CN101642451B - New application of amiodarone and derivatives thereof - Google Patents

New application of amiodarone and derivatives thereof Download PDF

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CN101642451B
CN101642451B CN2008100415131A CN200810041513A CN101642451B CN 101642451 B CN101642451 B CN 101642451B CN 2008100415131 A CN2008100415131 A CN 2008100415131A CN 200810041513 A CN200810041513 A CN 200810041513A CN 101642451 B CN101642451 B CN 101642451B
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amiodarone
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tumor
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俞强
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Xiangbei Welman Pharmaceutical Co Ltd
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Abstract

The invention relates to the field of pharmacology, in particular to new medical application of a known medicament-amiodarone and derivatives thereof in preparing a cell autophagy inductive agent. The invention also relates to a medicament composition containing the amiodarone.

Description

The new purposes of amiodarone and derivant thereof
Technical field
The present invention relates to field of pharmacology.More specifically, the present invention relates to the novel medical use of a kind of known drug-amiodarone or derivatives thereof.The invention still further relates to the pharmaceutical composition of Induces Autophagy.
Background technology
Amiodarone (Amiodarone) claim again atlansil, and clinical practice more than 40 year, its powerful antiarrhythmic effect is confirmed by increasing evidence-based medicine EBM result.At present, amiodarone has become clinical practice at most and one of antiarrhythmic drug the most widely.
Amiodarone is a derivant that contains the iodobenzene furan, found by Charlier, and synthetic at Belgian Ladas laboratory in 1962.Because amiodarone has the effect of blood vessel dilating, decreased heart rate, went on the market in France as a vasodilation in 1986, be used for anginal treatment.Subsequently, Rosenbaum at first uses it for the treatment of various tachyarrhythmias in South Africa, and obtains preferably clinical efficacy.1985, the ventricular arrhythmia that Food and Drug Administration (FDA) official approval amiodarone can be used for threat to life, repeatedly occurs, such as ventricle vibration or the unsettled ventricular tachycardia of hemodynamics, indication also comprises the bad arrhythmia that maybe can not tolerate of other antiarrhythmic drug therapeutic responses.Meanwhile, the application of amiodarone in treatment atrial fibrillation and atrial flutter is also increasingly extensive.
Amiodarone has resisting myocardial ischemia, increase cardiac output, reduce blood pressure and the effect such as antithyroid.The effect that amiodarone resists myocardial ischemia is from two aspects, and the one, lax vascular smooth muscle, directly dilating coronary blood vessel reduces coronary resistance, increases myocardial blood flow; The 2nd, the adrenergic antagonism of noncompetitive, but to the inhibition diastole coronary artery of α receptor.
In addition, amiodarone also has the inhibitory action of beta receptor, but its mechanism of action from beta-blocker is different.Amiodarone does not directly act on beta receptor, neither the perfect competition retardance, suppress the signal conduction in the retardance myocardial cell but belong to noncompetitive, can also reduce simultaneously the quantity of myocardial cell adrenoreceptor, these effects can weaken myocardial contraction.In theory, this effect has negative inotropic action to ill cardiac muscle.But amiodarone is used the rear negative inotropic action that substantially do not present, and can increase on the contrary the cardiac output of most of patients, and the net effect after it is used is significantly improved effect to cardiac function.Cause this paradox result former because: a little less than 1. amiodarone suppresses the degree of myocardial contraction to the intensity of calcium channel retardation than the IV class antiarrhythmic drug of other non-pyridines; 2. a little less than its inhibitory action to the calcium channel blocking action comparison normal myocardium contractility of Hypertrophic Cardiac; 3. the time-histories (APD) that amiodarone can the over reach current potential, its negative inotropic action can be compensated in the prolongation of action potential duration, APD; 4. amiodarone has obvious frequency dependence to the retardation of calcium channel, and comparatively fast then effect is strong for the rhythm of the heart during treatment; 5. the inhibitory action of myocardial contraction presented a property crossed; And only when dosage is larger, just present negative inotropic action.
Although this area is comparatively deep to the research of amiodarone, yet domestic and foreign literature is not all put down in writing amiodarone as the purposes of cell autophagy derivant aspect so far, does not provide the technology enlightenment of this respect yet.
The autophagy cell death is a kind of non-apoptosis programmed cell death, is different from apoptosis in the morphology, results from excessive autophagy, is also referred to as II type programmed cell death.In the cell of apoptosis defective, the Biotherapeutics of tumor uses the autophagy derivant that the potential of the tumor cell generation autophagy cell death of apoptosis opposing is improved mainly by the autophagy cell death, and this will become the new direction of chemotherapy.Therefore, thus this area in the urgent need to the medicine of exploitation by Induces Autophagy performance antitumor action.
Summary of the invention
The present invention aims to provide the amiodarone or derivatives thereof at the novel medical use aspect cell autophagy derivant and treatment tumor.
In a first aspect of the present invention, the purposes of chemical compound shown in a kind of formula I or its pharmaceutically acceptable salt is provided, they are used to prepare cell autophagy derivant:
Figure G2008100415131D00021
In the formula,
R 1Represent hydrogen atom or alkyl (C preferably 1-C 8Alkyl, more preferably C 1-C 5Alkyl);
R 2Represent hydrogen atom or alkyl (C preferably 1-C 8Alkyl, more preferably C 1-C 5Alkyl);
R 3Represent hydrogen atom or-NH-SO 2-CH 3
R 4Represent alkyl (C preferably 1-C 8Alkyl, more preferably C 1-C 5Alkyl) or ester group (the preferably straight or branched ester group of 1-8 carbon atom);
R 5Represent iodine atom or hydrogen atom;
R 6Represent iodine atom or hydrogen atom;
N is the positive integer (the preferably positive integer of 1-5) of 1-8.
In another preference, described cell autophagy derivant is used for the treatment of tumor, myopathy and nervous system degenerative disease.
In another preference, described derivant comprises pharmaceutical composition, food compositions or Halth-care composition.
In another preference, described formula I chemical compound is that structural formula is the chemical compound of II, III, IV, V, VI, VII, VIII, IX, X, XI or XII.
In another preference, described derivant comprises pharmaceutically acceptable carrier and is selected from lower group additional component: rapamycin, vincristine, tamoxifen, resveratrol, paclitaxel, temozolomide, tamoxifen, arsenic trioxide, clobetasone butyrate, carbamazepine, sodium valproate, SAHA (abbreviation SAHA).
In another preference, the dosage form of described derivant is selected from lower group: injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray or suppository.
In another preference, described myopathy is selected from lower group: myasthenia gravis, class myasthenia gravis, botulism, myasthenic syndrome, duchenne muscular dystrophy, tetanic property myopathy, inflammatory myositis, metabolic/endocrine myopathy, congenital and baby's property myopathy; And/or
Described nervous system degenerative disease is selected from lower group: alzheimer disease, parkinson, peripheral neuritis, Peripheral neuropathy, brain stem neuropathy, craniocerebral injury, cerebral ischemia, spinal cord injury, amyotrophic lateral sclerosis, HuntingtonShi disease.
In a second aspect of the present invention, the purposes of chemical compound shown in a kind of above-mentioned formula I or its pharmaceutically acceptable salt is provided, they are used to prepare the pharmaceutical composition for the treatment of tumor.
In another preference, described tumor is selected from lower group: neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer.
In another preference, described formula I chemical compound is that structural formula is the chemical compound of II, III, IV, V, VI, VII, VIII, IX, X, XI or XII; And/or
Comprise pharmaceutically acceptable carrier in the described pharmaceutical composition and be selected from lower group additional component: rapamycin, vincristine, tamoxifen, resveratrol, paclitaxel, the temozolomide, tamoxifen, arsenic trioxide, clobetasone butyrate, carbamazepine, sodium valproate, SAHA (SAHA), camptothecine, teniposide, colchicine, homoharringtonine, etoposide, procarbazine, asparaginase, cisplatin, carboplatin, mitoxantrone, cyclophosphamide, mustine hydrochlcride, lomustine, semustine, phosphinothioylidynetrisaziridine, busulfan, formylmerphalan, chlorambucil, fluorouracil, tegafur, excellent fluorine pyridine, carmofur, mercaptopurine, methotrexate, cytosine arabinoside, ancitabine, the mercapto guanine, altretamine, hydroxyurea, mitomycin, amycin, epirubicin, bleomycin, training Lay mycin, acrivastine, Trastuzumab, imatinib mesylate, gemcitabine, hycamtin, docetaxel, leuprorelin.
In another preference, the pharmaceutical composition of described treatment tumor is induced mammiferous tumor cell generation cell autophagy.
In a third aspect of the present invention, a kind of pharmaceutical composition is provided, it contains
(a) as the 0.01-99.9wt% of main active suc as formula the chemical compound shown in the I or its pharmaceutically acceptable salt,
Figure G2008100415131D00041
In the formula,
R 1, R 2, R 3, R 4, R 5, R 6With n as defined above,
(b) be selected from one or more auxiliary activity compositions of lower group: rapamycin, vincristine, tamoxifen, resveratrol, paclitaxel, the temozolomide, tamoxifen, arsenic trioxide, the Semen sojae atricolor triterpenoid saponin, novel vitamin D analogues, clobetasone butyrate, carbamazepine, sodium valproate, SAHA (SAHA), camptothecine, teniposide, colchicine, homoharringtonine, etoposide, procarbazine, asparaginase, cisplatin, carboplatin, mitoxantrone, cyclophosphamide, mustine hydrochlcride, lomustine, semustine, phosphinothioylidynetrisaziridine, busulfan, formylmerphalan, chlorambucil, fluorouracil, tegafur, excellent fluorine pyridine, carmofur, mercaptopurine, methotrexate, cytosine arabinoside, ancitabine, the mercapto guanine, altretamine, hydroxyurea, mitomycin, amycin, epirubicin, bleomycin, training Lay mycin, acrivastine, Trastuzumab, imatinib mesylate, gemcitabine, hycamtin, docetaxel, leuprorelin; With
(c) pharmaceutically acceptable carrier.
In another preference, the content of described (b) auxiliary activity composition is 0.0001-20wt%.
In another preference, the dosage form of described pharmaceutical composition is selected from lower group: injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray or suppository.
In a fourth aspect of the present invention, method a kind of non-therapeutic, external evoked cell generation cell autophagy is provided, it comprises step:
Cultured cells is contacted with the chemical compound shown in the above-mentioned formula I or its pharmaceutically acceptable salt, thus inducing cell generation cell autophagy.
In another preference, described cell is to be selected from lower group mammalian tumor cell: neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer.
In another preference, described cell comes from people, rat or mice.
The specific embodiment
The inventor finds the effect that the amiodarone or derivatives thereof has remarkable inducing cell generation autophagy through extensive and deep research, and In vitroandin vivotrial shows that it can suppress tumor (cell) growth effectively.Therefore, the amiodarone or derivatives thereof is the chemical compound that has Induces Autophagy and suppress tumor growth that the inventor finds.Accordingly, the invention provides the amiodarone or derivatives thereof by Induces Autophagy, thus the effect of performance treatment relevant disease.
Particularly, the autophagy cell death is a kind of non-apoptosis programmed cell death, is different from apoptosis in the morphology, results from excessive autophagy, is also referred to as II type programmed cell death.The autophagosome that forms in the autophagy process completely cuts off the Cytoplasm structure and it is degraded to nucleotide, aminoacid, free fatty, and it is re-used with synthetic macromolecule material or generation ATP.Therefore, " autophagy " is a kind of lysosomal pathway of the kytoplasm content of degrading, can the interior long-standing protein of degradation of cell and organelle.Its participates in cell stimulates to external world and reacts, and participates in growth course, and antineoplastic action is arranged, closely related with tumor, myopathy and nervous system degenerative disease.The death of spontaneity or chemotherapy induction can occur by autophagy in tumor cell.In the cell of apoptosis defective, the Biotherapeutics of tumor uses the autophagy derivant that the potential of the tumor cell generation autophagy cell death of apoptosis opposing is improved mainly by the autophagy cell death, and this will become the new direction of chemotherapy.The inventor finds through further investigation, and the amiodarone or derivatives thereof can inducing cell generation autophagy, and in vivo, the external growth that all can significantly suppress tumor, stop tumorigenesis, bring into play obvious antitumor action.
As used herein, term " the compounds of this invention " refers to have formula I chemical compound or its pharmaceutically acceptable salt of following structure:
In the formula,
R 1And R 2Be hydrogen atom or alkyl, perhaps R independently 1And R 2(more preferably described heterocycle is to consist of 4-7 unit heterocycle with adjacent N atom
Figure G2008100415131D00062
Or
Figure G2008100415131D00063
);
R 3Represent hydrogen atom or-NH-SO 2-CH 3
R 4Represent alkyl or ester group;
R 5Represent iodine atom or hydrogen atom;
R 6Represent iodine atom or hydrogen atom;
N is the positive integer (preferred 1-5) of 1-8.
As used herein, term " alkyl " refers to have the alkyl of the straight or branched of 1-8 carbon atom, such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, hexyl, heptyl or octyl group etc.The straight or branched alkyl that preferably has 1-5 carbon atom, most preferable, ethyl, propyl group, isopropyl, butyl, isobutyl group or neopentyl.
As used herein, term " ester group " refers to have the straight or branched ester group of 1-8 carbon atom, such as carbomethoxy, ethoxycarbonyl, propyl ester base, isopropyl ester group, butyl ester base, isobutyl ester group, tert-butyl ester base, Zhong Ding ester group, pentyl ester base, hot pentyl ester base etc.The straight or branched ester group that preferably has 1-5 carbon atom, most preferably carbomethoxy, ethoxycarbonyl, isopropyl ester group, isobutyl ester group or peopentyl ester base.
Preferred R 1, R 2Represent independently of one another hydrogen atom, methyl, ethyl, isopropyl or butyl.
Preferred R 4Represent propyl group, carbomethoxy, ethoxycarbonyl, isopropyl ester group, isobutyl ester group or peopentyl ester base.
Particularly preferably, R 1, R 2Represent independently of one another hydrogen atom or C 1-4Alkyl, R3 represent hydrogen atom or-NH-SO 2-CH 3, R4 represents propyl group or C 1-4Ester group, R 5Represent iodine atom or hydrogen atom, and R 6Represent iodine atom or hydrogen atom.
Most preferred chemical compound comprises the formula II-XII chemical compound that is selected from lower group:
Figure G2008100415131D00071
Figure G2008100415131D00081
Figure G2008100415131D00091
A kind of particularly preferred chemical compound is amiodarone, and its structure is suc as formula shown in the II:
Figure G2008100415131D00092
As used herein, term " amiodarone and derivant thereof " or " amiodarone and reactive derivative thereof " are used interchangeably, and refer to that amiodarone and structure and amiodarone are similar and have the derivant of the inducing cell autophagy function (or active) of amiodarone.Described formula III can be considered as the derivant of amiodarone to the XII chemical compound.In addition, derivant also can comprise form, the especially pharmaceutically acceptable salt such as ester, salt of formula I chemical compound.
Among the present invention, term " pharmaceutically acceptable salt " refers to inorganic acid addition salt and the organic acid addition salt of relatively nontoxic the compounds of this invention.Exemplary salt comprises hydrobromate, hydrochlorate, sulfate, sulphite, acetate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate, phosphate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, mesylate, gluconate, Lactobionate or lauryl sulfonate etc.They can comprise the cation based on alkali and alkaline earth metal ions, such as sodium, lithium, potassium, calcium, magnesium etc., and without toxic amine, quaternary amine and amine cation, include but not limited to: amine, tetramethyl amine, tetraethyl amine, methylamine, dimethylamine, trimethylamine, triethylamine, ethamine etc.
The present invention includes the represented chemical compound of general formula (I) and possible various isomer patterns thereof.Comprise: non-mirror image isomer, mirror image isomer, tautomer or " E " or " Z " configurational isomer etc.
In addition, the represented chemical compound of general formula (I) is also contained solvation or the non-solvent form of this chemical compound on using.Therefore, the various chemical compound with specified structure that includes comprises its hydration or without the hydration form.
Except the represented chemical compound of general formula (I), different specific embodiments comprise: the active metabolite of pharmaceutically acceptable salt, prodrug, this chemical compound or the pharmaceutically acceptable salt of this metabolite.
" prodrug " is the represented derivant of a kind of general formula (I), by means of the mode of in vivo metabolism it become the represented chemical compound of general formula (I) in vivo transforming (hydrolysis, reduction or oxidation).The acid that is fit to preparation " prodrug " includes, but is not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-beta-hydroxyethyl base naphthoic acid, gentisic acid, hydroxyethylsulfonic acid., methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid etc.
As used herein, " compositions of the present invention " refers to contain the compositions suc as formula chemical compound shown in the I or its pharmaceutically acceptable salt, wherein the weight of contained formula I chemical compound or its pharmaceutically acceptable salt is the 0.01-99% of composition total weight, preferably be 0.1-95%, more preferably being 1-90%, is 10-80% best.Compositions of the present invention comprises (a) cell autophagy derivant, (b) compositions for the treatment of tumor.
Compositions of the present invention can be pharmaceutical composition, food compositions or Halth-care composition.
Medical usage
Amiodarone or derivatives thereof of the present invention can be used as the cell autophagy derivant.Described cell autophagy derivant can be used for treating tumor, myopathy and nervous system degenerative disease, and described purposes can realize by Induces Autophagy.
Amiodarone or derivatives thereof of the present invention can be used for treating tumor, and described purposes can realize by Induces Autophagy.The representational example of the tumor for the treatment of comprises (but being not limited to): neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer.
Amiodarone or derivatives thereof of the present invention can be used as or for the preparation of the cell autophagy derivant.Described derivant can be used for treating tumor, myopathy and nervous system degenerative disease.
Described tumor comprises (but being not limited to): neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer;
Described myopathy comprises (but being not limited to): myasthenia gravis, class myasthenia gravis, botulism, myasthenic syndrome, duchenne muscular dystrophy, tetanic property myopathy, inflammatory myositis, congenital or baby's property myopathy or metabolic/endocrine myopathy;
Described nervous system degenerative disease comprises (but being not limited to): alzheimer disease, parkinson, peripheral neuritis, Peripheral neuropathy, brain stem neuropathy, craniocerebral injury, cerebral ischemia, spinal cord injury, amyotrophic lateral sclerosis or HuntingtonShi are sick.
Pharmaceutical composition and method of application
The present invention also provides the method for pharmaceutical composition and inducing cell generation autophagy, and it comprises the compounds of this invention to the administration medicine effective quantity.
The present invention also provides the method for pharmaceutical composition and treatment tumor, and it comprises the compounds of this invention to the administration medicine effective quantity.
The present invention also provides the method for the treatment of and cell autophagy relevant disease, and it comprises the compounds of this invention to the administration medicine effective quantity.
The effective dose of used active component can change with the order of severity of mode of administration and disease to be treated.Yet, usually when chemical compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect, preferably give with the dosage that separates for 2-4 time every day, or with the slow release form administration.For most of large mammal, the accumulated dose of every day is about 1-100mg.The dosage form that is applicable to take orally comprises the reactive compound of the about 0.5-500mg that mixes with solid-state or liquid pharmaceutically acceptable carrier.This therapeutic scheme of scalable is to reach optimum therapeuticing effect.For example, can be according to the needs for the treatment of situation, every day, several times separated administration, or dosage is reduced in proportion.Usually, becoming the scope of human oral clinical dosage is 1-1000mg/ day, is preferably 10-200mg/ day, and the non-oral dosage of being grown up is 0.1-100mg/ day, preferred 1-100mg/ day.
When using amiodarone of the present invention as the cell autophagy derivant, also can with other therapeutic agent coupling.For example (but being not limited to) and be selected from one or more auxiliary activity composition couplings of lower group: rapamycin, vincristine, tamoxifen, resveratrol, paclitaxel, temozolomide, tamoxifen, arsenic trioxide, clobetasone butyrate, carbamazepine, sodium valproate, SAHA (SAHA).
SAHA is the abbreviation of suberoylanilide hydroxamic acid, and its structural formula is as follows:
When using the compounds of this invention treatment tumor, also can with other treatment agent coupling.For example with one or more auxiliary activity composition couplings that are selected from lower group: rapamycin, vincristine, tamoxifen, resveratrol, paclitaxel, the temozolomide, tamoxifen, arsenic trioxide, clobetasone butyrate, carbamazepine, sodium valproate, SAHA (SAHA), camptothecine, teniposide, colchicine, homoharringtonine, etoposide, procarbazine, asparaginase, cisplatin, carboplatin, mitoxantrone, cyclophosphamide, mustine hydrochlcride, lomustine, semustine, phosphinothioylidynetrisaziridine, busulfan, formylmerphalan, chlorambucil, fluorouracil, tegafur, excellent fluorine pyridine, carmofur, mercaptopurine, methotrexate, cytosine arabinoside, ancitabine, the mercapto guanine, altretamine, hydroxyurea, mitomycin, amycin, epirubicin, bleomycin, training Lay mycin, acrivastine, Trastuzumab, imatinib mesylate, gemcitabine, hycamtin, docetaxel, leuprorelin.
When using the compounds of this invention treatment myopathy, also can with other treatment agent coupling.For example with one or more auxiliary activity composition couplings that are selected from lower group: this bright of neostigmine, edrophonium chloride, galantamine, ambenonium chloride, demecarium bromide, physostigmine, pyrrole.
When using the compounds of this invention treatment nervous system degenerative disease, also can with other treatment agent coupling.For example with one or more auxiliary activity composition couplings that are selected from lower group: levodopa, carbidopa, amantadine, Si Lijilan, bromocriptine, benserazide, benzhexol, benzatropine, procyclidine.
Usually, when the compounds of this invention is used for such use, they can make with one or more pharmaceutically acceptable carriers or mixed with excipients the pharmaceutical dosage form of different way of administration, such as injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray, suppository etc.
Chemical compound of the present invention can be through oral, intravenous, intramuscular or subcutaneous route administration.
But the dosage form of oral administration administration is in the above-mentioned dosage form: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, kaolin, micropowder silica gel, Pulvis Talci, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, Polyethylene Glycol, nonionic surfactant and edible oil (such as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).Normally used adjuvant comprises in the process of pharmaceutical compositions: flavoring agent, coloring agent, antiseptic (such as oxybenzene alkyl butyl ester, sodium benzoate, sorbic acid) and antioxidant (such as vitamin E, vitamin C, sodium pyrosulfite and dibenzylatiooluene).
The dosage form that can be used for injection administration in the above-mentioned dosage form comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerol, propylene glycol, Polyethylene Glycol.In addition, also need add antibacterial (such as benzyl alcohol, butyl hydroxybenzoate, thimerosal), isoosmotic adjusting agent (such as sodium chloride, glucose), suspending agent (such as sodium carboxymethyl cellulose, methylcellulose), solubilizing agent (tween 80, lecithin), antioxidant (such as vitamin E, vitamin C, sodium pyrosulfite) and filler (such as lactose, mannitol).
From being easy to prepare the position with administration, preferred pharmaceutical composition is solid-state composition, especially the capsule of tablet and solid-filling or liquid filling.The preferred oral administration.
Major advantage of the present invention is:
1, amiodarone or derivatives thereof of the present invention can be used for preparing effective cell autophagy derivant.
2, amiodarone or derivatives thereof of the present invention can effectively be treated tumor.
3, amiodarone or derivatives thereof of the present invention also can effectively be treated the disease relevant with cell autophagy.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that better implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
The amiodarone or derivatives thereof is to the inhibitory action of S180 tumor-bearing mice tumor growth
Laboratory animal: the female SPF BALB/c mouse, autotrophy, body weight are 18-20g, and SPF level Animal House is raised, and 12h illumination/12h is dark, freely absorbs feedstuff and water.
Experimental drug: amiodarone (formula II chemical compound) is available from upper Hisense friendship nine good fortune pharmaceutcal corporation, Ltds, compound vi (shown in VI) is synthetic by this laboratory, synthetic method is seen document (Laurent Bigler, CarloSpirli, Romina Fiorotto et al.Synthesis and cytotoxicity propertiesof amiodarone analogues.European Journal of MedicinalChemistry, 2007,42:861-867); Compounds X I (shown in XI) is synthetic by this laboratory, synthetic method is seen document (Huy Riem Ha, Laurent Bigler, Barbara Wendt et al.Identification and quantitation of novel metabolites of amiodarone inplasma of treated patients.European Journal of Pharmaceutical Sciences, 2005,24:271-279), paclitaxel is available from the natural Pharmaceutical of Sichuan Jiu Feng limited company, and cyclophosphamide is available from Changzhou new power medication chemistry company limited.
Experimental technique: get 7 days S180 ascites mice of inoculation, extract ascites under the aseptic condition, adjust cell concentration to 5 * 10 with normal saline 6/ ml.It is subcutaneous that S180 cell suspension is seeded in mice right fore armpit with 0.2ml/ amount only.Behind the inoculation 24h, mice is divided into respectively 6 groups (10 every group) at random: amiodarone group, dosage are 300mg/kg; Compound IV group, dosage are 300mg/kg; Compounds X I group, dosage is 300mg/kg; Cyclophosphamide group, dosage are 20mg/kg; The drug combination group is given and the amiodarone of 150mg/kg and the paclitaxel of 2mg/kg respectively; Matched group gives distilled water, and the administration volume is 0.1ml/10g, more than respectively organize equal every day of gastric infusion 1 time, continuous 7 days.Next day is put to death mice in drug withdrawal, strips the tumor piece and weighs, and calculates every cell mean, carries out the t check.Calculate tumour inhibiting rate:
Tumour inhibiting rate=(matched group tumor weight-administration group tumor is heavy)/matched group tumor heavy * 100%.
Table 1 amiodarone or its analog are to the inhibitory action of S180 tumor-bearing mice tumor growth
Figure G2008100415131D00141
* represent p＜0.01, compare with matched group to have significant difference.The amiodarone or derivatives thereof can significantly suppress the growth of S180 tumor-bearing mice tumor when 300mg/kg dosage, difference has significance (p＜0.01), and suppression ratio is respectively 70.41%, 56.12%, 60.2%.When amiodarone (150mg/kg) and paclitaxel (2mg/kg) administering drug combinations, suppression ratio is 80.61%, shows that both have significant synergistic function.Compare with the cyclophosphamide group, the body weight of amiodarone group, compound IV group, compounds X I group, drug combination group mice does not obviously descend, and illustrates that medicine is substantially nontoxic.
Embodiment 2
Amiodarone and derivant thereof are to the inhibitory action of kinds of tumor cells growth in the in vitro tests
In-vitro Culture of Human Fetal renal carcinoma 293 cells, human hepatoma HepG2 cell, people's pulmonary carcinoma A549 and CRL-5895 cell, people's gastric cancer HGC cell, MCF-7 Human Breast Cancer Cells, human leukemia HL-60 cell, human lymphoma U937 cell, human colon carcinoma HT-29 cell, human osteosarcoma MG-63 cell, human ovarian cancer 3AO cell, human glioma U251 cell.Growth of Cells is used trypsin digestion cell to the logarithmic growth after date, and centrifugal 5 minutes of 1000rpm abandons supernatant, and an amount of culture medium suspends, and adjusts cell concentration to 8 * 10 4/ ml.With cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, place (37 ℃ of cell culture incubators, 5%) after cultivating 24h in, amiodarone group, compound IV group, the respectively every hole of compounds X I group add the medicine to be measured 100 μ l of cell culture medium dilution, final concentration is 0.5 μ g/ml, and the blank group adds the cell culture medium of equivalent, and each group is all established 6 multiple holes.After cultivating 66h in the incubator, every hole adds the MTT 20 μ l of 5mg/ml, places 4h for 37 ℃, abandons supernatant, adds 150 μ l DMSO, the vibration mixing, and 492nm surveys absorbance (OD).Calculate medicine to the suppression ratio of each growth of tumour cell:
Suppression ratio=(matched group OD value-administration group OD value)/matched group OD value * 100%.
Table 2 amiodarone is to the inhibitory action of kinds of tumor cells growth
The cell title Amiodarone group OD value Matched group OD value Suppression ratio (%)
293 0.125±0.012 0.967±0.045 87.07
HepG2 0.121±0.011 0.977±0.033 87.62
A549 0.102±0.009 0.975±0.063 89.54
CRL-5895 0.118±0.011 0.958±0.071 87.68
HGC 0.119±0.007 0.985±0.025 87.92
MCF-7 0.129±0.012 0.996±0.038 87.05
HL-60 0.138±0.013 0.963±0.017 85.67
HT-29 0.178±0.009 0.942±0.012 81.10
MG-63 0.126±0.012 0.967±0.018 86.97
U937 0.112±0.009 0.952±0.015 88.24
3AO 0.126±0.011 0.989±0.013 87.26
U251 0.135±0.008 0.998±0.016 86.47
Table 3 compound IV is to the inhibitory action of kinds of tumor cells growth
The cell title Compound III group OD value Matched group OD value Suppression ratio (%)
293 0.098±0.006 0.967±0.045 89.87
HepG2 0.123±0.009 0.977±0.033 87.41
A549 0.153±0.008 0.975±0.063 84.31
CRL-5895 0.136±0.009 0.958±0.071 85.80
HGC 0.122±0.011 0.985±0.025 87.61
MCF-7 0.144±0.009 0.996±0.038 85.54
HL-60 0.156±0.011 0.963±0.017 83.80
HT-29 0.116±0.011 0.942±0.012 87.69
MG-63 0.162±0.008 0.967±0.018 83.25
U937 0.201±0.009 0.952±0.015 78.89
3AO 0.198±0.011 0.989±0.013 79.98
U251 0.125±0.008 0.998±0.016 87.47
Table 4 compounds X I is to the inhibitory action of kinds of tumor cells growth
The cell title Compound IV group OD value Matched group OD value Suppression ratio (%)
293 0.193±0.008 0.967±0.045 80.04
HepG2 0.117±0.012 0.977±0.033 88.02
A549 0.113±0.009 0.975±0.063 88.41
CRL-5895 0.124±0.010 0.958±0.071 87.06
HGC 0.156±0.005 0.985±0.025 84.16
MCF-7 0.117±0.011 0.996±0.038 88.25
HL-60 0.158±0.008 0.963±0.017 83.59
HT-29 0.118±0.009 0.942±0.012 87.47
MG-63 0.152±0.013 0.967±0.018 84.28
U937 0.119±0.008 0.952±0.015 87.50
3AO 0.116±0.011 0.989±0.013 88.27
U251 0.153±0.009 0.998±0.016 84.67
Table 2, table 3 and table 4 result show, when the dosage of amiodarone, compound IV, compounds X I is respectively 0.5 μ g/ml, external human embryo kidney (HEK) cancerous cell, hepatoma carcinoma cell, lung carcinoma cell, stomach cancer cell, breast cancer cell, leukaemia, colon cancer cell, osteosarcoma cell, lymphoma cell, Proliferation of Human Ovarian Cell, human glioma cell are all had the effect of very strong its growth of inhibition, antitumor spectra is wide.
Embodiment 3
The preparation of tablet
Utilize routine techniques, mix following component, direct compression then, the pharmaceutical composition of preparation tablet form, its prescription is as follows:
Composition Recipe quantity (g/1000 sheet)
Amiodarone 100
Lactose 50
Microcrystalline Cellulose 40
Corn starch 6
Carboxymethyl starch sodium 3
Magnesium stearate 1
Total amount 200
Composition Recipe quantity (g/1000 sheet)
Compound IV 100
Lactose 50
Microcrystalline Cellulose 40
Corn starch 6
Carboxymethyl starch sodium 3
Magnesium stearate 1
Total amount 200
Embodiment 4
The preparation of injection
Composition Recipe quantity (g/1000ml)
Amiodarone 10
Sodium sulfite 0.2
Sodium carboxymethyl cellulose 5
Tween 80 1.5
Water for injection Add to 1000ml
1. sodium sulfite is added in the 500ml water for injection, adds sodium carboxymethyl cellulose, mixing, soaked overnight (24 hours), complete molten after, filter with 210 order nylon cloths;
2. with 1. heating in water bath of solution, add tween 80, mixing;
3. to the water-bath boiling, add amiodarone, mixing continues heating 30 minutes, takes out and is cooled to room temperature, G 3Sintered glass funnel filters;
4. inject water to 1000ml, mixing, embedding is with 100 ℃ of sterilizations in 30 minutes.
Embodiment 5
The preparation of compound tablet
Utilize routine techniques, mix following component, direct compression then, the pharmaceutical composition of preparation tablet form, its prescription is as follows:
Composition Recipe quantity (g/1000 sheet)
Amiodarone 50
Paclitaxel 0.5
Lactose 99.5
Microcrystalline Cellulose 40
Corn starch 6
Carboxymethyl starch sodium 3
Magnesium stearate 1
Total amount 200
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (9)

1. the purposes of chemical compound or its pharmaceutically acceptable salt shown in a formula II, formula IV or the formula XI,
Figure FDA00002227602700011
, it is characterized in that, for the preparation of the pharmaceutical composition for the treatment of tumor;
Chemical compound shown in the formula II or its pharmaceutically acceptable salt and paclitaxel share.
2. purposes as claimed in claim 1 is characterized in that, described tumor is selected from lower group: neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer.
3. purposes as claimed in claim 1 is characterized in that, comprises pharmaceutically acceptable carrier in the described pharmaceutical composition.
4. purposes as claimed in claim 1 is characterized in that, the pharmaceutical composition of described treatment tumor is induced mammiferous tumor cell generation cell autophagy.
5. a pharmaceutical composition is characterized in that it contains
(a) as the 0.01-99.9wt% of main active suc as formula chemical compound or its pharmaceutically acceptable salt shown in II, formula IV or the formula XI,
Figure FDA00002227602700021
(b) paclitaxel; With
(c) pharmaceutically acceptable carrier.
6. compositions as claimed in claim 5 is characterized in that, the content of described (b) is 0.0001-20wt%.
7. compositions as claimed in claim 5, it is characterized in that the dosage form of described pharmaceutical composition is selected from lower group: injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray or suppository.
8. a method non-therapeutic, external evoked cell generation cell autophagy is characterized in that, comprises step:
With cultured cells with contact suc as formula chemical compound or its pharmaceutically acceptable salt shown in II, formula IV or the formula XI, thereby inducing cell generation cell autophagy
Figure FDA00002227602700031
Chemical compound shown in the formula II or its pharmaceutically acceptable salt and paclitaxel share.
9. method as claimed in claim 8, it is characterized in that described cell is to be selected from lower group mammalian tumor cell: neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia or ovarian cancer.
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