected to the minification of reagent thing group and positive controls that significant difference (p＜0.01) is arranged.
8, conclusion:
The antitumor action of new compound of the present invention (5) significantly is better than control drug formula II compound.
The antitumor action of test example 2 each compound of the present invention and with water miscible relation
1, is subjected to the tablet of reagent thing: embodiment 1～7 each compound
2, experimental animal: the purebred mouse of C57BL/6 that grows up, body weight 20 ± 2g, male and female dual-purpose, 10 every group.
3, be subjected to reagent agent amount and medication:
Oral (to mix the administration of food method): each group is 0.4mg/kg/ week.Dosage is in bulk drug.
4, experimental control:
Positive control: the tablet of formula II compound (parent compound of The compounds of this invention)
Blank, promptly oral blank.
5, test method:
The pathological model test of mouse.Produce papilloma with dimethylbenzanthracene and Oleum Tiglii induced animal, animal oral test medicine is given in modeling success back, the oral blank of control group, and in two weeks of successive administration, total dose weekly is divided into 7 times to be finished, and be administered once every day.Put to death animal in 24 hours after the drug withdrawal, calculate and respectively organize the percentage that diameter of tumor dwindles,, and analyze the relation that diameter of tumor dwindles percentage and compound water soluble the minification and the comparison of blank group of each group.
6, test-results:
After 2 weeks of medication, positive controls, embodiment 1～7 medicine group and blank group diameter of tumor have dwindled 38%, 55%, 56%, 58%, 60%, 61%, 67%, 72% ,-28% successively respectively, significant difference (p＜0.01) is all arranged between the percentage of each test group and control group, and the relation of being proportionate between diameter of tumor minification and compound water-soluble.
7, conclusion:
New compound of the present invention is oral to have a definite antitumor action, its antitumor action and water-soluble between be proportionate.
The curative effect of test example 3 The compounds of this invention treatment rheumatic arthritis
Experimental animal: healthy adult SD rat, 2～3 monthly ages, body weight 150 ± 30g, male and female dual-purpose, 10 every group.
Be subjected to the reagent thing:
Contain new compound 4-[(E of the present invention)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] capsule of phenylformic acid hexahydropyridine salt,
Experimental control:
Blank: only contain with being subjected to the identical assistant agent of reagent thing and do not contain the capsule of activeconstituents.
Positive control: the capsule that contains Compound I I (parent compound of new compound of the present invention).
Dosage: 1mg/kg/ days (in bulk drug).
Medication: oral.
Test method:
The pathological model of rat test (rat granuloma swell method).Laboratory animal is divided into 3 groups at random, 10 every group.With ether light anaesthesia animal, aseptic technique, it is subcutaneous through the epigastrium otch two sterilization rayon balls to be implanted rat both sides axillary region respectively, postoperative began administration the same day, successive administration 7 days, and rat is put to death in dislocation in the 8th day, take out cotton balls, put 60 ℃ of baking boxs and dry to constant weight, deduct the raw cotton ball weight, be granuloma weight.Granuloma weight is respectively organized granuloma weight, and is calculated inhibiting rate, and carry out test of significance with mg (granuloma)/100g (body weight) expression.
Test-results: new compound of the present invention (5) and its parent compound are oral to have definite curative effect to rheumatic arthritis, the average inhibiting rate of new compound (5), parent compound and blank group is respectively 83%, 61% and 0%, and each difference of organizing between inhibiting rate all has statistical significance.
Conclusion: the The compounds of this invention curative effect is to rheumatic arthritis its parent compound that is better than evident in efficacy.
Test example 4 new compounds of the present invention are treated psoriatic curative effect
Be subjected to the reagent thing: new compound 4-[(E of the present invention)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] emulsifiable paste of phenylformic acid hexahydropyridine salt.
Experimental animal: the new southwestern rabbit of healthy adult, body weight 2～3kg, male and female dual-purpose, 6 every group.
Dosage: 1.5g/kg/ days (in bulk drug).
Experimental control:
Blank: contain and be subjected to the reagent thing identical but do not contain the emulsifiable paste matrix of activeconstituents
Positive control: the emulsifiable paste that contains the parent compound (Compound I I) of new compound of the present invention.
Medication: external application.
Test method: laboratory animal is divided into 3 groups at random, 10 every group.Make psoriasis model in accordance with the law.The emulsifiable paste and the blank emulsifiable paste of the parent compound that modeling success back is coated with the emulsifiable paste of putting new compound of the present invention (5) on the skin respectively on the psoriatic lesion of animal, contain new compound of the present invention, once a day, in totally two weeks, its curative effect is investigated from antiproliferative effect, adjusting cytodifferentiation, anti-inflammatory action three aspects.
Test-results:
1, antiproliferative effect: the emulsifiable paste of new compound of the present invention (5) and contain the expression that the emulsifiable paste of the parent compound of new compound of the present invention all can be reduced psoriatic lesion mesocuticle growth factor receptors (EGF-R), ornithine decarboxylase (ODC) and antioncogene albumin A P1 isogonism protein cell proliferation sign, but the downward modulation effect of the emulsifiable paste of new compound of the present invention (5) obviously is better than the latter (p＜0.01), and both downward modulation effects are compared with blank emulsifiable paste and all had significant difference (p＜0.01).
2, regulate the cytodifferentiation effect: the emulsifiable paste of new compound of the present invention (5) all can be reduced the expression that the various kinds of cell differentiation indicates in the psoriatic lesion with the emulsifiable paste that contains the parent compound of new compound of the present invention, as keratinocyte trans-glutaminases (TGase-K), migration inhibition factor associated protein (MRP-8), Keratin sulfate 6,10,16, silk polymeric protein etc.But modulation factor of amplitude modulation big (89%) is in the emulsifiable paste (73%) of the parent compound that contains new compound of the present invention under the emulsifiable paste of new compound of the present invention (5), and this difference has statistical significance (p=0.04), and both downward modulation effects are compared with blank emulsifiable paste and all had significant difference (p＜0.01).
3, anti-inflammatory action: the three reduces the effect that inflammatory sign in the psoriatic lesion (as: HLA-DR, I-CAM-1, IL-6 etc.) expresses and is followed successively by: the emulsifiable paste of new compound of the present invention (5)＞the contain emulsifiable paste＞blank emulsifiable paste of the parent compound of new compound of the present invention.Triangular difference all has statistical significance (P＜0.01).
Conclusion: The compounds of this invention all has definite therapeutic action with its parent compound is oral to psoriatic, but its parent compound that is better than evident in efficacy of The compounds of this invention.
Claims (10)
1,4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt, described organic amine is primary amine, stretch amine or tertiary amine; Can be chain or cyclic amine; Described chain is a straight or branched.
2, the described 4-[(E of claim 1)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt, described organic amine is by hydroxyl, amino, carboxyl, aminoacid replacement.
3, the described 4-[(E of claim 1)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt, described cyclic amine is to contain heteroatomic hexa-atomic cyclammonium, described heteroatoms is nitrogen or oxygen.
4, the described 4-[(E of claim 1)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt, described organic amine is 2-methylol-2-amino-1, ammediol, meglumine, Methionin, piperazine, hexahydropyridine, dimethylethanolamine, quadrol.
5, the described 4-[(E of claim 1)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] preparation method of phenylformic acid organic amine salt, with 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid and ammonia or organic amine compound reaction, generate corresponding organic amine salt.
6, the described 4-[(E of claim 5)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] preparation method of phenylformic acid organic amine salt, wherein temperature of reaction is the solvent refluxing state; Reaction times is 0-5～4 hour; Reaction solvent is methyl alcohol, ethanol, chloroform, water or their mixture.
7, any one described 4-[(E in the claim 1 to 4)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt is used to prepare the purposes of prevention and treatment tumour and precancerous lesion medicine.
8, any one described 4-[(E in the claim 1 to 4)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] the phenylformic acid organic amine salt is used to prepare the purposes of treatment connective tissue disease (CTD) or dermatosis treating medicine.
9, a kind of pharmaceutical composition is characterized by and contains the described 4-[(E of claim 1)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl] phenylformic acid organic amine salt and the acceptable assistant agent of medicine, carrier.
10, the described pharmaceutical composition of claim 9, it is characterized by formulation is oral preparations, injection or external preparation.
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