CN101941953A - Nitrogenous heterocyclic substituted hydrazide compounds as well as preparation methods and applications thereof - Google Patents
Nitrogenous heterocyclic substituted hydrazide compounds as well as preparation methods and applications thereof Download PDFInfo
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- CN101941953A CN101941953A CN 201010254144 CN201010254144A CN101941953A CN 101941953 A CN101941953 A CN 101941953A CN 201010254144 CN201010254144 CN 201010254144 CN 201010254144 A CN201010254144 A CN 201010254144A CN 101941953 A CN101941953 A CN 101941953A
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- 0 CC(C)NCC***C=C Chemical compound CC(C)NCC***C=C 0.000 description 6
- UJRKBSAJINSODM-UITAMQMPSA-N CCO/C(/CC(C)(C1)C1(C)Br)=C\C Chemical compound CCO/C(/CC(C)(C1)C1(C)Br)=C\C UJRKBSAJINSODM-UITAMQMPSA-N 0.000 description 1
- DSENHWWEHUNHMF-YZSQISJMSA-N N=C(CCN1CCN(Cc2ccccc2)CC1)N/N=C/c1cccc(CC=[IH])c1O Chemical compound N=C(CCN1CCN(Cc2ccccc2)CC1)N/N=C/c1cccc(CC=[IH])c1O DSENHWWEHUNHMF-YZSQISJMSA-N 0.000 description 1
- OJEODYSCLICYOF-KOEQRZSOSA-N Oc1c(CC=[IH])cccc1/C=N/NC(CCN1CCN(Cc2ccccc2)CC1)=O Chemical compound Oc1c(CC=[IH])cccc1/C=N/NC(CCN1CCN(Cc2ccccc2)CC1)=O OJEODYSCLICYOF-KOEQRZSOSA-N 0.000 description 1
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Abstract
The invention relates to nitrogenous heterocyclic substituted hydrazide compounds as well as preparation methods and applications thereof, in particular to novel nitrogenous heterocyclic substituted hydrazide compounds shown in formulas (I, II and III) or pharmaceutically acceptable salts, solvate, stereomers or prodrugs thereof, wherein various symbols are shown in the specification. The invention also relates to preparation methods of the compounds shown in the formulas (I, II and III), the applications of the compounds in the formulas (I, II and III) to preparing medicines for treating and/or preventing tumors and/or cancers, methods for treating and/or preventing tumors and/or cancers by using the compounds in the formulas (I, II and III) and effective amounts of pharmaceutical compositions of the compounds in the formulas (I, II and III) for treatment and/or prevention. The compounds in the formulas (I, II and III) in the invention can selectively kill a certain cancer cells, have strong anti-cancer activity and can inhibit the growth of tumors.
Description
Technical field
The present invention relates to the hydrazide kind compound of the nitrogen heterocyclic ring replacement of a class novelty, the invention still further relates to the method for the hydrazide kind compound of the described nitrogen heterocyclic ring replacement of preparation, the hydrazide kind compound that described nitrogen heterocyclic ring replaces 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 the hydrazide kind compound that described nitrogen heterocyclic ring replaces.
Background technology
Tumour has become threat people health and has planted with the important disease of surviving, cause human death as a kind of global disease.The treatment terminal cancer mainly adopts amic therapy method at present clinically.But present employed chemotherapeutics does not all have selectivity to cancer cells basically, kills a large amount of normal cells in kill cancer cell yet, brings very big injury for cancer patients's body and mind.If chemotherapeutics only just can reduce toxic side effect for cancer patient provides personalized treatment to the effect of cancer cell selectivity ground, prolong patient's life.
Molecular targeted treatment is a new way of selective therapy tumour, and molecular targeted agents provides feasibility for cancer patients's personalized treatment.People have found a class important protein matter procaspase-3 in cell in recent years, and the procaspase-3 activation can cause cellular metabolism death for caspase-3.Bibliographical information is (as Clin Cancer Research 2004,6807; PNAS 2001,6132) procaspase-3 concentration illustrates that procaspase-3 can not be activated in tumour cell and is caspase-3 than high hundred times in the corresponding normal cell in the multiple cancer cells, not energy metabolism death of cancer cells, and be converted into tumour.Modern molecular pharmacology has been illustrated the mechanism of action of procaspase-3 in the tumor development process, and the compound that proposes to activate procaspase-3 can be used as targeted molecular and lures cancer cell death into.Therefore, exploitation procaspase-3 activator has good application prospects.
The professor Paul J.Hergenrother of illinois university department of chemistry etc. are by more than 22000 kind of compound of screening, obtained micromolecular compound PAC-1 (4-(phenyl methyl)-1-piperazine acetate [[2-hydroxyl-3-(2-propenyl) phenyl] methylene radical] hydrazides, CAS No:315183-21-2), thus it can directly activate Procaspase-3 activation and be the caspase-3 cell death inducing.And the expression ratio normal cell of Procaspase-3 wants high doubly a lot of in the tumour cell, thereby PAC-1 kill tumor cell and to not damage of normal cell optionally.
This paper designs the hydrazide kind compound of the nitrogen heterocyclic ring replacement of having synthesized a series of novelties, and active result shows that this compounds has the activity and the little advantage of side effect of very strong inhibition tumour cell.
Summary of the invention
The purpose of first aspect present invention provides the hydrazide kind compound of the nitrogen heterocyclic ring replacement of a class novelty.The purpose of a second aspect of the present invention provides the preparation method of the hydrazide kind compound that the nitrogen heterocyclic ring of described novelty replaces.The purpose of third aspect present invention provides the purposes of hydrazide kind compound in pharmacy of the nitrogen heterocyclic ring replacement of described novelty.In addition, fourth aspect present invention provides the pharmaceutical composition of the hydrazide kind compound that comprises nitrogen heterocyclic ring replacement of the present invention.The inventor is surprisingly found out that, the hydrazide kind compound that the nitrogen heterocyclic ring of novelty provided by the invention replaces has effective antitumour activity, the present invention is based on above-mentioned discovery and is accomplished.
Put it briefly, first aspect present invention provides the compound of formula I, formula II and formula III:
Wherein,
Ar[or with
The group part of expression] be selected from and replace or unsubstituted aryl [for example is to replace or unsubstituted phenyl, the phenyl of Qu Daiing particularly], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl], wherein said substituting group is selected from hydroxyl, halogen (for example fluorine, chlorine, bromine, iodine), C
2-C
6Alkenyl (C for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfydryl, amino, carboxyl, sulfoamido;
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-[promptly with
The group part of expression];
Z is nitrogen-atoms or carbon atom;
N is selected from 1,2 or 3; With
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 for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl, is preferably to replace or unsubstituted phenyl;
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 1,2 or 3; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is a nitrogen-atoms;
N is selected from 1,2 or 3; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is 1; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 2; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 3; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 1,2 or 3; With
R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, vinyl, 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 compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is 1;
R
1It is hydroxyl;
R
2It is allyl group; With
R
3, R
4And R
5Be hydrogen atom,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is 1;
R
5It is hydroxyl;
R
4It is allyl group; With
R
1, R
2And R
3Be hydrogen atom,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each compound of first aspect present invention, it has following each or multinomial feature:
1) Ar is selected from aryl [for example phenyl] or heteroaryl [for example nitrogenous aryl], and wherein said aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: hydroxyl, halogen (for example fluorine, chlorine, bromine, iodine), C
2-C
6Alkenyl (C for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described Ar is a phenyl, and it is chosen wantonly by 1-3 (for example 1-2, for example 1) and is selected from following substituting group replacement: hydroxyl, halogen (for example fluorine, chlorine, bromine, iodine), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example C
1-C
2Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described Ar is a phenyl, and it is optional by C
1-C
4Alkyl (C for example
1-C
2Alkyl, for example methyl, ethyl) replace;
2) X is selected from-CH
2-,-CH
2CH
2-and-SO
2-; In one embodiment, described X is selected from-CH
2-and-SO
2-;
3) Z is nitrogen-atoms or carbon atom;
4) n is selected from 1,2 or 3; In one embodiment, described n is 1 or 2; With
5) 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 for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
4Alkenyl (for example vinyl, propenyl, allyl group), C
1-C
4Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
4Alkyl oxy (for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
4Alkenyl (for example vinyl, propenyl, allyl group), C
1-C
4Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl).
According to each compound of first aspect present invention, wherein:
Ar is selected from and replaces or unsubstituted aryl, is preferably to replace or unsubstituted phenyl;
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 1,2 or 3; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to the arbitrary described compound of first aspect present invention, it is following compound:
1,3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
2,4-(4-benzyl-piperazine-1-yl)-butyryl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
3,3-(4-benzyl-piperidines-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
4,3-(4-p-toluenesulfonyl-piperazine-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
5,3-(4-benzyl-piperazine-1-yl)-tetrahydroform acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
6,2-(4-benzyl-Gao piperazine-1-yl)-ethyliminum acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
According to each described compound of first aspect present invention, it is 3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine.
Second aspect present invention provides the method for preparing the described compound of first aspect present invention formula I, and it may further comprise the steps:
(1) in the presence of alkali, make 3-ethyl bromide, 4-bromo-butyric acid ethyl ester or 5-bromine Valeric acid ethylester and react with following formula Ia compound,
Generation is as shown in the formula the Ib compound:
(2) in organic solvent, make the reaction of hydrazine hydrate and above-mentioned formula Ib compound, generate with following formula Ic compound:
(3) the formula Ic compound that step (2) is obtained, and with following formula Id compound reaction,
Generation is with compound shown in the following formula I:
Wherein each symbol is as first aspect present invention as described in each.
According to each described method of second aspect present invention, wherein said step (1) is carried out in solvent, and described solvent can be an organic solvent, and this organic solvent comprises, but be not limited to, methylene dichloride, toluene, benzene, tetrahydrofuran (THF) or its be two or more mixture arbitrarily.
According to each described method of second aspect present invention, the used alkali of wherein said step (1) includes, but not limited to triethylamine, salt of wormwood.
According to each described method of second aspect present invention, carry out in solvent wherein said step (2) and (3), two used solvents of step can be organic solvents independently of one another, this organic solvent can each include but not limited to methyl alcohol, ethanol independently, and preferred organic is an ethanol.
According to each described method of second aspect present invention, the formula 1d compound of wherein said step (3)
In, described R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of first aspect present invention.In the preferred embodiment of the compound shown in the formula 1d, R
1Be hydroxyl, R
2Be allyl group, R
3, R
4And R
5It is hydrogen atom.In the preferred embodiment of the compound shown in the formula 1d, R
5Be hydroxyl, R
4Be allyl group, R
1, R
2And R
3It is hydrogen atom.
Second aspect present invention provides the method for preparing the described compound of first aspect present invention formula II, and it may further comprise the steps:
(1) under anhydrous condition, hydrogenchloride and ethanol are reacted in organic solvent and 3-bromoacetonitrile, 4-bromine butyronitrile or 5-bromine valeronitrile, generate as shown in the formula the IIa compound;
(2) in the organic solvent that is fit to, make the reaction of hydrazine hydrate and following IIb compound,
Generation is with following formula IIc compound:
(3) under the condition that alkali exists, following IIa compound and above-mentioned formula IIc compound are reacted in the organic solvent that is fit to, generate with following formula IId compound
(4) under the alkali existence condition, the IId compound that step (3) is obtained reacts in the organic solvent that is fit to with following formula IIe compound,
Generate compound shown in the following II::
Wherein each symbol is as first aspect present invention as described in each.
According to each described method of second aspect present invention, carry out in solvent wherein said step (1) and (2), described solvent can be an organic solvent, this organic solvent comprises, but be not limited to, ether, methylene dichloride, toluene, benzene, ethanol, methyl alcohol or its be two or more mixture arbitrarily.
According to each described method of second aspect present invention, wherein said step (3) and (4) used alkali include, but not limited to triethylamine, salt of wormwood.
According to each described method of second aspect present invention, the formula IIb compound of wherein said step (2)
In, described R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of first aspect present invention.In the preferred embodiment of the compound shown in the formula IIb, R
1Be hydroxyl, R
2Be allyl group, R
3, R
4And R
5It is hydrogen atom.In the preferred embodiment of the compound shown in the formula 1d, R
5Be hydroxyl, R
4Be allyl group, R
1, R
2And R
3It is hydrogen atom.
Second aspect present invention provides the method for preparing the described compound of first aspect present invention formula III, and it may further comprise the steps:
(1) under anhydrous condition, hydrogenchloride and ethanol are reacted in organic solvent and 2-chloromethyl cyanide, 3-chloroethyl nitrile or 4-chlorobutyronitrile, generate as shown in the formula the IIIa compound;
(2) in the organic solvent that is fit to, make the reaction of hydrazine hydrate and following IIIb compound,
Generate following formula III c compound:
(3) under the condition that alkali exists, IIIa compound and above-mentioned formula III c compound are reacted in the organic solvent that is fit to, generate following formula III d compound
(4) under the alkali existence condition, the IIId compound that step (3) is obtained reacts with following formula III e compound in the organic solvent that is fit to,
Generate compound shown in the following III::
Wherein each symbol is as first aspect present invention as described in each.
According to each described method of second aspect present invention, carry out in solvent wherein said step (1) and (2), described solvent can be an organic solvent, this organic solvent comprises, but be not limited to, ether, methylene dichloride, toluene, benzene, ethanol, methyl alcohol or its be two or more mixture arbitrarily.
According to each described method of second aspect present invention, wherein said step (3) and (4) used alkali include, but not limited to triethylamine, salt of wormwood.
According to each described method of second aspect present invention, the formula III b compound of wherein said step (2)
In, described R
1, R
2, R
3, R
4And R
5Definition separately is with each compound of first aspect present invention.In the preferred embodiment of the compound shown in the formula IIb, R
1Be hydroxyl, R
2Be allyl group, R
3, R
4And R
5It is hydrogen atom.In the preferred embodiment of the compound shown in the formula 1d, R
5Be hydroxyl, R
4Be allyl group, R
1, R
2And R
3It is hydrogen atom.
According to each described method of second aspect present invention, the compound of wherein said formula I is: 3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine, or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
In the embodiment of the described method of second aspect present invention, the synthetic route of described formula I compound is as follows:
In the embodiment of the described method of second aspect present invention, the synthetic route of described formula II compound is as follows:
In the embodiment of the described method of second aspect present invention, the synthetic route of described formula III compound is as follows:
According to each described method of second aspect present invention, commercially available the getting of wherein said each raw material or intermediate (for example formula Ia compound), perhaps those skilled in the art can obtain according to existing knowledge is synthetic.
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 minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, 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 Brukett`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 the maincenter origin cause of formation includes but not limited to fibrosarcoma and band sarcoma;
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 look purple 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 described compound of first aspect present invention of described experimenter's administering therapeutic and/or prevention 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 minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, 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 Brukett`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 the maincenter origin cause of formation includes but not limited to fibrosarcoma and band sarcoma;
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 look purple 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 minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, 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 Brukett`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 the maincenter origin cause of formation includes but not limited to fibrosarcoma and band sarcoma;
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 look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.
Be further described with characteristics to various aspects of the present invention below.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this more detailed description and interpretation to be made in these terms and phrase, term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
As used herein, for example the definition Ar (or
) shown in use during the group part, term " aryl of replacement " is " phenyl of replacement " for example, and term " heteroaryl of replacement " for example " replacement contain heteroaryl ", and substituting group wherein is selected from: hydroxyl, nitro, cyano group, sulfydryl, amino, carboxyl, sulfoamido, halogen be fluorine, chlorine, bromine for example, the C of straight or branched
1-C
6Alkyl is such as but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, isopentyl, basic, the C of straight or branched
2-C
6Alkenyl is such as but not limited to vinyl, propenyl, allyl group, 2-butyne base.
Term used herein " alkyl " is meant and comprises the straight chain that specifies number carbon atom and the saturated hydrocarbyl of side chain, for example is methyl, ethyl usually, and straight chain propyl group, butyl, amyl group, base 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 " is meant and comprises 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 alkoxy base 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 those skilled in the art existing knowledge in the above reaction scheme.Perhaps, those skilled in the art also can instruction according to the present invention prepare other formula I, formula II and the formula III compound that the inventive method fails to contain.
Formula I of the present invention, formula II and formula III 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, formula II and formula III compound promptly can itself also can its pharmacologically acceptable salts or the form of solvate use.The pharmacologically acceptable salts of formula I, formula II and formula III 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, 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, formula II and formula III compound and pharmacologically acceptable salts or solvate.The compounds of this invention free alkali form 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 are 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, and " composition " can exchange use with " pharmaceutical composition " in some cases.According to the difference of administering mode, can contain weight ratio 0.1% in the present composition, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 1-500 milligram activeconstituents.
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., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977) wherein describes in detail pharmacologically acceptable salts.Described salt can react by the free alkali functionality and the appropriate organic of The compounds of this invention, in the final separation and purge process of The compounds of this invention, and in-situ preparing or preparation separately.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, the 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.Equally, alkaline nitrogen-containing group can be quaternized with following material; The muriate of elementary alkyl halide such as methyl, ethyl, 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 the oxyhydroxide of the acceptable metallic cation of pharmacy for example, carbonate and supercarbonate, 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 amine 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, formula II and formula III 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 preceding derivative 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 sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, Eye ointments, powder and solution also are considered within the scope of the present invention.
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 required effect.In general, The compounds of this invention is used for Mammals, and particularly people's dosage can be between 0.0001～1000mg/kg body weight/day, for example between 0.001～100mg/kg body weight/day, for example between 0.01～100mg/kg body weight/day, for example between 0.01～10mg/kg body weight/day.
The contriver finds that the formula I of novelty provided by the invention, formula II and formula III 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 that described method comprises first aspect present invention each described I, formula II and formula III compound or its pharmacologically acceptable salts, solvate, steric isomer or the prodrug to described experimenter's administering therapeutic significant quantity to treating and/or preventing tumour and/or method for cancer among the described experimenter." experimenter is meant to suffer from maybe and will suffers from the animal that maybe may suffer from tumour of the present invention and/or cancer term, preference such as vertebrates, more preferably Mammals for example, more preferably people for example particularly again.Term " treatment significant quantity " is a kind of dosage, and 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 that composition of the present invention and physiology can tolerate the pharmaceutical composition of thinner.Comprise one or more above-claimed cpds in invention, 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,, can determine to prevent action of microorganisms as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc.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 ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and the yellow mixture of showing glue or these materials etc.
In some cases, be the action time of prolong drug, expect to slow down absorption subcutaneous or the intramuscular injection 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.
Injectable depot formulations can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-poly-glycollide (polylatide-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 also 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.
The injectable agent can be for example by filtering with the bacteriological filtration 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.
Comprise capsule, tablet, pill, powder and granule for the solid dosage that can obey administration.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 silica gel; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) heat preserving agent 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, described formulation also can comprise buffer reagent.
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 with bag and and shell material such as enteric coating material and known other clothing materials of pharmaceutical preparation prepare.These solid dosages can be chosen wantonly and contain opalizer, and its composition 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 solution, solubilizing agent and emulsifying agent be fat and the acid esters and their mixture of ethanol, Virahol, ethyl-carbonate, ethyl ester ethyl ester, 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 alcochol), polyoxyethylene glycol and glue sorbyl alcohol for example.Oral compositions also can comprise auxiliary material except that comprising inert diluent, for example wetting agent, emulsifying agent 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, but next at body temperature is liquid, but therefore rectal cavity or intravaginal fusing and discharge active compound.
The compounds of this invention also can the liposome form administration.Well known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift water 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, New York, N.Y. (1976), p.33.
The prodrug of The compounds of this invention represented in term used herein " salt before pharmacy is acceptable ", it is suitable for human the contact with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur in reliable medical judgment scope, 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 above-mentioned parent compound by hydrolysis in blood in vivo fast.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., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), it incorporates this paper by reference into.
I of the present invention, formula II and formula III 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 I, formula II and the formula III compound of novelty provided by the invention, the result shows, I of the present invention, formula II and formula III 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 SM-3 (for the code name of the embodiment of the invention 1 compound) to the Hela cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, SM-3 (1 μ M), SM-3 (10 μ M), SM-3 (20 μ M), SM-3 (40 μ M), SM-3 (60 μ M), SM-3 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to SM-3 to the Hela cell.
Fig. 2 is the influence of SM-3 to the HPF cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, SM-3 (1 μ M), SM-3 (10 μ M), SM-3 (20 μ M), SM-3 (40 μ M), SM-3 (60 μ M), SM-3 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to SM-3 to the HPF cell.
Fig. 3 is the influence of SM-3 to the A549 cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, SM-3 (1 μ M), SM-3 (10 μ M), SM-3 (20 μ M), SM-3 (40 μ M), SM-3 (60 μ M), SM-3 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to SM-3 to the A549 cell.
Fig. 4 is the influence of SM-3 to the HepG-2 cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, SM-3 (1 μ M), SM-3 (10 μ M), SM-3 (20 μ M), SM-3 (40 μ M), SM-3 (60 μ M), SM-3 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to SM-3 to the HepG-2 cell.
Fig. 5 is the influence of SM-3 to the human peripheral blood single nucleus cell survival rate.X-coordinate is the treatment time among the figure, be respectively two time points of 24h, 48h, each time point has seven cylindricalitys, from left to right expression respectively: blank, DMSO contrast, SM-3 (10 μ g/ml), SM-3 (20 μ g/ml), SM-3 (40 μ g/ml), SM-3 (80 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that SM-3 is smaller to the effect of mononuclearcell growth-inhibiting.
Fig. 6 is the influence of PAC-1 to the Hela cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, PAC-1 (1 μ M), PAC-1 (10 μ M), PAC-1 (20 μ M), PAC-1 (40 μ M), PAC-1 (60 μ M), PAC-1 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to PAC-1 to the Hela cell.
Fig. 7 is the influence of PAC-1 to the HPF cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, PAC-1 (1 μ M), PAC-1 (10 μ M), PAC-1 (20 μ M), PAC-1 (40 μ M), PAC-1 (60 μ M), PAC-1 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows, growth does not have obvious restraining effect to the HPF cell for PAC-1 effect 24 hours, but effect obviously strengthens after 48 hours.。
Fig. 8 is the influence of PAC-1 to the A549 cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, PAC-1 (1 μ M), PAC-1 (10 μ M), PAC-1 (20 μ M), PAC-1 (40 μ M), PAC-1 (60 μ M), PAC-1 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to PAC-1 to the A549 cell.
Fig. 9 is the influence of PAC-1 to the HepG-2 cell survival rate.X-coordinate is the treatment time among the figure, be respectively 24h, 48h, three time points of 72h, each time point has ten cylindricalitys, from left to right expression respectively: blank, DMSO contrast, PAC-1 (1 μ M), PAC-1 (10 μ M), PAC-1 (20 μ M), PAC-1 (40 μ M), PAC-1 (60 μ M), PAC-1 (80 μ M), cis-platinum (5 μ g/ml), cis-platinum (10 μ g/ml).Ordinate zou is cell survival rate (%).Experimental result shows that growth has obvious restraining effect to PAC-1 to the HepG-2 cell.
More than among each figure, at each test period point, from left to right Dui Ying some rods are corresponding with this coordinate diagram right side respective icon from top to bottom respectively.For example in Fig. 1,10 rods in the time of 24 hours, they from left to right respectively with this coordinate diagram right side (promptly 10 icons from blank (0M) to cis-platinum (10ug/ml) are corresponding) from top to bottom.
Embodiment
Further specify the present invention below by specific embodiment and/or test example, still, should be understood to, these embodiment and/or test example are only used for the more detailed usefulness that specifically describes, and limit the present invention in any form and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that use 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.
Embodiment 1,3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
Preparation
Reaction process is as follows:
Step 1.Under the room temperature, under the condition of induction stirring, in the reaction flask of salt of wormwood that 1.76g (10mmol) 1-benzyl diethylenediamine, 1.66g (12mmol) are housed and 10ml acetone, dropwise add 2.17g (12mmol) 3-ethyl bromide.Dropwise, stir 5min under the room temperature, be warmed up to 60 ℃ of constant temperature then and stirred 5 hours, after reaction finishes, filter, filter cake washs with small amount of acetone, and merging filtrate concentrates and obtains orange liquid 2g, productive rate 72.5%.Mass spectrum: 277 (M+1).
Step 2.Under the room temperature, under the condition of induction stirring, 3-(4-benzyl-piperazine-1-the yl)-ethyl propionate that in reaction flask, adds 5ml ethanol and 2g (7.24mmol), be warmed up to 70 ℃ then, slowly drip 85% hydrazine hydrate of 1.28g (21.74mmol), back flow reaction 6 hours, after detection reaction finishes, stopped reaction.Concentration of reaction solution adds 5ml water, uses twice of dichloromethane extraction again.Merge organic layer, anhydrous magnesium sulfate drying, filtration concentrate and obtain faint yellow oily thing 1.36g, productive rate 66.3%.Mass spectrum: 285 (M+23).
Step 3.Under the room temperature, under the condition of induction stirring, in reaction flask, add 3-(4-benzyl-piperazine-1-yl)-propionyl hydrazine of 5ml ethanol and 1.31g (5mmol), stir, then, slowly drip 2-hydroxyl-3-allyl benzene formaldehyde of 0.81g (5mmol).React after 20 minutes, have solid constantly to separate out, after detection reaction finishes, stopped reaction.Solid by filtration is collected, and the product that obtains obtains 1.45g product 3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine (SM-3), productive rate 71.4%, fusing point 132-134 ℃ with ethyl acetate and normal hexane two-phase recrystallization.The hydrogen spectrum (400MHz, DMSO): 11.88 (s, 1H); 11.76 (s, 1H); 8.28 (s, 1H); 7.1-7.33 (m, 7H); 6.84-6.9 (m, 1H); 6.00 (m, 1H); 5.03 (m, 2H); 3.44 (s, 2H); 3.35 (d, 2H); 2.4-2.65 (m, 12H).Mass spectrum: 407 (M+1).
Embodiment 2, (4-benzyl-piperazine-1-yl)-butyryl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
Preparation
Reaction process is as follows:
Step 1.Under the room temperature, under the condition of induction stirring, in the reaction flask of salt of wormwood that 1.76g (10mmol) 1-benzyl diethylenediamine, 1.66g (12mmol) are housed and 10ml acetone, dropwise add 2.34g (12mmol) 4-bromo-butyric acid ethyl ester.Dropwise, stir 5min under the room temperature, be warmed up to 60 ℃ of constant temperature then and stirred 5 hours, after reaction finishes, filter, filter cake washs with small amount of acetone, and merging filtrate concentrates and obtains orange liquid 3.2g, productive rate 110%.Mass spectrum: 291 (M+1).
Step 2.Under the room temperature, under the condition of induction stirring, 4-(4-benzyl-piperazine-1-the yl)-ethyl butyrate that in reaction flask, adds 5ml ethanol and step 1 product 3.2g (theoretical amount 10mmol), be warmed up to 70 ℃ then, slowly drip 85% hydrazine hydrate of 1.76g (30mmol), back flow reaction 6 hours, after detection reaction finishes, stopped reaction.Concentration of reaction solution adds 5ml water, uses twice of dichloromethane extraction again.Merge organic layer, anhydrous magnesium sulfate drying, filtration concentrate and obtain faint yellow oily thing 2.4g, productive rate 87%.Mass spectrum: 277 (M+1).
Step 3.Under the room temperature, under the condition of induction stirring, in reaction flask, add 4-(4-benzyl-piperazine-1-yl)-daminozide of 5ml ethanol and 2g (7.24mmol), be warmed up to 70 ℃, slowly drip 2-hydroxyl-3-allyl benzene formaldehyde of 1.17g (7.24mmol).Isothermal reaction 1 hour, after detection reaction finishes, stopped reaction.Concentration of reaction solution, the product that obtains obtains 1.96g product 4-(4-benzyl-piperazine-1-yl)-butyryl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine, productive rate 66.58% with ethyl acetate and normal hexane two-phase recrystallization.The hydrogen spectrum (400MHz, DMSO): 11.93 (s, 1H); 11.65 (s, 1H); 8.35 (s, 1H); 7.1-7.33 (m, 7H); 6.84-6.9 (m, 1H); 5.95 (m, 1H); 5.03 (m, 2H); 3.4 (s, 2H); 3.3 (d, 2H); 2.4-2.65 (m, 12H); 1.86 (m, 2H).Mass spectrum: 421 (M+1).
The preparation of embodiment 3,3-(4-benzyl-piperidines-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
Reaction process is as follows:
Step 1.Under the room temperature, under the condition of induction stirring, in the reaction flask of salt of wormwood that 1.76g (10mmol) 1-benzyl diethylenediamine, 1.66g (12mmol) are housed and 10ml acetone, dropwise add 2.17g (12mmol) 3-ethyl bromide.Dropwise, stir 5min under the room temperature, be warmed up to 60 ℃ of constant temperature then and stirred 5 hours, after reaction finishes, filter, filter cake washs with small amount of acetone, and merging filtrate concentrates and obtains orange liquid 2.5g, productive rate 91%.Mass spectrum: 276 (M+1).
Step 2.Under the room temperature, under the condition of induction stirring, 3-(4-benzyl-piperidines-1-the yl)-ethyl propionate that in reaction flask, adds 5ml ethanol and 2.5g (9.1mmol), be warmed up to 70 ℃ then, slowly drip 85% hydrazine hydrate of 1.6g (27.3mmol), back flow reaction 6 hours, after detection reaction finishes, stopped reaction.Concentration of reaction solution adds 5ml water, uses twice of dichloromethane extraction again.Merge organic layer, anhydrous magnesium sulfate drying, filtration concentrate and obtain faint yellow oily thing 1.85g, productive rate 78%.Mass spectrum: 262 (M+1).
Step 3.Under the room temperature, under the condition of induction stirring, in reaction flask, add 3-(4-benzyl-piperidines-1-yl)-propionyl hydrazine of 5ml ethanol and 1.31g (5mmol), stir, then, slowly drip the 2-hydroxy benzaldehyde of 0.61g (5mmol).React after 20 minutes, have solid constantly to separate out, after detection reaction finishes, stopped reaction.Solid by filtration is collected, and the product that obtains obtains 1.4g product 3-(4-benzyl-piperidines-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine, productive rate 76.9% with ethyl acetate and normal hexane two-phase recrystallization.The hydrogen spectrum (400MHz, DMSO): 11.82 (s, 1H); 11.34 (s, 1H); 8.31 (s, 1H); 7.1-7.33 (m, 8H); 3.4 (s, 2H); 3.3 (d, 2H); 2.4-2.65 (m, 12H).Mass spectrum: 366 (M+1)
Embodiment 4,3-(4-p-toluenesulfonyl-piperazine-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
Preparation
Reaction process is as follows:
Step 1.Under the ice bath, under the condition of induction stirring, in the reaction flask that 6g (60mmol) Piperazine anhydrous, 10ml tetrahydrofuran (THF) are housed, dropwise add 1.9g (10mmol) Tosyl chloride.Dropwise in half an hour, reaction permission nature is warmed up to the stirring at room reaction and spends the night, and after reaction finishes, filters, and filter cake washs with a small amount of tetrahydrofuran (THF), merging filtrate, the concentrated small amount of liquid that obtains.In raffinate, add 20ml water, use ethyl acetate extraction, anhydrous magnesium sulfate drying.Concentrate, raffinate separates with silicagel column, and the product 1-that obtains 2g is to the Methyl benzenesulfonyl piperazine, productive rate 83.3%.Mass spectrum: 241 (M+1).
Step 2.Under the room temperature, under the condition of induction stirring, in being housed, the reaction flask of 2g (8.3mmol) 1-to the salt of wormwood of Methyl benzenesulfonyl piperazine, 1.38g (10mmol) and 10ml acetone dropwise add 1.81g (10mmol) 3-ethyl bromide.Dropwise, stir 5min under the room temperature, be warmed up to 60 ℃ of constant temperature then and stirred 5 hours, after reaction finishes, filter, filter cake washs with small amount of acetone, and merging filtrate concentrates and obtains orange liquid 2.5g, productive rate 88%.Mass spectrum: 341 (M+1).
Step 3.Under the room temperature; under the condition of induction stirring; 3-(4-p-toluenesulfonyl-piperazine-1-the yl)-ethyl propionate that in reaction flask, adds 5ml ethanol and 2.5g (7.35mmol); be warmed up to 70 ℃ then; slowly drip 85% hydrazine hydrate of 1.30g (22.1mmol); back flow reaction 6 hours, after detection reaction finishes, stopped reaction.Concentration of reaction solution adds 5ml water, uses twice of dichloromethane extraction again.Merge organic layer, anhydrous magnesium sulfate drying, filtration concentrate and obtain faint yellow oily thing 2g, productive rate 83%.Mass spectrum: 327 (M+1).
Step 4.Under the room temperature, under the condition of induction stirring, in reaction flask, add 3-(4-p-toluenesulfonyl-piperazine-1-yl)-propionyl hydrazine of 5ml ethanol and 2g (6.1mmol); stir; be warmed up to 70 ℃, then, slowly drip the 2-hydroxy benzaldehyde of 0.74g (6mmol).After dripping off, isothermal reaction 1 hour, after detection reaction finishes, stopped reaction.Concentration of reaction solution, the product that obtains obtains 2.05g product 3-(4-p-toluenesulfonyl-piperazine-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine, productive rate 77% with ethyl acetate and normal hexane two-phase recrystallization.The hydrogen spectrum (400MHz, DMSO): 11.82 (s, 1H); 11.34 (s, 1H); 8.31 (s, 1H); 7.1-7.33 (m, 8H); 3.3 (d, 2H); 2.4-2.65 (m, 12H).Mass spectrum: 431 (M+1).
Reaction process is as follows:
(1), the preparation of the inferior acyl carbethoxy hydrochloride of 3-bromine propionyl:
Under the ice bath, under the magnetic agitation, 3-bromopropionitrile and 4.6g (100mmol) dehydrated alcohol of 13.4g (100mmol) are dissolved in the anhydrous diethyl ether of 100ml, in reaction solution, feed dry hydrogen chloride gas, have a large amount of white solids to separate out after about 40 minutes, filter out solid, solid washs three times with anhydrous diethyl ether, drain, obtain the inferior acyl carbethoxy hydrochloride of 17.6g 3-bromine propionyl, productive rate 81.5%.The hydrogen spectrum (400MHz, DMSO): 4.45 (t, 2H); 4.28 (q, 2H); 3.5 (t, 2H); 1.24 (t, 3H).
(2), the preparation of 2-allyl group-6-(N-amido formamino) phenol:
Under the room temperature, under the magnetic agitation, in reaction flask, add 15ml methyl alcohol, 14.7g (250mmol), 85% hydrazine hydrate solution, drip 2-hydroxyl-3-allyl benzene formaldehyde of 8.1g (50mmol), the continuous flavescence of solution then.Restir reaction 10min after dripping off.After having reacted, methyl alcohol is removed in decompression.Add DCM (20ml) and water (40ml) in the raffinate.Stir, leave standstill.Tell organic layer then, wash secondary again, used anhydrous magnesium sulfate (4g) at last dry 0.5 hour, filter, filtrate concentrating obtains 7.9g yellow oil 2-allyl group-6-(N-amido formamino) phenol, productive rate 90%.Mass spectrum: 177.1 (M+1).
(3), the preparation of 3-bromine tetrahydroform acyl (N-amido formamino-3-hydroxybenzene) hydrazine:
Under the room temperature, under the magnetic agitation, add the inferior acyl carbethoxy hydrochloride of 10.8g (50mmol) 3-bromine propionyl in reaction flask, rubber stopper seal is injected into the absolute dehydrated alcohol of 70ml.Inject 6.06g (60mmol) exsiccant triethylamine then, stirring reaction 10min dissolves solid gradually, adds 8.8g (50mmol) 2-allyl group-6-(N-amido formamino) phenol then, continues stirring reaction and spends the night.After reaction finished, the ethanol decompression was removed.With the DCM dissolving, add an amount of water then, tell the DCM layer, anhydrous magnesium sulfate drying concentrates, and the separation of raffinate silicagel column obtains 11g 3-bromine tetrahydroform acyl (N-amido formamino-3-hydroxybenzene) hydrazine, productive rate 71%.Mass spectrum: 311.2 (M+1).
(4), the preparation of 3-(4-benzyl-piperazine-1-yl)-tetrahydroform acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine:
Under the room temperature, under the magnetic agitation, in reaction flask, add the K of 7.93g (25mmol) 3-bromine tetrahydroform acyl (N-amido formamino-3-hydroxybenzene) hydrazine, 20ml acetone, 2.76g (20mmol)
2CO3 and 3.52g (20mmol) 1-benzyl diethylenediamine.Stirring reaction 10min is warmed up to 60 ℃ of back flow reaction then.About 4-5 hour finishes, and filters filter cake washing with acetone, pressure reducing and steaming acetone afterwards.And then adding DCM, washing is told the DCM layer, anhydrous MgSO
4Dry.Concentrate, the raffinate silicagel column separates, and obtains the faint yellow oily thing of 7.5g, productive rate 74.2%.Hydrogen spectrum (400MHz, D
2O): 11.24 (1H); 10.01 (1H); 8.44 (1H); 7.20-7.32 (5H); 7.10 (2H); 6.82 (1H); 5.04-5.07 (2H); 3.46 (4H); 3.19 (2H); 2.63 (8H).Mass spectrum: 406.6 (M+1)
Embodiment 6,2-(4-benzyl-Gao piperazine-1-yl)-ethyliminum acyl (3-allyl group-2-hydroxyl-methylene radical
Benzene) preparation of hydrazine
Reaction process is as follows:
(1), the preparation of the inferior acyl carbethoxy hydrochloride of 2-chloracetyl:
Under the ice bath, under the magnetic agitation, chloromethyl cyanide and 6.1g (130mmol) dehydrated alcohol of 10g (130mmol) are dissolved in the anhydrous diethyl ether of 100ml, in reaction solution, feed dry hydrogen chloride gas, have a large amount of white solids to separate out after about 40 minutes, filter out solid, solid washs three times with anhydrous diethyl ether, drain, obtain 16g 2-chloracetyl imine ethyl ester hydrochloride, productive rate 98%; Fusing point 84-86 ℃.The hydrogen spectrum (400MHz, DMSO): 4.40 (s, 2H); 4.20 (q, 2H); 1.24 (t, 3H).
(2), the preparation of 2-allyl group-6-(N-amido formamino) phenol:
Under the room temperature, under the magnetic agitation, in reaction flask, add 15ml methyl alcohol, 14.7g (250mmol), 85% hydrazine hydrate solution, drip 2-hydroxyl-3-allyl benzene formaldehyde of 8.1g (50mmol), the continuous flavescence of solution then.Restir reaction 10min after dripping off.After having reacted, methyl alcohol is removed in decompression.Add DCM (20ml) and water (40ml) in the raffinate.Stir, leave standstill.Tell organic layer then, wash secondary again, used anhydrous magnesium sulfate (4g) at last dry 0.5 hour, filter, filtrate concentrating obtains 7.9g yellow oil 2-allyl group-6-(N-amido formamino) phenol, productive rate 90%.Mass spectrum: 177.1 (M+1)
(3), the preparation of 2-chloroethene imines acyl (N-amido formamino-3-hydroxybenzene) hydrazine:
Under the room temperature, under the magnetic agitation, add 7.9g (50mmol) 2-chloracetyl imine ethyl ester hydrochloride in reaction flask, rubber stopper seal is injected into the absolute dehydrated alcohol of 70ml.Inject 6.06g (60mmol) exsiccant triethylamine then, stirring reaction 10min dissolves solid gradually, adds 8.8g (50mmol) 2-allyl group-6-(N-amido formamino) phenol then, continues stirring reaction and spends the night.After reaction finished, the ethanol decompression was removed.With the DCM dissolving, add an amount of water then, tell the DCM layer, anhydrous magnesium sulfate drying concentrates, and the separation of raffinate silicagel column obtains 11g 2-chloroethene imines acyl (N-amido formamino-3-hydroxybenzene) hydrazine, productive rate 87.3%.Mass spectrum: 252.2 (M+1)
(4), the preparation of 2-(4-benzyl-Gao piperazine-1-yl)-ethyliminum acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine:
Under the room temperature, under the magnetic agitation, in reaction flask, add the K of 5.04g (25mmol) 2-chloroethene imines acyl (N-amido formamino-3-hydroxybenzene) hydrazine, 20ml acetone, 2.76g (20mmol)
2The high piperazine of CO3 and 3.8g (20mmol) 1-benzyl.Stirring reaction 10min is warmed up to 60 ℃ of back flow reaction then.About 4-5 hour finishes, and filters filter cake washing with acetone, pressure reducing and steaming acetone afterwards.And then adding DCM, washing is told the DCM layer, anhydrous MgSO
4Dry.Concentrate, the raffinate silicagel column separates, and obtains the faint yellow oily thing of 7g, productive rate 69.3%.Hydrogen spectrum (400MHz, D
2O): 11.24 (1H); 10.01 (1H); 8.44 (1H); 7.20-7.32 (5H); 7.10 (2H); 6.82 (1H); 5.04-5.07 (2H); 3.46 (2H); 3.19 (2H); 2.63 (8H); 1.41 (2H).Mass spectrum: 406.5 (M+1)
Experimental example 1, biological test
The external activity screening adopts mtt assay to detect SM-3, the PAC-1 growth-inhibiting effect to lung cell A549, breast cancer cell Hela, lung fibroblast HPF, liver cancer cell HepG-2 and human peripheral blood single nucleus cell, and does the contrast experiment with the PAC-1 medicine.Concrete grammar is: the cell in the vegetative period of taking the logarithm, and conventional digestion back counting is inoculated in 96 orifice plates with the density in 3000/hole, and adherent growth is spent the night.Add the SM-3 (mother liquor is dissolved among the DMSO) of 1,10,20,40,60,80 μ M and PAC-1 respectively and handle cell, each concentration is provided with 3 multiple holes, with the DMSO of maximum dose level as negative control, with the positive contrast of the cis-platinum of 5,10 μ g/ml.After handling 24,48,72 hours respectively, every hole adds 10 μ l MTT (5mg/ml), continues to cultivate 2～4 hours.Nutrient solution is abandoned in suction, adds the DMSO of 100 μ l in every hole, and concussion dissolving 5 minutes with the light absorption value at microplate reader detection 570nm place, is calculated the inhibiting rate of SM-3 and PAC-1 cell growth.
In addition, adopt normal people's peripheral blood and separate mononuclearcell with lymphocyte separation medium, the density with 5 * 104 is inoculated in 96 orifice plates, grow overnight.The SM-3 (mother liquor is dissolved among the DMSO) that adds 1,10,20,40,60,80 μ M respectively handles cell, and each concentration is provided with 3 multiple holes, with the DMSO of maximum dose level as negative control, with the positive contrast of the cis-platinum of 10 μ g/ml.After handling 24,48 hours respectively, every hole adds 10 μ l MTT (5mg/ml), continue to cultivate 2～4 hours, centrifugal 5 minutes of entire plate 1000rpm, nutrient solution is abandoned in suction, adds the DMSO of 100 μ l in every hole, concussion dissolving 5 minutes, with the light absorption value at microplate reader detection 570nm place, calculate the inhibiting rate of SM-3 cell growth.With similar approach test PAC-1.
Experimental result shows that SM-3 follows concentration and action time to be proportionate to several cell inhibiting effects.After effect 24 hours, medicine is not clearly to the influence of HPF cell, A549 cell, but to 48 hours inhibiting rates have significantly and rise, more obvious by 72 hours, but difference is little between the several concentration of 10,20,40 μ M.Recently see mutually, SM-3 is stronger to Hela cell, the effect of HepG-2 cell inhibiting, and dose-effect and time-effect relationship are also more obvious, especially the Hela cell, 24 hours inhibiting rates of effect just reach 77% when concentration is 60 μ M, and other several cells have only about 40%.SM-3 relatively relaxes monocytic effect, and it is not very big prolonging difference in time, and other several cells of medication concentration ratio are high a lot, do not have significant difference between 40 μ g/ml and the 80 μ g/ml.But SM-3 all is better than PAC-1 to several cell inhibiting effects, and concentration gradient is more obvious.PAC-1 does not obviously influence HPF cell, A549 cell after 24 hours in effect, and is obvious gradually with prolonging effect action time.Test-results is respectively referring to the detailed description of Fig. 1 to Fig. 9 and description of drawings part to them.
In addition, calculate SM-3 and PAC-1 IC50 value respectively, the results are shown in Table 1 and 2 several cell different time points inhibiting rates.
Table 1:SM-3 is to the IC50 value of various cells
Table 2:PAC-1 is to the IC50 value of various cells
Can find out the IC50 value of SM-3 to several cell different time points inhibiting rates from table 1 result, wherein HPF cell and A549 cell inhibiting rate when drug effect 24h is lower.
Can find out the IC50 value of PAC-1 to several cell different time points inhibiting rates from table 2 result, wherein HPF cell, A549 cell and HepG-2 inhibiting rate when drug effect 24h is all very low.
The contriver finds that also other compound that the present invention relates to the particularly compound of other several embodiment also has and the identical or similar result of the foregoing description 1 compound.
Claims (12)
1. the compound of formula I, formula II or formula III:
Wherein,
Ar is selected from and replaces or unsubstituted aryl, replacement or unsubstituted heteroaryl, and wherein said substituting group is selected from hydroxyl, halogen, C
2-C
6Alkenyl, C
1-C
6Alkyl, C
1-C
6Alkyl oxy, nitro, cyano group, sulfydryl, amino, carboxyl, sulfoamido;
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 1,2 or 3; With
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, C
1-C
6Alkyl oxy, nitro, cyano group,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
2. the compound of claim 1, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is a nitrogen-atoms;
N is selected from 1,2 or 3; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
3. the compound of claim 1, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is 1; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
4. the compound of claim 1, wherein:
Ar is selected from and replaces or unsubstituted aryl [for example being to replace or unsubstituted phenyl, the particularly phenyl of Qu Daiing], replacement or unsubstituted heteroaryl [for example replacing or unsubstituted nitrogenous aryl];
X is selected from-CH
2-,-CH
2CH
2-and-SO
2-;
Z is nitrogen-atoms or carbon atom;
N is selected from 2; With
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, C
1-C
6Alkyl oxy,
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
5. the compound of claim 1, it has following each or multinomial feature:
1) Ar is selected from aryl [for example phenyl] or heteroaryl [for example nitrogenous aryl], and wherein said aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: hydroxyl, halogen (for example fluorine, chlorine, bromine, iodine), C
2-C
6Alkenyl (C for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described Ar is a phenyl, and it is chosen wantonly by 1-3 (for example 1-2, for example 1) and is selected from following substituting group replacement: hydroxyl, halogen (for example fluorine, chlorine, bromine, iodine), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example C
1-C
2Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group, sulfoamido; In one embodiment, described Ar is a phenyl, and it is optional by C
1-C
4Alkyl (C for example
1-C
2Alkyl, for example methyl, ethyl) replace;
2) X is selected from-CH
2-,-CH
2CH
2-and-SO
2-; In one embodiment, described X is selected from-CH
2-and-SO
2-;
3) Z is nitrogen-atoms or carbon atom;
4) n is selected from 1,2 or 3; In one embodiment, described n is 1 or 2; With
5) 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 for example
2-C
4Alkenyl, for example vinyl, propenyl, allyl group), C
1-C
6Alkyl (C for example
1-C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
6Alkyl oxy (C for example
1-C
4Alkyl oxy, for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group; In one embodiment, described R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
4Alkenyl (for example vinyl, propenyl, allyl group), C
1-C
4Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl), C
1-C
4Alkyl oxy (for example methoxyl group, oxyethyl group, propoxy-), nitro, cyano group; In one embodiment, described R
1, R
2, R
3, R
4And R
5Be selected from hydrogen atom, hydroxyl, halogen, C independently of one another
2-C
4Alkenyl (for example vinyl, propenyl, allyl group), C
1-C
4Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl).
6. each compound of claim 1-5, it is following compound:
3-(4-benzyl-piperazine-1-yl)-propionyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
4-(4-benzyl-piperazine-1-yl)-butyryl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
3-(4-benzyl-piperidines-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
3-(4-p-toluenesulfonyl-piperazine-1-yl)-propionyl (2-hydroxyl-methylene-benzene) hydrazine
3-(4-benzyl-piperazine-1-yl)-tetrahydroform acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
2-(4-benzyl-Gao piperazine-1-yl)-ethyliminum acyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine
Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.
7. prepare the method for the described compound of claim formula I, it may further comprise the steps:
(1) in the presence of alkali, make 3-ethyl bromide, 4-bromo-butyric acid ethyl ester or 5-bromine Valeric acid ethylester and react with following formula Ia compound,
Generation is as shown in the formula the Ib compound:
(2) in organic solvent, make the reaction of hydrazine hydrate and above-mentioned formula Ib compound, generate with following formula Ic compound:
(3) the formula Ic compound that step (2) is obtained, and with following formula Id compound reaction,
Generation is with compound shown in the following formula I:
Wherein each symbol according to claim 1.
8. prepare the method for the described compound of claim formula II, it may further comprise the steps:
(1) under anhydrous condition, hydrogenchloride and ethanol are reacted in organic solvent and 3-bromoacetonitrile, 4-bromine butyronitrile or 5-bromine valeronitrile, generate as shown in the formula the IIa compound;
(2) in the organic solvent that is fit to, make the reaction of hydrazine hydrate and following IIb compound,
Generation is with following formula IIc compound:
(3) under the condition that alkali exists, following IIa compound and above-mentioned formula IIc compound are reacted in the organic solvent that is fit to, generate with following formula IId compound
(4) under the alkali existence condition, the IId compound that step (3) is obtained reacts in the organic solvent that is fit to with following formula IIe compound,
Generate compound shown in the following II::
Wherein each symbol is as first aspect present invention as described in each.
9. prepare the method for the described compound of claim formula III, it may further comprise the steps:
(1) under anhydrous condition, hydrogenchloride and ethanol are reacted in organic solvent and 2-chloromethyl cyanide, 3-chloroethyl nitrile or 4-chlorobutyronitrile, generate as shown in the formula the IIIa compound;
(2) in the organic solvent that is fit to, make the reaction of hydrazine hydrate and following IIIb compound,
Generate following formula III c compound:
(3) under the condition that alkali exists, IIIa compound and above-mentioned formula III c compound are reacted in the organic solvent that is fit to, generate following formula III d compound
(4) under the alkali existence condition, the IIId compound that step (3) is obtained reacts with following formula III e compound in the organic solvent that is fit to,
Generate compound shown in the following III::
Wherein each symbol is as first aspect present invention as described in each.
Claim 1-6 each compound preparation be used for the treatment of and/or the medicine of prophylaxis of tumours and/or cancer in purposes.
11. the purposes of claim 10, wherein said 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 minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, 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 Brukett`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 the maincenter origin cause of formation includes but not limited to fibrosarcoma and band sarcoma;
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 look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.
12. a pharmaceutical composition, it comprise treat and/or prevent significant quantity claim 1-6 each compound and optional pharmacy acceptable diluent, carrier, vehicle, auxiliary material or vehicle.
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| CN105085421A (en) * | 2015-07-24 | 2015-11-25 | 深圳市湘雅生物医药研究院 | Orbit azine-fumarate, hydrates, crystal forms and preparation methods therefor |
| WO2017015784A1 (en) * | 2015-07-24 | 2017-02-02 | 深圳市湘雅生物医药研究院 | 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 |
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