CN101503394B - High piperazine acetydrazide derivatives, and preparation and use thereof - Google Patents
High piperazine acetydrazide derivatives, and preparation and use thereof Download PDFInfo
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- CN101503394B CN101503394B CN200910127432A CN200910127432A CN101503394B CN 101503394 B CN101503394 B CN 101503394B CN 200910127432 A CN200910127432 A CN 200910127432A CN 200910127432 A CN200910127432 A CN 200910127432A CN 101503394 B CN101503394 B CN 101503394B
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Abstract
The invention relates to a novel high piperazidine acethydrazide-type derivative indicated by formula I or II. In the formula, the definitions of various symbols are the same as those in the Description. The invention also relates to a method for preparing the high piperazidine acethydrazide-type derivative, the usage of the high piperazidine acethydrazide-type derivative in preparing medicines for curing and/or preventing tumors and/or cancers, and a pharmaceutical composition containing the high piperazidine acethydrazide-type derivative. The high piperazidine acethydrazide-type derivative has effective antitumor activity.
Description
Technical field
The present invention relates to the high piperazine acetydrazide derivatives of a class novelty, the invention still further relates to the method for the described high piperazine acetydrazide derivatives of preparation, described high piperazine acetydrazide derivatives preparation be used for the treatment of and/or the medicine of prophylaxis of tumours and/or cancer in purposes, and the pharmaceutical composition that comprises described high piperazine acetydrazide derivatives.
Background technology
Treating the employed chemicals of terminal cancer does not at present clinically all have selectivity to cancer cells basically, and Side effects of pharmaceutical drugs bring very big injury for cancer patients's body and mind.Molecular targeted treatment is a new way of selective therapy tumour, and molecular targeted agents provides feasibility for cancer patients's personalized treatment, and advantage is both to reduce toxic side effect, prolongs cancer patients's life again.
Bibliographical information (referring to, WO2006128173 for example) the piperazine acetydrazide heterogeneous ring compound is the micromolecular compound of a class biologically active, it can optionally lure cancer cell death in cancer cells, this compound can be used as the antineoplastic molecular targeted agents of potential.But the compound of bibliographical information only is confined on the cyclosubstituted heterogeneous ring compound of piperazine, does not also have bibliographical information high piperazine acetydrazide compound as the targeted drug of luring cancer cell death into.On the other hand, the high piperazine of nitrogen-containing heterocycle compound is a medicine synthetic important intermediate, in the structural modification of chemicals and structure of modification, important role is arranged, as document [Carl B.Ziegler, et al., J.Med.Chem.1990,33 (1), 142] described, in drug molecule, the existence of high piperazine group significantly improves the activity of related drugs.But the organic compound of the contained high piperazine of bibliographical information does not relate to compounds relevant with the present invention and their possible purposes.Therefore, have in the drug molecule of antitumour activity in research, the synthetic derivative that contains high piperazine with novel structure is still the problem that those skilled in the art make great efforts to study.
Summary of the invention
The purpose of first aspect present invention provides the high piperazine acetydrazide derivatives of a class novelty.The purpose of second aspect present invention provides the preparation method of the high piperazine acetydrazide derivatives of described novelty.The inventor is surprisingly found out that, the high piperazine acetydrazide derivatives of novelty provided by the invention has effective antitumour activity, the present invention is based on this discovery and be accomplished the present invention, thereby the purpose of third aspect present invention provides the purposes of high piperazine acetydrazide derivatives in pharmacy of described novelty.In addition, fourth aspect present invention provides the pharmaceutical composition of the high piperazine acetydrazide derivatives that comprises novelty of the present invention.
Put it briefly, first aspect present invention provides the compound of formula I or formula II:
Wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom or nitrogen-atoms independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
6Alkenyl, C
1-C
6Alkyl or C
1-C
6Alkoxyl group,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to the compound of first aspect present invention, wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
6Alkenyl, C
1-C
6Alkyl or C
1-C
6Alkoxyl group,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to the compound of first aspect present invention, wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, allyl group, crotyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base independently of one another,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to the compound of first aspect present invention, wherein:
N is 1;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, allyl group, crotyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base independently of one another,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each described compound of first aspect present invention, it is selected from following compound:
(4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine [English name: (4-Benzyl-[1,4] diazepan-1-yl)-acetic acid (3-allyl-2-hydroxy-benzylidene)-hydrazide] and
(4-is to Methyl benzenesulfonyl base-[1; 4] Diazesuberane-1-yl)-acetyl (3; 5-two chloro-2-hydroxyl-methylene-benzene) hydrazine [English name: (4-(Toluene-4-sulfonyl-[1; 4] diazepan-1-yl)-acetic acid (3; 5-dichloro-2-hydroxy-benzylidene)-hydrazide], or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each described compound of first aspect present invention, it is selected from compound or its pharmacologically acceptable salts, solvate, steric isomer or the prodrug of the arbitrary embodiment of the present invention.
According to each described compound of first aspect present invention, it is (4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine fumarate.
Second aspect present invention provides the method for preparation formula I or formula II compound, and it may further comprise the steps:
(1) under alkaline condition, makes formula
Chlorination aromatic hydrocarbon compound and high piperazine in organic solvent, react and generate with following formula Ib or formula IIb compound:
(2) under alkaline condition, make the compound of formula Ib or formula IIb compound and ethyl chloroacetate reaction generation with following formula Ic or formula IIc:
(3) in organic solvent, make the compound of the compound reaction generation of hydrazine hydrate and above-mentioned formula Ic or formula IIc with following formula Id or formula IId:
(4) in ethanolic soln, formula Id that step (3) obtains or compound and the formula of formula IId
The compound reaction obtains the compound of formula I or formula II; With optional
(5) make compound and the acid-respons of formula I or formula II, obtain the corresponding salt of the compound of formula I or formula II,
Wherein, n, A, B, C, D, E, R, R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of first aspect present invention.
According to the method for second aspect present invention, wherein the organic solvent described in the step (1) can be ethanol, tetrahydrofuran (THF); Organic solvent described in the step (2) can be triethylamine, sodium bicarbonate etc. for acetone and described alkali; Organic solvent described in step (3) and (4) can be ethanol; Organic solvent described in the step (5) can be methyl alcohol.
According to each described method of second aspect present invention, wherein the acid described in the step (5) is fumaric acid.According to each described method of second aspect present invention, wherein step (5) is to react under reflux.
According to each described method of second aspect present invention, wherein the corresponding salt of the compound of the formula I of gained or formula II is with the compound shown in following formula Ie or the formula IIe in the step (5):
Wherein, n, A, B, C, D, E, R, R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of first aspect present invention.
According to each described method of second aspect present invention, the compound of wherein said formula I or formula II is selected from:
1, (4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine and
2, (4-p-toluenesulfonyl-[1,4] Diazesuberane-1-yl)-acetyl (3,5-two chloro-2-hydroxyl-methylene-benzene) hydrazine,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
In The compounds of this invention, with group part " [1,4] Diazesuberane base " corresponding compounds, promptly [1,4] Diazesuberane also can be described as high piperazine (homopiperazine).
Compound of the present invention can be called " high piperazine acetyl (formimino benzene) hydrazine of replacement " prevailingly, and for example, some compound of the present invention can be called " the high piperazine acetyl of 4-benzyl (formimino benzene) hydrazine " prevailingly.
Above compound (4-benzyl-[1,4] Diazesuberane-1-yl)-and acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine, also can be: the high piperazine of 4-benzyl-1-acetyl (N-amido formamino-3-allyl group-2-hydroxybenzene) hydrazine according to different naming systems with its called after.
According to each described method of second aspect present invention, the compound of wherein said formula I or formula II is (4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine fumarate.
In an embodiment of the described method of second aspect present invention, described formula I compound or its pharmacy acceptable salt for example synthetic method of fumarate are illustrated as follows:
In an embodiment of the described method of second aspect present invention, described formula II compound or its pharmacy acceptable salt for example synthetic method of fumarate are illustrated as follows:
Third aspect present invention provide each described compound of first aspect present invention preparation be used for the treatment of and/or the medicine of prophylaxis of tumours and/or cancer in purposes.
Purposes according to a third aspect of the invention we, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:
Malignant tumour includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);
Lymphoid hematopoiesis tumour includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphocytoblast leukemia, B-cell lymphatic cancer, T-cell lymphatic cancer, Huo Qijin lymphatic cancer, non--Huo Qijin lymphatic cancer, hair cell lymphatic cancer, mantle cell lymphoma, myelomatosis and Burkett ' sShi lymphatic cancer;
The hematopoiesis tumour of marrow system includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;
Between the tumour of the matter origin cause of formation, include but not limited to fibrosarcoma and rhabdosarcoma;
The tumour of maincenter and peripheral nervous system comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And
Other tumours include but not limited to melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.
Fourth aspect present invention is provided among the experimenter who needs and treats and/or prevents tumour and/or method for cancer, and described method comprises each the described compound of first aspect present invention to described experimenter's administering therapeutic significant quantity.
Method according to a forth aspect of the invention, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:
Malignant tumour includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);
Lymphoid hematopoiesis tumour includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphocytoblast leukemia, B-cell lymphatic cancer, T-cell lymphatic cancer, Huo Qijin lymphatic cancer, non--Huo Qijin lymphatic cancer, hair cell lymphatic cancer, mantle cell lymphoma, myelomatosis and Burkett ' sShi lymphatic cancer;
The hematopoiesis tumour of marrow system includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;
Between the tumour of the matter origin cause of formation, include but not limited to fibrosarcoma and rhabdosarcoma;
The tumour of maincenter and peripheral nervous system comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And
Other tumours include but not limited to melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.
Fifth aspect present invention provides a kind of pharmaceutical composition, and it comprises each described compound of first aspect present invention and optional pharmacy acceptable diluent, carrier, vehicle, auxiliary material or the vehicle that treats and/or prevents significant quantity.
Pharmaceutical composition according to a fifth aspect of the invention, it can be used for treating and/or preventing tumour and/or cancer.Pharmaceutical composition according to a fifth aspect of the invention, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:
Malignant tumour includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);
Lymphoid hematopoiesis tumour includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphocytoblast leukemia, B-cell lymphatic cancer, T-cell lymphatic cancer, Huo Qijin lymphatic cancer, non--Huo Qijin lymphatic cancer, hair cell lymphatic cancer, mantle cell lymphoma, myelomatosis and Burkett ' sShi lymphatic cancer;
The hematopoiesis tumour of marrow system includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;
Between the tumour of the matter origin cause of formation, include but not limited to fibrosarcoma and rhabdosarcoma;
The tumour of maincenter and peripheral nervous system comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And
Other tumours include but not limited to melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.
The term that the present invention uses has to give a definition, unless description is arranged in addition:
Term used herein " alkyl " comprises and contains the straight chain that specifies number carbon atom and the saturated hydrocarbyl of side chain, for example is methyl, ethyl usually, and propyl group of straight chain and side chain, butyl, amyl group, hexyl etc.Term " alkyl " also comprises cycloalkyl, i.e. ring-type C
3-C
6Alkyl is as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferably, term used herein " alkyl " is meant and comprises the straight chain that specifies number carbon atom and the chain-like alkyl of side chain.
Term used herein " thiazolinyl " comprises and contains the straight chain that specifies number carbon atom and the alkylene of side chain, usually for example be vinyl, allyl group, propenyl, and straight chain and side chain comprise one or more pairs of keys and double bond position in the butenyl of any feasible location, pentenyl, hexenyl etc.
Term used herein " alkoxyl group " is independent or making up middle finger alkyl ether groups, wherein the same definition of term " alkyl ".The example of suitable alkyl ether groups includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
Term " halogen " is defined as in this article and comprises fluorine, chlorine, bromine or iodine, can also comprise their isotropic substance.
The various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the document known method, or can buy by commerce. used intermediate, starting material, reagent, reaction conditions etc. all can be made appropriate change according to the existing knowledge of those skilled in the art in the above reaction scheme. and perhaps, those skilled in the art also can instruction according to the present invention prepare other formula I or the formula II compound that the inventive method fails to contain.
Formula I of the present invention or formula II compound can exist by stereoisomer form.The present invention includes all possible steric isomer, promptly along or the mixture of anti-single stereoisomers or the two any required ratio.The present invention has considered the purified form and the mixed form of all this isomer (for example enantiomer and diastereomer), comprises racemic mixture.The enol form is also included within the scope of the invention.
Formula I of the present invention or formula II compound both can itself also can its pharmacologically acceptable salts or the form of solvate use.The pharmacologically acceptable salts of formula I or formula II compound comprises the conventional salt with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases formation.The example of suitable acid salt comprises with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, pounces on the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc. form.Pharmaceutical salts comprises its inorganic or organic acid salt, comprising but be not limited to: hydriodate, hydrosulfate, hydrophosphate, butyrates, oxalate, pivalate, adipate, alginate, picrate, aspartate, gluconate, esilate, tosilate, embonate, pyruvate salt, glycollate, trifluoroacetate, para-aminosalicylic acid salt, pamoate and ascorbate salt etc.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, the salt that N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-methylglucosamine and PROCAINE HCL, PHARMA GRADE etc. form.When relating to The compounds of this invention herein, comprise formula I or formula II compound and pharmacologically acceptable salts or solvate.The free alkali form of The compounds of this invention and they salt form is separately gone up slightly different in some physical properties (as the solubleness in polar solvent), but for the object of the invention, each acid salt and they free alkali form separately is suitable.(referring to for example S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977), it incorporates this paper by reference into.
Term used herein " composition " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount, those skilled in the art can similarly understand the implication that " pharmaceutical composition " had according to this explanation.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers in reliable medical judgment scope, be suitable for contacting with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur with the mankind, and with rational effect/risk than the salt that matches.Pharmacologically acceptable salts is well known in the art.For example, S.M.Berge, et al.J.PharmaceuticalSciences, 1977, among the 66:1 pharmacologically acceptable salts to be described in detail. described salt can be by free alkali functionality and the appropriate organic reaction that makes The compounds of this invention, final separation and purge process made acid-stable in situ or preparation separately at The compounds of this invention. representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate. same, alkaline nitrogen-containing group can be quaternized with following material: elementary alkyl halide such as methyl, ethyl, the muriate of propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; The muriate of long-chain halogenide such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide such as bromotoluene and phenethyl bromide and other. therefore dissolved in or be scattered in the product of water or oil. the sour example that can be used to form the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid such as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt can contain carboxylic moiety and suitable alkali reaction by what make The compounds of this invention, final separation and purge process made acid-stable in situ at The compounds of this invention, described alkali is oxyhydroxide, carbonate and the supercarbonate of the acceptable metallic cation of pharmacy for example, perhaps ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to based on the positively charged ion of basic metal or alkaline-earth metal such as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other representative organic amines that can be used for forming base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Formula I of the present invention or formula II compound or its pharmacologically acceptable salts can also form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of pharmacy acceptable solvent such as water, ethanol etc.
Dosage form for the topical administration The compounds of this invention comprises powder, sprays, ointment and inhalation.Under aseptic condition with active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution also are considered within the scope of the present invention.
The active compound amount of gained can change the actual dose level of each activeconstituents in the pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response at concrete patient, composition and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result of treatment requires, up to obtaining required effect.
When being used for above-mentioned treatment or other treatment, a kind of The compounds of this invention of treatment significant quantity can be used with pure form, perhaps uses with pharmacologically acceptable salts, ester or prodrug forms (under the situation that has these forms).Perhaps, described compound can be to contain the pharmaceutical composition administration of this purpose compound and the acceptable vehicle of one or more pharmacy.The The compounds of this invention of word " treatment significant quantity " refers to the compound of the reasonable effect that is applicable to any therapeutic treatment/risk than the q.s of treatment obstacle.But the total daily dosage portion that it should be understood that The compounds of this invention and composition must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root of treatment effective dose is decided according to multiple factor, and described factor comprises the severity of the obstacle of being treated and this obstacle; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that is adopted, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with the particular compound that is adopted; And the known similar factor of medical field.For example, the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result of treatment requires, up to obtaining required effect.
The contriver finds, the formula I of novelty provided by the invention or formula II compound have effective antitumour and/or antitumour activity. on this basis, the invention provides and a kind ofly in the experimenter who needs is arranged, treat and/or prevent tumour and/or method for cancer, described method comprises each described formula I of first aspect present invention or formula II compound or its pharmacologically acceptable salts to described experimenter's administering therapeutic significant quantity, solvate, steric isomer or prodrug. term " experimenter " is meant to suffer from maybe will suffer from the animal that maybe may suffer from tumour of the present invention and/or cancer, preference such as vertebrates, more preferably Mammals for example, more preferably people for example particularly again. term " treatment significant quantity " is meant a kind of dosage, it is applied to the physiologic response that can produce expectation behind this experimenter, particularly produces the physiologic response at tumour of the present invention and/or related to cancer.
The present invention also provides the pharmaceutical composition that comprises randomly with one or more no toxicology acceptable diluent, carrier, vehicle, auxiliary material or vehicle The compounds of this invention formulated together.That described pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, for the parenteral injection or for rectal administration.
Pharmaceutical composition of the present invention can by in oral, rectum, parenteral, the pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
In yet another aspect, the invention provides and comprise the pharmaceutical composition that composition of the present invention and physiology can tolerate thinner.The present invention includes one or more above-claimed cpds, its can tolerance with one or more nontoxic physiology or acceptable diluent, carrier, auxiliary material or vehicle (this paper is referred to as thinner with them) be mixed with composition, for transmit in parenteral injection, the nose, with solid or liquid form oral administration, rectum or topical or the like.
The composition that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.Also expectation comprises isotonic agent, for example carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin can reach the prolongation absorption of injectable drug form.
Remove the active ingredient beyond the region of objective existence in the suspensoid and also can contain suspension agent, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or the intramuscularly medicine.This can realize by the crystal of use poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Perhaps, the delay of the medicament forms of parenteral admin absorb by with this medicine dissolution in or be suspended in the oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-poly-glycollide (polylactide-polyglycolide).Can drug releasing rate be controlled according to the character of medicine with ratio with the concrete polymkeric substance that is adopted of polymkeric substance.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering with bacterial filter or sterilizing by the disinfectant that mixes the aseptic solid composite form, and described solids composition can face with before being dissolved or dispersed in sterilized water or other sterile injectable medium.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule. in this type of solid dosage, active compound can mix with the acceptable vehicle of at least a inert pharmacy or carrier such as Trisodium Citrate or Lin Suanergai and/or following material: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture. under the situation of capsule, tablet and pill, also can comprise buffer reagent in the described formulation.
The solids composition of similar type uses vehicle for example lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and the hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can prepare with dressing and shell material such as enteric coating material and known other clothing materials of field of medicine preparations.These solid dosages can be chosen wantonly and contain opalizer, and its composition also can make it just or preferentially choose wantonly with the delayed mode release of active ingredients at certain position of enteron aisle.The example of operable embedding composition comprises polymer substance and wax class.If be fit to, active compound also can be made into the micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except that containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material except that comprising inert diluent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by for example theobroma oil, polyoxyethylene glycol or suppository wax are mixed and prepared with The compounds of this invention and suitable non-irritating excipient or carrier, they at room temperature are solid, therefore but next at body temperature is liquid, can melt in rectal cavity or vaginal canal and discharges active compound.
The compounds of this invention also can the liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in the water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stablizer, sanitas, vehicle etc. except that containing The compounds of this invention.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p.33.
The prodrug of The compounds of this invention represented in term used herein " pharmacy acceptable prodrugs ", it is suitable for contacting with zootic tissue with the mankind in reliable medical judgment scope and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur, match with rational effect/risk ratio and effective, under possible situation, also represent the zwitterionic form of The compounds of this invention its intended purpose.Prodrug of the present invention can for example change into the parent compound of following formula in vivo fast by hydrolysis in blood.Discuss fully and be provided in T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S.Symposium Series and Edward B.Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Associationand Pergamon Press (1987), it incorporates this paper by reference into.
Formula I of the present invention or formula II compound also comprise the pharmaceutical composition that is formed by them certainly, are being useful aspect antitumor and/or the cancer.
The inventor has carried out the research that antitumor/antitumour activity is tested to the formula I or the formula II compound of novelty provided by the invention, the result shows, formula I of the present invention or formula II compound can optionally kill some cancer cells, has very strong antitumour activity, and can suppress growth of tumor, compare with other cancer therapy drug, demonstrate and have advantages such as efficient, selectivity and side effect be less.
Description of drawings
Fig. 1 is the influence of GPQ-cl (for the code name of the embodiment of the invention 1 compound) to the HL-60 cell survival rate.X-coordinate is the treatment time among the figure; Ten rods of 24h, 48h, three treatment time points of 72h, 1 to 10 expression respectively from left to right: blank (0 μ g/ml), DMSO contrast, cis-platinum (20 μ g/ml), cis-platinum (10 μ g/ml), cis-platinum (5 μ g/ml), GPQ (80 μ g/ml), GPQ (40 μ g/ml), GPQ (30 μ g/ml), GPQ (20 μ g/ml), GPQ (10 μ g/ml).Experimental result shows: growth has the obvious suppression effect to GPQ-cl to the HL-60 cell.
Fig. 2 is the influence of GPQ-cl to the NCI-H460 cell survival rate.X-coordinate is the treatment time among the figure; Ten rods of 24h, 48h, three treatment time points of 72h, 1 to 10 expression respectively from left to right: blank (0 μ g/ml), DMSO contrast, cis-platinum (20 μ g/ml), cis-platinum (10 μ g/ml), cis-platinum (5 μ g/ml), GPQ (80 μ g/ml), GPQ (40 μ g/ml), GPQ (30 μ g/ml), GPQ (20 μ g/ml), GPQ (10 μ g/ml).Growth has the obvious suppression effect to GPQ-cl to the NCI-H460 cell.
Fig. 3 is that GPQ-cl is to HepG2 cell inhibitory effect effect (570nm).X-coordinate is the treatment time among the figure; Ten rods of 24h, 48h, three treatment time points of 72h, 1 to 10 expression respectively from left to right: blank, DMSO contrast, GPQ-cl (80 μ g/ml), GPQ-cl (40 μ g/ml), GPQ-cl (30 μ g/ml), GPQ-cl (20 μ g/ml), GPQ-cl (10 μ g/ml), cis-platinum (20 μ g/ml), cis-platinum (10 μ g/ml), cis-platinum (5 μ g/ml).Growth has the obvious suppression effect to GPQ-cl to the HepG2 cell.
Fig. 4 is that GPQ-cl is to A549 cell inhibitory effect effect (570nm).X-coordinate is the treatment time among the figure; Ten rods of 24h, 48h, three treatment time points of 72h, 1 to 10 expression respectively from left to right: blank, DMSO contrast, GPQ-cl (80 μ g/ml), GPQ-cl (40 μ g/ml), GPQ-cl (30 μ g/ml), GPQ-cl (20 μ g/ml), GPQ-cl (10 μ g/ml), cis-platinum (20 μ g/ml), cis-platinum (10 μ g/ml), cis-platinum (5 μ g/ml).Growth has the obvious suppression effect to GPQ-cl to the A549 cell.
Fig. 5 is the influence of GPQ-cl to the human peripheral blood single nucleus cell survival rate.X-coordinate is the treatment time among the figure; Six rods of 24h, 48h, three treatment time points of 72h, 1 to 6 expression respectively from left to right: cis-platinum (10 μ g/ml), GPQ-cl (80 μ g/ml), GPQ-cl (40 μ g/ml), GPQ-cl (20 μ g/ml), GPQ-cl (10 μ g/ml), blank.The result shows that GPQ-cl is to the no obvious restraining effect of normal people's peripheral blood mononuclear cell growth.
Embodiment
Further specify the present invention below by concrete intermediate and embodiment, still, should be understood to, these intermediates and embodiment are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
The reaction process diagram is as follows:
Step 1.In 500 milliliters reaction flask, add the Benzyl Chlorides of 50 grams (395 mmole) and the high piperazine of 40 grams (400 mmole), it is dissolved in 300 milliliters the tetrahydrofuran (THF) reflux 5 hours.Cooling is filtered, and steams and removes tetrahydrofuran (THF) to a small amount of.The water that adds 300 milliliters is used ethyl acetate extraction, uses Na
2SO
4Dry.Steam and remove ethyl acetate, obtain crude product, silica gel separates, and obtains the pure high piperazine of product 1-benzyl, productive rate 95%.
Step 2.Under the condition of, induction stirring angry, in the 2-ethyl chloroacetate of high piperazines of 1-benzyl that 9.5 grams (50 mmole) are housed and 7.35 grams (60 mmole) and 100 milliliters of toluene solution reaction flasks, add the triethylamine of 7.0 grams (70 mmole) in the chamber.After the reaction solution reflux 8 hours, stopped reaction boils off solvent.Product is dissolved in 100 milliliters the ethyl acetate, and each is washed twice with 20 milliliters.Organic phase boils off solvent through dried over mgso, and the product that obtains separates with column chromatography, obtains the high piperazine of 12.4 gram liquid 4-benzyls-1-ethyl acetate, productive rate 90%.
Hydrogen spectrum (400MHz, CDCl
3): 7.15-7.27 (m, 5H); 4.06-4.11 (q, 2H); 3.57 (s, 2H); 3.31 (s, 2H); 2.78-2.81 (m, 4H); 2.61-2.65 (m, 4H); 1.73-1.76 (m, 2H); 1.19 (t, 3H).
Step 3.The high piperazine of the 4-benzyl-1-ethyl acetate that adds 2.76 grams (10 mmole) in 300 milliliters round-bottomed flask, agitation condition slowly drip 85% hydrazine hydrate of 0.56 gram (15 mmole) down.After mixed solution reflux, detection reaction are finished substantially, stopped reaction.Concentration of reaction solution adds a small amount of saturated common salt water washing, uses dichloromethane extraction, and organic layer with anhydrous magnesium sulfate drying, filtration, is concentrated, and obtains oily matter 2.3 grams, productive rate 88%.Hydrogen spectrum (400MHz, CDCl
3): 8.31 (s, 1H), 7.22-7.33 (m, 5H); 3.89-4.00 (br, 2H); 3.65 (s, 2H); 3.63 (m, 10H); 1.75-1.81 (m, 2H).
Step 4.With the high piperazine acethydrazide of 2.62 gram (10 mmole) 4-benzyls, 1.6 gram (10 mmole) 3-allyl group-2-hydroxy benzaldehyde and 50 milliliters of dehydrated alcohols add in 250 milliliters the flask, the hydrochloric acid that adds 0.5 milliliter. reaction reflux 48 hours (TLC detection), stopped reaction, boil off ethanol, the product that obtains separates with column chromatography, obtain 3.5 gram product (4-benzyls-[1,4] Diazesuberane-1-yl)-acetate (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine [this compound also can be described as: the high piperazine of 4-benzyl-1-acetyl (N-amido formamino-3-allyl group-2-hydroxybenzene) hydrazine], productive rate 85%. hydrogen spectrum (400MHz, CDCl
3): 11.30 (s, 1H); 10.60 (br, 1H); 8.41 (s, 1H); 7.07-7.33 (m, 7H); 6.84-6.86 (m, 1H); 6.00 (m, 1H); 5.07 (m, 1H); 3.67 (s, 2H); 3.47 (m, 2H); 3.45 (m, 2H); 2.70-2.84 (m, 9H); 1.83 (m, 2H).
Mass spectrum: 406 (M+1).
Step 5.The 4.06 gram high piperazine acetyl of (10 mmole) 4-benzyl (N-amido formimino-3-allyl group-2-hydroxybenzene) hydrazines, 1.16 gram (10 mmole) fumaric acid are dissolved in 50 milliliters of anhydrous methanols.Mixed solution reflux 2 hours, stopped reaction, cooling, the adularescent solid is separated out, (4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) the hydrazine fumarate that filter, drying obtains 5.0 grams.Fusing point 155.4-156.4 ℃.
The reaction process diagram is as follows:
Step 1.Under the condition of, induction stirring angry, in the 2-ethyl chloroacetate of high piperazines of 1-phenyl that 8.6 grams (50 mmole) are housed and 7.35 grams (60 mmole) and 100 milliliters of toluene solution reaction flasks, add the triethylamine of 7.0 grams (70 mmole) in the chamber.After the reaction solution reflux 8 hours, stopped reaction boils off solvent.Product is dissolved in 100 milliliters the ethyl acetate, and each is washed twice with 20 milliliters.Organic phase boils off solvent through dried over mgso, and the product that obtains separates with column chromatography, obtains the high piperazine of 12.4 gram liquid 4-phenyl-1-ethyl acetate, productive rate 92%.
Hydrogen spectrum (400MHz, CDCl
3): 7.18-7.30 (m, 5H); 4.08-4.13 (q, 2H); 2.78-2.81 (m, 4H); 2.61-2.65 (m, 4H); 1.73-1.76 (m, 2H); 1.19 (t, 3H).
Step 2.The high piperazine of the 4-phenyl-1-ethyl acetate that in 300 milliliters round-bottomed flask, adds 2.62 grams (10 mmole), agitation condition slowly drips 85% hydrazine hydrate of 0.56 gram (15 mmole) down. the mixed solution reflux, after detection reaction is finished substantially, stopped reaction. concentration of reaction solution adds a small amount of saturated common salt water washing, use dichloromethane extraction, organic layer with anhydrous magnesium sulfate drying, filtration, is concentrated, obtain oily matter 2.2 grams, productive rate 88%. hydrogen spectrum (400MHz, CDCl
3): 8.31 (s, 1H), 7.22-7.33 (m, 5H); 3.89-4.00 (br, 2H); 3.63 (m, 10H); 1.75-1.81 (m, 2H).
Step 3.2.5 gram (10 mmole) 4-phenyl high piperazine-1-acethydrazides, 1.2 gram (10 mmole) 2-hydroxy benzaldehydes and 50 milliliters of dehydrated alcohols added in 250 milliliters the flask, add 0.5 milliliter hydrochloric acid.Reaction reflux 48 hours (TLC detection), stopped reaction, boil off ethanol, the product that obtains separates with column chromatography, obtain 3.2 gram product (4-phenyl-[1,4] Diazesuberane-1-yl)-and acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine [this compound also can be described as: the high piperazine of 4-phenyl-1-acetyl (N-amido formamino-2-hydroxyl-benzene) hydrazine], productive rate 91%.Mass spectrum: 353 (M+1).
Step 4.The high piperazine of 3.53 gram (10 mmole) 4-phenyl-1-acetyl (N-amido formimino-2-hydroxybenzene) hydrazine, 1.16 gram (10 mmole) fumaric acid are dissolved in 50 milliliters of anhydrous methanols.Mixed solution reflux 2 hours, stopped reaction, cooling, the adularescent solid is separated out, (4-phenyl-[1,4] Diazesuberane-1-yl)-acetyl (2-hydroxyl-methylene-benzene) the hydrazine fumarate that filter, drying obtains 4.2 grams.
The reaction process diagram is as follows:
Step 1.In 500 milliliters reaction flask, add the 2-chloroethyl benzene of 50 grams (355 mmole) and the high piperazine of 40 grams (400 mmole), it is dissolved in 300 milliliters the tetrahydrofuran (THF) reflux 5 hours.Cooling is filtered, and steams and removes tetrahydrofuran (THF) to a small amount of.The water that adds 300 milliliters is used ethyl acetate extraction, uses Na
2SO
4Dry.Steam and remove ethyl acetate, obtain crude product, silica gel separates, and obtains the pure high piperazine of product 1-styroyl, productive rate 80%.
Step 2.Under the condition of, induction stirring angry, in the 2-ethyl chloroacetate of high piperazines of 1-styroyl that 10.2 grams (50 mmole) are housed and 7.35 grams (60 mmole) and 100 milliliters of toluene solution reaction flasks, add the triethylamine of 7.0 grams (70 mmole) in the chamber.After the reaction solution reflux 8 hours, stopped reaction boils off solvent.Product is dissolved in 100 milliliters the ethyl acetate, and each is washed twice with 20 milliliters.Organic phase boils off solvent through dried over mgso, and the product that obtains separates with column chromatography, obtains the high piperazine of 12.0 gram liquid 4-styroyls-1-ethyl acetate, productive rate 83%.
Step 3.The high piperazine of the 4-styroyl-1-ethyl acetate that adds 2.90 grams (10 mmole) in 300 milliliters round-bottomed flask, agitation condition slowly drip 85% hydrazine hydrate of 0.56 gram (15 mmole) down.After mixed solution reflux, detection reaction are finished substantially, stopped reaction.Concentration of reaction solution adds a small amount of saturated common salt water washing, uses dichloromethane extraction, and organic layer with anhydrous magnesium sulfate drying, filtration, is concentrated, and obtains oily matter 2.4 grams, productive rate 86%.
Step 4.With 2.76 gram (10 mmole) 4-styroyls high piperazine-1-acethydrazides, 2.02 gram (10 mmoles) 3,5-diallyl-2-hydroxy benzaldehyde and 50 milliliters of dehydrated alcohols add in 250 milliliters the flask, add 0.5 milliliter hydrochloric acid.Reaction reflux 48 hours (TLC detection), stopped reaction, boil off ethanol, the product that obtains separates with column chromatography, product (4-styroyl-[1,4] Diazesuberane-1-yl)-[this compound also can be described as acetyl (3,5-diallyl-2-hydroxyl-methylene-benzene) hydrazine: the high piperazine of 4-styroyl-1-acetyl (N-amido formamino-3 to obtain 4.1 grams, 5-diallyl-2-hydroxybenzene) hydrazine], productive rate 85%.
Step 5.The 4.60 gram high piperazine acetyl of (10 mmole) 4-styroyl (N-amido formimino-3,5-diallyl-2-hydroxybenzene) hydrazines, 1.16 gram (10 mmole) fumaric acid are dissolved in 50 milliliters of anhydrous methanols.Mixed solution reflux 2 hours, stopped reaction, cooling, the adularescent solid is separated out, (4-styroyl-[1,4] Diazesuberane-1-yl)-acetyl (3,5-diallyl-2-hydroxyl-benzylidene) the hydrazine fumarate that filter, drying obtains 5.0 grams.
The reaction process diagram is as follows:
Step 1.In 500 milliliters reaction flask, add the p-methyl benzene sulfonic chlorides of 50 grams (262 mmole) and the high piperazine of 40 grams (400 mmole), it is dissolved in 300 milliliters the toluene, add 30 milliliters triethylamine, reflux 5 hours.Cooling is filtered, and steams and removes toluene to a small amount of.The water that adds 300 milliliters is used ethyl acetate extraction, uses Na
2SO
4Dry.Steam and remove ethyl acetate, obtain crude product, silica gel separates, and obtains the pure high piperazine of product 1-tolysulfonyl, productive rate 85%.
Step 2.Under the condition of, induction stirring angry, in the 2-ethyl chloroacetate of high piperazines of 1-tolysulfonyl that 12.7 grams (50 mmole) are housed and 7.35 grams (60 mmole) and 100 milliliters of toluene solution reaction flasks, add the triethylamine of 7.0 grams (70 mmole) in the chamber.After the reaction solution reflux 8 hours, stopped reaction boils off solvent.Product is dissolved in 100 milliliters the ethyl acetate, and each is washed twice with 20 milliliters.Organic phase boils off solvent through dried over mgso, and the product that obtains separates with column chromatography, obtains the high piperazine of 12.4 gram liquid 4-p-toluenesulfonyls-1-ethyl acetate, productive rate 85%.
Step 3.The 4-that adds 3.4 grams (10 mmole) in 300 milliliters round-bottomed flask is to the high piperazine of Methyl benzenesulfonyl-1-ethyl acetate, and agitation condition slowly drips 85% hydrazine hydrate of 0.56 gram (15 mmole) down.After mixed solution reflux, detection reaction are finished substantially, stopped reaction.Concentration of reaction solution adds a small amount of saturated common salt water washing, uses dichloromethane extraction, and organic layer with anhydrous magnesium sulfate drying, filtration, is concentrated, and obtains oily matter 2.3 grams, productive rate 86%.
Step 4.To the high piperazine of Methyl benzenesulfonyl-1-acethydrazide, 1.91 gram (10 mmoles) 3,5-two chloro-2-hydroxy benzaldehydes and 50 milliliters of dehydrated alcohols add in 250 milliliters the flask with 3.26 gram (10 mmole) 4-, add 0.5 milliliter hydrochloric acid.Reaction reflux 48 hours (TLC detection), stopped reaction, boil off ethanol, the product that obtains separates with column chromatography, [this compound also can be described as: 4-is to the high piperazine of Methyl benzenesulfonyl-1-acetyl (N-amido formamino-3 to obtain 4.0 gram product (4-is to Methyl benzenesulfonyl-[1,4] Diazesuberane-1-yl)-acetyl (3,5-two chloro-2-hydroxyl-methylene-benzene) hydrazines, 5-two chloro-2-hydroxybenzenes) hydrazine], productive rate 81%.
Step 5.Restrain (10 mmole) 4-to the high piperazine acetyl of Methyl benzenesulfonyl (N-amido formimino-3 with 4.99,5-two chloro-2-hydroxybenzenes) hydrazine, 1.16 gram (10 mmole) fumaric acid are dissolved in 50 milliliters of anhydrous methanols. mixed solution reflux 2 hours, stopped reaction, cooling, the adularescent solid is separated out, (4-is to Methyl benzenesulfonyl-[1,4] Diazesuberane-1-yl)-acetyl (3,5-two chloro-2-hydroxyl-methylene-benzene) the hydrazine fumarate that filter, drying obtains 5.0 grams.
Experimental example 1, biological test
Detect the proliferation inhibiting effect of GPQ-Cl (compound of embodiment 1) by MTT to leukemia clone HL60, K562, hepatoma cell line Hepa G2 and lung cancer cell line A549, NCI-H460.Concrete grammar is: use 2 * 10
4Inoculate 96 orifice plates, after adherent growth is spent the night, add 80 respectively, 40,20, the GPQ-Cl of 10 and 5 μ g/ml (being dissolved among the DMSO) drug level is handled cell, 3 multiple holes are set, with the DMSO of same dose as negative control, with the positive contrast of the cis-platinum of 10 μ g/ml, and handle 24 respectively, 48, after 72 hours, every hole add 10 μ l MTT (5mg/ml, Sigma), continue to cultivate 4 hours, nutrient solution is abandoned in suction, adds the DMSO of 100 μ l in every hole, and dissolving is 10 minutes on the shaking table, on nucleic acid/protein analyzer, detect the absorption value of 570nm, calculate GPQ-Cl on cell proliferation inhibiting rate.
In addition, adopt normal people's peripheral blood 10ml and separate mononuclearcell, get 4 * 10 with lymphocyte separation medium
4Inoculate 96 orifice plates, GPQ-Cl (being dissolved among the DMSO) drug level that adds 80,40,20,10 μ g/ml is respectively handled cell, 3 multiple holes are set, with the DMSO of same dose as negative control, with the positive contrast of the cis-platinum of 10 μ g/ml, and after handling 24,48,72 hours respectively, every hole adds 10 μ l MTT (5mg/ml, Sigma), continue to cultivate 4 hours, inhale and abandon nutrient solution, the DMSO that adds 100 μ l in every hole, dissolving is 10 minutes on the shaking table, detects the absorption value of 570nm on nucleic acid/protein analyzer, the influence of calculating the GPQ-Cl cell growth.
Experimental result shows: the GPQ-cl medicine is under 10 μ g/mL to 80 μ g/mL concentration, increase along with concentration, the survival rate of HepG2 and A549 cell all descends to some extent, cis-platinum also has same result, calculates IC50 respectively, and the result shows, the IC50 value of cis-platinum is lower than GPQ-cl, and along with the prolongation in treatment time, cis-platinum has great decline to the IC50 value of HepG2 and A549 cell, GPQ-cl then fall less than the fall of cis-platinum.
Simultaneously relatively GPQ-cl to HepG2 and the discovery of A549 cell inhibiting effect: under high density, during 80 μ g/mL, probably about 80%, under 40 μ g/mL, both difference is also little to HepG2 and A549 cell inhibiting rate for GPQ-cl.But when low concentration, during such as 30 μ g/mL, GPQ-cl obviously is better than restraining effect to A549 to the restraining effect of HepG2, and the IC50 value that calculates also is that A549 is higher than the HepG2 cell.
The GPQ-cl medicine has the obvious suppression effect to leukemia cell HL60 and the growth of lung cancer cell line NCI-H460 cell under 10 μ g/mL to 80 μ g/mL concentration, the IC50 value is significantly less than other cell strains.
Test-results respectively referring in Fig. 1 to Fig. 5 and the description of drawings part to their detailed description.
The contriver finds that also other compound that the present invention relates to also has and the identical or similar result of the foregoing description 1 compound.
Claims (12)
1. the compound of formula I or formula II:
Wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom or nitrogen-atoms independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
6Alkenyl, C
1-C
6Alkyl or C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts.
2. according to the compound of claim 1, wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
6Alkenyl, C
1-C
6Alkyl or C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts.
3. according to the compound of claim 1, wherein:
N is selected from 0,1 or 2;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, allyl group, crotyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base independently of one another,
Or its pharmacologically acceptable salts.
4. according to the compound of claim 1, wherein:
N is 1;
A, B, C, D and E are carbon atom independently of one another; And
R, R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, allyl group, crotyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base independently of one another,
Or its pharmacologically acceptable salts.
5. according to the compound of claim 1, it is selected from following compound:
(4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine and
(4-p-toluenesulfonyl-[1,4] Diazesuberane-1-yl)-acetyl (3,5-two chloro-2-hydroxyl-methylene-benzene) hydrazine,
Or its pharmacologically acceptable salts.
6. according to the compound of claim 1, it is (4-benzyl-[1,4] Diazesuberane-1-yl)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine fumarate.
7. prepare the method for each described compound of claim 1 to 6, it may further comprise the steps:
(1) under alkaline condition, makes formula
Or formula
Chlorination aromatic hydrocarbon compound and high piperazine in organic solvent, react and generate with following formula Ib or formula IIb compound:
(2) under alkaline condition, make the compound of formula Ib or formula IIb compound and ethyl chloroacetate reaction generation with following formula Ic or formula IIc:
(3) in organic solvent, make the compound of the compound reaction generation of hydrazine hydrate and above-mentioned formula Ic or formula IIc with following formula Id or formula IId:
(4) in ethanolic soln, formula Id that step (3) obtains or compound and the formula of formula IId
Compound reacts, and obtains the compound of formula I or formula II; With optional
(5) make compound and the acid-respons of formula I or formula II, obtain the corresponding salt of the compound of formula I or formula II,
Wherein, n, A, B, C, D, E, R, R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of claim 1 to 6.
Each described compound of claim 1 to 6 preparation be used for the treatment of and/or the medicine of prophylaxis of tumours and/or cancer in purposes.
9. purposes according to Claim 8, wherein said tumour and/or cancer are selected from:
Bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer, head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma;
Leukemia;
Fibrosarcoma and rhabdosarcoma;
Astrocytoma, one-tenth neurofibroma, neurospongioma and schwannoma; And
Melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck knurl, Tiroidina filter capsule cancer and Kaposi's sarcoma.
10. purposes according to Claim 8, wherein said tumour and/or cancer are selected from:
Acute lymphoblastic leukemia, acute lymphocytoblast leukemia, B-cell lymphatic cancer, T-cell lymphatic cancer, Huo Qijin lymphatic cancer, non--Huo Qijin lymphatic cancer, hair cell lymphatic cancer, mantle cell lymphoma, myelomatosis and Burkett ' sShi lymphatic cancer;
Acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;
11. according to the purposes of claim 9, wherein,
Described lung cancer is selected from small cell lung cancer, nonsmall-cell lung cancer; With
Described skin carcinoma is a squamous cell carcinoma.
12. a pharmaceutical composition, it comprises each described compound of claim 1 to 6 and optional pharmacy acceptable diluent, carrier, vehicle, auxiliary material or the vehicle that treats and/or prevents significant quantity.
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| PCT/CN2010/000293 WO2010102513A1 (en) | 2009-03-11 | 2010-03-10 | Homopiperazine acethydrazide derivatives, preparation method and uses thereof |
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| CN102452990B (en) * | 2010-10-19 | 2015-11-25 | 深圳市湘雅生物医药研究院 | High piperazine acetydrazide derivatives that neurotoxicity is low and its production and use |
| EP3327007B1 (en) | 2015-07-24 | 2020-06-03 | Shenzhen Zhenxing Medical Technology Co., Ltd. | Orbit azine-fumarate, hydrate, crystal form and preparation method therefor |
| CN105085421B (en) * | 2015-07-24 | 2017-12-26 | 深圳市湘雅生物医药研究院 | Bit piperazine fumarate difficult to understand, hydrate, crystal formation and preparation method thereof |
| CN111743876B (en) * | 2020-08-07 | 2022-05-10 | 深圳市真兴医药技术有限公司 | Oxetazine fumarate enteric-coated pellet and preparation method and application thereof |
| CN114259570A (en) * | 2022-01-20 | 2022-04-01 | 长沙创新药物工业技术研究院有限公司 | Polyethylene glycol modified anti-tumor prodrug and preparation method and application thereof |
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