CN100566712C - The polyamine compounds that is used for the treatment of chemokine receptor mediated disease - Google Patents
The polyamine compounds that is used for the treatment of chemokine receptor mediated disease Download PDFInfo
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- CN100566712C CN100566712C CNB2004800150889A CN200480015088A CN100566712C CN 100566712 C CN100566712 C CN 100566712C CN B2004800150889 A CNB2004800150889 A CN B2004800150889A CN 200480015088 A CN200480015088 A CN 200480015088A CN 100566712 C CN100566712 C CN 100566712C
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Abstract
The present invention relates to a kind of method for the treatment of inflammatory diseases or immune disease, developmental character or degenerative disease or tissue injury.Described method comprises the chemical compound of one or more following formulas of the individual effective dose that needs it: each variable-definition in (seeing right formula) this formula is in description.
Description
The cross reference of related application
According to 35USC § 119 (e), the application requires the priority of U.S. Provisional Application of submitting on April 2nd, 2,003 60/459,768 and the U.S. Provisional Application of submitting on January 28th, 2,004 60/539,763, and the content of these two pieces of patent applications is incorporated herein by reference.
Background technology
Chemotactic factor belongs to cytokine family, its leukocytic adhesion of adjusting and through migration (Mackay C.R., Nat.Immunol., (2001) 2:95 of endothelium in immunity and inflammatory reaction; Olson etc., Am.J.Physiol.Regul.Integr.Comp.Physiol., (2002) 283:R7).Chemotactic factor is also regulated the migration of T cell and B cell, and the growth (Ajuebor etc., Biochem.Pharmacol., (2002) 63:1191) that promotes lymphocyte generation system and hemopoietic system.About 50 kinds of chemotactic factors in human body, have been identified.Position based on the conservative cysteine residues of N-end can be divided into them four subfamilies, i.e. CXC, CX3C, CC and C chemotactic factor (Onuffer etc., Trends Pharma Col Sci., (2002) 23:459).The biological function of chemotactic factor is that the g protein coupled receptor (GPCR) by their combinations and activating cell surface is mediated.With the CXCR4 receptor is example, and it can be activated by a member stroma cell derivative factor-1 or the SDF-1 of CXC chemotactic factor.
SDF-1 is at first by marrow stromal cell clone, and finds its somatomedin as ancestral B cell work (Nishikawa etc., Eur.J.Immunol., (1988) 18:1767).SDF-1 also induces the bone marrow of hemopoietic forebody cell to build group (Bleul etc., J.Exp.Med., (1996) 184:1101) in the embryo is taken place.The physiological function of SDF-1 is mediated by the CXCR4 receptor.The mice that lacks SDF-1 or CXCR4 receptor shows lethal unusual (Nagasawa etc., Nature (1996) 383:635 in the formation of bone marrow myelocyte, the formation of B cell lymphocyte and cerebellum development; Ma etc., Proc.Natl.Acad.Sci., (1998) 95:9448; Zou etc., Nature (1998) 393:595; Lu etc., Proc.Natl.Acad.Sci. (2002) 99:7090).The CXCR4 receptor is wide expression in multiple tissue, and particularly in immune system and central nervous system, and to have described it be the main accessory receptor (co-recepter) of HIV-1/2 on the T lymphocyte.Though the interest to the CXCR4 antagonism focuses on it at first to (Bleul etc. in the potential application of AIDS treatment, Nature (1996) 382:829), but know gradually that at present CXCR4 receptor and SDF-1 also participate in other pathological condition, as rheumatoid arthritis, asthma and neoplasm metastasis (Buckley etc., J.Immunol., (2000) 165:3423).Also find CXCR4 receptor and SDF-1 in fetal development in a lot of tissues wide expression.In addition, shown that the CXCR4/SDF-1 approach plays a key role in the regeneration of several tissue injurys model.Particularly, the level of having found the SDF-1 of damage location raises and the CXCR4 positive cell plays an active part in the tissue regeneration process.
Summary of the invention
The present invention is based on this discovery, and promptly some polyamine compounds combines with chemokine receptors (for example CXCR3 or CXCR4 receptor) by them and treats inflammatory and immune disease effectively.
On the one hand, feature of the present invention is the polyamine compounds of following formula:
In following formula, X is-CH
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-C (O)-,-SO
2-or do not exist; Y is aryl, heteroaryl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl or C
5-C
8Heterocycloalkenyl; Z
1And Z
2Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH=CH-,-CH=N-,-CH=N-NR-,-S-,-O-,-NR-,-C (O)-or-SO
2-; R
1Be H, C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl, aryl or heteroaryl; R
2Be-A
1-B
1-D
1-E
1R
3Be-A
2-B
2-D
2-E
2, do not exist or and R
4Be C together
4-C
20Cycloalkyl, C
4-C
20Cycloalkenyl group, C
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl; Condition is if R
3Do not exist, then-Z
2-N-is-CH=N-; And R
4Be-A
3-B
3-D
3-E
3Or and R
3Be C together
4-C
20Cycloalkyl, C
4-C
20Cycloalkenyl group, C
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl.A
1, A
2And A
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-C
4H
8-,-C
5H
10-,-CH
2C (O)-,-C (O) CH
2-,-CH
2SO
2-,-SO
2CH
2-,-CH
2-CH=CH-,-CH=CH-CH
2-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-,-CH (CH
2COOR)-,-CH (C (O) NR
2)-or do not exist.B
1, B
2And B
3Independently be separately-NR-,-CH
2-or do not exist.D
1, D
2And D
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-C (O)-,-SO
2-,-C (O)-NR-,-C (S)-NR-,-NR-C (O)-,-NR-C (S)-,-CH (OR)-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-, 1,1-cyclopropylidene or do not exist.E
1, E
2And E
3Independent separately is H, C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl, aryl or heteroaryl.R independently is H or C separately
1-C
10Alkyl.
About following formula, just the subclass of the chemical compound of describing is such chemical compound, and wherein X is-CH
2-or-CH (CH
3)-, Y is phenyl or 4,4 '-xenyl, Z
1Be-CH
2-or-SO
2-, Z
2Be-CH
2-or-SO
2-, perhaps R
3Do not exist.
That term " alkyl " is meant is saturated, straight or branched, nonaromatic hydrocarbyl group, as CH
3,-CH
2-or side chain C
3H
7About following formula ,-C
2H
4-and-C
3H
6-can be straight or branched.Term " alkenyl " is meant straight or branched, nonaromatic hydrocarbyl group, and it has at least one two key, as-CH=CH
2Or-CH=CH-.Term " alkynyl " is meant straight or branched, nonaromatic hydrocarbyl group, and it has at least one triple bond, as-C ≡ CH or-C ≡ C-.Term " cycloalkyl " is meant saturated non-armaticity cyclic hydrocarbon group.Term " cycloalkenyl group " is meant non-armaticity cyclic hydrocarbon group, and it has at least one two key in ring.Term " Heterocyclylalkyl " is meant saturated non-armaticity cyclic group, and it has at least one ring hetero atom (for example O, N and S).Term " heterocycloalkenyl " is meant non-armaticity cyclic group, and it has at least one ring hetero atom and at least one two key in ring.Term " aryl " is meant the hydrocarbyl group with at least one aromatic ring.The example of aryl comprises phenyl, phenylene, xenyl, naphthyl, naphthylene, pyrenyl, anthryl and phenanthryl.Term " heteroaryl " is meant the group with at least one aromatic ring, and described aromatic ring contains at least one hetero atom.The example of heteroaryl comprises furyl, furylidene, fluorenyl, pyrrole radicals, thienyl, oxazolyl, imidazole radicals, thiazolyl, pyridine radicals, pyrimidine radicals, quinazolyl and indyl.
Alkyl mentioned in this article, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl comprise and replacing and unsubstituted group.The substituent example of cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl comprises C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
1-C
10Alkoxyl, aryl, aryloxy group, heteroaryl, heteroaryloxy, amino, C
1-C
10Alkyl amino, C
1-C
20Dialkyl amido, arylamino, ammonia diaryl base, heteroaryl amino, two heteroaryl aminos, C
1-C
10Alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, C
1-C
10Alkyl sulfonamide, aryl sulfonic acid amides, heteroaryl sulfonamide, hydroxyl, halogen, sulfydryl, C
1-C
10Alkyl thiol, aryl sulfydryl, cyano group, nitro, acyl group, acyloxy, carboxyl, acylamino-, carbamoyl and carboxylate.The substituent example of alkyl, alkenyl and alkynyl comprises the above-mentioned C of removing
1-C
10Alkyl, C
2-C
10Alkenyl and C
2-C
10All substituent groups outside the alkynyl.Cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl also comprise and condense group.
On the other hand, feature of the present invention is the polyamine compounds of phase cotype as implied above.About this formula, each variable representative and identical as mentioned above group are except X is-CH
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-SO
2-or do not exist; Y is aryl, heteroaryl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl or do not exist; D
1, D
2And D
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-SO
2,-C (O)-NR-,-C (S)-NR-,-NR-C (O)-,-NR-C (S)-,-CH (OR)-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-, 1,1-cyclopropylidene or do not exist; And E
1Be H, C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl, aryl, 5-unit heteroaryl, condensed heteroaryl, the 6-unit heteroaryl of replacement, unsubstituted pyranose, unsubstituted pyrazinyl, unsubstituted pyrimidine radicals or unsubstituted pyridazinyl.
About following formula, just the subclass of the chemical compound of describing is such chemical compound, and wherein X is-CH
2-or-CH (CH
3)-, Y does not exist, Z
1Be-CH
2-, perhaps Z
2Be-CH
2-.
On the other hand, feature of the present invention is the method for treatment inflammatory or immune disease, developmental character or degenerative disease or tissue injury.This method comprises the chemical compound of one or more phase cotypes as implied above of the individual effective dose that needs it.About this formula, X is-CH
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-C (O)-,-SO
2-or do not exist; Y is aryl, heteroaryl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl or do not exist; Z
1And Z
2Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH=CH-,-CH=N-,-CH=N-NR-,-S-,-O-,-NR-,-C (O)-or-SO
2-; R
1Be H, C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl, aryl or heteroaryl; R
2Be-A
1-B
1-D
1-E
1R
3Be-A
2-B
2-D
2-E
2, do not exist or and R
4Be C together
4-C
20Cycloalkyl, C
4-C
20Cycloalkenyl group, C
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl; Condition is if R
3Do not exist, then-Z
2-N-is-CH=N-; And R
4Be-A
3-B
3-D
3-E
3Or and R
3Be C together
4-C
20Cycloalkyl, C
4-C
20Cycloalkenyl group, C
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl.A
1, A
2And A
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-C
4H
8-,-C
5H
10-,-CH
2C (O)-,-C (O) CH
2-,-CH
2SO
2-,-SO
2CH
2-,-CH
2-CH=CH-,-CH=CH-CH
2-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-,-CH (CH
2COOR)-,-CH (C (O) NR
2)-or do not exist.B
1, B
2And B
3Independently be separately-NR-,-CH
2-or do not exist.D
1, D
2And D
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH
2-CH=CH-,-CH=CH-CH
2-,-C (O)-,-SO
2-,-C (O)-NR-,-C (S)-NR-,-NR-C (O)-,-NR-C (S)-,-CH (OR)-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-, 1,1-cyclopropylidene or do not exist.E
1, E
2And E
3Independent separately is H, C
1-C
10Alkyl, C
2-C
10Alkenyl, C
2-C
10Alkynyl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, C
5-C
8Heterocycloalkenyl, aryl or heteroaryl.R independently is H or C separately
1-C
10Alkyl.
For example, can suffer from the chemical compound of the individual following formula of disease as mentioned above, X is-CH in the formula
2-or-CH (CH
3)-, Y is a phenyl, 4,4 '-biphenyl or do not have Z
1Be-CH
2-or-SO
2-, Z
2Be-CH
2-or-SO
2-, perhaps R
3Do not exist.
" treatment " is meant the individuality that one or more polyamine compounds are suffered from disease as mentioned above, have the symptom of this disease or easily suffer from this disease tendency, its objective is the acquisition therapeutic effect, as curing, alleviate, improve, work, alleviate or preventing above-mentioned disease, its symptom or suffer from its tendency.
Inflammatory diseases is a feature with part or general, acute or chronic inflammatory disease.Example comprises inflammatory dermatosis (for example dermatitis, eczema, atoipc dermatitis, contact dermatitis, urticaria, necrotizing vasculitis, cutaneous vasculitis, allergic angiitis, acidophil myositis, polymyositis, dermatomyositis and eosinophilic fasciitis); Inflammatory bowel (for example clone disease and ulcerative colitis); Anaphylaxis pneumonopathy (for example hypersensitivity pneumonitis, eosinophilic pneumonia, delayed hypersensitivity, interstitial lung disease or ILD, idiopathic pulmonary fibrosis and the ILD relevant), asthma and allergic rhinitis with rheumatoid arthritis.
Immune disease with immune system send out should be excessively or deficiency be feature.Example comprises autoimmune disease (for example rheumatoid arthritis, psoriasis arthropathica, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, ankylosing spondylitis, systemic sclerosis and multiple sclerosis disease); Acute and chronic inflammation inflammatory diseases (for example systemic anaphylaxis or allergy, drug allergy, insecticide sting allergy, comprise the transplant rejection of allograft rejection and graft versus host disease); The Si Yegelun syndrome; The human immunodeficiency virus infection; Cancer (for example brain cancer, breast carcinoma, carcinoma of prostate, colon cancer, renal carcinoma, ovarian cancer, thyroid carcinoma, pulmonary carcinoma and hematopoietic system cancer); And neoplasm metastasis.
The developmental character disease is growth or the relevant disease of differentiation that causes afunction or function to obtain.The miopragia of degenerative disease general reference tissue or the change of minimizing.The example of developmental character or degenerative disease comprises Duchenne-Arandisease, Duchenne muscular dystrophy, parkinson and Alzheimer.Tissue injury can be caused by oxidative stress when apoplexy (for example ischemia-reperfusion or myocardial infarction), complement activation, transplant rejection, chemical drugs (for example mucosal tissue damage in alcohol-induced hepatic damage or the treatment of cancer), viral infection (for example relevant glomerular injury of hepatitis C infection) and mechanical force (for example athletic injury).The example of tissue injury comprises brain injury, heart and injury, hepar damnification, Skeletal muscle injury, kidney injury, injury of pancreas, injury of lung, skin injury and injury of gastrointestinal tract.
Also can give aforesaid polyamine compounds and one or more other therapeutic activity agent to the individuality that needs are treated above-mentioned disease simultaneously.The example of this therapeutic activity agent comprises steroidal or NSAID (non-steroidal anti-inflammatory drug), COX2 inhibitor, leukotriene receptor inhibitor, prostaglandin regulator, TNF regulator and immunosuppressant (for example cyclosporin A).Term " gives simultaneously " to be meant that identical time during treating or different time give polyamine compounds and one or more other medicine.
On the other hand, feature of the present invention is to strengthen the method that bone marrow derived cell migrates to blood.Described method comprises the chemical compound of one or more phase cotypes as implied above of the individual effective dose that needs it.About this formula, each variable representative and identical as mentioned above group.Term " bone marrow derived cell " is meant the cell that derives from bone marrow.The example of bone marrow derived cell includes but are not limited to CD34+ cell and CD133+ cell.
The pharmaceutical composition that comprises at least a above-mentioned polyamine compounds of effective dose and pharmaceutically acceptable carrier is also in model scope of the present invention.
Above-mentioned polyamine compounds comprises chemical compound itself, and their suitable salt, prodrug and solvate.For example, salt can be formed by the positive charge group (as amino) on anion and the polyamine compounds.Suitable anion comprises chlorine, bromine, iodine, sulfate radical, nitrate anion, phosphate radical, citrate, methanesulfonate, trifluoroacetic acid root and acetate.In addition, salt also can be formed by the negative charge group (as carboxylate radical) on cation and the polyamine compounds.Suitable cation comprises sodium ion, potassium ion, magnesium ion, calcium ion and ammonium cation such as tetramethyl ammonium.Polyamine compounds comprises that also those contain the salt of quaternary nitrogen atoms.The example of prodrug comprises ester and other pharmacy acceptable derivates, and when giving individuality with it, it can provide the active polyamine chemical compound.Solvate is meant the complex that is formed by active polyamine chemical compound and pharmacy acceptable solvent.The example of pharmacy acceptable solvent comprises water, ethanol, isopropyl alcohol, ethyl acetate, acetic acid and ethanolamine.
In addition, the application in the medicine of treatment is also within the scope of the invention as mentioned above in preparation to comprise the compositions of one or more aforesaid polyamine compounds that are used for the treatment of institute's disease and said composition.
One or more embodiments of the present invention have been elaborated in the specific embodiment below.It is clear that other features, objects and advantages of the present invention will become from this embodiment and claim.
Embodiment
What show below is example compound of the present invention, chemical compound 1-126:
Can comprise by means commonly known in the art that at the polyamine compounds described in the foregoing invention content part synthetic route as herein described prepares.
For example, can use sodium borohydride to carry out reduction reaction afterwards and prepare chemical compound 1-11 respectively by with three (2-amino-ethyl) amine and three normal corresponding aldehyde reactions.
In another example, can be with 1,4-dibromo xylene and two normal two (tertbutyloxycarbonyl aminoethyl) amine reactions.Use the hydrochloric acid reaction mixture subsequently, obtain intermediate 1,4-two [two (2-amino-ethyl) aminomethyl] benzene.This intermediate and four normal corresponding aldehyde compounds and sodium borohydride reaction can be obtained chemical compound 12-14.Perhaps, this intermediate and two normal pyridine-2-formaldehyde reactions with the sodium borohydride reaction, can be obtained chemical compound 15 then.Also can be with 1, other amines reaction of two (tertbutyloxycarbonyl aminoethyl) amine of 4-dibromo xylene and monovalent and monovalent.Chemical compound 56-57,65,66,68,80,86,91,93-95 and 106-109 can pass through this synthetic route, handle with hydrochloric acid, two normal corresponding aldehyde and sodium borohydride successively afterwards to prepare.In a similar fashion, chemical compound 49 can pass through 1, and two (2-pyridine imino group ethyl) amine reactions of the cyclam of three tertbutyloxycarbonyls of 4-dibromo xylene and monovalent protection and monovalent are used sodium borohydride to carry out reduction reaction afterwards and prepared.
In another example, can use following synthetic route synthetic compound 16-48,58-64,69-79,81-85,87-90,92,96-105,115,121,122,125 and 126.Two (tertbutyloxycarbonyl aminoethyl) amine reactions of 4-cyano-benzyl bromide and monovalent then with hydrochloric acid reaction, can be obtained two (2-amino-ethyl) amino-methyls of 4-[]-benzonitrile.This benzonitrile can be formed successively two (2-replacement-aminoethyl) amino-methyls of 4-[then with two normal aldehyde, sodium borohydride and diisobutyl reactive aluminum]-benzaldehyde.Can prepare the chemical compound of just having mentioned by corresponding amine, sodium borohydride and this benzaldehyde of salt acid treatment with monovalent successively then.Chemical compound 110,111,116,117,120,123 and 124 can be prepared by similar mode, except benzonitrile is handled with the ketone of the aldehyde of monovalent and monovalent.
In another example, can be with the amine reaction of 4-bromomethyl benzene sulfonyl chloride and monovalent, two (tertbutyloxycarbonyl aminoethyl) amine with monovalent react then.Then, after with the above-mentioned reactant mixture of salt acid treatment, obtain intermediate.Can prepare chemical compound 51-55 respectively by handling intermediate with corresponding aldehyde, handling with sodium borohydride afterwards then.Can use the step identical to prepare chemical compound 50,67,112 and 113, except handling the 4-bromomethyl benzene sulfonyl chloride with two normal two (tertbutyloxycarbonyl aminoethyl) amine with chemical compound 51-55.
In another example, can with the 4-cyanobenzaldehyde successively with the 2-methyl-2-ethylaminoethanol of monovalent, sodium borohydride and 2-(2-bromo-ethyoxyl)-tetrahydrochysene-pyrans reaction, the aminomethyl benzonitrile that obtains replacing.When removing the Pentamethylene oxide. protecting group, handle with the benzonitrile methylsulfonylization and with the 2-aminomethyl-pyridine successively.After the secondary amine that obtains was protected, the corresponding amine of available then diisobutyl aluminum, monovalent, sodium borohydride, trifluoromethanesulfonic acid (triflic acid) and salt acid treatment benzonitrile obtained chemical compound 114,118 and 119.
Synthetic thus polyamine compounds can be further purified by for example methods such as column chromatography, high performance liquid chromatography or recrystallization.
Other polyamine compounds can use other proper raw material by above synthetic route and other path of preparing known in the art.Said method also can comprise step in addition, this step this paper before or after the special step of describing, make final synthetic polyamine chemical compound to add or to remove suitable protecting group.In addition, multiple synthesis step can carry out with synthetic needed chemical compound with alternative order.Being used for the synthetic synthetic chemistry conversion of polyamine compounds (tranformations) and protecting group methodology (protect and go and protect) is well known in the art, and comprise for example following document described those: R.Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for OrganicSynthesis, John Wiley and Sons (1994); And L.Paquetee, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and the version after them.
The polyamine compounds that this paper mentions can comprise nonaromatic pair of key and one or more asymmetric center.Therefore, they can be used as racemate and racemic mixture, single enantiomer, single diastereomer, non-enantiomer mixture and cis or the generation of trans-isomerism form.All these isomeric form are contained.
The pharmaceutical composition that comprises at least a aforesaid polyamine compounds of effective dose and pharmaceutically acceptable carrier also within the scope of the present invention.In addition, the present invention includes the method for one or more polyamine compounds of effective dose being suffered from the individuality of the described disease of foregoing invention content part.The present invention comprises that also one or more polyamine compounds that give effective dose are used to strengthen the method that bone marrow derived cell migrates to blood." effective dose " is meant treating the individual amount that produces the needed active polyamine chemical compound of therapeutic effect.As recognized by those skilled in the art, effective dose will depend on treatment disease type, route of administration, excipient use and with the common probability of using of other treatment and change.
For putting into practice method of the present invention, can be with compositions with one or more polyamine compounds through parenteral, mouth, nose, rectum, part or suck (buccally) and give.As used herein, that term " parenteral " is meant is subcutaneous, in the Intradermal, intravenous, intramuscular, intraarticular, intra-arterial, synovial membrane, in the breastbone, in the sheath, in the damage zone or intracranial injection and other any suitable infusion techniques.
Sterile injectable can be solution or a suspension in nontoxic, parenteral acceptable diluent or solvent with compositions, as the solution in 1,3 butylene glycol.Operable acceptable carrier and solvent are mannitol, water, ringer's solution and isotonic sodium chlorrde solution.In addition, fixedly oil uses as solvent or suspension media (as synthetic monoglyceride or diglyceride) routinely.Fatty acid such as oleic acid and glyceride ester derivatives thereof, and the acceptable oil of natural pharmacy such as olive oil or Oleum Ricini, particularly their polyoxyethylene form is used to prepare injection.These oil solutions or suspension also can comprise long-chain alcohol diluent or dispersant, carboxymethyl cellulose or similar dispersant.Be generally used for the purpose that other surfactant commonly used of preparation of the acceptable solid of pharmacy, liquid or other dosage form such as Tweens or Spans or other similar emulsifying agent or bioavailability reinforcing agent also can be used for formulated.
The compositions of orally give can be any oral acceptable forms, comprises capsule, tablet, Emulsion and water suspension, dispersion and solution.Under the situation of tablet, carrier commonly used comprises lactose and corn starch.Typically also add lubricant such as magnesium stearate.For the capsule form of orally give, the diluent of use comprises lactose and dried corn starch.When giving water suspension or Emulsion, active component can or be dissolved in the oil phase with Emulsion or suspending agent mix suspending when oral.If necessary, can add some sweeting agent, correctives or coloring agent.
Nose can be according to the known technology preparation of field of pharmaceutical preparations with aerosol or composition for inhalation.For example, can use benzyl alcohol or other suitable antiseptic, the absorption enhancer, fluorocarbon and/or other solubilizing agent known in the art that strengthen bioavailability or dispersant that these preparation of compositions are formed in solution in the saline.
Having one or more active polyamine compound compositions also can give with the suppository form of rectally.
Carrier in the pharmaceutical composition must be " acceptable ", and it means active component compatible (and preferably can stablize this active component) in it and the compositions and individual harmless to what treated.One or more solubilizing agent useful as drug excipient are with the delivery of active polyamine compounds.The example of other carrier comprises colloidal silica, magnesium stearate, cellulose, sodium lauryl sulphate and D﹠amp; C Yellow#10.
Above-mentioned polyamine compounds is treated as mentioned above the effect of disease can carry out Preliminary screening (referring to embodiment 127) by in vitro tests, confirms by animal experiment and clinical trial then.Other method also will be clearly for those of ordinary skills.
Following specific embodiment is only made illustration usefulness, and limits other parts of the present disclosure never in any form.Do not need further elaboration, believe that those skilled in the art can maximally utilise the present invention based on the description of this paper.All publications that this paper quotes all are incorporated herein by reference with their full content.
Embodiment 1: chemical compound 1:N-(4-fluoro-benzyl)-N ', N '-two-[2-(4-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
Three (2-amino-ethyl) amine (0.01mol) and 4-fluoro-benzaldehyde (0.03mol) are dissolved among the MeOH (50mL).25 ℃ down stir 15 hours after, under 0 ℃ with NaBH
4(1.90g 0.05mol) adds in the above-mentioned solution.Reactant mixture was stirred 2 hours down at 25 ℃.Use CH then
2Cl
2(100mL) and aqueous ammonium chloride solution (10%, 70mL) dilution.Separate organic layer, MgSO is passed through in water (100mL) washing
4Solid drying, and concentrated down in decompression, obtain the oily product.(EtOAc/MeOH=8: 2) purification crude product obtains chemical compound 1 to use alumina column chromatography.
LC/MS(M
++1)：471。
Embodiment 2: chemical compound 2:N-(3-trifluoromethyl-benzyl)-N ', N '-two-[2-(3-trifluoromethyl-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 2 is similar to embodiment 1.
LC/MS(M
++1)：621。
Embodiment 3: chemical compound 3:N-(3,4-two fluoro-benzyls)-N ', N '-two-[2-(3,4-two fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 3 is similar to embodiment 1.
LC/MS(M
++1)：525。
Embodiment 4: chemical compound 4:N-benzyl-N ', N '-two-(2-benzyl amino-ethyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 4 is similar to embodiment 1.
LC/MS(M
++1)：417。
Embodiment 5: chemical compound 5:N-(2-chloro-4-fluoro-benzyl)-N ', N '-two-[2-(2-chloro-4-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 5 is similar to embodiment 1.
LC/MS(M
++1)：574。
Embodiment 6: chemical compound 6:N-(2-fluoro-benzyl)-N ', N '-two-[2-(2-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 6 is similar to embodiment 1.
LC/MS(M
++1)：471。
Embodiment 7: chemical compound 7:N-(5-methyl-thiophene-2-ylmethyl)-N ', and N '-two-2-[(5-methyl-thiophene-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 7 is similar to embodiment 1.
LC/MS(M
++1)：477。
Embodiment 8: chemical compound 8:N-naphthalene-1-ylmethyl-N ', and N '-two-2-[(naphthalene-1-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 8 is similar to embodiment 1.
LC/MS(M
++1)：567。
Embodiment 9: chemical compound 9:N-(2,3-two chloro-benzyls)-N ', N '-two-[2-(2,3-two chloro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 9 is similar to embodiment 1.
LC/MS(M
++1)：624。
Embodiment 10: chemical compound 10:N-(1H-draws diindyl-6-ylmethyl)-N ', and N '-two-2-[(1H-indole-6-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 10 is similar to embodiment 1.
LC/MS(M
++1)：534。
Embodiment 11: chemical compound 11:N-(1-methyl isophthalic acid H-pyrroles-2-ylmethyl)-N ', and N '-two-2-[(1-methyl isophthalic acid H-pyrroles-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 11 is similar to embodiment 1.
LC/MS(M
++1)：426。
Embodiment 12: chemical compound 12:N-[4-({ two-[2-(2-fluoro-benzyl amino)-ethyl]-amino }-methyl)-benzyl]-N '-(2-fluoro-benzyl)-N-[2-(2-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
With 1,4-dibromo xylene (0.012mol) is at 60 ℃ with in CH
3K among the CN (60mL)
2CO
3(0.5mol) exist down with two (tert-butoxy aminoethyl) amine (0.024mol) processing.Stir after 12 hours, make solution be cooled to room temperature, filter and concentrate.Handle concentrate and use K with the HCl/ ether then
2CO
3Neutralization quantitatively obtains 1,4-two [two (2-amino-ethyl) amino-methyl] benzene.
With thus obtained 1,4-two [two (2-amino-ethyl) amino-methyl] benzene (0.01mol) and 4-fluoro-benzaldehyde (0.04mol) are dissolved among the MeOH (50mL).25 ℃ down stir 15 hours after, under 0 ℃ with NaBH
4(2.28g 0.06mol) adds in the above-mentioned solution.Reactant mixture was stirred other 2 hours down at 25 ℃.Use CH then
2Cl
2(100mL) and aqueous ammonium chloride solution (10%, 70mL) dilution.Separate organic layer, MgSO is passed through in water (100mL) washing
4Solid drying, and concentrated down in decompression, obtain the oily product.(EtOAc/MeOH=7: 3) purification crude product obtains chemical compound 12 to use alumina column chromatography.
LC/MS(M
++1)：741。
Embodiment 13: chemical compound 13:N-[4-({ two-[2-(4-fluoro-benzyl amino)-ethyl]-amino }-methyl)-benzyl]-N '-(4-fluoro-benzyl)-N-[2-(4-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 13 is similar to embodiment 12.
LC/MS(M
++1)：741。
Embodiment 14: chemical compound 14:N-{4-[(pair-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 14 is similar to embodiment 12.
LC/MS(M
++1)：673。
Embodiment 15: chemical compound 15:N-(2-amino-ethyl)-N-{4-[((2-amino-ethyl)-and 2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl }-N '-pyridine-2-ylmethyl-ethane-1, the preparation of 2-diamidogen
With 1,4-two [two (2-amino-ethyl) amino-methyl] benzene (0.01mol) and pyridine-2-formaldehyde (0.02mol) are dissolved among the MeOH (40mL).25 ℃ down stir 15 hours after, under 0 ℃ with NaBH
4(1.14g 0.03mol) adds in this solution.Reactant mixture was stirred other 2 hours down at 25 ℃.Use CH then
2Cl
2(100mL) and aqueous ammonium chloride solution (10%, 70mL) dilution.Separate organic layer, MgSO is passed through in water (100mL) washing
4Solid drying, and concentrated down in decompression, obtain the oily product.(EtOAc/MeOH=6: 4) purification crude product obtains chemical compound 15 to use alumina column chromatography.
LC/MS(M
++1)：491。
Embodiment 16: chemical compound 16:N-(4-fluoro-benzyl)-N '-[2-(4-fluoro-benzyl amino)-ethyl]-N '-4-[(4-fluoro-benzyl amino)-methyl]-benzyl }-ethane-1, the preparation of 2-diamidogen
Will be in CH
3Two (2-tertbutyloxycarbonyl aminoethyl) amine (0.01mol), 4-cyano-benzyl bromide (0.01mol) and K among the CN (70mL)
2CO
3(0.05mol) heated 10 hours down at 60 ℃.Two (the 2-tertbutyloxycarbonyl aminoethyl) amino-4-aminomethyl phenyl cyanogen that obtains is gone to protect with the HCl/ ether, and with 4-fluoro-benzaldehyde (0.02mol) condensation in MeOH.Use NaBH successively
4, after Bis(tert-butoxycarbonyl)oxide and diisobutyl aluminum handle, obtain two (2-replacements-aminoethyl) amino-4-tolyl aldehyde, and further with the condensation of 4-fluoro-benzylamine, generation Schiff's base.Then with Schiff's base NaBH
4Reduction, and by going protection with the HCl reaction.Also (EtOAc/MeOH=7: 3) purification obtains chemical compound 16 with alumina column chromatography to obtain crude product.
LC/MS(M
++1)：747。
Embodiment 17: chemical compound 17:N-{4-[(3-imidazoles-1-base-third amino)-and methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 17 is similar to embodiment 16.
LC/MS(M
++1)：513。
Embodiment 18: chemical compound 18:1-({ 4-[(is two-{ 2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-methyl)-preparation of Hexalin
The preparation method of chemical compound 18 is similar to embodiment 16.
LC/MS(M
++1)：517。
Embodiment 19: chemical compound 19:N-{4-[(3-morpholine-4-base-third amino)-and methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 19 is similar to embodiment 16.
LC/MS(M
++1)：532。
Embodiment 20: chemical compound 20:N-(4-{[2-(2,5-dimethoxy-phenyl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 20 is similar to embodiment 16.
LC/MS(M
++1)：569。
Embodiment 21: chemical compound 21:N-(4-{[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 21 is similar to embodiment 16.
LC/MS(M
++1)：555。
Embodiment 22: chemical compound 22:N-(4-{[2-(3-fluoro-phenyl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 21 is similar to embodiment 16.
LC/MS(M
++1)：527。
Embodiment 23: chemical compound 23:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 23 is similar to embodiment 16.
LC/MS(M
++1)：535。
Embodiment 24: chemical compound 24:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-(4-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 24 is similar to embodiment 16.
LC/MS(M
++1)：496。
Embodiment 25: chemical compound 25:N-(4-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzyl)-N '-(2,3,5-three chloro-benzyls)-N-[2-(2,3,5-three chloro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 25 is similar to embodiment 16.
LC/MS(M
++1)：488。
Embodiment 26: chemical compound 26:N-(3,4-two fluoro-benzyls)-N '-[2-(3,4-two fluoro-benzyl amino)-ethyl]-N '-(4-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 26 is similar to embodiment 16.
LC/MS(M
++1)：566。
Embodiment 27: chemical compound 27:N-(4-fluoro-benzyl)-N '-[2-(4-fluoro-benzyl amino)-ethyl]-N '-(4-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 27 is similar to embodiment 16.
LC/MS(M
++1)：530。
Embodiment 28: chemical compound 28:N-(4-chloro-benzyl)-N '-[2-(4-chloro-benzyl amino)-ethyl]-N '-(4-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 28 is similar to embodiment 16.
LC/MS(M
++1)：563。
Embodiment 29: chemical compound 29:N-(4-{[2-(3-chloro-phenyl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 29 is similar to embodiment 16.
LC/MS(M
++1)：543。
Embodiment 30: chemical compound 30:N-(4-{[2-(4-chloro-phenyl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 30 is similar to embodiment 16.
LC/MS(M
++1)：543。
Embodiment 31: chemical compound 31:N-{4-[(4-fluoro-benzyl amino)-and methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 31 is similar to embodiment 16.
LC/MS(M
++1)：513。
Embodiment 32: chemical compound 32:N-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 32 is similar to embodiment 16.
LC/MS(M
++1)：548。
Embodiment 33: chemical compound 33:N-(4-{[2-(5-fluoro-1H-draws diindyl-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 33 is similar to embodiment 16.
LC/MS(M
++1)：566。
Embodiment 34: chemical compound 34:N-(4-{[2-(5-methoxyl group-1H-indol-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 34 is similar to embodiment 16.
LC/MS(M
++1)：578。
Embodiment 35: chemical compound 35:N-(4-{[2-(6-methoxyl group-1H-indol-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 35 is similar to embodiment 16.
LC/MS(M
++1)：578。
Embodiment 36: chemical compound 36:N-(4-{[2-(7-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 36 is similar to embodiment 16.
LC/MS(M
++1)：562。
Embodiment 37: chemical compound 37:N-{4-[(2-hexamethylene-1-thiazolinyl-ethylamino)-and methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 37 is similar to embodiment 16.
LC/MS(M
++1)：513。
Embodiment 38: chemical compound 38:N-{4-[(1H-indole-5-base is amino)-methyl]-benzyl }-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 38 is similar to embodiment 16.
LC/MS(M
++1)：520。
Embodiment 39: chemical compound 39:2-{4-[(pair-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-4,5,6, the preparation of 7-tetrahydrochysene-benzo [b] thiophene-3-carboxylic acid, ethyl ester
The preparation method of chemical compound 39 is similar to embodiment 16.
LC/MS(M
++1)：613。
Embodiment 40: chemical compound 40:N-(4-{[2-(4-fluoro-phenyl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 40 is similar to embodiment 16.
LC/MS(M
++1)：527。
Embodiment 41: chemical compound 41:N-(4-{[2-(4-chloro-phenyl)-third amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 41 is similar to embodiment 16.
LC/MS(M
++1)：558。
Embodiment 42: chemical compound 42:N-(4-{[2-(5-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 42 is similar to embodiment 16.
LC/MS(M
++1)：562。
Embodiment 43: chemical compound 43:N-(4-fluoro-benzyl)-N '-[2-(3-fluoro-benzyl amino)-ethyl]-N '-(4-{[6-(pyridine-2-oxygen base)-pyridin-3-yl amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 43 is similar to embodiment 16.
LC/MS(M
++1)：609。
Embodiment 44: chemical compound 44:6-(5-{4-[(two-{ 2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-pyridine-2-oxygen base }-preparation of pyridine-2-carboxylic acids methyl ester
The preparation method of chemical compound 44 is similar to embodiment 16.
LC/MS(M
++1)：633。
Embodiment 45: chemical compound 45:N-(4-{[6-(5-chloro-pyridine-2-oxygen base)-pyridin-3-yl amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 45 is similar to embodiment 16.
LC/MS(M
++1)：609。
Embodiment 46: chemical compound 46:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-(4-{[6-(pyridine-2-oxygen base)-pyridin-3-yl amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 46 is similar to embodiment 16.
LC/MS(M
++1)：575。
Embodiment 47: chemical compound 47:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzyl)-N '-(4-fluoro-benzyl)-N-[2-(4-fluoro-benzyl amino)-ethyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 47 is similar to embodiment 16.
LC/MS(M
++1)：569。
Embodiment 48: chemical compound 48:6-{5-[4-({ two-[2-(4-fluoro-benzyl amino)-ethyl]-amino }-methyl)-benzyl amino]-pyridine-2-oxygen base }-preparation of pyridine-2-carboxylic acids methyl ester
The preparation method of chemical compound 48 is similar to embodiment 16.
LC/MS(M
++1)：667。
Embodiment 49: chemical compound 49:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(1,4,8, the 11-four azepines-ring tetradecane-1-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
Under 60 ℃ with K
2CO
3(0.05mol) be incorporated in CH
3The Sai Kelun (0.01mol) and 1 of the three tertbutyloxycarbonyls protection among the CN is in 4-xylylene bromide (0.01mol) solution.Behind the stirred reaction mixture 12 hours, obtain the bromomethyl benzyl Sai Kelun (0.007mol) of three tertbutyloxycarbonyls protection.Then at 60 ℃ and K
2CO
3(0.05mol) exist down, be same as CH
3Two (2-pyridine imino group ethyl) amine (0.01mol) reactions among the CN (100mL).Stir after 12 hours, filter and concentrated reaction mixture.Under 25 ℃, MeOH (50mL) is added in this mixture, add NaBH afterwards
4(0.03mol).Reactant mixture was stirred other 2 hours.Solution is distributed between EtOAc and water.Separate organic layer then, pass through MgSO
4Solid drying filters and concentrates, and obtains residue.Residue is handled with the HCl/ ether, and (EtOAc/MeOH=1: 2) purification obtains chemical compound 49 to use alumina column chromatography.
LC/MS(M
++1)：588。
Embodiment 50: chemical compound 50:4-[(is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-N ' N-is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-preparation of benzsulfamide
At 60 ℃ and K
2CO
3(0.1mol) exist down, 4-bromomethyl benzene sulfonyl chloride (0.01mol) is used for CH
3Two (2-tertbutyloxycarbonyl aminoethyl) amine (0.02mol) among the CN (100mL) are handled.Stir after 12 hours, solution is filtered and filtrate is concentrated, obtain residue.Then residue is handled and neutralization with the HCl/ ether, obtained polyamines.Handle this polyamines with pyridine-2-formaldehyde, produce Schiff's base.The NaBH that then Schiff's base is used for MeOH
4Reduction.(EtOAc/MeOH=1: 1) purification obtains chemical compound 50 with alumina column chromatography with crude product.
LC/MS(M
++1)：723。
Embodiment 51: the preparation of chemical compound 51:4-({ two-[2-(3,4-two chloro-benzyl amino)-ethyl]-amino }-methyl)-N-pyridine-2-ylmethyl-benzsulfamide
4-bromomethyl benzene sulfonyl chloride (0.01mol) and 2-aminomethyl-pyridine (0.01mol) be dissolved in contain Et
3In the ether (100mL) of N (0.02mol).After stirring 5 hours under 25 ℃, wash solution with water.At 60 ℃ and K
2CO
3(0.05mol) exist down, the bromine sulfonamide (0.01mol) that obtains is used for CH
3Two (2-tertbutyloxycarbonyl aminoethyl) amine (0.01mol) among the CN (100mL) are handled.Stir after 12 hours, reactant mixture is filtered and filtrate is concentrated, obtain residue.This residue is handled and neutralization with the HCl/ ether, obtained polyamines.Then with polyamines with 3, the 4-dichlorobenzaldehyde is handled, and produces Schiff's base.Schiff's base is used for MeOH NaBH
4Reduction.The crude product that obtains is thus passed through alumina column chromatography, and (EtOAc/MeOH=6: 4) purification obtains chemical compound 51.
LC/MS(M
++1)：680。
Embodiment 52: the preparation of chemical compound 52:4-({ two-[2-(3,4-two fluoro-benzyl amino)-ethyl]-amino }-methyl)-N-pyridine-2-ylmethyl-benzsulfamide
The preparation method of chemical compound 52 is similar to embodiment 51.
LC/MS(M
++1)：616。
Embodiment 53: the preparation of chemical compound 53:4-({ two-[2-(4-fluoro-benzyl amino)-ethyl]-amino }-methyl)-N-pyridine-2-ylmethyl-benzsulfamide
The preparation method of chemical compound 53 is similar to embodiment 51.
LC/MS(M
++1)：580。
Embodiment 54: the preparation of chemical compound 54:4-({ two-[2-(4-chloro-benzyl amino)-ethyl]-amino }-methyl)-N-pyridine-2-ylmethyl-benzsulfamide
The preparation method of chemical compound 54 is similar to embodiment 51.
LC/MS(M
++1)：612。
Embodiment 55: the preparation of chemical compound 55:4-({ two-[2-(2-chloro-benzyl amino)-ethyl]-amino }-methyl)-N-pyridine-2-ylmethyl-benzsulfamide
The preparation method of chemical compound 55 is similar to embodiment 51.
LC/MS(M
++1)：612。
Embodiment 56: chemical compound 56:N-[4-(6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
At 0 ℃ with in CH
2Cl
2Et (50mL)
3N (2.74mmol) exists down, and with 1,4-dibromo xylene (13.64mmol) is handled with two (tert-butoxy aminoethyl) amine (2.74mmol).Stir after 16 hours, solution is filtered, concentrate and purification, obtain single bromide that replaces.At 60 ℃ and K
2CO
3(3.39mmol) exist down, should single replacement bromide (0.68mmol) and in CH
36-methoxyl group-1,2,3 among the CN (10mL), 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (0.68mmol) reaction.Stir after 12 hours, this solution is filtered, concentrated filtrate, and use chromatography purification, obtain the residue (0.57mmol of butoxy carbonyl protection; Yield 84%).Residue (0.26mmol) is handled and neutralization with the HCl/ ether, obtained polyamines.Then this polyamines is handled with pyridine-2-formaldehyde, produced Schiff's base.The NaBH that Schiff's base is used for MeOH
4Reduction.(EtOAc/MeOH=7: 3) purification obtains chemical compound 56 with alumina column chromatography with thus obtained crude product.
LC/MS(M
++1)：590。
Embodiment 57: chemical compound 57:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 57 is similar to embodiment 56.
LC/MS(M
++1)：560。
Embodiment 58: chemical compound 58: the .gamma.-pyridinecarboxylic acid 4-[(is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzal }-preparation of hydrazides
With two (2-tertbutyloxycarbonyl aminoethyl) amine (0.01mol), 4-cyano-benzyl bromide (0.01mol) and K
2CO
3(0.05mol) add CH
3Among the CN (70mL), and mixture stirred 10 hours simultaneously 60 ℃ of following heating.Two (the 2-tertbutyloxycarbonyl aminoethyl) amino-4-aminomethyl phenyl cyanogen that obtains is gone to protect by handling with the HCl/ ether, then with pyridine-2-benzaldehyde (0.02mol) condensation in MeOH.Use NaBH successively
4, after Bis(tert-butoxycarbonyl)oxide and DIBAL handle, with two (2-replacements-aminoethyl) amino-4-tolyl aldehyde and the isonicotinic acid hydrazide condensation that obtains, generation Schiff's base.Handle Schiff's base with the HCl/ ether then.(EtOAc/MeOH=7: 3) purification obtains chemical compound 58 with alumina column chromatography with thus obtained crude product.
LC/MS(M
++1)：523。
Embodiment 59: chemical compound 59: thiophene-2-carboxylic acid 4-[(is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzal }-preparation of hydrazides
The preparation method of chemical compound 59 is similar to embodiment 58.
LC/MS(M
++1)：528。
Embodiment 60: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 60:1-[]-4-[2-(3-indole)-1-((S)-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 60 is similar to embodiment 16 (yield: 80%).
LC-MS(C
35H
43N
7O.7HCl)(M
++1-7HCl)：578。
Embodiment 61: two [(2-(2-pyridine radicals-2-ethyl) the aminoethyl)] amino-methyls of chemical compound 61:1-[]-4-[2-(3-indole)-1-((S)-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 61 is similar to embodiment 16 (yield: 80%).
LC-MS(C
35H
43N
7O.7HCl)(M
++1-7HCl)：606。
Embodiment 62: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 62:1-[]-4-[2-(phenyl)-1-((R)-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 62 is similar to embodiment 16 (yield: 81%).
LC-MS(C
33H
42N
6O.6HCl)(M
++1-6HCl)：539。
Embodiment 63: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 63:1-[]-4-[2-(phenyl)-1-((S)-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 63 is similar to embodiment 16 (yield: 85%).
LC-MS?(C
33H
42N
6O.6HCl)(M
++1-6HCl)：539。
Embodiment 64: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 64:1-[]-4-[2-(3-indole)-1-((R)-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 64 is similar to embodiment 16 (yield: 78%).
LC-MS(C
35H
43N
7O.7HCl)(M
++1-7HCl)：578。
Embodiment 65: two [(2-(2-pyridine radicals-2-ethyl) the aminoethyl)] amino-methyls of chemical compound 65:1-[]-4-[(1,2,3,4-tetrahydrochysene-9H-pyrido-6-methoxyl group [3,4-b] indole-2-methyl) preparation of benzene
The preparation method of chemical compound 65 is similar to embodiment 56.
LC/MS(M
++1)：618。
Embodiment 66: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 66:1-[]-4-[(1,2,3,4-tetrahydrochysene-9H-pyrido-6-benzyloxy [3,4-b] indole-2-methyl) preparation of benzene
The preparation method of chemical compound 65 is similar to embodiment 56.
LC/MS(M
++1)：666。
Embodiment 67: two [(2-(2-picolyl) aminoethyl)] amino-sulfonyls of chemical compound 67:1-[]-preparation of 4-(1,2,3,4-tetrahydrochysene-9H-pyrido-6-methoxyl group [3,4-b] indole-2-methyl) benzene
Will two (2-tertbutyloxycarbonyl aminoethyl) amine (3.03g, 0.01mol) add 1-bromomethyl benzene-4-sulfonic acid chloride (2.68g, 0.01mol), CH
2Cl
2(160mL) and Et
3(1.01g is 0.01mol) in the solution for N.Reactant mixture was stirred 2.5 hours down at 0 ℃.Be dissolved in CH with solvent evaporation and with residue then
3CN (180mL), K
2CO
3(4.14g, 0.03mol) with 1,2,3, the 4-tetrahydrochysene-(1.72g is in mixture 0.01mol) for 9H-pyrido-6-methoxyl group [3,4-b] indole.Reactant mixture was stirred other 10 hours down at 60 ℃.Then mixture is filtered, concentrate, and use CH
2Cl
2(35mL) with HCl/ ether (1.0M, mixture process 80mL) 12 hours.Afterwards reactant mixture is concentrated, and with in CH
2Cl
2Anhydrous K (150mL)
2CO
3Stir together (10.0g, 30 minutes).Thus obtained mixture is filtered and concentrates, obtain intermediate 1, two [(2-the amino-ethyl)] amino-sulfonyls of 1-[]-4-[(1; 2,3,4-tetrahydrochysene-9H-pyrido-6-methoxyl group [3; 4-6] indole-2-methyl) (2.56g, 0.006mol), yield is 60% to benzene.(1.50g 0.014mol) handles 14 hours, uses NaBH afterwards then this intermediate to be used for the pyridine-2-formaldehyde of MeOH (40mL)
4(1.60g 0.042mol) handled 4 hours, obtained rough intermediate 2.With intermediate 2 usefulness alumina column chromatography (EtOAc/MeOH=7: 3) (3.19g, 0.005mol, yield 83%) purification.Afterwards intermediate 2 is used for CH
2Cl
2HCl/ ether (125mL) (50mL) is handled, and obtains chemical compound 67.
LC-MS(C
35H
41N
7O
3S.6HCl)(M
++1-6HCl)：640。
Embodiment 68: chemical compound 68:N-[4-(6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-2-hydroxyl ethylamino]-ethyl }-ethane-1, the preparation of 2-diamidogen
By chemical compound 56 selective alkylations are prepared chemical compound 68 (yield: 40%).
LC-MS(C
38H
47N
7O
2.7HCl)(M
++1-7HCl)：634。
Embodiment 69: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 69:1-[]-4-[2-(phenyl)-1-((R)-hydroxyl carbonyl) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 69 is similar to embodiment 16 (yield: 70%).
LC-MS(C
33H
40N
6O
2.6HCl)(M
++1-6HCl)：553。
Embodiment 70: chemical compound 70:1-[two [2-(2-picolyl) aminoethyl)] amino-methyl]-preparation of 4-[2-(3-(5-oxyindole)-1-((R)-hydroxyl carbonyl) ethylamino methyl) benzene
The preparation method of chemical compound 70 is similar to embodiment 16 (yield: 75%).
LC-MS(C
35H
41N
7O
3.7HCl)(M
++1-7HCl)：608。
Embodiment 71: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 71:1-[]-4-[2-(3-(7-methylindole)) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 71 is similar to embodiment 16 (yield: 70%).
LC-MS(C
37H
47N
7.7HCl)(M
++1-7HCl)：590。
Embodiment 72: two [(2-(2-pyridine radicals-2-ethyl) the aminoethyl)] amino-methyls of chemical compound 72:1-[]-4-[2-(3-chlorphenyl) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 72 is similar to embodiment 16 (yield: 80%).
LC-MS(C
34H
43ClN
6.6HCl)(M
++1-6HCl)：571。
Embodiment 73: two [(2-(2-pyridine radicals-2-ethyl) the aminoethyl)] amino-methyls of chemical compound 73:1-[]-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl) preparation of benzene
The preparation method of chemical compound 73 is similar to embodiment 16 (yield: 84%).
LC-MS(C
34H
42N
8.7HCl)(M
++1-6HCl)：563。
Embodiment 74: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 74:1-[]-4-[(2-phenyl-2-hydroxyl-1-methoxy) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 74 is similar to embodiment 16 (yield: 71%).
LC-MS(C
34H
44N
6O
2.6HCl)(M
++1-6HCl)：569。
Embodiment 75: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 75:1-[]-4-[(2-(4-chlorphenyl)-1-methylol) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 75 is similar to embodiment 16 (yield: 70%).
LC-MS(C
33H
41ClN
6O.6HCl)(M
++1-6HCl)：573。
Embodiment 76: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 76:1-[]-4-[(2-phenyl-(2R)-hydroxyl-(1R)-methylol) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 76 is similar to embodiment 16 (yield: 68%).
LC-MS(C
33H
42N
6O
2.6HCl)(M
++1-6HCl)：555。
Embodiment 77: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 77:1-[]-4-[(2-phenyl-(2S)-hydroxyl-(1S)-methylol) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 77 is similar to embodiment 16 (yield: 70%).
LC-MS(C
33H
42N
6O
2.6HCl)(M
++1-6HCl)：555。
Embodiment 78: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 78:1-[]-4-[2-(4-bromophenyl)-1-((R)-hydroxyl carbonyl) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 78 is similar to embodiment 16 (yield: 77%).
LC-MS(C
33H
39BrN
6O
2.6HCl)(M
++1-6HCl)：631。
Embodiment 79: chemical compound 79:2-({ 4 '-[(two-{ 2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-xenyl-4-ylmethyl]-pyridine-2-ylmethyl-amino)-preparation of 3-phenyl-third-1-alcohol
The preparation method of chemical compound 79 is similar to embodiment 16 (yield: 70%).
LC-MS(C
45H
51N
7O.7HCl)(M
++1-7HCl)：706。
Embodiment 80: chemical compound 80:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(6-chloro-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 80 is similar to embodiment 56.
LC-MS(C
35H
40ClN
7.7HCl)(M
++1-7HCl)：594。
Embodiment 81: chemical compound 81:N-[4-({ ethyl-[2-(7-Methyl-1H-indole-3-yl)-ethyl]-amino }-methyl)-benzyl]-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 81 is similar to embodiment 56.
LC-MS(C
37H
47N
7.7HCl)(M
++1-7HCl)：590。
Embodiment 82: chemical compound 82:N-[4-({ [2-(3-chloro-phenyl)-ethyl]-ethyl-amino }-methyl)-benzyl]-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 82 is similar to embodiment 56.
LC-MS(C
34H
43ClN
6.6HCl)(M
++1-6HCl)：571。
Embodiment 83: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 83:1-[]-4-[(2S)-and hydroxymethyl pyrrolidine-N-methyl] preparation of benzene
The preparation method of chemical compound 83 is similar to embodiment 56 (yield: 80%).
LC-MS(C
29H
40N
6O.6HCl)(M
++1-6HCl)：489。
Embodiment 84: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 84:1-[]-4-[(2R)-and hydroxymethyl pyrrolidine-N-methyl] preparation of benzene
The preparation method of chemical compound 84 is similar to embodiment 56 (yield: 80%).
LC-MS(C
29H
40N
6O.6HCl)(M
++1-6HCl)：489。
Embodiment 85: chemical compound 85:2-({ 4 '-[(two-{ 2-[(pyridine-2-ylmethyl)-amino]-ethyl } amino)-methyl]-xenyl-4-ylmethyl }-amino)-preparation of 3-phenyl-third-1-alcohol
The preparation method of chemical compound 85 is similar to embodiment 16.
LC-MS(C
39H
46N
6O.6HCl)(M
++1-6HCl)：615。
Embodiment 86: chemical compound 86:N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(6-fluoro-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 86 is similar to embodiment 56.
LC-MS(C
35H
40FN
7.7HCl)(M
++1-7HCl)：578。
Embodiment 87: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 87:1-[]-4-[2-(5-chloro-6-hydroxy phenyl-1-hydroxyl carbonyl) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 87 is similar to embodiment 16 (yield: 76%).
LC-MS(C
35H
39ClN
6O
3.6HCl)(M
++1-6HCl)：603。
Embodiment 88: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 88:1-[]-4-[(2-thiophene-1-hydroxyl carbonyl) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 88 is similar to embodiment 16 (yield: 70%).
LC-MS(C
31H
38ClN
6O
2S.6HCl)(M
++1-6HCl)：559。
Embodiment 89: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 89:1-[]-4-{[2-(4-chlorphenyl)-2-cyclopropyl] the ethylamino methyl) preparation of benzene
The preparation method of chemical compound 89 is similar to embodiment 16 (yield: 78%).
LC-MS(C
34H
41ClN
6.6HCl)(M
++1-6HCl)：569。
Embodiment 90: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 90:1-[]-4-{[2-(3-chloro-6-methoxyphenyl)] the ethylamino methyl } preparation of benzene
The preparation method of chemical compound 90 is similar to embodiment 16 (yield: 80%).
LC-MS(C
33H
41ClN
6O.6HCl)(M
++1-6HCl)：573。
Embodiment 91: chemical compound 91:N-pyridine-2-base-2-ethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 91 is similar to embodiment 56 (yield: 65%).
LC-MS(C
37H
45N
7O.7HCl)(M
++1-7HCl)：604。
Embodiment 92: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 92:1-[]-4-[(2-thiophene-2-hydroxyl carbonyl) the ethylamino methyl] preparation of benzene
The preparation method of chemical compound 92 is similar to embodiment 16 (yield: 85%).
LC-MS(C
31H
38N
6O
2S.6HCl)(M
++1-6HCl)：559。
Embodiment 93: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 93:1-[]-4-[3-methylol-(S)-1,2,3,4-tetrahydroisoquinoline-N-ylmethyl] preparation method of preparation chemical compound 93 of benzene is similar to embodiment 56.
LC-MS(C
34H
42N
6O.6HCl)(M
++1-6HCl)：551。
Embodiment 94: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 94:1-[]-preparation of 4-(4-hydroxy-4-phenyl piperidine-N-ylmethyl) benzene
The preparation method of chemical compound 94 is similar to embodiment 56.
LC-MS(C
35H
44N
6O.6HCl)(M
++1-6HCl)：565。
Embodiment 95: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 95:1-[]-4-[4-hydroxyl-4-(4-chlorphenyl piperidines)-N-ylmethyl] preparation of benzene
The preparation method of chemical compound 95 is similar to embodiment 56.
LC-MS(C
35H
43ClN
6O.6HCl)(M
++1-6HCl)：599。
Embodiment 96: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 96:1-[]-preparation of 4-(1-indane aminomethyl) benzene
The preparation method of chemical compound 96 is similar to embodiment 16.
LC-MS(C
33H
40N
6.6HCl)(M
++1-6HCl)：521。
Embodiment 97: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 97:1-[]-preparation of 4-(3,4-dichloro-benzenes methyl aminomethyl) benzene
The preparation method of chemical compound 97 is similar to embodiment 16.
LC-MS(C
31H
36Cl
2N
6.6HCl)(M
++1-6HCl)：563。
Embodiment 98: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 98:1-[]-preparation of 4-(3-chlorophenylmethyl aminomethyl) benzene
The preparation method of chemical compound 98 is similar to embodiment 16.
LC-MS(C
31H
37ClN
6.6HCl)(M
++1-6HCl)：529。
Embodiment 99: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 99:1-[]-4-[4-hydroxy phenyl (1-methylol) ethylamino methyl] preparation of benzene
The preparation method of chemical compound 99 is similar to embodiment 16.
LC-MS(C
33H
42N
6O
2.6HCl)(M
++1-6HCl)：555。
Embodiment 100: chemical compound 100:N-(4-{[2-(7-Methyl-1H-indole-3-yl)-1-(hydroxyl carbonyl methyl) ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 100 is similar to embodiment 16.
LC-MS(C
37H
45N
7O
2.6HCl)(M
++1-6HCl)：620。
Embodiment 101: chemical compound 101:N-(4-{[2-(7-Methyl-1H-indole-3-yl)-1-(ethoxy) ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 101 is similar to embodiment 16.
LC-MS(C
37H
47N
7O.7HCl)(M
++1-7HCl)：606。
Embodiment 102: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 102:1-[]-4-{[2-(3-chloro-4-ethylphenyl)] the ethylamino methyl } preparation of benzene
The preparation method of chemical compound 102 is similar to embodiment 16 (yield: 80%).
LC-MS(C
33H
41ClN
6O.6HCl)(M
++1-6HCl)：573。
Embodiment 103: chemical compound 103:N-(4-{[2-(7-Methyl-1H-indole-3-yl) ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-propane-1, the preparation of 3-diamidogen
The preparation method of chemical compound 103 is similar to embodiment 16.
LC-MS(C
36H
45N
7.7HCl)(M
++1-7HCl)：576。
Embodiment 104: chemical compound 104:N-(4-{[2-(3-chlorphenyl) ethylamino] methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-propane-1, the preparation of 3-diamidogen
The preparation method of chemical compound 104 is similar to embodiment 16.
LC-MS(C
33H
41ClN
6.6HCl)(M
++1-6HCl)：557。
Embodiment 105: chemical compound 105:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl) amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-propane-1, the preparation of 3-diamidogen
The preparation method of chemical compound 105 is similar to embodiment 16.
LC-MS(C
33H
40N
8.7HCl)(M
++1-7HCl)：549。
Embodiment 106: chemical compound 106:N-pyridine-2-base-ethoxy-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-ylmethyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 106 is similar to embodiment 56 (yield: 65%).
LC-MS(C
37H
45N
7O
2.7HCl)(M
++1-7HCl)：620。
Embodiment 107: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 107:1-[]-4-(preparation of 2-methoxy pyrrolidine-N-methylbenzene
The preparation method of chemical compound 107 is similar to embodiment 56 (yield: 82%).
LC-MS(C
30H
42N
6O.6HCl)(M
++1-6HCl)：503。
Embodiment 108: chemical compound 108:N-pyridine-2-base-ethoxy-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(1-methylol-6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-base-methyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 108 is similar to embodiment 56.
LC-MS(C
37H
45N
7O
2.7HCl)(M
++1-7HCl)：620。
Embodiment 109: chemical compound 109:N-pyridine-2-base-ethoxy-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-methyl)-benzyl]-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 109 is similar to embodiment 56.
LC-MS(C
35H
42N
6.6HCl)(M
++1-6HCl)：547。
Embodiment 110: chemical compound 110:N-pyridine-2-base-2-ethyl-N '-2-[(pyridine-2-base-ethyl)-amino]-ethyl }-4-(cyano group benzyl)-ethane-1, the preparation of 2-diamidogen .5HCl
With two (2-tertbutyloxycarbonyl aminoethyl) amine (0.01mol), 4-cyano-benzyl bromide (0.01mol), K
2CO
3(0.05mol) and CH
3The mixture of CN (70mL) heated 10 hours down at 60 ℃.Use the HCl/ ether to go protection in two (the 2-tertbutyloxycarbonyl aminoethyl) amino-4-aminomethyl phenyl cyanogen that obtains,, use NaBH then with 2-acetopyridine (0.01mol) condensation in MeOH
4Reduction.Use pyridine-2-formaldehyde, NaBH successively
4After the HCl processing, obtain chemical compound 110, total recovery is 75%.
LC-MS(C
25H
30N
6.5HCl)(M
++1-5HCl)：415。
Embodiment 111: chemical compound 111:N-pyridine-2-base-2-ethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-N '-[4-(1H-benzimidazolyl-2 radicals-Ji-methyl)-aminomethyl] benzyl]-ethane-1, the preparation of 2-diamidogen
With two (2-tertbutyloxycarbonyl aminoethyl) amine (0.01mol), 4-cyano-benzyl bromide (0.01mol), K
2CO
3(0.05mol) and CH
3The mixture of CN (70mL) heated 10 hours down at 60 ℃.Two (the 2-tertbutyloxycarbonyl aminoethyl) amino-4-aminomethyl phenyl cyanogen that obtains is gone protection with the HCl/ ether, with 2-acetopyridine (0.01mol) condensation in MeOH, uses NaBH then
4Reduction.Use pyridine-2-formaldehyde, NaBH successively
4, after Bis(tert-butoxycarbonyl)oxide and diisobutyl aluminum handle,, produce Schiff's base with thus obtained aldehyde and the condensation of 2-aminomethyl benzimidazole.Then with Schiff's base NaBH
4Reduce, and go protection with HCl, obtain chemical compound 111, total recovery is 45%.
LC-MS(C
33H
40N
8.7HCl)(M
++1-7HCl)：549。
Embodiment 112: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 112:1-[]-4-[4-hydroxyl-4-(4-anisyl piperidines)-N-base-methyl] preparation of benzene
The preparation method of chemical compound 112 is similar to embodiment 67.
LC-MS(C
36H
46N
6O
2.6HCl)(M
++1-6HCl)：595。
Embodiment 113: two [(2-(2-picolyl) the aminoethyl)] amino-methyls of chemical compound 113:1-[]-4-[4-hydroxyl-4-(2-methoxybenzene phenylpiperidines)-N-base-methyl] preparation of benzene
The preparation method of chemical compound 113 is similar to embodiment 56.
LC-MS(C
36H
46N
6O
2.6HCl)(M
++1-6HCl)：595。
Embodiment 114: chemical compound 114:N-(4-{[2-(7-Methyl-1H-indole-3-yl) ethylamino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-1-methyl ethane-1, the preparation of 2-diamidogen
2-methyl-2-the ethylaminoethanol (0.01mol) that 4-cyanobenzaldehyde (0.01mol) is used for MeOH (20mL) under 60 ℃ was handled 12 hours.Then under 0 ℃ with NaBH
4(1.90g 0.05mol) adds in the above-mentioned solution.Under 25 ℃, reactant mixture was stirred other 2 hours.Use CH then
2Cl
2(100mL) and aqueous ammonium chloride solution (10%, 70mL) dilution.Separate organic layer, MgSO is passed through in water (100mL) washing
4Solid drying, and under reduced pressure concentrate, the oily intermediate obtained.Then at K
2CO
3(0.05mol) exist down, with the CH of oily intermediate in backflow
3Among the CN (30mL) with 2-(2-bromo-ethyoxyl)-tetrahydrochysene-pyrans (0.01mol) condensation.After going protection,, and make and the reaction of 2-aminomethyl-pyridine the oh group methylsulfonylization that obtains.Then the secondary amine that obtains is protected with tertbutyloxycarbonyl.Afterwards, cyano group is handled with diisobutyl aluminum, and the aldehyde that will obtain is thus used 6-methyl-3-aminoethyl indole, NaBH successively
4, trifluoromethanesulfonic acid and HCl handle, and obtains chemical compound 114, total recovery is 60%.
LC-MS(C
36H
45N
7.6HCl)(M
++1-6HCl)：576。
Embodiment 115: chemical compound 115:2-{4-[(pair-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-1-(3-chloro-phenyl)-alcoholic acid preparation
The preparation method of chemical compound 115 is similar to embodiment 16 (yield: 77%).
LC-MS(M
++1)：559。
Embodiment 116: chemical compound 116:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl } benzyl)-N '-piperidin-4-yl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 116 is similar to embodiment 111 (yield: 70%).
LC-MS(M
++1)：527。
Embodiment 117: chemical compound 117:N-(4-{[2-(7-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzyl)-N '-(1-pyridine-2-base-ethyl)-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 117 is similar to embodiment 111 (yield: 70%).
LC-MS(M
++1)：576。
Embodiment 118: compound 118: N2-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzyl)-N1-pyridine-2-ylmethyl-N2-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-propane-1, the preparation of 2-diamidogen
The preparation method of compound 118 is similar to embodiment 114 (yield: 68%).
LC-MS(M
++1)：549。
Embodiment 119: chemical compound 119:N2-(4-{[2-(3-chloro-phenyl)-ethylamino]-methyl }-benzyl)-N1-pyridine-2-ylmethyl-N2-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-propane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 119 is similar to embodiment 114 (yield: 69%).
LC-MS(M
++1)：557。
Embodiment 120: chemical compound 120:N-ethyl-N '-(4-{[2-(7-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzyl)-N-pyridine-2-ylmethyl-N '-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
By being similar to embodiment 111, afterwards with acetaldehyde and NaBH
4The mode of reaction prepares chemical compound 120 (yield: 75%).
LC-MS(M
++1)：590。
Embodiment 121: chemical compound 121:3-{4-[(is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-preparation of 1-(3-chloro-phenyl)-third-1-alcohol
The preparation method of chemical compound 121 is similar to embodiment 16 (yield: 70%).
CL-MS(M
++1)：573。
Embodiment 122: chemical compound 122:1-(3-benzyloxy-phenyl)-3-{4-[(is two-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-methyl]-benzyl amino }-preparation of third-1-alcohol
The preparation method of chemical compound 122 is similar to embodiment 16 (yield: 67%).
LC-MS(M
++1)：645。
Embodiment 123: chemical compound 123:3-[2-((4-{[2-(7-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzyl)-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-ethylamino]-preparation of 3-pyridine-2-base-third-1-alcohol
The preparation method of chemical compound 123 is similar to embodiment 111 (yield: 73%).
LC-MS(M
++1)：606。
Embodiment 124: chemical compound 124:3-[2-((4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzyl)-2-[(pyridine-2-ylmethyl)-amino]-ethyl }-amino)-ethylamino]-preparation of 3-pyridine-2-base-third-1-alcohol
The preparation method of chemical compound 124 is similar to embodiment 111 (yield: 60%).
LC-MS(M
++1)：579。
Embodiment 125: chemical compound 125:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 125 is similar to embodiment 16 (yield: 70%).
LC-MS(M
++1)：535。
Embodiment 126: chemical compound 126:N-(4-{[3-(3-chloro-phenyl)-third amino]-methyl }-benzyl)-N '-pyridine-2-ylmethyl-N-{2-[(pyridine-2-ylmethyl)-amino]-ethyl }-ethane-1, the preparation of 2-diamidogen
The preparation method of chemical compound 126 is similar to embodiment 16 (yield: 85%).
LC-MS(M
++1)：557。
Embodiment 127: external test
(Finland) test compounds 1-126 is in conjunction with the usefulness of CXCR4 receptor for Wallac Oy, Turku to use DELFIA GTP-binding kit.This DELFIA GTP binding assay is based on GDP-GTP exchange on the G-protein subunit, and the G-G-protein linked receptor is by the activated time-resolved fluorometry of its agonist afterwards.To be used for this mensuration from the Eu-GTP that Wallac Oy obtains activates with the proteic agonist dependency of monitoring G-.Stimulate the CXCR4 receptor to cause the GDP on the G-protein subunit to be substituted with SDF-1 by GTP.This GTP-G α complex is represented the proteic activated form of G-.Can use the GTP analog Eu-GTP of non-hydrolysable to come the proteic amount of quantitative activatory G-(Peltonen etc., Eur.J.Pharmacol. (1998) 355:27).
The plasma membrane of expressing the HEK293 cell of CXCR4 is suspended in mensuration buffer (50mMNaCl, 100 μ g/mL saponin, 3mM MgCl
2, 3 μ M GDP, 5%BSA, 50mMHEPES, pH7.4) in.(Pall Life Sciences, Ann Arbor add sample aliquot (4 μ g albumen) in every hole MI) to AcroPlate.After adding test compounds (10 μ M are in 0.1%DMSO) and stroma cell derivative factor-1 (4nM is in assay buffer), this test board was also slowly shaken down incubation 10 minutes in room temperature, dark place.Eu-GTP is added in every hole, and with this plate incubation 60 minutes again.Wash twice of this plate and measure stopping with the wash solution that provides in the test kit is provided.The combination of Eu-GTP is based on from the fluorescence signal of Victor 2multi-label reader and measures.
Unexpectedly, the IC that shows all test compounds
50Value all is lower than 10 μ M.Especially, show 97 kinds IC in the test compounds
50Value is lower than 1 μ M.In them, 56 kinds IC
50Value is between 0.004 μ M and 0.1 μ M.
Other embodiment
Disclosed all features can make up in any combination among the application.Disclosed each feature can be substituted by further feature identical by being used for, equivalent or similar purpose among the application.Therefore, unless bright stating arranged in addition, disclosed each feature only is the example of a series of equivalences or similar features.
From above-mentioned embodiment, those skilled in the art can easily determine essential feature of the present invention, and the present invention can be carried out variations and modifications to be fit to various uses and situation under the prerequisite that does not deviate from the spirit and scope of the present invention.Therefore, other embodiment is also in the scope of appended claim.
For example, above-mentioned polyamine compounds also can be by treating inflammatory or immune disease with CXCR4 receptors bind mechanism in addition.And other of these chemical compounds used also within the scope of the invention.
Claims (17)
1. the chemical compound of a following formula:
Wherein
X is-CH
2-or-CH (CH
3)-;
Y is phenyl or 4,4 '-xenyl;
Z
1And Z
2Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH=CH-or-SO
2-;
R
1Be C
3-C
8Heterocyclylalkyl, aryl or heteroaryl;
R
2Be-A
1-B
1-D
1-E
1
R
3Be-A
2-B
2-D
2-E
2, do not exist or and R
4Be C together
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl; Condition is if R
3Do not exist, then-Z
2-N-is-CH=N-; And
R
4Be-A
3-B
3-D
3-E
3Or and R
3Be C together
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl;
A wherein
1, A
2And A
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-CH
2SO
2-,-SO
2CH
2-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-,-CH (CH
2COOR)-or do not exist; B
1, B
2And B
3Independent separately for-NH-or do not exist; D
1, D
2And D
3Independently be-CH separately
2-,-C
2H
4-,-C
3H
6-,-C (O)-,-SO
2-,-CH (OR)-,-CH (CH
2OR)-,-CH (CH
2CH
2OR)-,-CH (COOR)-, 1,1-cyclopropylidene or do not exist; And E
1, E
2And E
3Independent separately is H, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group, C
3-C
8Heterocyclylalkyl, aryl or heteroaryl; R independently is H or C separately
1-C
10Alkyl.
2. the chemical compound of claim 1, wherein Y is a phenyl, Z
1Be-CH
2-or-SO
2-, and Z
2Be-CH
2-or-SO
2-.
3. the chemical compound of claim 1, wherein X is-CH
2-, Y is 4,4 '-xenyl, Z
1Be-CH
2-, and Z
2Be-CH
2-.
4, the chemical compound of claim 1, wherein X is-CH
2-, Y is a phenyl, and R
3Do not exist.
5. the chemical compound of claim 2, wherein R
3Be-A
2-B
2-D
2-E
2Or and R
4Be C together
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl; A
1Be-C
2H
4-or-CH (CH
3) CH
2-; A
2Be-C
2H
4-or do not exist; A
3Be-CH
2-,-C
2H
4-,-C
3H
6-,-CH (CH
2OH)-,-CH (COOH)-,-CH (CH
2OCH
3)-,-CH (CH
2CH
2OH)-,-CH (CH
2COOH)-or do not exist; B
1Be-NH-; D
1Be-CH
2-,-CH (CH
3)-,-CH (CH
2OH)-,-CH (CH
2CH
2OH)-or do not exist; D
2Be-CH
2-or do not exist; D
3Be-CH
2-,-CH (OH)-,-CH (COOH)-, 1,1-cyclopropylidene or do not exist; E
1Be H, C
3-C
8Heterocyclylalkyl, aryl or heteroaryl; And E
3Be aryl, heteroaryl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group or C
3-C
8Heterocyclylalkyl.
6. the chemical compound of claim 5, wherein said chemical compound is
7. the chemical compound of claim 3, wherein R
3Be-A
2-B
2-D
2-E
2R
4Be-A
3-B
3-D
3-E
3A
1Be-C
2H
4-; A
2Do not exist; A
3Be-CH (CH
2OH)-; B
1Be-NH-; B
2Do not exist; B
3Do not exist; D
1Be-CH
2-; D
2Be-CH
2-or do not exist; D
3Be-CH
2-; E
1It is heteroaryl; E
2Be H or heteroaryl; And E
3It is aryl.
8. the chemical compound of claim 7, wherein said chemical compound is
9. the chemical compound of claim 4, wherein R
1It is heteroaryl; R
4Be-A
3-B
3-D
3-E
3A
1Be-C
2H
4-; A
3Do not exist; B
1Be-NH-; B
3Be-NH-; D
1Be-CH
2-; D
3Be-C (O)-; E
1It is heteroaryl; And E
3It is heteroaryl.
10. chemical compound, wherein said chemical compound is
11. one kind comprises the chemical compound of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
12. the compositions of claim 11, wherein Y is a phenyl, Z
1Be-CH
2-or-SO
2-, and Z
2Be-CH
2-or-SO
2-.
13. the compositions of claim 11, wherein X is-CH
2-, Y is 4,4 '-xenyl, Z
1Be-CH
2-, and Z
2Be-CH
2-.
14. the compositions of claim 11, wherein X is-CH
2-, Y is a phenyl, and R
3Do not exist.
15. the compositions of claim 12, wherein R
3Be-A
2-B
2-D
2-E
2Or and R
4Be C together
4-C
20Heterocyclylalkyl or C
4-C
20Heterocycloalkenyl; A
1Be-C
2H
4-or-CH (CH
3) CH
2-; A
2Be-C
2H
4-or do not exist; A
3Be-CH
2-,-C
2H
4-,-C
3H
6-,-CH (CH
2OH)-,-CH (COOH)-,-CH (CH
2OCH
3)-,-CH (CH
2CH
2OH)-,-CH (CH
2COOH)-or do not exist; B
1Be-NH-; D
1Be-CH
2-,-CH (CH
3)-,-CH (CH
2OH)-,-CH (CH
2CH
2OH)-or do not exist; D
2Be-CH
2-or do not exist; D
3Be-CH
2-,-CH (OH)-,-CH (COOH)-, 1,1-cyclopropylidene or do not exist; E
1Be H, C
3-C
8Heterocyclylalkyl, aryl or heteroaryl; E
2Be H, aryl or heteroaryl; And E
3Be aryl, heteroaryl, C
3-C
8Cycloalkyl, C
5-C
8Cycloalkenyl group or C
3-C
8Heterocyclylalkyl.
16. the compositions of claim 13, wherein R
3Be-A
2-B
2-D
2-E
2R
4Be-A
3-B
3-D
3-E
3A
1Be-C
2H
4-; A
2Do not exist; A
3Be-CH (CH
2OH)-; B
1Be-NH-; B
2Do not exist; B
3Do not exist; D
1Be-CH
2-; D
2Be-CH
2-or do not exist; D
3Be-CH
2-; E
1It is heteroaryl; E
2Be H or heteroaryl; And E
3It is aryl.
17. the compositions of claim 14, wherein R
1It is heteroaryl; R
4Be-A
3-B
3-D
3-E
3A
1Be-C
2H
4-; A
3Do not exist; B
1Be-NH-; B
3Be-NH-; D
1Be-CH
2-; D
3Be-C (O)-; E
1It is heteroaryl; And E
3It is heteroaryl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45976803P | 2003-04-02 | 2003-04-02 | |
| US60/459,768 | 2003-04-02 | ||
| US60/539,763 | 2004-01-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1798551A CN1798551A (en) | 2006-07-05 |
| CN100566712C true CN100566712C (en) | 2009-12-09 |
Family
ID=36819155
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| CNB2004800150889A Expired - Fee Related CN100566712C (en) | 2003-04-02 | 2004-03-30 | The polyamine compounds that is used for the treatment of chemokine receptor mediated disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100566712C (en) |
-
2004
- 2004-03-30 CN CNB2004800150889A patent/CN100566712C/en not_active Expired - Fee Related
Non-Patent Citations (6)
| Title |
|---|
| A seven-coordinate manganese(II) complex formed withasingle tripodal heptadentate ligand as a newsuperoxidescavenger. Alain Deroche等.Journal of the America chemistry society,Vol.118 . 1996 |
| A seven-coordinate manganese(II) complex formed withasingle tripodal heptadentate ligand as a newsuperoxidescavenger. Alain Deroche等.Journal of the America chemistry society,Vol.118 . 1996 * |
| Acceleration of p-nitrophenyl estercleavagebyZn(II)-organized molecular receptors. Paolo Tecilla等.Journal of organic chemistry,Vol.62 . 1997 |
| Acceleration of p-nitrophenyl estercleavagebyZn(II)-organized molecular receptors. Paolo Tecilla等.Journal of organic chemistry,Vol.62 . 1997 * |
| 抗氧型丁二酰亚胺分散剂的研究. 周宇等.石油炼制与化工，第28卷第2期. 1997 |
| 抗氧型丁二酰亚胺分散剂的研究. 周宇等.石油炼制与化工，第28卷第2期. 1997 * |
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