CN1309719C - Derivative of phenylamide pyrimidine and application thereof - Google Patents
Derivative of phenylamide pyrimidine and application thereof Download PDFInfo
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- CN1309719C CN1309719C CNB200410014093XA CN200410014093A CN1309719C CN 1309719 C CN1309719 C CN 1309719C CN B200410014093X A CNB200410014093X A CN B200410014093XA CN 200410014093 A CN200410014093 A CN 200410014093A CN 1309719 C CN1309719 C CN 1309719C
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Abstract
The present invention relates to anilinopyrimidine derivates, a making technology, medicines using the substance as the active constituent and a method for treating cancer, etc. and diseases relevant to tyrosine kinase, especially Bcr-Abl. The anilinopyrimidine derivates can be used as drugs, and tyrosine kinase inhibition drugs are manufactured in order to reduce the action of the anilinopyrimidine derivates on warm-blooded animals, such as human beings.
Description
Technical field
The present invention and phenylamino pyrimidine derivatives, its preparation technology, adopt this material as the medicine of active ingredient, treatment such as cancer etc. and Tyrosylprotein kinase particularly the Bcr-Abl diseases associated method, as drug use and make Tyrosylprotein kinase to suppress the class medicine relevant to alleviate its effect institute to the warm-blooded animal such as the mankind.
Background technology
It is the key factor that cell is regulated that protein tyrosine kinase is confirmed to be.They are relevant with pathology with immunity, internal secretion and physiology of nervous system, and are considered to play an important role in the production process of many cancers.The tyrosine-kinase enzyme catalysis γ-phosphoryl from the transfer of ATP to proteinic tyrosine hydroxyl.It regulates many cellular activities, comprises differentiation, growth, metabolism and withered.
Protein tyrosine kinase has been represented a protein Superfamily changeable and that enlarge rapidly, comprises transmembrane receptor Tyrosylprotein kinase and soluble cell matter enzyme, and soluble cell matter enzyme is also referred to as nonreceptor tyrosine kinase.Acceptor proteinoid Tyrosylprotein kinase has the film of striding topology, and it is widely studied.Think that at present specific aglucon combines the phosphorylation of having brought out receptor dimerization and tyrosine residues with the zone, extracellular of receptor protein tyrosine kinase.In the cell, i.e. tenuigenin, non-receptor protein tyrosine kinase can be a protein tyrosine kinase by generalized definition, they do not comprise the hydrophobic diaphragm area of striding.According to this broad sense classification, known cytoplasm protein Tyrosylprotein kinase can be divided into four kinds of different shapes: SRC family, FES family, JAK family and ABL family.There is difference in their bulk molecule structure, but except having identical catalysis kinases zone, these different cytoplasm protein Tyrosylprotein kinases also have identical non-catalytic zone.
The ABL proto-oncogene comprises the protein with tyrosine kinase activity usually.This activity is strengthened in the cell that carries the bcr-abl fusion gene.
BCR-ABL protein Tyrosylprotein kinase carcinogenic protein may be by enzymic activity variation and/or change non-covalent protein-protein interaction and change cellular form.The gene that the BCR-ABL carcinogenic protein is encoded is a kind of chimeric oncogene, this chimeric oncogene is (the Kurzock et al. that is produced to No. 22 chromosomal BCR sequence transpositions by the sequence in the cABL protein tyrosine kinase on No. 9 karyomit(e), 1988, N.Enql.J.Med.319:990-998, Rosenberg et al., 1988, Adv.in Virus Res.35:39-81).The leukemoid parthenogenetic reproduction of BCR-ABL oncogene and Philadelphia chromosome (Ph@1) positive human has close relation.That is to say, in 90% to 95% the former leukemia of chronic marrow (CML) case, found Ph@l karyomit(e), CML be a kind of clone cancer that produces by the hemopoietic stem cell vicious transformation (Fialkow et al., 1977, Am.J.Med.63:125-130); Simultaneously in the former leukemia of acute marrow (AML) adult patients of about 20% acute lymphoblastic leukemia (ALL) adult patients, 5% ALL child patient and 2%, discovery (Whang-Peng et al., 1970, Blood 36:448-457 are arranged also; Look, A.T., 1985, Semin.Oncol.12:92-104).The BCR-ABL gene can produce P210 BCR-ABL or two kinds of chimeric proteins of P185 BCR-ABL, and this is respectively the feature of CML and ALL.And, prove directly that recently the BCR-ABL gene product is paathogenic factor (Skorski et al., 1993, the J.Clin Invest.92:194-202 of CML; Snyder etal., 1993, Blood 82:600-605).
Known two kinds of main ber-abl transposition forms have two kinds of different bcr-abl in conjunction with feature at present.A transposition appears between bcr exon 2 and the abl exon 2, and another appears at (Shivelman et al., Cell 47,277-284 (1986)) between bcr exon 3 and the abl exon 2.Two classes are in conjunction with being called as " L-6 " (or " b2a2 ") and " K-28 " (or " b3a2 ") combination respectively.Different bcr-abl exon and abl encoding sequence engage and have caused two kinds of different bcr-abl fusion albumen, a kind ofly comprise that another kind does not comprise by 25 amino acid of bcr exon 3 codings.Can detect one or both this combinations (Shtivelman et al., Blood 69,971 (1986)) in the positive CML patient's body of Ph@1.
Comprise the phenylamino pyrimidine derivatives example that has analog structure with this invention in the following patent: EP0564409, WO 9509847, WO 9509851, WO 9509852, WO 9509853, WO 0222597.
Summary of the invention
The object of the present invention is to provide a class can suppress the active phenylamino pyrimidine derivatives of Tyrosylprotein kinase.
Another object of the present invention provides uses the prepared medicinal preparations of such phenylamino pyrimidine derivatives.
Further aim of the present invention provides such phenylamino pyrimidine derivatives in preparation treatment former leukemia of chronic marrow (granulocyte leukemia) and acute lymphoblastic leukemia, the application in the medicine of gastrointestinal stromal tumors.
The phenylamino pyrimidine derivatives of finding general structure (I) at present is a class novel cpd, has the specific drugs characteristic and can suppress the activity of Tyrosylprotein kinase such as the activity of BCR-ABL Tyrosylprotein kinase, and the activity of other receptor tyrosine kinase such as PDGF.And has certain animal activity in vivo.Based on described characteristic, this compounds is suitable for Bcr-Abl male cancer and tumor treatment, as leukemia [former leukemia of particularly chronic marrow (granulocyte leukemia) and acute lymphoblastic leukemia are because find to have special action apoptosis mechanism]; Subgroup to leukemic stem cells also has effect, and has at these cells of purging in vitro and after removing cancer cells after having extractd above-mentioned cell (as extracing marrow) and carry out the latent effect that cell is replanted (as replanting the medullary cell of purification); (GIST) also has effect to gastrointestinal stromal tumors.General formula (I) compounds can not only use as being used for the treatment of small cell lung cancer as tumor inhibitor; can also be used for the treatment of non-malignant proliferation imbalance as arteriosclerosis, thrombus, psoriasis, scleroderma and cystic fibrosis; and can also be used to protect the hematotoxicity effect of stem cell as antagonism such as chemotherapeutics such as 5-fluor-uracil, can also be used for the treatment of asthma.It can be used in particular for treating the disease that pdgf receptor kinase inhibitor is had response.
The present invention is the phenylamino pyrimidine derivatives relevant with general formula (I)
Wherein
X is oxygen or sulphur;
Y is direct key, oxygen, nitrogen or lower paraffin hydrocarbons;
Z is an aliphatics, cycloaliphatic, aromatic series or heterocyclic group;
R
1It is heterocyclic group;
R
2Be hydrogen, halogen, lower halogenated alkane, lower paraffin hydrocarbons or lower alkoxy;
R
3Be hydrogen or low basic alkane;
R
4Be the oxo lower alkyl amino, low alkyl group oxo lower alkyl amino, oxo heterocycle base, low alkyl group oxo heterocycle base, oxo low alkyl group heterocyclic radical, low alkyl group oxo low alkyl group heterocyclic radical, low-grade halogenated alkyl amino, the low-grade halogenated alkyl heterocyclic radical, amino low-grade alkyl amino, lower alkyl amino low-grade alkyl amino, amino-heterocycles base, the lower alkyl amino heterocyclic radical, amino low alkyl group heterocyclic radical or lower alkyl amino low alkyl group heterocyclic radical;
Or its pharmacy acceptable salt.
Detailed introduction of the present invention:
The present invention is directly about a class new compound, they can suppress Tyrosylprotein kinase, especially Bcr-Abl Tyrosylprotein kinase and use these compounds and the restraining effect of Tyrosylprotein kinase is treated in the auxilliary newborn animal tumprigenicity or hyperplasia or chronic inflammation or the transplantability disease that the generation by too much or unsuitable Tyrosylprotein kinase causes.
In compound structure general formula (I) formula,
X is oxygen or sulphur, preferably oxygen;
Y is direct key, oxygen, and nitrogen or lower paraffin hydrocarbons, preferably NH or directly key are exactly that Y does not exist;
Z is an aliphatics, cycloaliphatic, aromatic series or heterocyclic group; Contain one or more ring nitrogen and 0,1 or 2 separate heteroatoms is selected from the group that contains oxygen and sulphur respectively; Preferably non-replacement or by hydrogen, rudimentary halogen alkyl, low alkyl group, lower alkoxy or cyanogen;
R
1It is heterocyclic group; Preferably contain one or more ring nitrogen and 0,1 or 2 separate heteroatoms is selected from the group that contains oxygen and sulphur respectively, this group is by non-replacement, and is mono-substituted or polysubstituted; 3 or 4 pyridines of preferably non-replacement or replacement;
R
2Be hydrogen; Halogen, preferably fluorine or chlorine; Rudimentary halogen alkyl, preferably trifluoromethyl; Low alkyl group, preferably methyl or ethyl; Or lower alkoxy, preferably methoxy or ethoxy;
R
3Be hydrogen or low alkyl group, preferably hydrogen;
R
4Be the oxo lower alkyl amino, low alkyl group oxo lower alkyl amino, oxo heterocycle base, low alkyl group oxo heterocycle base, oxo low alkyl group heterocyclic radical, low alkyl group oxo low alkyl group heterocyclic radical, low-grade halogenated alkyl amino, the low-grade halogenated alkyl heterocyclic radical, amino low-grade alkyl amino, lower alkyl amino low-grade alkyl amino, amino-heterocycles base, the lower alkyl amino heterocyclic radical, amino low alkyl group heterocyclic radical or lower alkyl amino low alkyl group heterocyclic radical;
Best R
4Be:
(a) the non-replacement of oxo low alkyl group, the single replacement or two substituted-amino; Oxo low alkyl group morpholinyl, oxo low alkyl group pyrrolidyl, oxo low alkyl group piperidyl, oxo low alkyl group piperazinyl, oxo low-grade alkyl amino pyridyl, oxo-pyrrolidine base, oxo-piperidine base;
(b) the non-replacement of low alkyl group oxo low alkyl group, the single replacement or two substituted-amino, low alkyl group oxo low alkyl group morpholinyl, low alkyl group oxo low alkyl group pyrrolidyl, low alkyl group oxo low alkyl group piperidyl, low alkyl group oxo low alkyl group piperazinyl, low alkyl group oxo low-grade alkyl amino pyridyl, low alkyl group oxo-pyrrolidine base, low alkyl group oxo-piperidine base;
(c) the non-replacement of rudimentary two fluoro-alkyls, the single replacement or two substituted-amino, rudimentary two fluoro-alkyl morpholinyls, rudimentary two fluoro-alkyl pyrrolidyls, rudimentary two fluoro-alkyl piperidyls, rudimentary two fluoro-alkyl piperazinyls, rudimentary two fluoro-alkyl aminopyridine bases, rudimentary two fluoro-alkyl pyrrolidyls, rudimentary two fluoro-alkyl piperidyls;
(d) the non-replacement of amino low alkyl group, the single replacement or two substituted-amino; Amino low alkyl group morpholinyl, amino low alkyl group pyrrolidyl, amino low alkyl group piperidyl, amino low alkyl group piperazinyl, amino low-grade alkyl amino pyridyl, amino-pyrroles alkyl, amino piperidine base;
(e) the non-replacement of lower alkyl amino low alkyl group, the single replacement or two substituted-amino; Lower alkyl amino low alkyl group morpholinyl, lower alkyl amino low alkyl group pyrrolidyl, lower alkyl amino low alkyl group piperidyl, lower alkyl amino low alkyl group piperazinyl, lower alkyl amino low-grade alkyl amino pyridyl, lower alkyl amino pyrrolidyl, lower alkyl amino piperidyl;
Or its pharmaceutically acceptable salt, preferably mesylate.
" halogen " is not meant fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine if this vocabulary illustrates in addition here.
" low-grade halogenated alkyl " explanation is not meant the alkyl that 1 to 6 halogen replaces, for example trifluoromethane if this vocabulary has in addition here.
" rudimentary alkyl " explanation is not meant that carbonatoms is 1 to 6 saturated alkyl if this vocabulary has in addition here, it can be (comprising monocycle and many rings) straight chain, Cheng Huan or the alkyl that side chain is arranged in other words, including, but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl and analogue thereof.
" rudimentary alkoxyl group " explanation is not meant-the rudimentary alkyl of O-that rudimentary alkyl is same as above here if this vocabulary has in addition here.
" aliphatics " if this vocabulary here not in addition explanation be not meant that at least five carbon atoms preferably are no more than 22 carbon atoms, be no more than ten carbon atoms usually, comprise replacement or the best alkynes of non-replacement, alkene is alkane group preferably, for example C
5-C
7Alkane, example such as Skellysolve A.
" cycloaliphatic " do not reach two ten monocycle replacement or best non-replacement or the dicyclos that especially reach ten carbon atoms if this vocabulary has explanation in addition to be meant to contain here, as cycloalkyl group, especially five yuan or hexavalent cycloalkyl group, example such as hexanaphthene.
" oxo lower alkyl amino " if this vocabulary does not have in addition explanation to be meant here to be contained-group of O-low alkyl group-N wherein nitrogen by low alkyl group, aliphatics, the non-replacement of cycloaliphatic base, the single replacement or two replacement, low alkyl group, aliphatics, cycloaliphatic is same as above; Example is as-OCH
2CH
2NHCH
3
" low alkyl group oxo lower alkyl amino " if the group that this vocabulary does not have in addition explanation to be meant here contains low alkyl group-O-low alkyl group-N wherein nitrogen by low alkyl group, aliphatics, the non-replacement of cycloaliphatic base, the single replacement or two replacement, low alkyl group, aliphatics, cycloaliphatic is same as above; Example is as-CH
2OCH
2CH
2NHCH
3
" lower halogenated alkylamino " is not meant by 1 to 6 halogen replacement lower alkyl amino if this vocabulary here illustrates in addition, preferably replaced by fluorine or chlorine, group wherein nitrogen by low alkyl group, aliphatics, the non-replacement of cycloaliphatic base, single replacement or two replacement, low alkyl group, aliphatics, cycloaliphatic is same as above; Example is as-CF
2NHCH
3
" aryl " if this vocabulary here not in addition explanation be meant that an organic group removes deriving of hydrogen and comes from aromatic hydrocarbon.Phenyl or naphthyl for example, they can not have substituting group, and a substituting group is arranged, and two substituting groups or three substituting groups are arranged.Substituting group can be selected from more following groups: halogen, rudimentary haloalkyl, rudimentary alkyl, rudimentary thiazolinyl, rudimentary alkynyl, cyano group, rudimentary alkane cyano group; Hydroxyl, rudimentary alkane hydroxyl, rudimentary alkoxyl group, rudimentary alkyl alkoxy, rudimentary alkoxyalkoxy group, rudimentary alkyl alkoxyalkoxy group, rudimentary alkoxy amino, rudimentary alkoxy amino alkyl, rudimentary alkoxy amino dialkyl group, rudimentary alkyl alkoxy amino, rudimentary alkyl alkoxy aminoalkyl group, the amino dialkyl group of rudimentary alkyl alkoxy; Rudimentary alcoxyl acyl alkyl, carboxyl, acyloxyalkyl group; Rudimentary alkyl alcoxyl acyl alkyl, carboxyl, acyloxyalkyl group; Amino, carbamyl, ammonia acyloxy, urea groups; Lower alkyl amino, carbamyl, ammonia acyloxy, urea groups; N-is single to replace or N the disubstituted amino of N-, carbamyl, urea groups, sulfydryl, sulfo group; Carbonylic alkyl, rudimentary alkyl-carbonyl alkyl; Cycloalkyl, cycloalkenyl group, phenyl ring, phenoxy group, benzene sulfydryl, the alkyl thiol that phenyl is rudimentary, rudimentary alkylbenzene sulfydryl, rudimentary alkyl sulfinyl, benzene sulfinyl, the alkyl sulfinyl that phenyl is rudimentary, rudimentary alkyl phenyl sulfinyl, rudimentary alkane alkylsulfonyl, benzenesulfonyl, the alkyl sulphonyl that phenyl is rudimentary, rudimentary benzene sulfonamide acyl group, heterocycle; Aromatic nucleus comprises an aromatic nucleus and a cycloaliphatic ring multiviscosisty, as the ring of saturated or fractional saturation: example such as tetrahydric naphthalene ring.
" heterocyclic radical " is not meant non-aromatic ring, monocycle and condensed ring if this vocabulary illustrates in addition here, and each ring has four heteroatomss at most.Each heteroatoms can be independent O, N and S, and each ring can not have substituting group or three substituting groups are arranged at most.Each heterocycle can be 4 yuan of ring to 7 yuan rings, preferably 5 yuan are encircled or 6 yuan of rings, each heterocyclic group can have carbocyclic ring but a heterocycle saturated or fractional saturation must be arranged, heterocycle comprises monocycle, dicyclo or trinucleated heteroaromatic ring system, best is a ring or two rings, and heterocyclic atom is selected from O, N and S.Each ring can have 4～7, preferably 5 or 6 annular atomses.Dicyclo or three-loop system can comprise a carbocyclic ring, carbocyclic ring can be a cycloalkyl, cycloalkenyl group or aryl, the example of heterocyclic radical comprises: tetramethyleneimine, pyrrolidone, piperidines, piperidone, piperazine, morpholine, imidazolidine, pyrazolidine and glycolylurea, the pyrroles, indoles, pyrazoles, the indoles azoles, triazole, benzotriazole, imidazoles, benzoglyoxaline, thiophene, thionaphthene, thiazole, benzothiazole, furans, cumarone, oxazole, benzoxazoles, isoxzzole, tetrazolium, pyridine, pyrimidine, three pyridines, quinoline, isoquinoline 99.9, quinazoline, indoline, dihydroindolone, the benzo tetrahydrofuran (THF), tetrahydroquinoline, tetrahydroisoquinoline, benzo (methylenedioxy) ring.Heterocycle can be replaced by the selected property of the aryl substituent of above definition ground.
" oxo heterocycle base " if this vocabulary here not in addition explanation be meant and contain-the O-heterocyclic radical that oxygen is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, heterocyclic radical defines as mentioned above.Example is as-O-piperidyl.
" low alkyl group oxo heterocycle base " if this vocabulary here not in addition explanation be meant and do not contain low alkyl group-O-heterocyclic radical, oxygen is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, low alkyl group and heterocyclic radical definition are as mentioned above. example is as-CH
2The O-piperidyl.
" oxo low alkyl group heterocyclic radical " if the not other here explanation of this vocabulary is meant contains-O-low alkyl group heterocyclic radical, oxygen is to be replaced on the low alkyl group, low alkyl group is replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, and low alkyl group and heterocyclic radical definition are as mentioned above. and example is as-CH
2OCH
2-piperidyl.
" low alkyl group oxo low alkyl group heterocyclic radical " contains low alkyl group-O-low alkyl group heterocyclic radical if the not other explanation of this vocabulary is meant here, oxygen is to be replaced between the low alkyl group, low alkyl group is replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, and low alkyl group and heterocyclic radical definition are as mentioned above. and example is as-CH
2OCH
2-piperidyl.
" junior alkyl halides heterocyclic radical " explanation is not meant the low alkyl group heterocyclic radical that is replaced by 1 to 6 halogen if this vocabulary has in addition here, is preferably replaced by fluorine or chlorine, and low alkyl group and heterocyclic radical definition are as mentioned above; Example is as-CF
2-piperazine and-CF
2CH
2-piperazine.
" amino lower alkyl amino " if the not other here explanation of this vocabulary is meant contains-N
1-low alkyl group-N
2The wherein amino N of group
1By hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, amino N
2By low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, and aliphatics or cycloaliphatic definition are as mentioned above.; Example is as-NHCH
2CH
2NHCH
3
" lower alkyl amino lower alkyl amino " contains low alkyl group-N if the not other explanation of this vocabulary is meant here
1-low alkyl group-N
2The wherein amino N of group
1By hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, amino N
2By low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, and aliphatics or cycloaliphatic definition are as mentioned above.; Example is as-CH
2NHCH
2CH
2NHCH
3
" amino-heterocycles base " if the not other here explanation of this vocabulary is meant contains-the N-heterocyclic radical, nitrogen is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, amino nitrogen is by hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, the definition of aliphatics cycloaliphatic or heterocyclic radical is as mentioned above. and example is as-NH-piperidyl.
" lower alkyl amino heterocyclic radical " contains low alkyl group-N-heterocyclic radical if the not other explanation of this vocabulary is meant here, nitrogen is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, amino nitrogen is by hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, the definition of aliphatics cycloaliphatic or heterocyclic radical is as mentioned above. and example is as-CH
2The NH-piperidyl.
" amino low alkyl group heterocyclic radical " if the not other here explanation of this vocabulary is meant contains-N-low alkyl group heterocyclic radical, nitrogen is to be replaced on the low alkyl group, low alkyl group is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, amino nitrogen is by hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, and the definition of aliphatics cycloaliphatic or heterocyclic radical is as mentioned above. and example is as-NHCH
2CH
2-piperidyl.
" lower alkyl amino low alkyl group heterocyclic radical " contains low alkyl group-N-low alkyl group heterocyclic radical if the not other explanation of this vocabulary is meant here, nitrogen is to be replaced between the low alkyl group, low alkyl group is to be replaced in that any position preferably is replaced in ring carbon atom on the heterocycle, amino nitrogen is by hydrogen, low alkyl group, aliphatics or cycloaliphatic replace, low alkyl group, and the definition of aliphatics cycloaliphatic or heterocyclic radical is as mentioned above. and example is as-CH
2NHCH
2CH
2-piperidyl.
External and activity in vivo detects
Tyrosylprotein kinase inhibition effect can detect with reference to following document in several bodies: E.Andrejauskas et al., CancerResearch 52,5353-5358 (1992), Trinks et al., J.Med.Chem.37,1015-27 (1994), N.Lydonet al., Oncogene Research 5,161-173 (1990) and J.F.Geissler et al., Cancer Research 52,4492-8 (1992).The inside and outside is active, and also detect can reference: Coutre P.et al., Journal of the NationalCancer Institute 91 (2), 163-168 (1990). and concrete operations step and result are as follows:
1. experiment in vitro
Contain 4 * 10
4The cell strain of two hectolambdas (KU812, MC3 and U937) solution injects in the little valency template of six group of 96 groove of The compounds of this invention (0.1-10 micromole different concns), 37 ℃, after 54 hours, adds the RPMI-1640/10%FCS that 20 microlitres contain thymidine in every groove.After 18 hours, harvested cell also is transferred to a strainer, and tritium is examined and determine by Beta-plate liquid scintillation counter for the picked-up of thymidine.IC
50Be defined as test-compound and compare the concentration that causes that the cell growth descended at 50% o'clock with the blank group.The result shows that The compounds of this invention has the inhibition activity of nmole (nM) to micromole (μ M) scope.
2. animal model in the body
Test-compound and tween 80,0.5%CMC are mixed into suspension.Select healthy female white mouse (17-19g) for use.Give every mouse subcutaneous injection cell strain (KU812, MC3 and U937), 50 * 10
6All mouse (n=12) are divided into experimental group and control group at random.After 1-8 days, the mouse of experimental group is pressed predetermined dose oral administration thing once by every day behind the implantation tumour cell strain.Self administration of medication played per 3 days with vernier caliper measurement tumour major diameter a (mm) same day, reached perpendicular tumour minor axis b (mm), gross tumor volume formula V (mm
3)=(a * b
2Calculate)/2.Per 3 days weighing mouse body weight, neck execution animal is taken off in inoculation back two after all around, weigh, and dissects and gets the knurl piece, claims knurl heavy, and the result judges according to following formula:
The result shows that The compounds of this invention has the tumor control rate of 30%-95% (knurl is heavy, volume) scope and is subjected to examination group experiment front and back no obvious body weight change mostly.
The compound of general structure (I) can use separately or with one or more therapeutical agent compatibilities, compatibility is treated available fixed form or is staggered with the compound among the present invention and one or more therapeutical agents and uses or independently a kind of use, or with fixed compatibility and the use of one or more therapeutical agent compatibilities.The compound of structure (I) is not limited to, especially in the oncotherapy with chemotherapy, radiotherapy, operation or with the use of the mixed phase compatibility of these means.Aforesaid way is according to the situation of therapeutic modality, and long-term treatment is identical possible with adjuvant treatment.Other possible treatment is the identity that keeps patient behind the tumour regression, or even the chemoprophylaxis treatment, for example, patient assumes full responsibility for risks.
Compound of the present invention not only is used for the mankind and is used for other warm-blooded animal, for example commercial useful animal.This compound can be used as reference standard and the contrast of other compound in experiment described above.
Salt is general structure (I) pharmacy acceptable salt especially.Pharmacy acceptable salt to the people who is proficient in this art be clearly and comprise that those are described in J.Pharm.Sci., 1977,66,1-19, the acid additive salt that forms with mineral acid for example, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid; Organic acid, as succsinic acid, toxilic acid, acetic acid, fumaric acid, Citric Acid, tartrate, oxalic acid, phenylformic acid, Phenylsulfonic acid, methylsulfonic acid or naphthene sulfonic acid.Mesylate preferably wherein.Also may use other salt, for example isolated or purified structure (I) and comprising belongs to the compound in the scope of the invention.
Compound of the present invention may be xln or noncrystal, if arbitrarily hydration or water-soluble of crystal.This invention has comprised its scope stoichiometric calculation hydrate, the water that this compounds has uncertain amount.
The present invention extends to the isomeric forms of compound in all general structures (I), steric isomer and geometrical isomer, comprise enantiomorph and its mixture, as raceme. different isomeric forms can separate or splits with ordinary method, specified isomer can with conventional synthetic method special space is synthetic or asymmetric synthesis or enzyme catalysis synthesize obtain.
The medicament preparation
Can prepare and the relevant non-toxic precursors medicine of general structure (I) compound with various manual methods.The people who is proficient in this art can recognize that equally a variety of nontoxic solvents can be used for dissolving the compound of discovery, water for example, ethanol, inorganic oil, vegetables oil, methyl-sulphoxide.
Compound with general structure (I) can be by the mode of suction, spraying or rectum, and the outer drug administration by injection of per os, part or intestines, the composition of medicine should be convenient nontoxic suitable medium thing, adjuvant and vehicle.Peroral administration formulation is tablet, capsule, elixir, syrup, lozenge etc.Here the outer injecting method of used intestines comprises in subcutaneous injection, the skin, technology is similarly injected or inculcated to (for example intravenously), intramuscular in the blood vessel, backbone, intrathecal injection or other.In addition, compound and the suitable carrier that provides a kind of combination to comprise general structure (I) here.One or more compounds with general structure (I) should have a kind of oral formulation that is fit to, for example suspension, loose powder or the particulate of tablet, medicament, lozenge, water or oil, emulsion, hard or soft capsule, syrup or elixir.
Be used for oral medicine and can adopt any known pharmaceutical methods production, medicine should comprise more than one following selected composition: sweeting agent, essence, pigment and sanitas can provide the finished product of an exquisiteness like this.Tablet comprises activeconstituents, and tablet is the mixture that contains nontoxic suitable vehicle, and these vehicle make that tablet is easy to produce.These vehicle can be inert diluents, for example lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granular and disintegrating agent such as W-Gum or alginic acid; Tackiness agent is starch, gelatin for example; Lubricant such as Magnesium Stearate, stearic acid and talcum.Tablet is dressing or dressing not, and well-known packaging technique has been postponed medicine in GI disintegration and absorption, makes it keep activity in long-time, and these postpone material such as glyceryl monostearate or the distearin etc. that decompose.
Being used for oral formulation can be the capsule that hard gelatin is made, its activeconstituents is blended in the inert solid diluent, for example lime carbonate, calcium phosphate or kaolin, or soft its activeconstituents of gelatin capsule is blended in water or the oily medium, for example peanut oil, whiteruss or sweet oil.Manufacturing comprises the waterborne suspension of activeconstituents and uses the vehicle that is fit to make usefulness.These vehicle are for example Xylo-Mucine, sodium carboxymethylcellulose pyce, hydrogen propyl methocel sodium, sodiun alginate, Povidone, tragcanth and gum arabics of suspension agent; Dispersion agent and wetting agent should be a kind of phosphatide that forms naturally, for example Yelkin TTS; Or the enriched material of lipid acid and alkylene oxide compound, for example polyoxyethylene stearic acid ester; Or have the ethylene oxide enriched material of long-chain fat family alcohol, for example 17 carbon vinyloxy grouies, 16 alcohol; Or the derivative polyoxyethylene sorbitol for example of part ester in ethylene oxide and lipid acid and the hexitol; Or ethylene oxide and the part ester that from lipid acid and hexitan, derives, for example polyoxyethylene sorbitol.Waterborne suspension should comprise one or more sanitass equally, and for example vinyl, n-propyl, para hydroxybenzene phenol also should comprise one or more pigments, one or more essence and one or more sweeting agents such as sucrose or asccharin.
The formation of oily suspensions is that activeconstituents is suspended in the vegetables oil, for example peanut oil, sweet oil, sesame oil, Oleum Cocois or as the mineral oil of whiteruss.Oily suspensions should have thickening material, for example beeswax, solid paraffin, hexadecyl ethanol.Above-mentioned sweeting agent and seasonings should be added in the good to eat oral patent medicine of regulation.These compositions should reach the rot-resistant purpose by adding antioxidant such as Vc.
Loose powder and particle are added some powder or wet medicament, suspension medicament and at least a sanitas through the suspension that water forms, and the mixture of making can provide active substance.Concrete suitable powder, humectant and suspension preamble listed, and the other additive also can be added as sweeting agent, essence, pigment or the like.
This new the effective elements of the medicine also can make the form of emulsion, and finish can be selected rape oil (as sweet oil, fatty alcohol) or mineral oil (as whiteruss) for use.Suitable emulsifying agent is the latex that nature forms, as gum arabic, tragcanth; Naturally form phosphatide such as soybean, Yelkin TTS and from lipid acid, derive and the ester class of coming; Acid anhydride is sorbitol for example.If this emulsion also can sweeting agent and essence.
Syrup and fragrance are produced by sweeting agent, and sweeting agent can be glycerine, 1,2-propylene glycol, Sorbitol Powder or sucrose.The medicament of this class also can add sustained release dosage, sanitas, essence and pigment.
This new the effective elements of the medicine can also be made suppository, is applicable to rectum and vagina.Stype is mixed by medicine and non-irritating forming agent.This forming agent is solid at normal temperatures, then becomes liquid in the temperature of rectum or vagina, and stype has just melted and discharged the property of medicine like this.This type of raw material comprises theobroma oil and polyoxyethylene glycol.
This medicine also can make aseptic, injectable watery or oily suspension.Suitable powder or humectant and solution formation that this suspension can adopt known technology to use preamble to mention.This aseptic injectable finished product also can be aseptic diluent or solution, for example 1,3-butanediol solution.Adoptable vehicle and solvent are the sodium hydroxide solution of water, Ringer's solution and isotonicity, and aseptic in addition solid-state finish is used as solvent or suspension medium usually.Any non-irritating solid finish that comprises artificial glyceryl ester or triglyceride all generally is suitable for.The lipid acid that resembles this class of oleic acid in addition helps injecting this kind medicine.
The human that this kind medicine also can be proficient in this art is in through subcutaneous injection (Chien:WO 94/04157).
The compound of general structure (I) can use without enteron aisle by sterile carrier.Attached to suspending or be dissolved in the carrier on the carrier and through spissated medicine, advantageously some adjuvants such as local anesthetic, sanitas, buffer reagent also can be dissolved in the carrier.
If be used on one's body the animal, this medicine can be added in the food and water of animal.Medicine must be convenient to combine with the diet of animal, to such an extent as to just can take in suitable medicine the animals eat thing time.If medicine is made a kind of thing that is pre-mixed just is more convenient for being added in water and the food.
Here in the usage of being spoken of about the compound of general structure (I), the taking dose of every day preferably according to body weight from 0.01mg/Kg to 200mg/Kg.The injected dose of every day comprises that intravenous injection, intramuscular injection, subcutaneous injection and injection of non-enteron aisle and bowel lavage art etc. need according to whole body weight from 0.01mg/Kg to 200mg/Kg.The local consumption of every day preferably one to four time from 0.01mg to 200mg every day.Preferably keep one day metering at 0.01-200mg/Kg through the enriched material of subcutaneous use.The amount of suck using every day best according to body weight from 0.01mg/Kg to 200mg/Kg.
Certainly also can use different dosage for special patient, this depends primarily on following factors: concrete effective constituent, age, body weight, healthy state, sex, appetite, medicine time, medicining mode, excretion rate, medication taboo.
Better this compounds should have some pharmacological characteristics, and these characteristics comprise oral bioavailability rate, hypotoxicity, low serum protein solidifiability and vivo and vitro transformation period and other preferably.
Analytical method can be used for predicting needed pharmacology attribute.The method that is used to predict bioavailability comprises by monolayer cell in the human body intestines transports, as the Caco-2 monolayer cell.The check of artificial liver cell toxicity can be used for the toxicity of predictive compound.This compound can be by detecting after breadboard this medicine of animal intravenous injection to the influence of blood viscosity.
The serum protein degree of adhesion can be predicted by the analysis of protein degree of adhesion.Correlation analysis can be commented on referring to Oravcova.
The transformation period of compound and the frequency of taking are inversely proportional to.Vitro half-lives can be by external metabolic transformation period analyses and prediction, and raw material can change and increase some steps to make this compound, can prove by following example.
Overall preparation method
Preparation general rule of the present invention is described in reaction formula 1-11.Expert personage will find that from following example starting raw material may change, and prepare compound of the present invention and may use more step.
Reaction formula 1
4-hydroxybenzene benzyl ester and various aminoalkyl group alcohol, amino cycloalkyl alcohol, heterocyclic amino alcohols is carried out the Mitsunobu reaction and is formed ehter bond under DEAD (azo-dicarboxylate) catalysis, and benzyl is removed formation free acid intermediate and is provided with the afterreaction use under hydrogenation conditions.
Reaction formula 2
Various aminoalkyl group alcohol, amino cycloalkyl alcohol, heterocyclic amino alcohols generates sulfonyl ester in 50 ℃-150 ℃ with the Tosyl chloride reaction under alkaline condition, generate ehter bond with the reaction of 4-hydroxybenzene benzyl ester then under DMF neutral and alkali condition, benzyl is removed formation free acid intermediate and is provided with the afterreaction use under hydrogenation conditions.
Reaction formula 3
Generate 4-(2 '-bromine) acetylbenzene benzyl ester behind 4-acetylbenzene benzyl ester and a part bromine reaction, generate carbonyl amine, this product (CH with various chain ammonia or ring ammonia react then
3OCH
2CH
2)
2NSF
3(Gauri S.Lal et al, J.Org.Chem.1999,64,7048-7054) fluoridize, benzyl is removed formation free acid intermediate and is provided with the afterreaction use under hydrogenation conditions then.
Reaction formula 4
The available above-mentioned chemical process preparation of compound (A) (US 5521184).Compound (B) is represented reaction formula 1,2, final intermediate in 3 is (A) with (B) at a part EDC[1-(3-dimethyl amine propyl group)-3-ethyl-carbodiimide hydrochloride] and HOBt (I-hydroxybenzotriazole) condition under the use appropriate solvent can obtain final product.
Reaction formula 5
When n was 0, the first step reaction can be used EDC described in reaction formula 4, and HOBt generates compound (C), and second step can carry out according to the reaction of the Mitsunobu described in the reaction formula 1.
Reaction formula 6
More than reaction can be with reference to the carrying out described in the reaction formula 2, and is identical in compound (C) and the reaction formula 5.
Reaction formula 7
Aminoalkyl tolysulfonyl ester can make from aminoalkyl oxy-compound and Tosyl chloride under alkaline condition; carrying out ammonia then replaces; methylate or the Boc-acidylate, hydrogenation is gone benzyl to form the free acid intermediate and is provided with the afterreaction use again, and reduction amination also can be used for preparing secondary amine.
Reaction formula 8
4-hydroxymethyl-benzoic acid benzyl ester is by SOCl
2Being replaced hydrogenation then by all kinds of ammonia after the chlorination goes benzyl formation free acid intermediate to be provided with the afterreaction use.
R and R ' they can be hydrogen, low alkyl group, and aliphatics, cycloaliphatic or heterocyclic radical, low alkyl group, aliphatics cycloaliphatic or heterocyclic radical are described as defined above.
Reaction formula 9
4-carboxaldehyde radicals phenylformic acid and (A) acidylate at first carry out all polyamines then and carry out reduction amination and must need product, these products can further methylate or protection earlier after its derivative of preparation that methylates again.
Reaction formula 10
Bromination again after starting raw material is fluoridized earlier produces further derivative with various amine reactions then, becomes carboxylic acid to carry out acylation reaction with (A) again after the hydrolysis and gets final product.
Reaction formula 11
Initial aldehyde and potassium cyanide are made solvent with acetic acid and are generated cyanogen secondary alcohol compound; fluoridize then be hydrolyzed into the fluorochemical acid amides be reoxidised into uncle ammonia; last become piperazine fluorochemical free acid intermediate with the cyclization of dichloro diethylamine hydrochloride, Boc is provided with the afterreaction use after to amido protecting.
Compound among the following general formula I I, but not only be confined to this can be with the method preparation that is similar to described in the reaction formula 1-reaction formula 11.
R
1Be: 3-pyridine or 4-pyridine R
2Be: 4-CH
3, 4-F, 4-Cl; 5-CH
3, 5-F, 5-Cl; 6-CH
3, 6-F, 6-Cl; 2-CH
3, 2-F, 2-Cl; Or H,
R
4Be following (R=H, CH
3):
(-----be the position that replaces with phenyl ring)
R
4Be:
R
4Be:
Or its pharmacy acceptable salt, and mesylate is for preferably selecting.
Embodiment
In some cases, some active groups are necessary to be protected to finish these chemical reactions, and it is very tangible needing on these protecting group or deprotection base for expert personage.And for expert personage, use different solvent or reagent also can finish these chemical reactions.
Disclosed all articles and reference comprise that patent is the reference section of whole document in this piece application form.
Example below this invention will utilize is explained that further this is not to be interpreted as described those steps and the scope of only limiting to.
All embodiment all can be prepared into pharmacy acceptable salt for expert personage.
The starting raw material of this invention and various intermediate can have been bought, and perhaps can use the commodity feedstock production, or use well-known synthetic method preparation.
Some representational methods that prepare this invention intermediate will be disclosed in the following embodiments.
Below some abbreviations be used in this article, other be the standard chemical formula.
EtOH: ethanol
RT: room temperature
TEA: triethylamine
EDCl:1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
The HOBt:1-hydroxy benzotriazole hydrate
EtOAc: ethyl acetate
THF: tetrahydrofuran (THF)
MeI: methyl iodide
DIEA: diisopropylethylamine
DMSO: dimethyl sulfoxide (DMSO)
Eq: equivalent
G: gram
Ml: milliliter
TLC: thin-layer chromatography
DEAD: diethyl azodiformate
DCM: methylene dichloride
Boc: tert-butoxycarbonyl
All following examples all can be prepared into pharmacy acceptable salt for expert personage, and mesylate is for preferably selecting.
Preparation I:N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (A)
At 0 ℃, nitric acid (the 4.6ml of slow dropping 65% in ethanol (20ml) suspension solution of 10.0g (0.065mol) 2-amino-4-nitrotoluene, 0.065mol) and stirred 10 minutes, cyanamide (8.32g, 0.198mol) aqueous solution (5ml) adds in this reaction mixture and refluxed 25 hours, be cooled to 0 ℃ and filtration, get 2-methyl-5-nitro phenyl-guanidine nitrate after the washing.
To 2-methyl-5-nitro phenyl-guanidine nitrate (25g, 96mmol) with 3-dimethylamino-1-(3-pyridyl)-2-propenyl-1-ketone (17g, 96mmol) in the mixture of Virahol (200ml), add sodium hydroxide (4.5g), stir this reaction and reflux and be cooled to 0 ℃ in 12 hours then, filtering-depositing also gets N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE with washed with isopropyl alcohol.
With N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (1.5g, 4.6mmol) and palladium charcoal (150mg, 10%) in the suspension normal pressure hydrogenation of ethyl acetate (100ml) two hours.Filter this reaction, evaporated filtrate gets N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (A), is not further purified to be used for the step down.
Preparation II:(4-hydroxy phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base)-amino] phenyl } methane amide (Z)
Add EDC (12.5mmol) and HOBt (10mmol) to 4-hydroxy-benzoic acid (10mmol) with (A) in the mixture of (10mmol) and DMF (40ml).Stirring at room should be reacted four hours, DCM (100ml) dilution. wash this mixture three times, Na
2SO
4Dry.This solution rotating evaporation, the residue column chromatography purification gets title compound (Z).
Embodiment 1
[4-(2-ammonia oxyethyl group) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
To N-Boc-monoethanolamine (160mg, 1mmol) with (4-hydroxy phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide is [(z), 0.85mmol] with the mixture of DCM (25ml) in add DEAD (40% toluene solution, 1.2mmol) stirred four hours down in RT. use the DCM extracting twice after adding water, blended organic layer washing back saturated common salt water washing, Na
2SO
4Dry.This solution decompression is evaporation down, the residue column chromatography purification gets [4-(2-Boc-ammonia oxyethyl group) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base)-amino] phenyl } methane amide, this compound and 4N HCl/ dioxan mix to be incorporated under the RT and stirred two hours.Behind this reactive evaporation with NaHCO
3The solution mixing is also used the EtOAc extracting twice.Blended organic layer washing back saturated common salt water washing, Na
2SO
4Dry. decompression gets title compound after the evaporation down.Mass spectrum: (M+1), 441
Embodiment 2
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } 4-[(1-methylpyrrolidin-3-yl) and amino] phenyl } methane amide
(4-nitrophenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2--amino] phenyl } methane amide is prepared according to preparation II described similar step, wherein uses 4-nitrobenzoyl acid substitution 4-hydroxy-benzoic acid.
Above-mentioned nitro-compound in ethanol under palladium charcoal (10%) catalysis normal pressure hydrogenation one hour and use diatomite filtration, filtrate and NaBHCN (1.3eq) and 1-methyl-3-pyrrolidone (1eq) mixes to be incorporated in to stir under the RT and spends the night, reduction vaporization should react, and the residue purification by silica gel column chromatography gets title compound.Mass spectrum: (M+1), 480
Embodiment 3
[4-(fluorine piperazine methyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
In the mixture of-78 ℃ 4-hydroxymethyl-benzoic acid ethyl esters (5mmol) and DCM (25ml), add (CH
3OCH
2CH
2)
2NSF
3(5.5mmol), this is reflected at-78 ℃ of stirrings and pours saturated NaHCO into after two hours
3In the solution, and the DCM extracting twice (2 * 30ml), dry (Na
2SO
4) back reduction vaporization get residue and get 4-methyl fluoride ethyl benzoate with purification by silica gel column chromatography.
4-methyl fluoride ethyl benzoate (2mmol) is mixed in CCl with NBS (2.3mmol)
4(20ml), six hours postcooling of this reaction backflow get residue to RT and reduction vaporization, and purification by silica gel column chromatography gets 4-fluorine bromomethyl-benzoic acid ethyl ester then.
The mixture of 4-fluorine bromomethyl-benzoic acid ethyl ester (1mmol) and N-Boc-piperazine (1.5mmol) and EtOH stir and be heated to 50 ℃ two hours.This reaction reduction vaporization gets residue and gets 4-fluoro-N-Boc-piperazine methyl ethyl benzoate with purification by silica gel column chromatography.This product got 4-fluoro-N-Boc-piperazine methyl phenylformic acid in two hours with 2N NaOH (1.3eq) RT hydrolysis in the EtOH solvent.
Title compound prepares gained according to the embodiment 1 described similar Boc of taking off protection and post-processing step then according to the described similar step of preparation II is prepared then.Mass spectrum: (M+1), 498
This compound and two molecular ratio methylsulfonic acids are mixed in the ethanol, and heating is cooled off to such an extent that crystallization is mesylate.
Embodiment 4
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } 4-[(1-methylpyrrolidin-2-yl) and methoxyl group] phenyl } methane amide
Title compound is prepared according to embodiment 1 described similar step, wherein uses 1-methylpyrrolidin-2-yl) methyl alcohol replacement N-Boc-monoethanolamine.Mass spectrum: (M+1), 495
Embodiment 5
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(tetramethyleneimine-3-base is amino) phenyl] methane amide
(4-nitrophenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } prepared according to the described similar step of preparation II, wherein use 4-nitrobenzoyl acid substitution 4-hydroxy-benzoic acid.
Above-mentioned nitro-compound in ethanol under the catalysis of palladium charcoal normal pressure hydrogenation one hour and use diatomite filtration, filtrate and NaBHCN (1.3eq) and 1-benzyl-3-pyrrolidone (1eq) mixes to be incorporated in to stir under the RT and spends the night, reduction vaporization should react, and the residue purification by silica gel column chromatography gets N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(N-benzyl-pyrrole alkane-3-base is amino) phenyl] methane amide.This compound in ethanol under palladium charcoal (10%) catalysis 50psi hydrogenation spend the night, filter, evaporate title compound.Mass spectrum: (M+1), 466
Embodiment 6
[4-(amino methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 3 described similar steps, wherein replaces the N-Boc-piperazine with ammonia/methanol solution.Mass spectrum: (M+1), 429
Embodiment 7
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(methylpyrrolidin-3-base is amino) phenyl] methane amide
Carry out reduction amination by intermediate N prepared among the embodiment 5 { 4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(N-benzyl-pyrrole alkane-3-base is amino) phenyl] methane amide and HCHO/NaBHCN (1.5eq), then in ethanol under palladium charcoal (10%) catalysis 50psi hydrogenation spend the night, filter, evaporate title compound.Mass spectrum: (M+1), 480
Embodiment 8
4-[fluorine (4-methylpiperazine base) methyl) phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 3 described similar steps, and wherein N methyl piperazine replaces the N-Boc-piperazine.Mass spectrum: (M+1), 512
Embodiment 9
[4-(amino difluoromethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 3 and 6 described similar steps, wherein replaces 4-hydroxymethyl-benzoic acid ethyl ester with 4-carboxaldehyde radicals methyl benzoate.Mass spectrum: (M+1), 447
Embodiment 10
4-[methyl (1-methylpyrrolidin-3-yl) amino] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 7 products therefroms through with HCHO/NaBHCN (1.5eq) reduction amination after title compound.Mass spectrum: (M+1), 494
Embodiment 11
(4-{ fluorine [(1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 6 products therefroms through with N-methyl-3-pyrrolidone/NaBHCN (1.1eq) reduction amination after title compound.Mass spectrum: (M+1), 512
Embodiment 12
4-[fluorine (methylpyrrolidin-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 6 products therefroms through with 1-benzyl-3-pyrrolidone/NaBHCN (1.1eq) reduction amination after { 4-[fluorine (benzyl-pyrrole alkane-3-base amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl methane amide.This product through with HCHO/NaBHCN (1.5eq) reduction amination after, then in ethanol under palladium charcoal (10%) catalysis 50psi hydrogenation spend the night, filter, evaporate title compound.Mass spectrum: (M+1), 512
Embodiment 13
[4-({ [2-(dimethylamino) ethyl] amino } methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 3 described similar steps, wherein uses N, and the N-dimethyl-ethylenediamine replaces the N-Boc-piperazine.Mass spectrum: (M+1), 500
Embodiment 14
[4-(difluoro piperazine methyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 3 described similar steps, wherein replaces 4-hydroxymethyl-benzoic acid ethyl ester with 4-carboxaldehyde radicals methyl benzoate.Mass spectrum: (M+1), 516
Embodiment 15
4-[difluoro (4-methylpiperazine) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 14 described similar steps, wherein replaces the 4-Boc-piperazine with the 4-methylpiperazine.Mass spectrum: (M+1), 530
Embodiment 16
[4-({ [2-(dimethylamino) ethyl] amino } difluoromethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 14 described similar steps, wherein uses N, and the N-dimethyl-ethylenediamine replaces the 4-Boc-piperazine.Mass spectrum: (M+1), 518
Embodiment 17
(4-{ fluorine [methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 11 products therefroms through with HCHO/NaBHCN (1.5eq) reduction amination after title compound.Mass spectrum: (M+1), 526
Embodiment 18
4-[fluorine (tetramethyleneimine-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 12 gained intermediates { 4-[fluorine (benzyl-pyrrole alkane-3-base amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl methane amide in ethanol under palladium charcoal (10%) catalysis 50psi hydrogenation spend the night, filter, evaporate title compound.Mass spectrum: (M+1), 498
Embodiment 19
4-[(4-ethyl piperazidine base) and difluoromethyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 14 products therefroms warp and CH
3Get title compound behind CHO/NaBHCN (1.5eq) reduction amination.Mass spectrum: (M+1), 544
Embodiment 20
4-[(4-ethyl piperazidine base) and methyl fluoride] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
From embodiment 3 products therefroms warp and CH
3Get title compound behind CHO/NaBHCN (1.5eq) reduction amination.Mass spectrum: (M+1), 526.
Embodiment 21
(4-{ difluoro [methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 17 described similar steps from embodiment 9 products therefroms.Mass spectrum: (M+1), 544
Embodiment 22
4-[difluoro (methylpyrrolidin-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 12 described similar steps from embodiment 9 products therefroms.Mass spectrum: (M+1), 530
Embodiment 23
[4-({ [2-(dimethylamino) ethyl] amino } methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 11 described similar steps from embodiment 9 products therefroms.Mass spectrum: (M+1), 530
Embodiment 24
4-[difluoro (tetramethyleneimine-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 8 described similar steps from embodiment 9 products therefroms.Mass spectrum: (M+1), 516
Embodiment 25
(4-{[methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Replace the 4-hydroxy-benzoic acid according to preparation II 4-that described similar step is used (BOC-aminomethyl) phenylformic acid, slough the Boc protecting group with the 4NHCl/ dioxan then and get [4-(aminomethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide.
Title compound is prepared according to embodiment 21 described similar steps, wherein uses [4-(aminomethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide replaces from embodiment 9 products therefroms.Mass spectrum: (M+1), 508
Embodiment 26
{ 4-(methylpyrrolidin-3-base is amino) aminomethyl phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 22 described similar steps, wherein uses [4-(aminomethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide replaces from embodiment 9 products therefroms.Mass spectrum: (M+1), 494
Embodiment 27
(4-{[(1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 23 described similar steps, wherein uses [4-(aminomethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide replaces from embodiment 9 products therefroms.Mass spectrum: (M+1), 494
Embodiment 28
{ 4-(tetramethyleneimine-3-base is amino) aminomethyl phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Title compound is prepared according to embodiment 24 described similar steps, wherein uses [4-(aminomethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide replaces from embodiment 9 products therefroms.Mass spectrum: (M+1), 480
Claims (7)
1. the compound of following general structural formula (I):
Wherein
X is oxygen or sulphur;
Y is direct key;
Z is single replacement, two replacement or three phenyl ring or the naphthalene nucleus that replaces; Substituting group can be selected from following group:
Halogen, 1 to 6 alkyl that halogen replaces, rudimentary alkyl, rudimentary thiazolinyl, rudimentary alkynyl, cyano group, rudimentary alkane cyano group, hydroxyl, rudimentary alkane hydroxyl, rudimentary alkoxyl group, rudimentary alkyl alkoxy, rudimentary alkoxyalkoxy group, rudimentary alkyl alkoxyalkoxy group, rudimentary alkoxy amino, rudimentary alkoxy amino alkyl, rudimentary alkoxy amino dialkyl group, rudimentary alkyl alkoxy amino, rudimentary alkyl alkoxy aminoalkyl group, the amino dialkyl group of rudimentary alkyl alkoxy, rudimentary alcoxyl acyl alkyl, carboxyl, acyloxyalkyl group, rudimentary alkyl alcoxyl acyl alkyl, amino, carbamyl, the ammonia acyloxy, urea groups, lower alkyl amino, N-is single to be replaced or N, the disubstituted amino of N-, carbamyl, urea groups, sulfydryl, sulfo group, carbonylic alkyl, rudimentary alkyl-carbonyl alkyl, cycloalkyl, cycloalkenyl group, phenyl ring, phenoxy group, the benzene sulfydryl, the alkyl thiol that phenyl is rudimentary, rudimentary alkylbenzene sulfydryl, rudimentary alkyl sulfinyl, the benzene sulfinyl, the alkyl sulfinyl that phenyl is rudimentary, rudimentary alkyl phenyl sulfinyl, rudimentary alkane alkylsulfonyl, benzenesulfonyl, the alkyl sulphonyl that phenyl is rudimentary, rudimentary benzene sulfonamide acyl group, heterocyclic radical;
R
1It is heterocyclic group; Heterocyclic group is meant non-aromatic ring, monocycle or condensed ring, and each ring has four heteroatomss at most; Each heteroatoms can be independent O, N or S, and each ring can not have substituting group or three substituting groups are arranged at most; Each heterocycle can be 4 yuan of ring to 7 yuan rings, and each heterocyclic group can have carbocyclic ring but a heterocycle saturated or fractional saturation must be arranged, and heterocycle comprises monocycle, dicyclo or trinucleated heteroaromatic ring system; Each ring can have 4～7 annular atomses; Dicyclo or three-loop system can comprise a carbocyclic ring, and carbocyclic ring can be cycloalkyl, cycloalkenyl group or aryl; Heterocyclic radical comprises: tetramethyleneimine, pyrrolidone, piperidines, piperidone, piperazine, morpholine, imidazolidine, pyrazolidine, glycolylurea, the pyrroles, indoles, pyrazoles, the indoles azoles, triazole, benzotriazole, imidazoles, benzoglyoxaline, thiophene, thionaphthene, thiazole, benzothiazole, furans, cumarone, oxazole, benzoxazoles, isoxzzole, tetrazolium, pyridine, pyrimidine, three pyridines, quinoline, isoquinoline 99.9, quinazoline, indoline, dihydroindolone, the benzo tetrahydrofuran (THF), tetrahydroquinoline, tetrahydroisoquinoline, benzo (methylenedioxy) ring; R
1Can be by the replacement of the selected property of the substituting group of the Z of above-mentioned definition;
R
2It is low alkyl group;
R
3Be hydrogen;
R
4Be:
(a) the non-replacement of oxo low alkyl group, the single replacement or two substituted-amino; Oxo low alkyl group morpholinyl, oxo low alkyl group pyrrolidyl, oxo low alkyl group piperidyl, oxo low alkyl group piperazinyl, oxo low-grade alkyl amino pyridyl, oxo-pyrrolidine base, oxo-piperidine base;
(b) the non-replacement of low alkyl group oxo low alkyl group, the single replacement or two substituted-amino, low alkyl group oxo low alkyl group morpholinyl, low alkyl group oxo low alkyl group pyrrolidyl, low alkyl group oxo low alkyl group piperidyl, low alkyl group oxo low alkyl group piperazinyl, low alkyl group oxo low-grade alkyl amino pyridyl, low alkyl group oxo-pyrrolidine base, low alkyl group oxo-piperidine base;
(c) the non-replacement of rudimentary two fluoro-alkyls, the single replacement or two substituted-amino, rudimentary two fluoro-alkyl morpholinyls, rudimentary two fluoro-alkyl pyrrolidyls, rudimentary two fluoro-alkyl piperidyls, rudimentary two fluoro-alkyl piperazinyls, rudimentary two fluoro-alkyl aminopyridine bases, rudimentary two fluoro-alkyl pyrrolidyls, rudimentary two fluoro-alkyl piperidyls;
(d) the non-replacement of amino low alkyl group, the single replacement or two substituted-amino; Amino low alkyl group morpholinyl, amino low alkyl group pyrrolidyl, amino low alkyl group piperidyl, amino low alkyl group piperazinyl, amino low-grade alkyl amino pyridyl, amino-pyrroles alkyl, amino piperidine base;
(e) the non-replacement of lower alkyl amino low alkyl group, the single replacement or two substituted-amino; Lower alkyl amino low alkyl group morpholinyl, lower alkyl amino low alkyl group pyrrolidyl, lower alkyl amino low alkyl group piperidyl, lower alkyl amino low alkyl group piperazinyl, lower alkyl amino low-grade alkyl amino pyridyl, lower alkyl amino pyrrolidyl, lower alkyl amino piperidyl;
Above-described rudimentary be that carbon 1 is to carbon 6;
Or its acceptable salt pharmaceutically.
2. the compound of following general structural formula (II):
General formula I I
R
1Be: 3-pyridine or 4-pyridine
R
4Be following (R=H, CH
3): R
2Be: 4-CH
3,
(-----be the position that replaces with phenyl ring)
R
4Be:
R
4Be:
Or its pharmacy acceptable salt.
3. according to the compound of the general structure (I) of claim 1, be selected from:
[4-(2-ammonia oxyethyl group) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } 4-[(1-methylpyrrolidin-3-yl) and amino] phenyl } methane amide
[4-(fluorine piperazine methyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } 4-[(1-methylpyrrolidin-2-yl) and methoxyl group] phenyl } methane amide
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(tetramethyleneimine-3-base is amino) phenyl] methane amide [4-(amino methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } [4-(methylpyrrolidin-3-base is amino) phenyl] methane amide
4-[fluorine (4-methylpiperazine base) methyl) phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
[4-(amino difluoromethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide 4-[methyl (1-methylpyrrolidin-3-yl) amino] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
(4-{ fluorine [(1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[fluorine (methylpyrrolidin-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
[4-({ [2-(dimethylamino) ethyl] amino } methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
[4-(difluoro piperazine methyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[difluoro (4-methylpiperazine) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
[4-({ [2-(dimethylamino) ethyl] amino } difluoromethyl) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
(4-{ fluorine [methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[fluorine (tetramethyleneimine-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[(4-ethyl piperazidine base) and difluoromethyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[(4-ethyl piperazidine base) and methyl fluoride] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
(4-{ difluoro [methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[difluoro (methylpyrrolidin-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
[4-({ [2-(dimethylamino) ethyl] amino } methyl fluoride) phenyl]-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
4-[difluoro (tetramethyleneimine-3-base is amino) methyl] phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
(4-{[methyl (1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
{ 4-(methylpyrrolidin-3-base is amino) aminomethyl phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
(4-{[(1-methylpyrrolidin-3-yl) amino] methyl } phenyl)-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
{ 4-(tetramethyleneimine-3-base is amino) aminomethyl phenyl }-N-{4-methyl-3-[(4-(3-pyridyl) pyrimidine-2-base) amino] phenyl } methane amide
Or its pharmacy acceptable salt.
According to compound any in the claim 1 to 3 prepared be the salt of methylsulfonic acid.
5. according to any one prepared a kind of pharmaceutically acceptable salt of compound in the claim 1 to 3, said pharmaceutically acceptable salt is and hydrochloric acid Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid; Succsinic acid, toxilic acid, acetic acid, fumaric acid, Citric Acid, tartrate, phenylformic acid, the salt that Phenylsulfonic acid or naphthene sulfonic acid form.
6. according to any one prepared medicament of compound in the claim 1 to 3, said medicament is said tablet on any pharmaceutics, capsule, elixir, syrup, lozenge, inhalation, sprays, injection, film, patch, powder, granule, piece agent, emulsion, suppository, compound preparation.
7. any one purposes of compound in the medicine of the former leukemia of the preparation chronic marrow of treatment, acute lymphoblastic leukemia, gastrointestinal stromal tumors disease in the claim 1 to 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410014093XA CN1309719C (en) | 2004-02-18 | 2004-02-18 | Derivative of phenylamide pyrimidine and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410014093XA CN1309719C (en) | 2004-02-18 | 2004-02-18 | Derivative of phenylamide pyrimidine and application thereof |
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| Publication Number | Publication Date |
|---|---|
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| CN1309719C true CN1309719C (en) | 2007-04-11 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
-
2004
- 2004-02-18 CN CNB200410014093XA patent/CN1309719C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
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| Publication number | Publication date |
|---|---|
| CN1560050A (en) | 2005-01-05 |
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