CN102603712A - S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application - Google Patents
S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application Download PDFInfo
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- CN102603712A CN102603712A CN201210031640XA CN201210031640A CN102603712A CN 102603712 A CN102603712 A CN 102603712A CN 201210031640X A CN201210031640X A CN 201210031640XA CN 201210031640 A CN201210031640 A CN 201210031640A CN 102603712 A CN102603712 A CN 102603712A
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- 0 Cc(c(N**)c1)ccc1NC(c1ccc([C@](*)CCC2)c2c1)=O Chemical compound Cc(c(N**)c1)ccc1NC(c1ccc([C@](*)CCC2)c2c1)=O 0.000 description 2
- WBQURVNATZTAMY-UHFFFAOYSA-N CC1C(Nc2nc(-c3cccnc3)ccn2)=CC(NC(c2ccc(C(CCC3)N4CCN(C)CC4)c3c2)=O)=CC1 Chemical compound CC1C(Nc2nc(-c3cccnc3)ccn2)=CC(NC(c2ccc(C(CCC3)N4CCN(C)CC4)c3c2)=O)=CC1 WBQURVNATZTAMY-UHFFFAOYSA-N 0.000 description 1
- KYTAPCRDWMOKKW-PMERELPUSA-N Cc(c(Nc1nc(-c2cccnc2)ccn1)c1)ccc1NC(c1ccc([C@H](CCC2)N3CCN(C)CC3)c2c1)=O Chemical compound Cc(c(Nc1nc(-c2cccnc2)ccn1)c1)ccc1NC(c1ccc([C@H](CCC2)N3CCN(C)CC3)c2c1)=O KYTAPCRDWMOKKW-PMERELPUSA-N 0.000 description 1
- KYTAPCRDWMOKKW-SSEXGKCCSA-N Cc(c(Nc1nc(-c2cnccc2)ccn1)c1)ccc1NC(c1ccc([C@@H](CCC2)N3CCN(C)CC3)c2c1)=O Chemical compound Cc(c(Nc1nc(-c2cnccc2)ccn1)c1)ccc1NC(c1ccc([C@@H](CCC2)N3CCN(C)CC3)c2c1)=O KYTAPCRDWMOKKW-SSEXGKCCSA-N 0.000 description 1
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Abstract
The invention relates to a novel compound R1 represented by general formula I. The compound R1 is an S-type or R-type tetrahydro-naphthalene amides compound, or a pharmaceutically acceptable salt or pro-drug of the compound, and is used as an antitumor drug. The invention also provides a preparation method of the compound, and a pharmaceutical composition containing the compound, and an antitumor research in vitro. The antitumor drug R1 obtained by the invention is the S-type or R-type tetrahydronaphthalene amides compound, is better in antitumor activity and safety and can be applied to treating tumors such as leukemia, lung cancer, liver cancer, colon cancer and ovarian cancer, so that the therapeutic window is wide, and the compound as an antitumor agent in the medicine field is very valuable.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to the tetraline amides and its pharmacy acceptable salt or prodrug and the Preparation method and use that suppress growth of tumour cell, performance antitumous effect.
Background technology
The binding site of imatinib competitive inhibition Triphosaden (ATP) and thymidine kinase (TK) acceptor such as KIT; Retardance TK phosphorylation; Thereby suppress the signal conduction, and can suppress that the KIT relevant with kinase activity suddenlys change (causing the KIT receptor activation) and the KIT of wild-type.Its target site mainly contains 3 kinds: Abelson (ABL) albumen, KIT albumen and Thr6 PDGF BB (PDGF) acceptor.Imatinib can cause that the activation that does not rely on STEMCELLFACTOR reduces the tyrosine phosphorylation of the clone (GIST882) from GIST, when concentration reaches 1 μ mol/L, can suppress tyrosine phosphorylation fully through the acquired KIT sudden change of function.
Be used to treat chronic myelocytic leukemia by FDA approval May calendar year 2001, was used to treat gastrointestinal stromal tumor (GIST) by the FDA approval in 2003.
Its structure is:
Be imatinib for the Buddhist nun obtain through structure of modification ring benzene, have the new compound with the same target spot of imatinib, but its pharmacological action obviously is better than imatinib, and it is synthetic to obtain argumentation with the pharmacodynamics evaluation in the CN102295635A patent, and its structure is:
Ring benzene shows through molecule and Bcr-Abl kinases docking study for the Buddhist nun: the cyclization of c-Kit kinases is modified and is caused local hydrophobicity to strengthen and flexible reduction.Hydrophobic enhancing; Make cyclization part and the hydrophobic pocket that Val379, Leu298, Ile293, Leu354, Val289 and Phe359 form produce more intense hydrophobic interaction; And causing the cyclization part to be moved to this hydrophobic region, this possibly be an interaction force enhanced reason between acceptor and the part.In addition; Cyclization has also caused the flexible reduction of part; Also certain promoter action possibly arranged to the enhancing of receptor-ligand interaction, ring benzene interacts for the interaction of hydrogen bond between Buddhist nun and the Bcr-Abl kinases, Pi-Pi and Pi-Sigma interacts, and sees accompanying drawing 1.
Ring benzene shows through molecule and c-Kit kinases docking study for the Buddhist nun: ring benzene analyzed for the interaction of hydrogen bond between Buddhist nun and the c-Kit kinases and Pi-Pi, Pi-Sigma interaction, and as shown in the figure.As can be seen from the figure; The side chain of Thr670, Glu640 and Cys673 has formed interaction of hydrogen bond with ring benzene for the Buddhist nun respectively; The side-chain benzene ring of Tyr672 forms Pi-Pi with ring benzene for the Buddhist nun and interacts; Lys623, Val603 and Leu595 have then formed the Pi-Sigma interaction with ring benzene for the Buddhist nun, and ring benzene interacts for the interaction of hydrogen bond between Buddhist nun and the c-Kit kinases, Pi-Pi and Pi-Sigma interacts, and sees accompanying drawing 2.
Imatinib has tangible untoward reaction, and most of patients some untoward reactions can occur during these article of taking, but most the genus gently to moderate.Consider that disease itself also can produce symptom, often be difficult to clear and definite their cause-effect relationship.
In the clinical trial process of CML, because of the relevant untoward reaction drug withdrawal person of medicine, in the chronic phase patient of alpha-interferon treatment failure, only account for 1%, account for 2% in acceleration period, CML-BC accounts for 5%.
In the GIST clinical trial, the adverse events drug withdrawal person relevant because of medicine accounts for 3.4%.
CML is similar with the untoward reaction that patient GIST is taken place; Have only two kinds of exceptions: it is less that bone marrow depression takes place patient GIST; The tumour internal hemorrhage is only observed in patient GIST in CML and patient GIST, and the adverse events relevant with pharmacological agent of common report has mild nausea (50～60%), vomiting; Diarrhoea, stomachache, weak, myalgia, myospasm and erythema, these adverse events are all handled easily.
All reporting in all researchs has edema and water retention, and incidence is respectively 47～59% and 7～13%, and wherein severe patient is respectively 1～3% and 1～2%.The edema of Most patients shows as socket of the eye week and edema of lower limbs.Glaucomatous indivedual report was once arranged, relevant with water retention.The report that also has hydrothorax, ascites, wet lung and body weight to increase sharply.These incidents can adopt usually to be suspended these article of use, use diuretic(s) or gives other supportive treatment and be able to alleviate.But the individual patient situation is serious, even life-threatening.There is 1 routine CML-BC patient dead because of the complex clinical situation of concurrent hydrothorax, congestive heart failure and renal failure.The incidence of these adverse events and dosage have certain relation, when being more common in dosage＞600mg/ days.
When the chemotherapeutic of imatinib and high dosage is united use, the liver toxicity of a mistake property can take place, raise and hyperbilirubinemia like transaminase.
Carry out for its drug research of Buddhist nun for ring benzene, do not find serious adverse effects.
Summary of the invention
For overcoming the above problems; The purpose of this invention is to provide than imatinib and ring benzene and replace the Buddhist nun to have better anti-tumor activity and security, and the antineoplastic compound S type of treatment window width or R type tetraline amides and its pharmacy acceptable salt or prodrug.
Another object of the present invention provide antineoplastic compound S type or R type tetraline amides and with the preparation method and the application thereof of its pharmacy acceptable salt or prodrug.
Among the present invention; For a change above-mentioned weakness of imatinib and enhanced electronic benzene are for Buddhist nun's drug effect; We carry out structural modification to it; Synthetic multiple S type or R type tetraline amides and with its pharmacy acceptable salt or prodrug, its anti-tumor activity is studied, the result finds that the compound of representing with formula [I], [II-1] [II-2] and [III] is the new compound with extremely good anti-tumor activity, stability and security.
The present invention relates to compound and its pharmacy acceptable salt or prodrug (accompanying drawing 3) with general formula [I] expression.
In the formula,
R
1What represent is that S type or R saturated cyclic are amino, alternatively by 1,2,3 or 4 R
1 aReplace;
R
1 aCan be Wasserstoffatoms, halogen, amino and C
1-6Alkyl;
R
2That represent is Wasserstoffatoms, halogen, amino, cyanic acid, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl.Perhaps two R
2Group can be linked to be the naphthenic base or the Heterocyclylalkyl of 3,4,5,6 or 7 yuan of rings with the atom that is connected with them, and is replaced by 1,2 or 3 group that independently is selected from cyanic acid, halogen alternatively;
R
3What represent is Wasserstoffatoms, halogen, amino, cyanic acid.Perhaps two R
3Group can be linked to be the naphthenic base or the Heterocyclylalkyl of 3,4,5,6 or 7 yuan of rings with the atom that is connected with them, and is replaced by 1,2 or 3 group that independently is selected from cyanic acid, halogen alternatively;
A-B is amido linkage or ester bond;
D is a heteroaryl, alternatively by 1,2 or 3 R
4Replace;
E is a Heterocyclylalkyl, or heteroaryl, alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from halogen, cyanic acid and amino;
N is an integer from 0-3;
M is an integer from 0-2;
The present invention relates to compound and its pharmacy acceptable salt or prodrug with general formula [II-1] [II-2] expression.
Or pharmacy acceptable salt or its prodrug, in the formula:
R
1Be that a S type or R type saturated cyclic are amino, be selected from piperidyl, piperazinyl, pyrrolidyl, heterocyclic butane group and morpholinyl, each group optional the is by 1,2,3 or 4 R
1aReplace;
R
1 aBe Wasserstoffatoms, halogen, amino, cyanic acid, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
D is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl or pyrazolyl, and alternatively by 1,2 or 3 R
4Replace;
E is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl, pyrazolyl 、 Dan oxazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, pyrazolopyrimidine base, quinolyl, isoquinolyl, quinazolyl, piperazinyl or morpholinyl, and alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from halogen, cyanic acid, amino, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
The present invention relates to compound and its pharmacy acceptable salt or prodrug with general formula [III] expression.
Or pharmacy acceptable salt or prodrug, wherein:
R
6And R
7Be independently selected from Wasserstoffatoms, cyanic acid, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
R
8Be independently selected from Wasserstoffatoms, C
1-6Alkyl, C
2-6Hydroxyalkyl, C
2-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
D is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl or pyrazolyl, and alternatively by 1,2 or 3 R
4Replace;
E is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl, pyrazolyl 、 Dan oxazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, pyrazolopyrimidine base, quinolyl, isoquinolyl, quinazolyl, piperazinyl or morpholinyl, and alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from Wasserstoffatoms, halogen, cyanic acid, amino, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
P is an integer from 1-2.
Preferred compound 1,2:
Or pharmacy acceptable salt or prodrug, each group of general formula [III] is expressed as following group:
R
6And R
7Be independently selected from Wasserstoffatoms;
R
8Be independently selected from methyl;
D is selected from pyrimidyl;
E is selected from pyridyl;
R
4And R
5Independently be selected from Wasserstoffatoms;
P is one 1 a integer.
Preferred compound 3,4:
Or pharmacy acceptable salt or prodrug, each group of general formula [III] is expressed as following group:
R
6And R
7Be independently selected from Wasserstoffatoms;
R
8Be independently selected from ethyl;
D is selected from pyrimidyl;
E is selected from pyrimidyl;
R
4And R
5Independently be selected from Wasserstoffatoms;
P is one 1 a integer.
A kind of drug regimen comprises any one described compound of claim 1-4 or its pharmacy acceptable salt or prodrug and at least a pharmaceutically acceptable carrier.
Compound or its pharmacy acceptable salt or prodrug, preparation is used for treating the application of the medicine of tumor disease.
Application in the medicine of treatment tumor disease, it is right to comprise: white blood disease, lung cancer, colorectal carcinoma, ovarian cancer and kidney etc.;
The invention has the beneficial effects as follows: antineoplastic compound S type that the present invention obtains or R type tetraline amides with or its pharmacy acceptable salt or prodrug; Have better anti-tumor activity and security; Can be in the application in the tumours such as treatment white blood disease, lung cancer, colorectal carcinoma, ovarian cancer and kidney; Anticancer spectrum is wide, and the treatment window width is so be that using value is arranged very much as antineoplastic agent in field of medicaments.
Description of drawings
Fig. 1 is that ring benzene interacts and Pi-Sigma interaction synoptic diagram for the interaction of hydrogen bond between Buddhist nun and the Bcr-Abl kinases, Pi-Pi;
Fig. 2 ring benzene interacts and Pi-Sigma interaction synoptic diagram for the interaction of hydrogen bond between Buddhist nun and the c-Kit kinases, Pi-Pi;
Fig. 3 S type or R type tetraline amides general formula
Fig. 4 is the synthesis mechanism figure of the compound of general formula of the present invention [II-1] expression;
Fig. 5 is the synthesis mechanism figure of the compound of general formula of the present invention [II-2] expression;
Fig. 6 is the chemical structural formula of The compounds of this invention 1;
Fig. 7 is the chemical structural formula of The compounds of this invention 2;
Fig. 8 is the chemical structural formula of The compounds of this invention 3;
Fig. 9 is the chemical structural formula of The compounds of this invention 4;
Embodiment
Below enumerate embodiment, the present invention further is described particularly, but the present invention does not receive the restriction of these embodiment.
To describe exemplary of the present invention in detail below.Yet these embodiments are merely illustration purpose, are not intended to restriction by scope of invention.
The compounds of this invention also comprises pharmacy acceptable salt.Pharmacy acceptable salt is meant changes salifiable form to the basic group in the parent compound.Pharmacy acceptable salt includes, but not limited to the for example inorganic or organic acid salt of amine (ammonia) base of basic group.
Pharmacy acceptable salt can be by inorganic or organic acid preparation, and mineral acid can include but are not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.Organic acid can include but are not limited to acetate, propionic acid, oxyacetic acid, pyruvic acid, lactic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, Hydrocerol A, phenylformic acid, styracin, racemic melic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc.
" pharmaceutically acceptable carrier " as used herein comprise any and whole solvents pharmaceutically, dispersion medium, dressing, etc. blend absorption delay agent etc.; Such medium and medicament are used for pharmaceutically active substances and are well known in the art; Only if any conventional media or medicament and activeconstituents are incompatible; Its application in therapeutic compsn can expect that supplementary active ingredients also can be incorporated in the compsn.
Pharmaceutical composition taking orally of the present invention, injection, spraying suction, external preparation for skin, rectum with, nasal cavity with, vagina with, abdominal cavity with or use through implanting purposes such as reservoir or transdermal patch.
Importance of the present invention be the present invention can be used for the treatment relate to tumor disease, comprising: white blood disease, lung cancer, colorectal carcinoma, ovarian cancer and kidney etc.
Another aspect of the present invention relates to the preparation method of preparation general formula I I-1 and general formula I I-2 compound.The compounds of this invention can use following method and prepared, sees accompanying drawing 3,4.
Raw material 1-1 is at (R)-2-methyl-CBS-oxazole borine (1 mmole) [or (S)-2-methyl-CBS-oxazole borine] toluene solution and borine-N, and N-diethylbenzene amine complex [borine dimethyl sulphide complex compound] toluene solution is reduced agent and reduces, and obtains midbody (S)-5-hydroxyl-5; 6,7,8-naphthane-2-carboxylate methyl ester [or (R)-5-hydroxyl-5; 6,7,8-naphthane-2-carboxylate methyl ester)]; Be respectively two enantiomorphs, compound 1-2 and 2-2.The hydroxyl of two enantiomorphs is chloro under the reagent effect of for example thionyl chloride; Obtain midbody 1-3, the cl radical of 2-3 is replaced by a cyclammonium base (or cyclic amino), with triethylamine or salt of wormwood as alkali; Thereby obtain midbody 1-4,2-4 in the trimethylaluminium toluene solution with 6-methyl-N
1-[(4-pyridin-3-yl) pyrimidine-2-base] benzene-1, the 3-diamine reactant obtains compound 1-6 and 2-6.Also can be by 1-4; Hydrolysis of ester group among the 2-4 obtains carboxylic acid 1-5 and 2-5; 1-5 and 2-5 after forming acyl chlorides under the sulfur oxychloride effect with alcohol or amino reaction or at coupling agent for example EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) or DCC (1; The 3-NSC 57182), obtain compound 1-6 and 2-6 for direct under the catalyzer condition with alcohol or amino reaction with DMAP (4, the 4-Dimethylamino pyridine) or HOBT (1-hydroxy benzo triazole).
Embodiment 1: (S)-and N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-acid amides
Steps A: (S)-5-hydroxyl-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
In reaction flask, add (R)-2-methyl-CBS-oxazole borine (1 mmole) toluene solution, 10 milliliters of borine-N of 1 milliliter of 1.0M, N-diethylbenzene amine complex (10.5 mmole) toluene solution is heated to 30 ℃ with mixing solutions; Slowly drip the 5-carbonyl-5,6 of 30 milliliters dilution with toluene, 7 this moment; 8-naphthane-2-carboxylate methyl ester (2.04 grams, 10 mmoles) dropwised in half a hour; 30 ℃ are continued down to stir after 2 hours, reduce to room temperature, add 5 ml methanol solution in the reaction solution; Stir after 10 minutes, slowly add 15 milliliters of 1N aqueous hydrochloric acids, mixture stirred 20 minutes; Use 100 milliliters of extracted with diethyl ether then, organic phase is with 1N Hydrogen chloride, water, saturated common salt solution washing.Organic phase is used anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates.Add 100 milliliters of hot normal hexane crystallizations in the oily resistates, obtain white solid (S)-5-hydroxyl-5,6,7,8-naphthane-2-carboxylate methyl ester 1.85 gram products, productive rate 89.8%, chirality OD-H post detects ee value 98%.MS(M+1)＝207.22。
Step B: (S)-5-chloro-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
(S)-5-hydroxyl-5,6,7,8-naphthane-2-carboxylate methyl ester (3.09 gram, 15 mmoles) is dissolved in 20 milliliters the dichloromethane solution, slowly drips 10 milliliters of dichloromethane solutions that contain sulfur oxychloride (7.08 grams, 60 mmoles) under 0-5 ℃.Rise to after dropwising under the room temperature and reacted 6 hours, with adding 50 milliliters in ETHYLE ACETATE behind the reaction solution concentrating under reduced pressure, with 2 times (50 milliliters) of salt washing, anhydrous sodium sulfate drying obtains 3.18 gram products, productive rate 94.5% after the filtering and concentrating.MS(M+1)＝225.21。
Step C: (S)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
(S)-5-chloro-5,6,7,8-naphthane-2-carboxylate methyl ester (2.41 grams; 10 mmoles) be dissolved in 20 milliliters of DMF solvents, add salt of wormwood (2.78 grams, 20 mmoles), N methyl piperazine (2 grams; 20 mmoles), 50 ℃ are reacted after 5 hours down, and reaction solution is added 80 milliliters in ETHYLE ACETATE, transfer pH value to neutrality with diluted hydrochloric acid aqueous solution; Tell ETHYLE ACETATE mutually also with saturated common salt water washing (80*3), anhydrous sodium sulfate drying filters, and silica gel column chromatography separated after filtrate decompression screwed out organic solvent; Methyl alcohol: methylene dichloride=condition under obtain product 2.12 restrain productive rate 73.9%, MS (M+1)=289.31 at 30: 1.
Step D: (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, synthetic (compound 1) of 8-naphthane-2-acid amides
With (S)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-carboxylate methyl ester (2.88 grams, 10 mmoles) and 6-methyl-N
1-[(4-pyridin-3-yl) pyrimidine-2-base] benzene-1,3-diamines (3.32 gram, 12 mmoles) are suspended in 30 milliliters the toluene, add the trimethylaluminium toluene solution (5 milliliters, 10 mmoles) of 2M, the reaction 6 hours down of 100 ℃ in mixture, solution cooling.Under agitation add soluble tartrate sodium water solution (50 milliliters).Its solution is with ethyl acetate extraction 3 times (100,100,50 milliliters); Extracting solution after the merging is washed (100 milliliters) and salt washing (100,100,50 milliliters) with sodium hydrogencarbonate; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Separate under 50% ethyl acetate/dichloromethane/1% triethylamine moving phase condition with the silicagel column purifying and to obtain product 2.32 gram, productive rate 43.5%.
MS(M+1)＝534.22。
1H-NMR(DMSO-d
6，ppm)：δ10.10(s，1H)；9.20(s，1H)；8.95(s，1H)；8.66(d，J＝6.0Hz，1H)；8.48(d，J＝6.0Hz，1H)；8.42(d，J＝8.4Hz，1H)；8.02(s，1H)；7.77(s，1H)；?7.74(d，J＝8.4Hz，1H)；7.48(dd，1H)；7.42(dd，1H)；7.40(d，J＝6.0Hz，1H)；7.32(d，J＝8.4Hz，1H)；7.18(d，J＝8.4Hz，1H)；4.26(t，J＝8.4Hz，1H)；2.2-3.0(m，10H)；2.20(s，3H)；2.12(s，3H)；2.02(m，2H)；1.84(m，2H).
Embodiment 2: (R)-and N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-acid amides
Steps A: (R)-5-hydroxyl-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
5 carbonyls-5,6,7,8-naphthane-2-carboxylate methyl ester (3.06 gram, 15 mmoles) is dissolved in 20 milliliters the tetrahydrofuran solution, adds active
Molecular sieve 5 grams, N
2Protection slowly drips (S)-2-methyl-CBS-oxazole borine (1.5 mmole) toluene solution of 1.5 milliliters of 1.0M down under-20 ℃; Add 5 milliliters of dry tetrahydrofuran solution that contain borine dimethyl sulphide complex compound (1.14 grams, 15 mmoles) again, dropwised the back and stirred 1 hour down in 20 minutes at-15～20 ℃; The careful usefulness 20 ml methanol solution of solution are quenched and are stopped; Rise to room temperature and continue to stir 12 hours, the vacuum-drying column chromatography for separation of reducing the price gets product 1.92 grams, productive rate 93.2%.Chirality OD-H post detects ee value 98%.MS(M+1)＝207.31。
Step B: (R)-5-chloro-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
(S)-5-hydroxyl-5,6,7,8-naphthane-2-carboxylate methyl ester (3.09 gram, 15 mmoles) is dissolved in 20 milliliters the dichloromethane solution, slowly drips 10 milliliters of dichloromethane solutions that contain sulfur oxychloride (7.08 grams, 60 mmoles) under 0-5 ℃.Rise to after dropwising under the room temperature and reacted 6 hours, with adding 50 milliliters in ETHYLE ACETATE behind the reaction solution concentrating under reduced pressure, with 2 times (50 milliliters) of salt washing, anhydrous sodium sulfate drying obtains 3.18 gram products, productive rate 94.5% after the filtering and concentrating.MS(M+1)＝225.21。
Step C: (R)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
(R)-5-chloro-5,6,7,8-naphthane-2-carboxylate methyl ester (2.41 grams; 10 mmoles) be dissolved in 20 milliliters of DMF solvents, add salt of wormwood (2.78 grams, 20 mmoles), N methyl piperazine (2 grams; 20 mmoles), 50 ℃ are reacted after 5 hours down, and reaction solution is added 80 milliliters in ETHYLE ACETATE, transfer pH value to neutrality with diluted hydrochloric acid aqueous solution; Tell ETHYLE ACETATE mutually also with saturated common salt water washing (80*3), anhydrous sodium sulfate drying filters, and silica gel column chromatography separated after filtrate decompression screwed out organic solvent; Methyl alcohol: methylene dichloride=condition under obtain product 2.12 restrain productive rate 73.9%, MS (M+1)=289.31 at 30: 1.
Step D: (R)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, synthetic (compound 2) of 8-naphthane-2-acid amides
With (R)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-carboxylate methyl ester (2.88 grams, 10 mmoles) and 6-methyl-N
1-[(4-pyridin-3-yl) pyrimidine-2-base] benzene-1,3-diamines (3.32 gram, 12 mmoles) are suspended in 30 milliliters the toluene, add the trimethylaluminium toluene solution (5 milliliters, 10 mmoles) of 2M, the reaction 6 hours down of 100 ℃ in mixture, solution cooling.Under agitation add soluble tartrate sodium water solution (50 milliliters).Its solution is with ethyl acetate extraction 3 times (100,100,50 milliliters); Extracting solution after the merging is washed (100 milliliters) and salt washing (100,100,50 milliliters) with sodium hydrogencarbonate; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Separate under 50% ethyl acetate/dichloromethane/1% triethylamine moving phase condition with the silicagel column purifying and to obtain product 2.32 gram, productive rate 43.5%.
MS(M+1)＝534.22。
1HNMR(DMSO-d
6，ppm)：δ10.10(s，1H)；9.20(s，1H)；8.95(s，1H)；8.66(d，J＝6.0Hz，1H)；8.48(d，J＝6.0Hz，1H)；8.42(d，J＝8.4Hz，1H)；8.02(s，1H)；7.77(s，1H)；7.74(d，J＝8.4Hz，1H)；7.48(dd，1H)；7.42(dd，1H)；7.40(d，J＝6.0Hz，1H)；7.32(d，J＝8.4Hz，1H)；7.18(d，J＝8.4Hz，1H)；4.26(t，J＝8.4Hz，1H)；2.2-3.0(m，10H)；2.20(s，3H)；2.12(s，3H)；2.02(m，2H)；1.85(m，2H).
Embodiment 3 (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-amino] phenyl }-5-(3-Methylimidazole alkane-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-acid amides
Steps A: 1-Methylimidazole alkane synthetic
N-methyl ethylenediamine (1 gram, 13.5 mmoles) joins formaldehyde (0.4 gram, 13.5 mmoles), salt of wormwood (6.4 grams; 47.2 mmole), in 25 milliliters of chloroform suspension-s of sal epsom (5.6 gram, 47.2 mmoles), stirred 18 hours under the room temperature; Filter, filtrate decompression concentrates, and the neutral alumina column chromatography is at methylene dichloride: methyl alcohol=condition under purify at 9: 1 product 1-Methylimidazole alkane 0.81 gram; Productive rate 70%, MS (M+1)=87.11.
Step B: (S)-5-(3-Methylimidazole alkane-1-yl)-5,6,7,8-naphthane-2-carboxylate methyl ester synthetic
(S)-5-chloro-5,6,7,8-naphthane-2-carboxylate methyl ester (2.41 grams; 10 mmoles) be dissolved in 20 milliliters of DMF solvents, add salt of wormwood (2.78 grams, 20 mmoles), 1-Methylimidazole alkane (1.72 grams; 20 mmoles), 50 ℃ are reacted after 5 hours down, and reaction solution is added 80 milliliters in ETHYLE ACETATE, transfer pH value to neutrality with diluted hydrochloric acid aqueous solution; Tell ETHYLE ACETATE mutually also with saturated common salt water washing (3*80 milliliter), anhydrous sodium sulfate drying filters, and silica gel column chromatography separated after filtrate decompression screwed out organic solvent; Methyl alcohol: methylene dichloride=condition under obtain product 2.03 restrain productive rate 74.1%, MS (M+1)=275.28 at 20: 1.
Step C: (S)-5-(3-Methylimidazole alkane-1-yl)-5,6,7,8-naphthane-2-carboxylic acid synthetic
(S)-5-(3-Methylimidazole alkane-1-yl)-5,6,7; 8-naphthane-2-carboxylate methyl ester (2.6 gram, 10 mmoles) is dissolved in 30 ml methanol and the 20 milliliters of tetrahydrofuran solutions, adds (10 milliliters of NaOH that contain 2N; 20 mmoles), reaction is 10 hours under the room temperature, behind 2N aqueous hydrochloric acid accent PH=3～4; Decompression back-out organic solvent adds 60 milliliters in ETHYLE ACETATE and with saturated common salt water washing (3*60 milliliter), ETHYLE ACETATE is used anhydrous sodium sulfate drying mutually; Filter, silica gel column chromatography separated methyl alcohol: methylene dichloride after filtrate decompression screwed out organic solvent: separate obtaining product 2.21 grams under the condition of glacial acetic acid=25: 1: 5; Productive rate 85.0%, MS (M+1)=261.33.
Step D: (S)-5-(3-Methylimidazole alkane-1-yl)-1,2,3,4-naphthane-5-acyl chloride hydrochloride synthetic
Add SOCl in the reaction flask
2(200 milliliters) add (S)-5-(3-Methylimidazole alkane-1-yl)-5,6,7, and 8-naphthane-2-carboxylic acid (26 gram) refluxed after 6 hours, reduced to room temperature, and decompression screws out SOCl
2, add toluene solution (50 milliliters) again, being cooled to 0 ℃ has a large amount of white solids to separate out, and suction filtration gets product (about 34.8 grams, productive rate 99.5%) with solid drying.
Step e: (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-amino]-phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-acid amides
With 6-methyl-N
1-[(4-pyridin-3-yl) pyrimidine-2-base] benzene-1,3-diamines (2.77 grams, 10 mmoles) is dissolved in the pyridine (30 milliliters).Slowly add (S)-5-(3-Methylimidazole alkane-1-yl)-1,2,3 under 0～5 ℃ of stirring, 4-naphthane-5-acyl chloride hydrochloride (2.78 grams, 10 mmoles) in batches.Add in about 30 minutes.Rise under the room temperature and stirred 4 hours.Under agitation reaction solution is added (50 milliliters) in the 2N aqueous sodium hydroxide solution, add methylene dichloride (50 milliliters) immediately.After stirring a little while, the separate dichloromethane phase, water is with dichloromethane extraction (2 * 50 milliliters).Merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure.Silica gel column chromatography separates, and wash-out gets product 4.68 grams, productive rate 90.2% under 5% ethanol/methylene/1% triethylamine condition.MS(M+1)＝520.16。δ9.99(s，1H)；9.11(s，1H)；8.85(s，1H)；8.66(d，J＝4.8Hz，1H)；8.52(d，J＝4.8Hz，1H)；8.47(d，J＝9.0Hz，1H)；8.02(s，1H)；7.74(s，1H)；7.72(d，J＝9.0Hz，1H)；7.43(dd，J＝8.0Hz，4.8Hz，1H)；7.38(d，J＝8.0Hz，1H)；7.34(d，J＝4.8Hz，1H)；7.27(d，J＝9.0Hz，1H)；7.16(d，J＝9.0Hz，1H)；4.22(t，J＝9.0Hz，1H)；3.46(s，2H)；2.2-2.7(m，6H)；2.11(s，3H)；2.03(s，3H)；2.0(m，2H)；1.86(m，2H).
Embodiment 4 (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-amide hydrochloride
Reaction flask is added (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7; 8-naphthane-2-acid amides (5.33 grams, 10 mmoles), 100 milliliters of absolute ethyl alcohols; Hydrochloric acid absolute ethyl alcohol saturated solution (10.5 mmole) adds reaction flask, and 70 ℃ of refluxed reactions added medicinal decolorizing charcoal 2 grams after 1 hour; After refluxing again 1 hour, suction filtration, filtrate decompression concentrates the back and adds 100 milliliters in acetone (or Virahol, ether) stirred crystallization.Filter, dry product (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-amide hydrochloride 5.94 restrains productive rate 94.5%, fusing point: 192～194 ℃.Ultimate analysis: C
32H
36ClN
7O
Calculated value: C, 67.41; H, 6.36; Cl, 6.22; N, 17.20; O, 2.81; Test value: C, 67.33; H, 6.42; Cl, 6.26; N, 17.38; O, 2.91.
Embodiment 5 (R)-N-{4-methyl 3-[(4-pyridine-3 base) pyrimidine 2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-amide hydrochloride
With (R)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7; 8-naphthane-2-acid amides (5.33 grams, 10 mmoles), 100 milliliters of absolute ethyl alcohols; Hydrochloric acid absolute ethyl alcohol saturated solution (10.5 mmole) adds reaction flask, and 70 ℃ of refluxed reactions added medicinal decolorizing charcoal 2 grams after 1 hour; After refluxing again 1 hour, suction filtration, filtrate decompression concentrates the back and adds 100 milliliters in acetone (or Virahol, ether) stirred crystallization.Filter, dry product (R)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-amide hydrochloride 5.72 restrains productive rate 90.9%, fusing point: 193～195 ℃.Ultimate analysis: C
32H
36ClN
7O
Calculated value: C, 67.41; H, 6.36; Cl, 6.22; N, 17.20; O, 2.81; Test value: C, 67.33; H, 6.42; Cl, 6.26; N, 17.38; O, 2.91.
Embodiment 6 (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-acid amides vitriol
With (S)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-acid amides (5.33 grams; 10 mmoles) add in 500 milliliters of hot ethanols, drip dissolved sulfuric acid (10 milliliters, 100 milliliters of ethanolic solns 1M), 80 ℃ of refluxed are after 2 hours; Reduce to room temperature, filter and separate out solid, drying; Get title product 3.56 grams, productive rate 52.4%, fusing point: 202～204 ℃.Ultimate analysis: C
32H
38N
7O7S
1.5, calculated value: C, 56.46; H, 5.63; N, 14.40; O, 16.45; Test value: C, 56.52; H, 5.55; N, 14.33; O, 16.37.
Embodiment 7 (R)-N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the preparation of 8-naphthane-2-acid amides vitriol
With (R)-N-[4-methyl-3-(4-pyridine-3 yl pyrimidines-2-is amino) phenyl]-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-acid amides (5.33 grams; 10 mmoles) add in 500 milliliters of hot ethanols, drip dissolved sulfuric acid (10 milliliters, 100 milliliters of ethanolic solns 1M), 80 ℃ of refluxed are after 2 hours; Reduce to room temperature, filter and separate out solid, drying; Get title product 3.44 grams, productive rate 50.7%, fusing point: 203～204 ℃.Ultimate analysis: C
32H
38N
7O
7S
1.5, calculated value: C, 56.46; H, 5.63; N, 14.40; O, 16.45; Test value: C, 56.33; H, 5.72; N, 14.55; O, 16.32.
Embodiment 8: (S)-and N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-acid amides (compound 3)
With (S)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-formic acid (1.37 grams, 5 mmoles), 6-methyl-N
1-[(4-pyridine-5-yl) pyrimidine-2-base] benzene-1,3-diamines (1.53 grams, 5.5 mmoles), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (1.15 grams; 6 mmoles), DMAP (4, the 4-methylamino pyridine) (0.31 gram, 2.5 mmoles) joins in 30 milliliters the THF and 10 milliliters of DMF mixed solutions; Reaction screwed out THF with the reaction solution decompression after 4 hours under the room temperature, added 50 milliliters in ETHYLE ACETATE; And with 3 times (60,60,30 milliliters) of salt solution washing; ETHYLE ACETATE is used anhydrous sodium sulfate drying mutually, filters, and filtrate decompression screws out solvent; Silica gel column chromatography separates under 50% ethyl acetate/dichloromethane/1% triethylamine moving phase condition and obtains title product 1.57 gram, productive rate 58.8%.
MS(M+1)＝535.54。
1H-NMR(DMSO-d
6ppm)：δ10.04(s，1H)；9.45(s，2H)；9.32(s，1H)；9.11(s，1H)；8.57(d，J＝6.0Hz，1H)；8.14(s，1H)；7.75(s，1H)；7.73(d，J＝9.0Hz，1H)；7.49(d，J＝6.0Hz，1H)；7.45(d，J＝9.0Hz，1H)；7.34(d，J＝9.0Hz，1H)；7.17(d，J＝9.0Hz，1H)；4.31(t，J＝6.0Hz，1H)；2.3-3.0(m，10H)；2.16(s，3H)；2.08(s，3H)；1.98(m，2H)；1.88(m，2H).
Embodiment 9: (S)-and N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-amide hydrochloride
Reaction flask is added (S)-N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-acid amides (5.34 grams; 10 mmoles), 100 milliliters of anhydrous methanols, methanesulfonic (1.01 grams; 10.5 mmole), 70 ℃ of refluxed reactions added medicinal decolorizing charcoal 2 grams after 1 hour; After refluxing again 1 hour, suction filtration, filtrate decompression concentrates the back and adds 100 milliliters of stirred crystallization of Virahol.Filter, dry product (S) N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-amide hydrochloride 5.72 restrains productive rate 90.8%.Fusing point: 201～203 ℃.Ultimate analysis: C
31H
35ClN
8O calculated value: C, 65.19; H, 6.18; Cl, 6.21; N, 19.62; O, 2.80; Test value: C, 65.23; H, 6.20; Cl, 6.29; N, 19.76; O, 2.85.
Embodiment 10: (R)-and N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-acid amides (compound 4)
With (R)-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-formic acid (1.37 grams, 5 mmoles), 6-methyl-N
1-[(4-pyridine-5-yl) pyrimidine-2-base] benzene-1,3-diamines (1.53 grams, 5.5 mmoles), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (1.15 grams; 6 mmoles), DMAP (4, the 4-methylamino pyridine) (0.31 gram, 2.5 mmoles) joins in 30 milliliters the THF and 10 milliliters of DMF mixed solutions; Reaction screwed out THF with the reaction solution decompression after 4 hours under the room temperature, added 50 milliliters in ETHYLE ACETATE; And with 3 times (60,60,30 milliliters) of salt solution washing; ETHYLE ACETATE is used anhydrous sodium sulfate drying mutually, filters, and filtrate decompression screws out solvent; Silica gel column chromatography separates under 50% ethyl acetate/dichloromethane/1% triethylamine moving phase condition and obtains title product 1.57 gram, productive rate 58.8%.
Embodiment 11: (S)-and N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7, the synthesizing of 8-naphthane-2-amide hydrochloride
Reaction flask is added (S)-N-{4-methyl-3-[(4-pyrimidine-5 base) pyrimidine-2-is amino] phenyl }-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-acid amides (5.34 grams; 10 mmoles), 100 milliliters of anhydrous methanols, methanesulfonic (1.01 grams; 10.5 mmole), 70 ℃ of refluxed reactions added medicinal decolorizing charcoal 2 grams after 1 hour; After refluxing again 1 hour, suction filtration, filtrate decompression concentrates the back and adds 100 milliliters of stirred crystallization of Virahol.Filter, dry product (S) N-{4-methyl-3-[(4-pyridine-3 base) pyrimidine-2-is amino] phenyl-5-(4-N-METHYL PIPERAZINE-1-yl)-5,6,7,8-naphthane-2-amide hydrochloride 5.72 restrains productive rate 90.8%.Fusing point: 201～203 ℃.Ultimate analysis: C
31H
35ClN
8O calculated value: C, 65.19; H, 6.18; Cl, 6.21; N, 19.62; O, 2.80; Test value: C, 65.23; H, 6.20; Cl, 6.29; N, 19.76; O, 2.85.
The hydrochloride pharmacodynamics test of embodiment 12 compounds 1, compound 2, compound 3 and compound 4
The ring benzene that provides with embodiment 1 and embodiment 6 is given the test agent for Buddhist nun and amine benzene for the Buddhist nun, has represented the good antitumor action shown in following pharmacodynamics test.
(1) for the inhibition growth activity (GI of various cancer cells
50) measuring method:
Tumour cell is dispersed into individual cells behind tryptic digestion, and it is suspended in the RPMI1640 substratum that contains penicillium mould (25U/ml) and Streptomycin sulphate (25 μ g/ml).Cell inoculation in 96 well culture plates (Corning Incorporated), at 37 ℃, is contained 5%CO
2Air, cultivate under relative humidity 100% condition after 24 hours, discard nutrient solution; Add the nutrient solution that contains a series of concentration given the test agent, each concentration is established parallel hole, cultivates after 24 hours; Discard the nutrient solution that contains given the test agent, add conventional nutrient solution and cultivate after 48 hours, discard nutrient solution; Replace and contain tetrazolium bromide (MTT, U.S. Sigma Company products) nutrient solution, the MTT final concentration is 0.5g/L; Continue incubation and add dmso solution liquid after 4 hours, purple crystal dissolves fully after 1 hour, detects the optical density(OD) (OD) of 570nm/630nm at SK601 type ELIASA (Seikagaku of Japan Company products).Be calculated as follows the given the test agent half growth inhibition ratio thin to tumour:
(T-T
0)/(C-T
0)×100％
Annotate: C representes the OD value of cellular control unit
T representes to add the OD value of given the test agent group cell
T
0Expression contrasts the OD value of dull and stereotyped cell when adding given the test agent
Given the test agent is for the restraining effect of various cancer cells, and the result sees table 1.
Compound provided by the invention 1, compound 2, compound 3, compound 4 hydrochlorides; Shown the good restraining effect shown in above-mentioned pharmacological tests to tumour; Show different pharmacological actions at different tumour cell (S) with (R) simultaneously, declaratives pharmacological action and configuration have very important relation.
The restraining effect of table 1 compound 1 and 2 pairs of tumour cells of compound
Show that like above-mentioned pharmacological tests The compounds of this invention has shown good antitumor action, as antineoplastic agent, for prevention, treatment disease, it is effective particularly disposing cancer.When compound of the present invention is used for such purposes, can be made into the carrier that the significant quantity that contains The compounds of this invention and pharmacy allow or the preparation of vehicle.
Use the administration form of The compounds of this invention as antineoplastic agent; Can select various forms, for example can enumerate the per os preparation of tablet, capsule, pulvis, granule or liquor etc. or for example solution or suspension-s etc. sterilization aqueous non-per os preparation, injection, suppository, ointment etc.
The solid preparation can directly be made with the form of tablet, capsule, granule or powder, but also can use the suitable additive manufacturing.As such additive; For example can enumerate the carbohydrate of lactose or glucose etc.; The starch based of corn, wheat or rice etc. for example; The for example synthetic macromolecule of inorganic salt, for example Vinylpyrrolidone polymer or the polyalkylene glycol etc. of lipid acid, for example metasilicic acid magnesium aluminate or the anhydrous ca phosphate etc. of Triple Pressed Stearic Acid etc., the for example alcohols of the soap of calcium stearate or hard magnesium etc., for example Stearyl alcohol or benzylalcohol etc., for example the synthetic cellulose verivate of methylcellulose gum, CMC 99.5, TKK 021 or Vltra tears etc.; Other, common spendable additives such as gelatin, talcum, vegetables oil, Sudan Gum-arabic.
The solid preparation of these tablets, capsule, granule and powder etc. can contain 0.1～99% (w/w), preferably the effective constituent of 0.1～50% (w/w) usually.
Aqueous preparation can use used usually suitable additive at water, alcohols or for example in the aqueous preparation of VT 18, peanut oil, sesame wet goods vegetables oil, with form manufacturings such as suspension-s, syrup, injection, some drops.
Appropriate solvent when particularly conduct is with para-oral intramuscular injection, intravenous injection or hypodermic form administration; For example can enumerate distilled water for injection, normal saline solution, D/W, ethanol, polyoxyethylene glycol, liquid for intravenous injection (the for example aqueous solution of Hydrocerol A and Trisodium Citrate etc.) or electrolyte solution (drop intravenous injection and used for intravenous injection) etc., or these mixing solutions.
Except these in advance the dissolved injection, also can make the form of dissolved in use that is added with powder or suitable additive.These injection liquids can contain 0.1～20% (w/w), the effective constituent of 0.5～5% (w/w) preferably usually.
In addition, the formulation of the suspension agent of oral administration, syrup etc. can contain the effective constituent of 0.5～10% (w/w) usually.
The preferred dosage of The compounds of this invention can change according to the compsn kind of the kind of the compound that uses, cooperation, the weight that is suitable for frequency and the privileged site that should treat, the state of an illness, patient's age, doctor's diagnosis, the kind of tumour etc., but as target roughly; For example every day per 1 adult dosage, when oral administration, can be in 1～500mg scope; In addition; When non-oral administration, when intravenous injection, preferably every day is in 1～300mg scope.In addition, administration number of times with symptom and different, but 1 day was 1～2 time according to medication.In addition, the administration next day of also can using, at a distance from medication such as administration intermittently such as administrations on the two.
Claims (7)
1. the present invention is the compound of general formula [I] expression:
Or pharmacy acceptable salt or its prodrug,
In the formula:
R
1What represent is that S type or R type saturated cyclic are amino, alternatively by 1,2,3 or 4 R
1 aReplace;
R
1 aCan be Wasserstoffatoms, halogen, amino;
R
2That represent is Wasserstoffatoms, halogen, amino, cyanic acid, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl.Perhaps two R
2Group can be linked to be the naphthenic base or the Heterocyclylalkyl of 3,4,5,6 or 7 yuan of rings with the atom that is connected with them, and is replaced by 1,2 or 3 group that independently is selected from cyanic acid, halogen alternatively;
R
3What represent is Wasserstoffatoms, halogen, amino, cyanic acid.Perhaps two R
3Group can be linked to be the naphthenic base or the Heterocyclylalkyl of 3,4,5,6 or 7 yuan of rings with the atom that is connected with them, and is replaced by 1,2 or 3 group that independently is selected from cyanic acid, halogen alternatively;
A-B is amido linkage or ester bond;
D is a heteroaryl, alternatively by 1,2 or 3 R
4Replace;
E is a Heterocyclylalkyl, or heteroaryl, alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from halogen, cyanic acid and amino;
N is an integer from 0-4;
M is an integer from 0-2;
2. the compound of representing at general formula I I of the present invention:
Or pharmacy acceptable salt or its prodrug, in the formula:
R
1Be that a S type or R type saturated cyclic are amino, be selected from piperidyl, piperazinyl, pyrrolidyl, heterocyclic butane group and morpholinyl, each group optional the is by 1,2,3 or 4 R
1 aReplace;
R
1 aBe Wasserstoffatoms, halogen, amino, cyanic acid, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
D is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl or pyrazolyl, and alternatively by 1,2 or 3 R
4Replace;
E is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl, pyrazolyl 、 Dan oxazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, pyrazolopyrimidine base, quinolyl, isoquinolyl, quinazolyl, piperazinyl or morpholinyl, and alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from halogen, cyanic acid, amino, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
3. at the compound of general formula III of the present invention:
Or pharmacy acceptable salt or prodrug, wherein:
R
6And R
7Be independently selected from Wasserstoffatoms, cyanic acid, amino, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
R
8Be independently selected from Wasserstoffatoms, C
1-6Alkyl, C
2-6Hydroxyalkyl, C
2-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
D is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl or pyrazolyl, and alternatively by 1,2 or 3 R
4Replace;
E is selected from pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, isothiazolyl, imidazolyl 、 oxazolyl 、 isoxazolyl, triazolyl, pyrazolyl 、 Dan oxazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, pyrazolopyrimidine base, quinolyl, isoquinolyl, quinazolyl, piperazinyl or morpholinyl, and alternatively by 1,2 or 3 R
5Replace;
R
4And R
5Independently be selected from Wasserstoffatoms, halogen, cyanic acid, amino, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6The cyanogen substituted alkyl;
P is an integer from 1-2.
4. according to any one said compound of claim 1-3 or pharmacy acceptable salt or its prodrug, wherein compound 1, compound 2, compound 3 and compound 4 are its preferred structure:
5. a drug regimen comprises any one described compound of claim 1-4 or its pharmacy acceptable salt or prodrug and at least a pharmaceutically acceptable carrier.
6. any one described compound of claim 1-5 or its pharmacy acceptable salt or prodrug, preparation are used for treating the application of the medicine of tumor disease.
7. the described application of claim 6, its described application in the medicine of treatment tumor disease, it is right to comprise: white blood disease, lung cancer, liver cancer, colorectal carcinoma, neural cancer, melanoma, ovarian cancer, kidney prostate cancer and mammary cancer etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210031640XA CN102603712A (en) | 2012-02-14 | 2012-02-14 | S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application |
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Cited By (3)
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| CN104045632A (en) * | 2014-06-03 | 2014-09-17 | 辽宁大学 | Antitumor drugs benzodihydropyran(thiapyran)amide compounds and pharmaceutically acceptable salts, and preparation method and application thereof |
| WO2018187894A1 (en) * | 2017-04-10 | 2018-10-18 | 师健友 | Drug for treating tumor diseases, and having antibacterial, antivirus and anti-inflammatory effects |
| CN110467620A (en) * | 2019-08-30 | 2019-11-19 | 辽宁大学 | Novel S type or R type tetrahydronaphthalene amides compound and its pharmaceutically acceptable salt and preparation method and application |
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| CN102295635A (en) * | 2011-07-12 | 2011-12-28 | 辽宁大学 | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds |
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| CN104045632A (en) * | 2014-06-03 | 2014-09-17 | 辽宁大学 | Antitumor drugs benzodihydropyran(thiapyran)amide compounds and pharmaceutically acceptable salts, and preparation method and application thereof |
| WO2018187894A1 (en) * | 2017-04-10 | 2018-10-18 | 师健友 | Drug for treating tumor diseases, and having antibacterial, antivirus and anti-inflammatory effects |
| CN110467620A (en) * | 2019-08-30 | 2019-11-19 | 辽宁大学 | Novel S type or R type tetrahydronaphthalene amides compound and its pharmaceutically acceptable salt and preparation method and application |
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