CN101103000A

CN101103000A - Carbazole, carboline, and indole derivatives useful in the inhibition of VEGF production

Info

Publication number: CN101103000A
Application number: CNA2005800466693A
Authority: CN
Inventors: 曹良弦; 崔珣奎; 文荣春; 纳达拉贾恩·塔米拉拉苏; 齐红彦; W·J·伦诺克斯; 黄盛禹
Original assignee: PTC Therapeutics Inc
Current assignee: PTC Therapeutics Inc
Priority date: 2004-11-23
Filing date: 2005-11-23
Publication date: 2008-01-09
Anticipated expiration: 2025-11-23
Also published as: CN101102765A; CN101103000B; CN101119717A

Abstract

In accordance with the present invention, compounds that inhibit the expression of VEGF post-transcriptionally have been identified, and methods for their use provided. In one aspect of the invention, compounds and compositions useful in the inhibition of BEGF production, and/or in the inhibition of angiogenesis, and/or in the treatment of cancer, diabetic retinopathy or exudative macular degeneration are provided. In another aspect of the invention, methods are provided for the inhibition of VEGF production, the inhibition of angiogenesis, and/or the treatment of cancer, diabetic retinopathy or exudative macular degeneration using the compounds of the invention.

Description

Be used to suppress carbazole, carboline and the indole derivatives that VEGF generates

Related application

According to the regulation of 35 U.S.C. § 119, the application requires the right of priority and the interests of the U.S. Provisional Application 60/629,889 of submission on November 23rd, 2004, and the full content of this application is incorporated herein by reference.According to the regulation of 35 U.S.C. § 119, the application also requires the right of priority and the interests of U.S. Provisional Application of submitting on December 6th, 2,004 60/633,738 and the U.S. Provisional Application of submitting on December 27th, 2,004 60/639,283.The full content that the application also introduces all the U.S. Provisional Patent Application 60/552,724 submitted on March 15th, 2004 and 60/552,725 as a reference.

Invention field

The present invention relates to be used to suppress method, compound and the composition that blood vessel takes place.More specifically, the present invention relates to be used to suppress method, compound and the composition that VEGF generates.

Background of invention

Unusual blood vessel occurs in the pathogeny of multiple disease and plays crucial effects, and that described disease comprises is pernicious, ischemia, inflammatory and Immunological diseases (4,18).In these diseases, what know most is cancer, exudative macular degeneration and diabetic retinopathy (DR), and in the U.S., back two kinds of diseases are the most important reason (6,7) that cause losing one's sight.In last decade, we are significantly improved to the understanding of the molecular basis that blood vessel takes place.Cytokine and growth factors such as VEGF, FGF-2, PDGF, IGF-1, TGF, TNF-α, G-CSF that multiple stimulation blood vessel takes place have obtained evaluation (2,5,19).In these somatomedins, vascular endothelial growth factor (VEGF) in blood vessel takes place, play the role of a nucleus (18).

VEGF also claims VEGF-A, is identified (23-25) because of the ability of its induction of vascular permeability and promotion vascular endothelial cell proliferation at first.VEGF is by the term single gene coding (26) that produces four kinds of isoforms through alternative splicing.All four kinds of isoforms have identical long unusually and 5 '-UTR of GC enrichment and the 3 '-UTR that comprises a plurality of rna stability determiners.The dimerization form (27,28) of acceptor VEGFR-2 (also claiming KDR or FIk-1) and VEGFR-1 (before being called Flt1) identification VEGF.The VEGFR-2 acceptor of high degree of specificity is expressed on endotheliocyte.Be bonded to the tyrosine kinase activity of the VEGF activated receptor of VEGFR-2 acceptor, cause that endothelial cell proliferation, differentiation and primitive vessel form (29).By suppressing signal transduction pathway as phantom target or by VEGFR-2, VEGFR-1 suppresses endothelial cell growth (30).

Before more than 30 years, propose, suppressing the tumor vessel generation may be the effective ways (31) of treatment cancer.Confirm that now VEGF and acceptor thereof take place to have central role (33) in the commitment of tumor growth (particularly) at tumor vessel.In fact, the vegf expression level of rising and microvessel density relevant (34) in the primary tumo(u)r tissue.In addition, the VEGF transcriptional level of rising all visible (35) in all common solid tumors.Usually, compare with no tumour individuality, lotus knurl patient has higher levels of VEGF, and the high VEGF level relevant with poor prognosis (36) in the blood serum.Consistent with the effect of VEGF in tumor vessel takes place, no VEGF embryonic stem cell shows the ability (37) of significantly reduced formation tumour in nude mice.VEGF has specific antibody in the people heterograft in the nude mice to implanting by using, and the direct evidence that relates to VEGF in tumour takes place has obtained displaying (38,39).In these researchs, the vascularization positive correlation that reduces in the inhibition of tumor growth and the tumour of Antybody therapy.The test subsequently of using soluble receptors to carry out has confirmed the importance (40) of VEGF activity in tumor growth, and show, directly cause the almost completely inhibition (41,42) of the neovascularization relevant with tumour by the VEGF inactivation of specific antibody treatment generation.

In exudative macular degeneration and diabetic retinopathy, preclinical test and clinical trial show that the excessive generation of VEGF is vital (summarizing) for abnormal retinal or choroid neovascularization in 6.Obtained in the patient who suffers from such as the disease of diabetic retinopathy and wet type macular degeneration the strong relevant evidence (43,44) of intraocular VEGF level and active retina/choroid neovascularization (CNV).In addition, what the use transgenic mice carried out studies show that, VEGF crossing in retinal pigment epithelium or photosensory cell expressed and caused choroid or retina neovascularization (45,46).Verified in nearest research, neutralizing antibody, soluble receptors, receptor antagonist or siRNA animal model and clinical in reducing in the vascularization of VEGF mediation effectively (17,47-50).

Vegf expression is regulated by multiple factor and reagent, comprises cytokine, somatomedin, steroid hormone and chemical and regulates oncogene such as ras or the active sudden change of tumor suppressor gene VHL (51,52).However, for regulating vegf expression, anoxic is the most significant physiological signal.By the stability that rising transcription rate and VEGF transcribe, anoxic causes the vegf expression (8-10) that raises.Can induce the anoxybiotic factor 1 α (HIF-1 α) to increase the transcription factor that the VEGF gene is expressed in cell, described cell stands anoxic (53,54) because of being bonded to the hypoxia response elements (HRE) that is positioned at the VEGF promotor.Because the factor combines at 3 '-UTR with element, the stability of VEGF mRNA has also obtained strengthening greatly (55).In addition, the VEGF translation of transcribing causes and has obtained unique adjusting.Under hypoxia condition, great majority have all obtained weakening greatly (56) by the translation of the cell transcription thing of cap dependency translation elicitation procedure mediation.Yet it is unique under hypoxia condition that the translation of VEGF mRNA causes, because its internal ribosome entry site (IRES) mediation (9-12) in VEGF 5 ' UTR.

Exist many tumor growths that show can be by the experimental evidence (40,72) that stops neovascularization to be inhibited.Tumor vessel is normally immature and constantly reinvent (4,73).Active and unusual blood vessel is the result that short blood vessel takes place and angiogenesis inhibitor factor normal equilibrium is broken, and the described factor comprises the various kinds of cell factor, somatomedin and steroid hormone.Although it is complicated regulating tumor vessel, the evidence of accumulation shows that target may just be enough to suppress tumor vessel generation and compacting tumor growth (38,74,75) in a kind of short angiogenesis factor.In multiple blood vessel generation target, VEGF and acceptor thereof are the most attractive (4,27).As mentioned above, with the tumor growth in the selectively targeted people heterograft in the mab treatment inhibition implantation nude mice of VEGF.Subsequently, the multiple method that is designed for deactivation VEGF signal transduction has obtained test in tumor model, and verified very effective in kinds of tumor cells system, and described tumor cell line comprises multiple cancer, sarcoma and neurospongioma (35,38,74-76).In addition, suppress VEGF by VEGF antibody and in rodent that reaches full growth or primate, do not produce pronounced side effects (77,78).Generally speaking, these results show that VEGF is the correct target of exploitation oncotherapy.In fact, VEGF inhibitor underway (3,39) is all used in multinomial clinical trial.

Though in the pathology of exudative age-related macular degeneration, relate to several short angiogenesis factors,, VEGF is in the pathogeny of this disease and development seemingly the most vital (6,90).The data that obtained by preclinical test and clinical trial show, only blocking VEGF just be enough to alleviate or the stable disease development (17,47-50).For example, suppress the VEGFR signal transduction and be enough to stop fully retina neovascularization (79) in the mouse retinopathy of precocious model by the specificity tyrosine kinase inhibitor.In addition, show recently, in mouse model, significantly suppress eye neovascularization (80) behind the photocoagulation at the siRNA (siRNA) of mouse VEGF.These results show that for treatment eye neovascular diseases such as exudative macular degeneration and diabetic retinopathy, the inhibition of the selectivity of vegf expression is attainable and the affirmation of this method is provided.

There have been three kinds of methods to be used to suppress the VEGF activity, comprised that (1) is by using specific antibody, soluble VEGF-receptor or the interactional fit oligopolymer of anti-VEGF/VEGFR (aptameroligos) neutralize VEGF activity (38,40,41,72,74,117,118); (2) suppress VEGFR Mediated Signal Transduction (75,82,119) by specificity small molecules tyrosine kinase inhibitor; (3) express (80,83,84,85) by using antisense, siRNA or ribozyme to suppress VEGF/VEGFR.Though all these methods show that all blood vessel suppresses in the significant body, they all have critical limitation.For example, treatment protein (antibody and soluble receptors) or oligopolymer (antisense, siRNA and ribozyme) all are to have bad infiltrative macromole and its productive expense height that needs parenteral admin usually.For the treatment of chronic eye neovascularization, multiple injection is because possible complication such as retinal detachment may be unpractical with the relevant infection of operation.In addition, tyrosine kinase inhibitor may have limited specificity.VEGF in normal eye and other tissue with low-level structural expression, therefore it may be deleterious suppressing the VEGF function fully by whole body administration antibody or tyrosine kinase inhibitor, particularly for the patient who suffers from AMD and DR, many in them also suffer from hypertension (86-89).

Therefore, the guide's molecule that still need to develop, sign and optimization is used to develop new angiogenesis inhibitor medicine.In view of the above, the purpose of this invention is to provide this compound.In addition, purpose of the present invention also provides the composition and the method for angiogenesis inhibitor.

All documents mentioned in this article all are incorporated herein by reference, and set forth fully at this as them.

Summary of the invention

According to the present invention, identified that suppressing VEGF transcribes the compound that express the back, and their using method is provided.

In one aspect of the invention, provide the compound that is used to suppress the VEGF generation, suppresses the formula (I)～(VIII) of blood vessel generation and/or treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration.

In one embodiment, the present invention includes and provide the compound of formula (I)

Wherein

X is hydrogen, hydroxyl; Halogen; Nitro; Cyano group; C ₁～C ₅Alkoxyl group, it is chosen wantonly and is replaced by at least one halogen; C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by at least one halogen; The optional amine that replaces; The optional carbonyl that replaces; The perhaps optional alkylsulfonyl that replaces;

R ₁Be hydrogen; C ₁～C ₆Alkyl, it is optional by at least one halogen or C ₆～C ₈Aryl replaces, and wherein said aryl is optional to be replaced by at least one halogen; C ₆～C ₈Aryl, it is chosen wantonly and is replaced by at least one halogen;-C (O)-R _a-C (O) O-R _AaPerhaps-S (O ₂)-aryl;

R ₂Be hydrogen; C ₁～C ₄Alkyl; Perhaps can with R ₃Altogether;

R ₃Be hydrogen; C ₁～C ₄Alkyl; C ₆～C ₈Aryl, it is optional by at least one halogen or C ₁～C ₅Alkoxyl group replaces; Perhaps R ₃Can with R ₂Form altogether (=O) ,=N-R _bPerhaps cycloalkyl, it is optional by C ₁～C ₆Alkyl-C ₆～C ₈Aryl or C ₆～C ₈Aryl replaces;

R ₄And R ₅Can be hydrogen independently of one another; C ₁～C ₆Alkyl; Perhaps R ₄And R ₅Can form altogether=the CH-cycloalkyl ,=CH-amino or=the CH-aryl, wherein said cycloalkyl and aryl are optional by at least one halogen group, C ₁～C ₄Alkyl, C ₁～C ₅Alkoxyl group ,-CF ₃,-OCF ₃,-NO ₂,-CN or-N (CH ₃) ₂Replace, and described amino is optional by at least one C ₁～C ₄Alkyl replaces;

R _aBe C ₁～C ₆Alkyl; C ₁～C ₅Alkoxyl group; Naphthyl;-CF ₃Perhaps C ₆～C ₈Aryl, it is optional by at least one halogen, C ₁～C ₄Alkyl, C ₁～C ₅Alkoxyl group, naphthyl ,-CF ₃,-OCF ₃,-NO ₂,-CN or-N (CH ₃) ₂Replace;

R _AaBe C ₁～C ₆Alkyl; Naphthyl;-CF ₃Perhaps C ₆～C ₈Aryl, it is optional by at least one halogen, C ₁～C ₄Alkyl, C ₁～C ₅Alkoxyl group, naphthyl ,-CF ₃,-OCF ₃,-NO ₂,-CN or-N (CH ₃) ₂Replace;

R _bBe hydroxyl or pyrryl; And

N is 0,1,2,3 or 4;

The perhaps pharmacy acceptable salt of described compound, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer.

In another embodiment, the present invention includes and provide the compound of formula (Ia)

Wherein X, R ₁, R ₂, R ₃, R ₄And R ₅As above about as described in the formula (I).

In another embodiment, the present invention includes and provide the compound of formula (Ib)

In another embodiment, the present invention includes and provide the compound of formula (II)

Wherein

X ₁Be halogen; And

R _zBe heteroaryl;

In another embodiment, the present invention includes and provide the compound of formula (III)

Wherein

X is a hydroxyl; Halogen; Nitro; Cyano group; C ₁～C ₅Alkoxyl group, it is chosen wantonly and is replaced by at least one halogen; C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by at least one halogen; The optional amine that replaces; The optional carbonyl that replaces; The perhaps optional alkylsulfonyl that replaces;

R ₀For H or-C (O) O-(C ₁-C ₆Alkyl);

R ₂Be hydrogen; C ₁～C ₄Alkyl; Perhaps can with R ₃Altogether;

R _bBe hydroxyl or pyrryl; And

N is 0,1,2,3 or 4;

R ₆Be hydrogen; C ₁～C ₆Alkyl, it is optional by C ₆～C ₈Aryl replaces, and wherein said aryl is optional to be replaced by at least one halogen;-C (O)-R _a-C (O) O-R _Aa-C (O)-NH-R _cPerhaps C ₆～C ₈Aryl, it is chosen wantonly and is replaced by at least one halogen; And

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl;

In another embodiment, the present invention also comprises and provides the compound of formula (IIIa)

Wherein

X, R ₁, R ₆With n as above about as described in the formula (III); And

R ₇Be hydrogen, phenyl or benzyl;

Pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of the compound of perhaps described formula (IIIa).

In another embodiment, the present invention also comprises and provides the compound of formula (IIIb)

Pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of the compound of perhaps described formula (IIIb).

In another embodiment, the present invention includes and provide the compound of formula (IV)

Wherein

X ₁Be halogen; And

R ₈Be C ₆～C ₈Aryl, it is optional by at least one halogen or alkoxyl group replacement,

In another embodiment, the present invention includes and provide the compound of formula V

Wherein

X ₁Be halogen;

R ₆Be hydrogen; C ₁～C ₆Alkyl, it is optional by C ₆～C ₈Aryl replaces, and wherein said aryl is optional to be replaced by at least one halogen;-C (O)-R _a-C (O) O-R _Aa-C (O)-NH-R _cPerhaps C ₆～C ₈Aryl, it is chosen wantonly and is replaced by at least one halogen;

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl; And

R _qFor hydrogen, phenyl or-OH;

In another embodiment, the present invention includes and provide the compound of formula (VI)

Wherein

X ₁Be halogen; And

R ₁And R ₆Such as above about formula (III) definition;

In another embodiment, the present invention includes and provide the compound of formula (VII)

X wherein ₁Be halogen;

In another embodiment, the present invention includes and provide the compound of formula (VIII)

Wherein

X ₁Be halogen;

R ₉For hydrogen or-C (O)-alkyl;

R ₁₀Be hydrogen;-CH ₂-R _d-C (O)-NH-R _dPerhaps-CH ₂-NH-R _d

R ₁₁Be hydrogen; C ₁～C ₆Alkyl;-CH=N-CH ₂-CH (OH)-R _dPerhaps-(CH ₂) _m-NH-R _e

R _dBe C ₆～C ₈Aryl, it is optional by at least one halogen or alkoxyl group replacement;

R _eFor-C (O)-R _fPerhaps-(CH ₂) _p-CH (OH)-R _Ff

R _fBe C ₁～C ₆Alkyl; C ₁～C ₅Alkoxyl group; Pyridyl; C ₅～C ₈Heteroaryl; Perhaps C ₆～C ₈Aryl, it is optional by at least one halogen or alkoxyl group replacement;

R _FfBe C ₁～C ₆Alkyl; Pyridyl; C ₅～C ₈Heteroaryl; Perhaps C ₆～C ₈Aryl, it is optional by at least one halogen or alkoxyl group replacement;

M is 1,2 or 3;

N is 0,1 or 2; And

P is 1,2 or 3;

In another embodiment, the present invention includes and provide the purposes of one or more compounds of the present invention in pharmaceutical compositions.

In another embodiment, the present invention includes and provide the pharmaceutical composition that comprises one or more compounds of the present invention.

In another embodiment of the present invention, the present invention includes and provide and suppress the method that VEGF generated and/or suppressed blood vessel generation and/or treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration, it uses one or more compounds of the present invention or one or more pharmaceutical compositions of the present invention.In another embodiment of the present invention, the present invention includes and provide and suppress the method that VEGF generated and/or suppressed blood vessel generation and/or treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration, it uses one or more compounds of the present invention and one or more pharmaceutical compositions of the present invention.

In another embodiment, the present invention includes and provide the method that suppresses the VEGF generation.In another embodiment, the present invention includes and provide the method that suppresses the blood vessel generation.In one embodiment, the present invention relates to suppress the method that VEGF generates, it comprises compound at least a of the present invention or pharmaceutical composition to the individual administration VEGF amount of suppression that these needs are arranged.

In another embodiment, the present invention includes and provide and suppress the method that blood vessel takes place, it comprises compound at least a of the present invention or pharmaceutical composition to the individual administration angiogenesis inhibitor amount that these needs are arranged.

In one embodiment, the present invention includes and provide and suppress VEGF method that generates and the method that suppresses the blood vessel generation, it comprises that administration VEGF suppresses or the pharmaceutical composition of the compound of the compound of one or more formulas (the I)～formula (VIII) of blood vessel generation amount of suppression and/or one or more formulas (I)～formula (VIII).

In another preferred embodiment, the present invention includes and provide one or more that comprise the drug treatment significant quantity to be selected from compound or one or more its method for compositions of compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24.

In another embodiment, the present invention relates to treat the method for cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration, described method comprises to one or more compounds of the present invention of the individual drug treatment significant quantity that these needs are arranged or one or more pharmaceutical compositions of the present invention.In preferred embodiments, the present invention includes and provide the method for pharmaceutical composition of the compound of one or more formulas (I)～formula (VIII) that the compound of one or more formulas (the I)～formula (VIII) that comprises the drug treatment amount or one or more can the delivery treatments amount.In a more preferred embodiment, the present invention includes and provide at least a method that is selected from the compound of compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 that comprises the drug treatment significant quantity.

Reference example such as following embodiment preferred, detailed description and claim, these and other aspect of the present invention will obtain clearer understanding.

Some embodiment

Embodiment suppresses the method that VEGF generates in the individuality for 1. 1 kinds, and it comprises to the formula that is selected from (I) of the individual administration VEGF amount of suppression that these needs are arranged～compound of formula (VIII) compound or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Embodiment suppresses the method that individual medium vessels takes place for 2. 1 kinds, and it comprises to the formula that is selected from (I) of the individual administration angiogenesis inhibitor amount that these needs are arranged～compound of formula (VIII) compound or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Method for cancer in 3. 1 kinds of the embodiments treatment individuality, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

4. 1 kinds of methods for the treatment of diabetic retinopathy in the individuality of embodiment, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

5. 1 kinds of methods for the treatment of exudative macular degeneration in the individuality of embodiment, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

6. 1 kinds of methods for the treatment of rheumatoid arthritis in the individuality of embodiment, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Psoriatic method in 7. 1 kinds of the embodiments treatment individuality, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Embodiment is treated the atherosis method of individual medium sized artery for 8. 1 kinds, and it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

9. 1 kinds of methods for the treatment of obesity in the individuality of embodiment, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

10. 1 kinds of methods for the treatment of chronic inflammatory diseases in the individuality of embodiment, it comprises the formula that is selected from (the I)～compound of formula (VIII) compound to the individual drug treatment significant quantity that these needs are arranged or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound

Embodiment 11. is according to each method of embodiment 1-10, and wherein said compound is the compound of numbering 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24.

12. 1 kinds of pharmaceutical compositions of embodiment, it comprises the formula of being selected from (the I)～compound of formula (VIII) compound or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer and the pharmaceutically acceptable vehicle of described compound.

Embodiment 13. is according to the pharmaceutical composition of embodiment 12, and wherein said compound is selected from compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24.

Detailed Description Of The Invention

The rise of vascular endothelial growth factor (VEGF) is the key factor that blood vessel takes place, and is the important factor that causes cancer, diabetic retinopathy and the morbidity of exudative macular degeneration (summarize in for example 1-7 in).According to the present invention, identified that suppressing VEGF transcribes the compound that express the back, and their using method is provided.Compound of the present invention has the low nmole activity that suppresses vegf expression.

Those skilled in the art understand, and some compound of the present invention can comprise chiral centre, and therefore can be used as the component existence of racemic mixture or enantiomeric pure.For example, described compound can exist as R or S isomer in the enantiomer pure component." enantiomeric pure " used herein is meant the component of being made up of individual isomer basically, preferably is made up of 75%, 80%, 85%, 90%, 92%, 95%, 98%, 99% or 100% individual isomer.

A. compound of the present invention

In one aspect of the invention, provide the compound of the present invention that is used to suppress VEGF generation or the generation of inhibition blood vessel or inhibition VEGF generation and the generation of inhibition blood vessel.The compound of the present invention of any combination that is used for the treatment of cancer, diabetic retinopathy or exudative macular degeneration or treatment cancer, diabetic retinopathy or exudative macular degeneration is provided in another aspect of this invention.

In one embodiment, compound of the present invention suppresses the VEGF generation especially.In another embodiment, compound of the present invention suppresses vegf expression and other angiogenesis factor, for example FGF-2.Thus, in the method that suppresses tumor growth, (pan-angiogenic) inhibitor takes place general blood vessel may be preferred, and for the eye neovascular diseases, the VEGF specific inhibitor may be preferred (17).

Be used to suppress the compound that compound preferred of the present invention that VEGF generates comprises formula as follows (I).

Wherein

X is a hydrogen; Hydroxyl; Halogen; Nitro; Cyano group; C ₁～C ₅Alkoxyl group, it is chosen wantonly and is replaced by at least one halogen; C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by at least one halogen; The optional amine that replaces; The optional carbonyl that replaces; The perhaps optional alkylsulfonyl that replaces;

R ₂Be hydrogen; C ₁～C ₄Alkyl; Perhaps can with R ₃Altogether;

R _bBe hydroxyl or pyrryl; And

N is 0,1,2,3 or 4;

In some preferred embodiment of formula (I), X be selected from F, Cl, Br ,-CH ₃,-CH ₂-CH ₃,-CF ₃With-O-CF ₃In other preferred embodiment of formula (I), n is 1.In other preferred embodiment of formula (I), X be selected from F, Cl, Br ,-CH ₃,-CH ₂-CH ₃,-CF ₃With-O-CF ₃And n is 1.In the preferred embodiment of formula (I), X is selected from Cl or Br.In another preferred embodiment of formula (I), X is Cl.In other preferred embodiment of formula (I), X is Br.In the more preferred of formula (I), X is selected from Cl or Br, and n is 1.In another more preferred of formula (I), X is Cl, and n is 1.In another more preferred of formula (I), X is Br, and n is 1.

In an embodiment of formula (I), X is the optional amine that replaces.In one embodiment, X is single amine that replaces.In another embodiment, X is two replacement amine.In other embodiments, X is a monoalkylamine.In other embodiments, X is a dialkylamine.In one embodiment, the monoalkylamine that replaced by one or more halogen of X.In another embodiment, the dialkylamine that replaced by another or a plurality of halogen of X.In one embodiment, the monoalkylamine that replaced by one or more fluorine of X.In another embodiment, the dialkylamine that replaced by one or more fluorine of X.

In another embodiment of formula (I), X is the optional carbonyl that replaces.In one embodiment, described carbonyl is not substituted and have-form of C (O) H.In one embodiment, X is by C ₁～C ₆The carbonyl that alkyl replaces (C (O)-(C for example ₁～C ₆Alkyl)).In another embodiment, X is by C ₁～C ₆The carbonyl that alkyl replaces, wherein said alkyl is replaced by one or more halogen.In another embodiment, X is by C ₁～C ₆The carbonyl that alkyl replaces, wherein said alkyl is replaced by one or more fluorine.

In another embodiment of formula (I), X is the optional alkylsulfonyl that replaces.In one embodiment, X is by C ₁～C ₆The alkylsulfonyl that alkyl replaces.In another embodiment of formula (I), X is the optional alkylsulfonyl that replaces.In one embodiment, X is by C ₁～C ₆The alkylsulfonyl that alkyl replaces, wherein said alkyl is replaced by one or more halogen.In one embodiment, X is by C ₁～C ₆The alkylsulfonyl that alkyl replaces, wherein said alkyl is replaced by one or more fluorine.

In other embodiment of formula (I), R ₁Be hydrogen; C ₁～C ₆Alkyl, it is optional by at least one halogen or C ₆～C ₈Aryl replaces, wherein said C ₆～C ₈Aryl is optional to be replaced by at least one halogen;-C (O)-R _a-C (O) O-R _AaPerhaps-S (O ₂)-aryl, wherein R _aAnd R _AaSuch as above about formula (I) definition.

In the preferred embodiment of formula (I), R ₁Be hydrogen.In another preferred embodiment of formula (I), R ₁Be C ₁～C ₆Alkyl, it is optional by C ₆～C ₈Aryl replaces.In other preferred embodiment, R ₁Be methyl, it is optional by C ₆～C ₈Aryl replaces.In another preferred embodiment of formula (I), R ₁Be C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by phenyl.In another preferred embodiment of formula (I), R ₁Be methyl, it is chosen wantonly and is replaced by phenyl.

In the preferred embodiment of formula (I), R ₁For-C (O) (O)-C ₆～C ₈Aryl.In another preferred embodiment of formula (I), R ₁For-C (O) (O)-phenyl.

In another preferred embodiment of formula (I), R ₁For-C (O)-aryl bicyclic.In another preferred embodiment of formula (I), R ₁For-C (O)-naphthyl.

In another preferred embodiment of formula (I), R ₁For-C (O)-C ₁～C ₆Alkyl.In other preferred embodiment of formula (I), R ₁For-C (O)-methyl.

In the preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by halogen.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by chlorine or bromine.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by chlorine.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by bromine.

In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-OCF ₃Replace.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl quilt-OCF ₃Replace.

In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by halogen.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by chlorine.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by bromine.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by halogen.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by chlorine.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by bromine.

In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-OCF ₃Replace.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-NO ₂Replace.In another preferred embodiment of formula (I), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-CN replaces.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl quilt-OCF ₃Replace.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl quilt-NO ₂Replace.In another preferred embodiment of formula (I), R ₁For-C (O)-phenyl, wherein said phenyl quilt-CN replaces.

In the preferred embodiment of formula (I), R ₁For-S (O ₂)-aryl.In another preferred embodiment of formula (I), R ₁For-S (O ₂)-phenyl.

In the preferred embodiment of formula (I), R ₂And R ₃All be hydrogen.In another preferred embodiment of formula (I), R ₂And R ₃Form altogether (=O).In another preferred embodiment of formula (I), R ₂And R ₃Formation=N-R altogether _b, R wherein _bAs being defined so that following formula (I) is middle.In another preferred embodiment of formula (I), R ₂And R ₃Formation=N-hydroxyl altogether.In another preferred embodiment of formula (I), R ₂And R ₃Formation=N-pyrryl altogether.

In the embodiment of formula (I), R ₄And R ₅The substituting group of formation=CH-aryl, and preferred aryl groups altogether comprises-CH ₃,-CF ₃,-NO ₂,-CN ,-OCH ₃,-OC (CH ₃) ₃,-OCF ₃, F, Br and Cl.In another embodiment of formula (I), R ₄And R ₅The substituting group of formation=CH-aryl, and preferred aryl groups altogether be independently selected from F and-OCH ₃In another preferred embodiment of formula (I), R ₄And R ₅Formation=CH-aryl altogether, wherein aryl is a phenyl.In another preferred embodiment of formula (I), R ₄And R ₅Formation=CH-aryl altogether, wherein aryl is a substituted-phenyl, and preferred phenyl substituent comprises-CH ₃,-CF ₃,-NO ₂,-CN ,-OCH ₃,-OC (CH ₃) ₃,-OCF ₃, F, Br and Cl.In another preferred embodiment of formula (I), R ₄And R ₅Comprise substituted-phenyl altogether, and preferred phenyl substituent be independently selected from F and-OCH ₃

In another preferred embodiment of formula (I), R ₁Be selected from following substituting group:

In another preferred embodiment of formula (I), R ₂And R ₃Form altogether:

In another preferred embodiment of formula (I), R ₄And R ₅Can be independently selected from:

Preferred compound in the formula (I) comprises the compound of formula (Ia) as shown below.

In another embodiment, the compound of preferred formula (I) comprises the compound of formula (Ib) as shown below

R wherein ₁Be hydrogen, and X is a halogen.

R wherein ₁Be hydrogen and X ₁For the preferred embodiment of the compound of the formula (Ib) of halogen as follows:

In one embodiment, the compound of formula (I) is not the compound of formula (Ia).In another embodiment, the compound of formula (I) is not the compound of formula (Ib).

In another embodiment, preferred compound of the present invention comprises the compound of formula shown below (II).

X wherein ₁Be halogen and R _zBe heteroaryl.

In the preferred embodiment of formula (II), X ₁Be halogen and R _zBe 5～6 yuan of heteroaryls.In another preferred embodiment of formula (II), X ₁Be halogen and R _zFor containing 5～6 yuan of heteroaryls of one or more bridged ring nitrogen-atoms.In another preferred embodiment of formula (II), X ₁Be halogen and R _zFor containing 5～6 yuan of heteroaryls of a bridged ring nitrogen-atoms.In the further preferred embodiment of formula (II), X ₁Be halogen and R _zBe pyrryl.In another preferred embodiment of formula (II), X ₁Be bromine and R _zBe pyrryl.

In another embodiment, the compound preferred of the present invention that is used to suppress vegf expression comprises the compound of formula as follows (III).

Wherein

X, R ₁, R ₂, R ₃, R _a, R _Aa, R _bWith n as above about as described in the formula (I);

R ₀For H or-C (O) O-(C ₁-C ₆Alkyl);

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl;

In the preferred embodiment of formula (III), n is 1.In another preferred embodiment, n is 0.

In another preferred embodiment of formula (III), X is a halogen.In the preferred embodiment of formula (III), X is Br or Cl.In another preferred embodiment of formula (III), X is Br.In another preferred embodiment of formula (III), X is Cl.

In the preferred embodiment of formula (III), R ₁Be hydrogen;-C (O)-R _a-C (O) O-R _Aa-S (O ₂)-aryl; Perhaps C ₁～C ₆Alkyl, it is optional by at least one C ₆～C ₈Aryl replaces, and wherein said aryl is optional to be replaced by at least one halogen.

In the preferred embodiment of formula (III), R ₁For-C (O) (O)-R _AaIn the preferred embodiment of formula (III), R ₁For-C (O) (O)-C ₆～C ₈Aryl.In the preferred embodiment of formula (III), R ₁For-C (O) (O)-phenyl.

In the preferred embodiment of formula (III), R ₁Be hydrogen.

In the preferred embodiment of formula (III), R ₁Be C ₁～C ₆Alkyl, it is optional by at least one C ₆～C ₈Aryl replaces, and wherein said aryl is optional to be replaced by at least one halogen.In another preferred embodiment of formula (III), R ₁Be C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by at least one phenyl, and wherein said phenyl is optional to be replaced by at least one halogen.In another preferred embodiment of formula (III), R ₁Be C ₁～C ₆Alkyl, it is chosen wantonly and is replaced by at least one phenyl, and wherein said phenyl is replaced by chlorine.

In another preferred embodiment of formula (III), R ₁Be methyl, it is chosen wantonly and is replaced by at least one phenyl, and wherein said phenyl is optional to be replaced by at least one halogen.In another preferred embodiment of formula (III), R ₁Be methyl, it is chosen wantonly and is replaced by at least one phenyl, and wherein said phenyl is replaced by chlorine.

In another preferred embodiment of formula (III), R ₁For-S (O ₂)-aryl.In another preferred embodiment of formula (III), R ₁For-S (O ₂)-phenyl.

In another preferred embodiment of formula (III), R ₁For-C (O)-R _aIn the preferred embodiment of formula (III), R ₁For-C (O)-C ₁～C ₅Alkoxyl group.In the preferred embodiment of formula (III), R ₁For-C (O)-oxyethyl group.

In another preferred embodiment of formula (III), R ₁For-C (O)-naphthyl.

In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl.In another preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by at least one halogen.In another preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by chlorine or bromine.In another preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by chlorine.In another preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by bromine.

In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is by C ₁～C ₅Alkoxyl group replaces.In another preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl is replaced by methoxyl group.

In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-CF ₃Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-OCF ₃Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-NO ₂Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-C ₆～C ₈Aryl, wherein said C ₆～C ₈Aryl quilt-CN replaces.In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl quilt-CF ₃Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl quilt-OCF ₃Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl quilt-NO ₂Replace.In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl quilt-CN replaces.

In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl.In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by at least one halogen.In another preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by chlorine or bromine.In another preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by chlorine.In another preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by bromine.

In the preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is by C ₁～C ₅Alkoxyl group replaces.In another preferred embodiment of formula (III), R ₁For-C (O)-phenyl, wherein said phenyl is replaced by methoxyl group.

The preferred embodiment of formula (III) comprises wherein R ₂And R ₃It all is the compound of hydrogen.Other preferred embodiment of formula (III) comprises wherein R ₂And R ₃All be C ₁～C ₄The compound of alkyl.Other preferred embodiment of formula (III) comprises wherein R ₂And R ₃It all is the compound of methyl.Other preferred embodiment of formula (III) comprises wherein R ₂And R ₃Form the compound of following group altogether:

With reference to formula (III), in one embodiment, the preferred aryl groups substituting group comprises :-CH ₃,-CF ₃,-NO ₂,-CN ,-OCH ₃,-OC (CH ₃) ₃,-OCF ₃, F, Br and Cl.

In another preferred embodiment of formula (III), R ₆Be selected from:

In other preferred embodiment of formula (III), R ₀Be hydrogen.In another preferred embodiment of formula (III), R ₀For:

In another preferred embodiment, the formula III compound is the component of enantiomeric pure.

Preferred compound in the formula (III) comprises the compound of formula as follows (IIIa).

Wherein X, R ₁, R ₆With n as above about as described in the formula (III), and R ₇Be hydrogen, phenyl or benzyl.

In another preferred embodiment, provide the compound of formula (IIIa), wherein R ₇Be hydrogen or phenyl.

Other preferred compound in the formula (III) comprises the compound of formula as follows (IIIb).

Wherein X, R ₁, R ₆With n as above about as described in the formula (III).

In another embodiment, preferred compound of the present invention comprises the compound of formula as follows (IV).

Wherein

X ₁Be halogen; And

R ₈Be C ₆～C ₈Aryl, it is optional by at least one halogen or alkoxyl group replacement.

In the preferred embodiment of formula (IV), X ₁Be chlorine.In another preferred embodiment of formula (IV), R ₈Be C ₆～C ₈Aryl.In another preferred embodiment of formula (IV), R ₈For by C ₁～C ₄The C that alkoxyl group replaces ₆～C ₈Aryl.In another preferred embodiment of formula (IV), R ₈Be the C that is replaced by methoxyl group ₆～C ₈Aryl.In another preferred embodiment of formula (IV), R ₈Be phenyl.In another preferred embodiment of formula (IV), R ₈For by C ₁～C ₄The phenyl that alkoxyl group replaces.In another preferred embodiment of formula (IV), R ₈Be the phenyl that is replaced by methoxyl group.

In another embodiment, preferred compound of the present invention comprises the compound of formula V as follows.

Wherein

X ₁Be halogen;

R _qFor hydrogen, phenyl or-OH; And

R ₁And R ₆Such as above about formula (III) definition.

In the preferred embodiment of formula V, X ₁Be chlorine or bromine.In another preferred embodiment, X ₁Be chlorine.In another preferred embodiment, X ₁Be bromine.

In the preferred embodiment of formula V, R ₁Be hydrogen.

In the preferred embodiment of formula V, R _qBe hydrogen.In another preferred embodiment of formula V, R _qFor phenyl or-OH.

In the preferred embodiment of formula V, R ₆Be hydrogen.In another preferred embodiment of formula V, R ₆For-C (O) O-alkyl.In another preferred embodiment, R ₆For-C (O) O-ethyl.

In another preferred embodiment, formula V compound is the component of enantiomeric pure.

In another embodiment, preferred compound of the present invention comprises the compound of formula as follows (VI).

X wherein ₁Be halogen, and R ₁And R ₆Such as above about formula (III) definition.

In the preferred embodiment of formula (VI), X ₁Be chlorine.In another preferred embodiment of formula (VI), R ₁Be hydrogen.In another preferred embodiment of formula (VI), R ₆For-C (O)-R _a, R wherein _aBe C ₁～C ₅Alkyl or phenyl.In another preferred embodiment of formula (VI), R ₆For-C (O)-R _a, R wherein _aBe C ₁～C ₅Alkyl.In another preferred embodiment of formula (VI), R ₆For-C (O)-R _a, R wherein _aBe methyl.In the preferred embodiment of formula (VI), R ₁Be hydrogen and R ₆For-C (O)-R _a, R wherein _aBe C ₁～C ₅Alkyl or phenyl.In the preferred embodiment of formula (VI), R ₁Be hydrogen and R ₆For-C (O)-R _a, R wherein _aBe phenyl.In the preferred embodiment of formula (VI), R ₁Be hydrogen and R ₆For-C (O)-R _a, R wherein _aBe C ₁～C ₅Alkyl.In the preferred embodiment of formula (VI), R ₁Be hydrogen and R ₆For-C (O)-R _a, R wherein _aBe methyl.

In another embodiment, preferred compound of the present invention comprises the compound of formula as follows (VII).

X wherein ₁Be halogen.

Other the preferred compound of the present invention that is used to suppress vegf expression comprises the compound of formula as follows (VIII):

Wherein

X ₁Be halogen;

R ₉For hydrogen or-C (O)-alkyl;

R ₁₀Be hydrogen;-CH ₂-R _d-C (O)-NH-R _dPerhaps-CH ₂-NH-R _d

R _eFor-C (O)-R _fPerhaps-(CH ₂) _p-CH (OH)-R _Ff

M is 1,2 or 3;

N is 0,1 or 2; And

P is 1,2 or 3.

In the preferred embodiment of formula (VIII), n is 1.In other preferred embodiment of formula (VIII), n is 0.

In the preferred embodiment of formula (VIII), X ₁Be chlorine or bromine.

In other embodiment preferred, R ₉Be selected from:

In another preferred embodiment of formula (VIII), R ₁₀Be selected from:

In another preferred embodiment of formula (VIII), R ₁₁Be selected from following:

The saturated hydrocarbyl of term used herein " alkyl " general reference straight chain, side chain or cyclic configuration comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl group and n-octyl or the like.In some embodiments, alkyl substituent can be C ₁～C ₈, C ₁～C ₆Perhaps C ₁～C ₄Alkyl.

In certain embodiments, described alkyl can be chosen wantonly by one or more halogen atom or alkoxyl group and replace.For example, described alkyl can be haloalkyl, dihalo alkyl or tri haloalkyl.

Term used herein " thiazolinyl " general reference has straight chain, side chain or the cyclic olefin group of one or more carbon-carbon double bond, as C ₂～C ₆Thiazolinyl comprises the 3-propenyl.

" aryl " used herein is meant the carbocyclic ring aromatic ring structure.Described aryl comprises the aromatic ring with 5～20 carbon atoms.The aryl rings structure comprises the compound with one or more ring structure, as monocycle, two ring or tricyclic compounds.The example of aryl comprises phenyl, tolyl, anthryl, fluorenyl, indenyl, Azulene base, phenanthryl (promptly luxuriant and rich with fragrance) and naphthyl (being naphthalene) ring structure.In certain embodiments, described aryl can be chosen wantonly and be substituted.

" heteroaryl " used herein is that one or more atom in the finger ring is the ring-type aromatic ring structure of the element (heteroatoms) of non-carbon.Heteroatoms is generally O, S or N atom.Heteroaryl comprises and can be independently selected from O, N and S heteroaryl ring structure.Described ring structure can comprise the compound with one or more ring structure, as monocycle, two ring or tricyclic compounds.In some embodiments, described heteroaryl can be selected from and contain two or more heteroatomss, three or more heteroatomss or four or more a plurality of heteroatomic heteroaryl.The heteroaryl ring structure can be selected from the ring structure that contains five or more a plurality of atom, six or more a plurality of atom or eight or more a plurality of atoms.The example of heteroaryl ring structure comprises: acridine, benzoglyoxaline, benzoxazole, benzo dioxole, cumarone, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-naphthyridine, furans, furazan, imidazoles, indoles, isoxazole, isoquinoline 99.9, isothiazole, oxazole, purine, pyridazine, pyrazoles, pyridine, pyrazine, pyrimidine, pyrroles, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazolium and quinazoline.

" heterocycle " used herein is that one or more atom in the finger ring is the cyclic rings structure of the element (heteroatoms) of non-carbon.Heteroatoms is generally O, S or N atom.Heterocycle comprises and can be independently selected from O, N and S heterocyclic ring structure.Described ring structure can comprise the compound with one or more ring structure, as monocycle, two ring or tricyclic compounds.The example of heterocyclic group comprises morpholinyl, pyrrolidone-base, pyrrolidyl, piperidyl, piperazinyl, glycolylurea base, Valerolactim base, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base (tetrahydroprimidinyl), tetrahydro-thienyl or tetrahydro thiapyran base or the like.In certain embodiments, described heterocycle can be chosen wantonly and be substituted.

" alkoxyl group " used herein general reference structure is-group of O-R.In certain embodiments, R can be alkyl, as C ₁～C ₈Perhaps C ₁～C ₅Alkyl.In certain embodiments, the R group of described alkoxyl group can be chosen wantonly by at least one halogen and replace.For example, the R group of described alkoxyl group can be haloalkyl, dihalo alkyl or tri haloalkyl.

Be purpose of the present invention, halogenic substituent can be independently selected from halogen such as fluorine, chlorine, bromine, iodine and astatine.

The present invention also comprises pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid and the steric isomer of the compound of formula (I)～(VIII).

Be the object of the invention, when comprising such as but not limited to X, X ₁, R _z, R ₀, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₉, R ₁₀, R ₁₁, R _a, R _Aa, R _b, R _c, R _d, R _e, R _fAnd R _FfWhen one or more interior functional group is introduced in the molecule (comprising embodiment preferred) of formula (I)～(VIII), each functional group that occurs on any position in disclosed scope can select independently, and in the time of suitably, can be substituted independently.In addition, when more general substituting group is listed in any position in the molecule of the present invention, should be appreciated that this general substituting group can replace with substituting group more specifically, and the gained molecule is in the scope of molecule of the present invention.

Preferred compound of the present invention comprises following:

Particularly preferred compound of the present invention is a compound number: 2,4,5,6 and 8～24.

Above-claimed cpd is only enumerated and is used for providing the example that can be used for method of the present invention.Based on content disclosed by the invention, this area the end personnel can understand, and other compound that can be used for method as herein described also is intended to be included in the invention scope of claim protection.

B. The preparation of compound of the present invention

Compound of the present invention can be prepared according to any way known in the art.For example, compound of the present invention can be prepared according to following general route.

More specifically, the general route that is used for the compound of preparation formula (I) is described in following route I.

Route I

In another embodiment, the compound of formula (Ib) can be prepared according to following route Ib.

Route Ib

The compound of formula II can be prepared according to route II shown below usually.

Route II

For R wherein ₀Be hydrogen and R ₆For H ,-C (O)-R _a,-C (O) O-R _AaPerhaps-C (O)-NH-R _cThe compound of formula III, the compound of such formula (III) can be prepared shown in following route III usually.

Route III

Route III has shown to have identical R ₁And R ₆Group (is expressed as-C (O)-R _a) several compounds can be prepared by the following method: make 2-(1H-indol-3-yl) ethamine and acyl chlorides R _a-C (O) Cl reaction is subsequently with R ₂C (O) R ₃Reaction.Has identical R ₁And R ₆Other compound of group can be prepared similarly.For example, has-C (O) O-R _AaThe identical R of form ₁And R ₆The compound of group can be prepared by the following method: make corresponding acyl chlorides (R _a'-O-C (O) Cl) with the reaction of 2-(1H-indol-3-yl) ethamine, subsequently with R ₂C (O) R ₃Carry out ring-closure reaction.

In special embodiment, the compound of formula III b can be prepared by using the method based on phosgene, is illustrated in for example 6-bromo-2,3,4, in 9-tetrahydrochysene-b-carboline-1-ketone (compound 9, embodiment 1F) synthetic.

The compound of formula IV can be prepared shown in following route IV usually.

Route IV

The compound of formula V can be prepared shown in following route V usually.

Route V

Ref：Chem.Pharm.Bull.1987，4700.

The compound of formula VI, for example R wherein ₆For-C (O)-R _a,-C (O) O-R _AaPerhaps-compound of C (O)-NH-Rc can be prepared shown in following route VI usually.

Route VI

The compound of formula VII can be prepared shown in following route VII usually.

Route VII

The compound of formula VIII can be prepared shown in following route VIII usually.

Route VIII

As understood by those skilled in the art, these and other reaction method can be used to prepare compound of the present invention.The multiple modification of above-mentioned route and method can be that significantly the present invention is not specifically prepared the restriction of the method for compound of the present invention for those skilled in the art.

Usually, synthetic method as herein described can be used known raw material in multiple marketable material, the document and by use standard synthetic method and the program raw material of preparation easily.The standard synthetic method that is used for preparing organic molecule and conversion and handles functional group can be obtained from relevant scientific and technical literature with program or be obtained from the canonical reference textbook of this area.Though be not limited to any or several sources, the organic synthesis of generally acknowledging makes reference to the text-book and comprises, for example: Smith, M.B.; March, J.March ' s Advanced Organic Chemistry:Reactions, Mechanisms, andStructure, the 5th edition; John Wiley ﹠amp; Sons:New York, 2001; And Greene, T.W.; Wuts, P.G.M.Protective Groups in Organic Synthesis, the third edition; John Wiley﹠amp; Sons:New York, 1999.The description of above-mentioned synthetic method is illustrative rather than definitive thereof the general method that is used to prepare compound of the present invention.

C. Method of the present invention

In another aspect of this invention, provide the method that suppresses the VEGF generation.In others of the present invention, provide and suppressed the method that blood vessel takes place.In another aspect of this invention, provide method by the arbitrary combination of utilizing compounds for treating cancer as herein described, diabetic retinopathy, exudative macular degeneration or these diseases.In one embodiment, provide inhibition VEGF generation and blood vessel that the method for the two takes place.In another embodiment, providing inhibition VEGF to generate, suppress blood vessel takes place or suppresses the VEGF generation the two to take place and treat the method that one or more are selected from the disease of cancer, diabetic retinopathy and exudative macular degeneration with blood vessel.

Be not intended to be limited by theory, believe that method of the present invention is by regulating the active machine-processed combinations of VEGF.

In one embodiment, the present invention relates to suppress the method that VEGF generates, it comprises the compound at least a of the present invention to the individual administration VEGF amount of suppression that these needs are arranged.

In another embodiment, provide and suppressed the method that blood vessel takes place, it comprises the compound at least a of the present invention to the individual administration angiogenesis inhibitor amount that these needs are arranged.

In one embodiment, method of the present invention comprises the method that suppresses VEGF generation in the individuality, and it comprises the compound to the formula that is selected from (I) of the individual administration VEGF amount of suppression that these needs are arranged～compound of formula (VIII) or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In another embodiment, method of the present invention comprises the method that suppresses individual medium vessels generation, and it comprises the compound to the formula that is selected from (I) of the individual administration angiogenesis inhibitor amount that these needs are arranged～compound of formula (VIII) or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In another embodiment, method of the present invention comprises method for cancer in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Method of the present invention also comprises the method for diabetic retinopathy in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

Another embodiment of the present invention comprises the method for exudative macular degeneration in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In another embodiment, method of the present invention comprises the method for rheumatoid arthritis in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In another embodiment, method of the present invention comprises psoriatic method in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In another embodiment, method of the present invention comprises treatment individual medium sized artery atherosis method, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In other embodiments, method of the present invention comprises the method for obesity in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In other embodiments, method of the present invention comprises the method for chronic inflammatory diseases in the treatment individuality, and it comprises the formula that is selected from (the I)～compound of formula (VIII) to the individual drug treatment significant quantity that these needs are arranged or the compound of pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.

In other embodiments, the method that suppresses VEGF generation, the generation of inhibition blood vessel, treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration is provided, and it comprises the compound at least a of the present invention to the individual drug treatment significant quantity that these needs are arranged.In preferred embodiments, one or more compounds of the present invention that are used for method of the present invention are formula (I), (II), (III), (IV), (V), (VI), (VII) or compound (VIII).In a more preferred embodiment, the method for inhibition VEGF generation and/or the generation of inhibition blood vessel and/or treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration comprises at least a compound that is selected from compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 of drug treatment significant quantity.

The method according to this invention can be extremely individual with one or more compound administrations through any medicine route of delivery known in the art.In preferred embodiments, described individuality is a Mammals.In a more preferred embodiment, described individuality is the people.Concrete exemplary route of administration for example includes but not limited to by oral, eye, rectum, contain that clothes, part, nose, eyes, subcutaneous, intramuscular, intravenously (injecting and infusion), brain are interior, transdermal and pulmonary administration.

Term used herein " VEGF amount of suppression ", " angiogenesis inhibitor amount " and " treatment significant quantity " are meant treatment, improve or prevent described disease or symptom, perhaps show the amount of detectable treatment or inhibiting medicament.Described effect can be by for example disclosed assay method detection in following examples.Body weight, the size and healthy that can depend on described individuality for the accurate and effective amount of individuality; The nature and extent of disease; And the treatment or the therapeutic combination of the administration of selecting.For given situation, the treatment significant quantity can be determined by routine test of this area and clinician's judgement.

For any compound, its treatment significant quantity can at first be cultivated in the mensuration or assessment in animal model (being generally rat, mouse, rabbit, dog or pig) at cell (for example oncocyte).Animal model can also be used for determining suitable concentration range and route of administration.Then, can use such information to determine the effective dose and the approach of administration in the people.Treatment/prevention effects and toxicity can be definite in cell culture or experimental animal by standard pharmaceutical procedures, for example, and ED ₅₀(colony 50% in the effective dosage of treatment) and LD ₅₀(to 50% lethal dosage of colony).Dosage between therapeutic action and the toxic action is than being therapeutic index, and it can be expressed as LD ₅₀/ ED ₅₀Ratio.The pharmaceutical composition of the high therapeutic index of preferred performance.Can be used to draft the dosage range that is used for the people by the data that cell cultures is measured and zooscopy obtains.The dosage that preferred package is contained in this composition is comprising ED ₅₀And almost do not have or do not have in the toxic circulation composition scope.The susceptibility and the route of administration that depend on employed formulation, patient, described dosage can change in this scope.

More specifically, the observed concentration of compound of the present invention-biological action relation is shown that the primary target plasma concentration is about 5 μ g/mL～about 100 μ g/mL, preferred about 10 μ g/mL～about 50 μ g/mL, more preferably from about 10 μ g/mL～about 25 μ g/mL.In order to realize such plasma concentration, depend on route of administration, the dosage of compound of the present invention can be 0.1 μ g～100000mg.Guidance about concrete dosage and delivering method is provided in the document, and this area doctor can obtain usually.For body weight is the patient of about 40～about 100kg, usually dosage can be about 1mg/ days～about 10g/ days, perhaps about 0.1g～about 3g/ days, perhaps about 0.3g～about 3g/ days, perhaps about 0.5g～about 2g/ days, it is single, separation or successive doses (be higher than or be lower than the patient of this weight range for body weight, particularly be lower than the children of 40kg, can adjust this dosage).

Accurately dosage can be determined according to the factor relevant with the individuality of needs treatment by the doctor.Adjust dosage and administration with promoting agent that enough levels are provided or the effect that keeps expectation.Admissible factor comprises the severity of morbid state, individual general health situation, individual age, body weight and sex, diet, administration time and frequency, medication combined, reaction sensibility and tolerance/response to treating.The transformation period and the clearance rate that depend on concrete preparation, depot drug product composition can per 3～4 days, weekly or administration biweekly whenever.

D. The meta-bolites of compound of the present invention

The interior metabolism product that also comprises compound as herein described in the scope of the present invention.These products can be for example produced by the oxidation of the compound of administration, reduction, hydrolysis, amidation, esterification or the like, mainly are owing to enzyme process produces.Therefore, the present invention includes the compound that generates by the following method, described method comprises makes compound of the present invention contact one period that is enough to produce its meta-bolites with mammalian tissues or Mammals.These products are generally identified by the following method: preparation radio-labeling (C for example ¹⁴Perhaps H ³) compound of the present invention, (for example greater than about 0.5mg/kg) is administered to Mammals such as rat, mouse, cavy, monkey or people with it with detectable dosage, give time enough so that (general about 30 seconds～30 hours) take place in metabolism, and from urine, blood or other biological sample, separate its converted product.Because these products are through mark, so they are easy to separate (other separates by utilizing the antibody that can be combined in the epi-position that exists in the meta-bolites).The meta-bolites structure is determined in a usual manner, for example analyzes by MS or NMR and determines.Usually, the analysis of meta-bolites can be carried out according to the mode identical with conventional medicine metabolism research well known to those skilled in the art.Converted product as long as they are not to be found in vivo, may be used in the diagnostic assay of therapeutic dose of compound of the present invention, even they itself do not have biological activity.

E. Pharmaceutical composition of the present invention

Though compound of the present invention may may preferably be mixed with pharmaceutical composition with described compound with the pure substance administration.Therefore, in another aspect of this invention, provide the pharmaceutical composition that is used for method of the present invention.Pharmaceutical composition of the present invention can be prepared with pharmaceutically acceptable vehicle, described vehicle such as carrier, solvent, stablizer, auxiliary agent, thinner or the like, and this depends on the concrete pattern and the formulation of administration.Described pharmaceutical composition should be prepared usually to realize compatible pH on the physiology, and described pH can be about pH3～about pH11, preferably about pH3～about pH7, and this depends on preparation and route of administration.In another embodiment, can be with pH regulator to about pH4～about pH7.In another embodiment, may be preferably with pH regulator to about pH5～about pH8.

More specifically, pharmaceutical composition of the present invention comprises compound at least a of the present invention and one or more pharmaceutically acceptable vehicle of treatment or prevention significant quantity.Randomly, pharmaceutical composition of the present invention can comprise combination of compounds of the present invention, perhaps can comprise the second kind of activeconstituents that is used for the treatment of cancer, diabetic retinopathy or exudative macular degeneration.

In one embodiment, pharmaceutical composition of the present invention comprises the compound and the pharmaceutically acceptable vehicle of the formula of being selected from (the I)～compound of formula (VIII) or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or the steric isomer of described compound.In a more preferred embodiment, pharmaceutical composition of the present invention comprises pharmaceutically acceptable vehicle and is selected from compound number: 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 compound.

Preparation of the present invention for example is used for the preparation of parenteral or oral administration, and great majority are generally solid, liquor, emulsion or suspensoid, and the inhalative solution formulation that is used for pulmonary administration is generally liquor or pulvis, usually preferred pulvis.Preferred pharmaceutical composition of the present invention can also be mixed with before the administration with physiology on the lyophilized solid that duplicates of compatible solvent.Perhaps, pharmaceutical composition of the present invention can be mixed with syrup, emulsifiable paste, ointment, tablet or the like.

Term " pharmaceutically acceptable vehicle " is meant the vehicle that is used for administration medicament such as compound of the present invention.This term be meant any can administration and can not produce inappropriate toxic drug excipient.Pharmaceutically acceptable vehicle part is by the concrete composition decision of institute's administration, also by the concrete grammar decision that is used for the described composition of administration.Therefore, the suitable formulations (referring to for example Remington ' s Pharmaceutical Sciences) that has multiple pharmaceutical composition of the present invention.

Suitable vehicle can be to comprise big slow metabolic macromolecular carrier molecule such as protein, polysaccharide, poly(lactic acid), polyglycolic acid, polymeric amino acid, amino acid copolymer and inertia virion.Other Exemplary excipients comprises antioxidant such as xitix; Sequestrant such as EDTA; Carbohydrate such as dextrin, hydroxy alkyl cellulose, hydroxyalkyl methylcellulose gum, stearic acid; Liquid is as oil, water, salt solution, glycerine and ethanol; Wetting agent or emulsifying agent; The pH buffer substance; Or the like.Liposome is also included within the definition of pharmaceutically acceptable vehicle.

Pharmaceutical composition of the present invention can be mixed with any form that is suitable for being intended to medication.When the intention oral application; for example, but can prepare tablet, lozenge, lozenge, water or oil suspension, non-aqueous solution agent dispersion powder or granule (comprising micronized particle or nano particle), emulsion, hard or soft capsule, syrup or elixir.The composition of intention oral application can be according to any methods known in the art preparation that is used for pharmaceutical compositions, and for good to eat preparation is provided, this composition can contain one or more reagent that comprises sweeting agent, perfume compound, tinting material and sanitas.

The pharmaceutically acceptable vehicle that is particularly suitable for being used in combination with tablet comprises for example inert diluent such as Mierocrystalline cellulose, lime carbonate or yellow soda ash, lactose, calcium phosphate or sodium phosphate; Disintegrating agent such as croscarmellose, polyvinylpolypyrrolidone, W-Gum or alginic acid; Tackiness agent such as polyvidone, starch, gelatin or gum arabic; With lubricant such as Magnesium Stearate, stearic acid or talcum.Tablet can not have dressing or can carry out dressing with disintegration and the absorption of delay in gi tract by known technology (comprising micro encapsulation), thereby the continuous action in the long period is provided.For example, time-delay material such as Zerol or Stearic diglyceride can use separately or use with paraffin.

The preparation that is used for oral application can also exist as hard gelatin capsule, wherein activeconstituents mixes with inert solid diluent (for example Mierocrystalline cellulose, lactose, calcium phosphate or kaolin), perhaps exist, wherein activeconstituents and non-water or oily medium such as glycerine, propylene glycol, polyoxyethylene glycol, peanut oil, whiteruss or mixed with olive oil as soft gelatin capsule.

In another embodiment, pharmaceutical composition of the present invention can be mixed with suspensoid, it comprises and at least a compound of the present invention that is suitable for preparing the pharmaceutically acceptable mixed with excipients of suspensoid.In another embodiment, but pharmaceutical composition of the present invention can be mixed with and be suitable for preparing the dispersion powder and the granule of suspensoid by adding suitable vehicle.

The vehicle that is suitable for being used in combination with suspensoid comprises suspending agent such as Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, Tragacanth, Sudan Gum-arabic; The condensation product (for example heptadecaethyleneoxycethanol) of condensation product (for example polyoxyethylene stearic acid ester), ethylene oxide and the long chain aliphatic alcohol of dispersion agent or wetting agent such as naturally occurring phosphatide (for example Yelkin TTS), alkylene oxide and lipid acid, ethylene oxide and by the condensation product (for example polyoxyethylene sorbitan monoleate) of lipid acid and hexitan deutero-partial ester; With thickening material such as carbomer, beeswax, paraffinum durum or hexadecanol.Described suspensoid can also contain one or more sanitass such as acetate, methyl p-hydroxybenzoate and/or n-propyl; One or more tinting materials; One or more perfume compound; With one or more sweeting agents such as sucrose or asccharin.

Pharmaceutical composition of the present invention can also be the form of oil-in-water emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil, mineral oil such as whiteruss, perhaps their mixture.Examples of suitable emulsifiers comprises naturally occurring natural gum such as Sudan Gum-arabic and Tragacanth; Naturally occurring phosphatide such as soybean lecithin, derived from the ester or the partial ester of lipid acid; Hexitan such as dehydrating sorbitol monooleate; Condensation product such as polyoxyethylene sorbitan monoleate with these partial esters and ethylene oxide.Described emulsion can also contain sweeting agent and perfume compound.Syrup and elixir can be prepared with sweeting agent such as glycerine, sorbyl alcohol or sucrose.This preparation can also contain negative catalyst, sanitas, perfume compound or tinting material.

In addition, pharmaceutical composition of the present invention can be the form of sterile injectable preparation, as sterile injectable aqueous emulsions or oiliness suspensoid.This emulsion or suspensoid can utilize those suitable dispersion agents or wetting agent and suspending agent to prepare according to methods known in the art, those that described dispersion agent or wetting agent and suspending agent have been mentioned more than for example.Described sterile injectable preparation can also be at nontoxic parenteral acceptable diluent or sterile injectable solution or the suspension in the solvent, as 1, and the solution in the 2-propylene glycol.Described sterile injectable preparation can also be prepared into lyophilisate.Operable acceptable vehicle and solvent are water, Ringer's solution and isotonic sodium chlorrde solution.In addition, can be with aseptic fixed oil as solvent or suspension medium.Be this purpose, the fixed oil of any gentleness can be used, and comprises synthetic monoglyceride or triglyceride.In addition, lipid acid such as oleic acid can be used for preparing injectable formulation equally.

Usually, the compound of the present invention that is used for method of the present invention is gone up water insoluble substantially and is slightly soluble in most of pharmaceutically acceptable protonic solvents and vegetables oil.Yet described compound dissolves in medium chain fatty acid (for example sad or capric acid) or the tri-glyceride usually, and has high-dissolvability in the propylene glycol ester of medium chain fatty acid.The present invention also comprises by the replacement of chemistry or biological chemistry part or adding and adorned compound, for example modified by esterification, glycosylation or PEGization or the like, described replacement or adding make them be more suitable for sending (for example strengthening solvability, biological activity, palatability, reduction adverse effect or the like).

In preferred embodiments, compound of the present invention can be formulated in the preparation based on lipid that is suitable for the low solubility compound for oral administration.Usually can strengthen the oral administration biaavailability of this compound based on the preparation of lipid.Therefore, preferred pharmaceutical composition of the present invention comprises the compound of the present invention of treatment or prevention significant quantity and at least aly is selected from following pharmaceutically acceptable vehicle: medium chain fatty acid or its propylene glycol ester (for example propylene glycol ester of edible fat acid as sad and capric acid lipid acid) and pharmaceutically acceptable tensio-active agent such as polyoxyethylene (40) hydrogenated castor oil (polyoxyl 40 hydrogenated castor oil)).

In another preferred embodiment, can add cyclodextrin as water-soluble toughener.Preferred cyclodextrin comprise α-, β-and hydroxypropyl, hydroxyethyl, glucosyl, malt-base and the trisaccharide maltose radical derivative of γ-Huan Hujing.Particularly preferred cyclodextrin solubility enhancer is hydroxypropyl-beta-cyclodextrin (HPBC), it can be joined in any above-mentioned composition the water-soluble characteristic with further improvement compound of the present invention.In one embodiment, described composition comprises 0.1%～20% hydroxypropyl-beta-cyclodextrin, more preferably 1%～15% hydroxypropyl-beta-cyclodextrin, and more preferably 2.5%～10% hydroxypropyl-beta-cyclodextrin.The amount of the solubility enhancer of using will depend on the amount of the compound of the present invention in composition.

F. Combination therapy

The activeconstituents (comprising compound) that also any compound of the present invention and one or more may be used for the treatment of cancer is combined in the patient's who supplies the while or be administered to the needs treatment in proper order unit dosage or separates in the formulation.When the order administration, described composition can be carried out administration in twice or multiple dosing.In another embodiment, one or more compounds of the present invention and one or more other activeconstituentss may be passed through the different approaches administration.

Those skilled in the art will recognize that the various active composition can with compound Combined Preparation of the present invention, this can strengthen or the collaborative VEGF that strengthens compound of the present invention suppresses and/or the angiogenesis inhibitor activity.

The method according to this invention, the combination of activeconstituents can: (1) is altogether preparation and administration simultaneously or send in combination preparation; (2) replace or parallel sending as isolating preparation; Perhaps (3) are by any other combined treatment administration known in the art.When in rotational therapy, sending, method of the present invention can comprise order administration or send described activeconstituents, for example with the form of the solution, emulsion, suspensoid, tablet, pill or the capsule that separate or by the different drug administration by injection in the syringe that separates or send.Usually, during rotational therapy, the effective dose of each activeconstituents order (promptly continuously) administration, and at the same time in the therapy, the administration together of the effective dose of two kinds or more of activeconstituentss.Can also use the intermittently multiple order of conjoint therapy.

In order to help to understand the present invention, following examples have been comprised.Test related to the present invention should not be considered to specifically limit the present invention certainly, thinks that the present invention's variant known now or development afterwards in those skilled in the art's limit of power all falls within this paper and the described scope of the present invention of claims.

Embodiment

More at large describe the present invention with reference to following non-limiting example, provide these embodiment to be used for illustrating more fully the present invention, but it should be considered as limiting the scope of the present invention.These embodiment have illustrated the preparation of some compound of the present invention and the external and/or body build-in test of these compounds.Skilled person in the art will appreciate that technology representative function well in putting into practice the present invention of describing in these embodiments, and therefore constitute the technology of the present inventor's description of the optimal way of putting into practice it.However, it should be understood that those skilled in the art should understand according to disclosure of the present invention, under the situation that does not deviate from the spirit and scope of the present invention, can carry out multiple change and still obtain identical or similar result disclosed concrete grammar.

Embodiment 1: the preparation of compound of the present invention

Compound of the present invention can be according to aforesaid general path of preparing.For example, some preferred compound of the present invention can be prepared as follows.Other preferred compound of the present invention can prepare (for example compound in the following table 1) similarly.

A.6-bromo-2,3,4,9-tetrahydrochysene-carbazole-1-ketone (compound 1):

Under 60 ℃, in 1.5 hours time, with the methyl alcohol of 4-bromophenyl-hydrazine hydrochloride (MeOH, 250mL) solution joins 1, (10.03g is 89mmol) in the solution in the mixture of AcOH (225mL) and dense HCl (80mL) for the 2-cyclohexanedione.After the adding, at room temperature reaction mixture is stirred and spend the night.The solid of filtering-depositing is with MeOH washing and dry.Behind the evaporated filtrate, obtain resistates, with methanol wash it, obtain other product.The output that merges is 8.75g (74%).ES-MS：264.03(MH) ⁺。

Utilize 4-trifluoro phenylhydrazine, 4-chlorophenyl hydrazine, 4-trifluoromethoxy phenylhydrazine, 4-procarbazine, 2 bromo phenyl hydrazine and 3-bromophenyl-hydrazine respectively, by identical method synthetic compound 31,26,25,54 and 118.Utilize 4-bromophenyl-hydrazine and pimelinketone, also by this method synthetic compound 39.By using 4-bromophenyl-hydrazine and 1-phenyl-Ding-2-ketone synthetic compound 10.

B.6-bromo-2,3,4,9-tetrahydrochysene-carbazole-1-ketoxime (compound 41):

Compound 41 is by compound 1 preparation as described below.(5.64ml, (5.25g, 19.9mmol) (2.76g is 39.8mmol) in the mixture in ethanol (EtOH) with azanol HCl salt 39.8mmol) to join compound 1 with pyridine.Mixture was refluxed about 1 hour, and solid is dissolved by heating.Then reaction mixture is concentrated into dried.With hexane (3 *) are handled and washed to the gained viscous solid, obtain the powder of dark brown compound 41,6.1g, 100%.

By the method identical, synthetic compound 44,52 and 55 with compound 41.

C.6-bromo-9-methyl-2,3,4,9-tetrahydrochysene-carbazole-1-ketone (compound 53):

Compound 53 can be prepared as follows.

Under 0 ℃, with NaH (in mineral oil 60%, 0.18g, (0.795g, 3.0mmol) at N, (DMF is 20ml) in the solution in for dinethylformamide 4.5mmol) to join 1.At room temperature mixture was stirred 30 minutes, and adding MeI (0.56ml, 9.0mmol).At room temperature mixture was stirred 2 days, the water termination reaction also concentrates to remove most of DMF.Resistates is placed EtOAc, use saturated NH ₄Cl and salt water washing.Organism is concentrated and chromatographic separation (10%EtOAc in hexane), obtain being 53 of white solid, 0.27g, 34%.

D.6-bromo-1-oxo-1,2,3,4-tetrahydrochysene-carbazole-9-carboxylic acid tert-butyl ester (compound 36):

((0.795g, 3.0mmol) (3.6mmol) (tetrahydrofuran (THF) is 30ml) in the solution at THF for di-t-butyl pyrocarbonate, 0.785g with the Boc acid anhydrides 4.5mmol) to join 1 for Dimethylamino pyridine, 0.55g with DMAP.After at room temperature stirring 2 days, concentrated solution.Resistates is placed ethyl acetate (EtOAc), use saturated NH ₄Cl and salt water washing.Evaporating solvent obtains being 36 of oil, 1.148g, 100%.

E.1-(6-bromo-1,2,3,4-tetrahydrochysene-carbazole-9-yl)-ethyl ketone (compound 48):

To 39 (0.75g, 3.0mmol) add in the suspension in acetate (3ml) Acetyl Chloride 98Min. (0.21ml, 3.0mmol).Mixture heating up to refluxing, is obtained settled solution.After 2 hours, reaction soln is cooled to room temperature (rt).Be settled out solid.Filter this solid 48 and wash 0.24g, 27% with hexane (2 *).

F.6-bromo-2,3,4,9-tetrahydrochysene-b-carboline-1-ketone (compound 9):

Under 0 ℃, with triethylamine (10.92mmol, 1.52mL) and triphosgene (2.4mmol, (1g is 3.64mmol) in the suspension in the 25mL methylene dichloride 712mg) to join the bromo tryptamines.At room temperature with described suspension stir about 1 hour and concentrate it in a vacuum.Resistates is dissolved in the 20mL acetate again, and in 120 ℃ of oil baths, solution was refluxed 2 hours, concentrate subsequently.Add 1N NaOH then and with dichloromethane extraction gained aqueous mixture.Use K ₂CO ₃The dry organic layer that merges.With spissated resistates recrystallization from ethyl acetate, obtain for example 370mg expected product.Concentrated mother liquor and be used in 50% ethyl acetate purifying in the hexane on silicon-dioxide is measured the expected product 9 of (for example 220 mg) in addition.Be total to 590mg (61%).

Compound 5 can prepare in a similar way.

G.1-(6-chloro-1,3,4,9-tetrahydrochysene-β-Ka Lin-2-yl)-2,2,2-three fluoro-ethyl ketones:

With 5-chlorine tryptamine hydrochloride (1.2g 5.14mmol) is dissolved in 5% trifluoroacetic acid solution in acetonitrile, and under nitrogen reflux.In 15 minutes, (37%, 385 μ L, 5.14mmol) drips of solution in acetonitrile (25mL) is added in the reaction mixture of heating with water-containing acetal.After heating 3 hours, remove in a vacuum and desolvate, crude mixture is placed ethyl acetate (200mL), (2 * 50mL) washings are used salt solution (50mL) washing then, and are used anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution.Remove in a vacuum and desolvate and on silicagel column, be used in 10-20% ethyl acetate gradient purifying in the hexane.Collect product, it is yellow oil (200mg, 18%).LC/MS?RT＝3.67.M/Z+305，33％；303，100％；190，50％。

H.2,3,4,9-tetrahydrochysene-1H-β-Ka Lin:

(1.0g 6.24mmol) suspends and to be in 5% trifluoroacetic acid (100mL) in the acetonitrile and to be heated to backflow with tryptamines.In 30 minutes, (37%, 465 μ L, 6.24mmol) drips of solution in acetonitrile (25mL) is added in the reaction mixture of heating with water-containing acetal.After heating 24 hours, remove in a vacuum and desolvate, crude mixture is placed ethyl acetate (200mL), (2 * 50mL) washings are used salt solution (50mL) washing then, and are used anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution.The thick brown oil of gained (1.4g) is not further purified and to be used for the downstream synthetic.LC/MS?RT＝1.64min；M/Z+173，20％；145，20％，144，100％。

I.6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin:

Under nitrogen, with 5-chlorine tryptamine hydrochloride (2.0g, 8.65mmol) and Methylal(dimethoxymethane) (850 μ L 9.52mmol) are dissolved in the Glacial acetic acid (50mL) and are heated to 80 ℃.Reactant was stirred 68 hours, be cooled to room temperature then.Filtering-depositing, with acetonitrile (50mL) washing, and dry in a vacuum, obtain product (1.68g, 73%) into acetate.LC/MS?RT＝2.02min；M/Z-207，33％；205，100％。

J.6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-3-carboxylic acid, ethyl ester (compound 116):

With 5-bromine tryptophane ethyl ester (685mg, 2.2mmol) and Methylal(dimethoxymethane) (215 μ L 2.42mmol) are dissolved in the Glacial acetic acid (14mL).Solution is divided into 7 parts, and (CEM Corporation, Matthews are heated to 120 ℃ in NC), continue 10 minutes in CEM Explorer microwave synthesis system.After being cooled to room temperature,,, and under nitrogen gas stream, washed 3 days with acetate (10mL) washing to filtering-depositing.Collect product 116, it is acetate (459mg, 54%).LC/MS?RT＝2.24min；M/Z-323，100％；321，100％。

K.6-chloro-1,3,4,9-tetrahydrochysene-β-Ka Lin-2-carboxylic acid, ethyl ester (compound 62,64):

At room temperature, in nitrogen atmosphere, with 6-chloro-2,3,4, the acetate of 9-tetrahydrochysene-1H-β-Ka Lin (1.79g, 8.65mmol) and triethylamine (6mL 43.3mmol) is dissolved among the anhydrous THF (100mL), and stirs 15 minutes.Add Vinyl chloroformate and reactant stirred and spend the night, salt is leached and remove in a vacuum and desolvate.The 10-25% ethyl acetate gradient of utilization in hexane by the silica gel column chromatography purifying, obtains the expectation compound (1.0g, 42%) into pale solid.LC/MS?RT＝3.56min；M/Z+281，33％；279，100％。(114、116、117、118、119)

Compound 46 can synthesize in a similar way.

L.6-chloro-3,4-dihydro-1H-β-Ka Lin-2, and the 9-diethyl dicarboxylate:

Title compound is separated by the identical silicagel column of separating compound 64.LC/MS?RT＝4.17min；M/Z+353，33％；351，100％。

M.9-benzyl-6-chloro-1,3,4,9-tetrahydrochysene-b-carboline-2-carboxylic acid, ethyl ester:

At room temperature, with compound 64 (56mg, 0.2mmol), (50 μ L 0.4mmol) dissolve/are suspended among the THF (5mL) for the potassiumiodide of catalytic amount and bromotoluene.(60%, 25mg 0.6mmol) joins in the reactant and at room temperature stirred 30 minutes sodium hydride that will be in mineral oil.Add the 1N HCl aqueous solution (1mL) and water (8mL) and wash gained solution with methylene dichloride (5mL, 2mL then).Under nitrogen gas stream dry solvent and by the preparation HPLC carry out purifying.Collect final compound, it is glassiness yellow solid (32mg, 43%).LC/MS?RT＝4.22min；M/Z+371，33％，369，100％。

N.9-benzoyl-6-chloro-1,3,4,9-tetrahydrochysene-b-carboline-2-carboxylic acid, ethyl ester (compound 86):

At room temperature, with compound 64 (56mg, 0.2mmol), (46.5 μ L 0.4mmol) dissolve/are suspended among the THF (5mL) for 4-(dimethylamino) pyridine of catalytic amount and Benzoyl chloride.(60%, 25mg 0.6mmol) joins in the reactant and at room temperature stirred 20 hours sodium hydride that will be in mineral oil.Add the 1N HCl aqueous solution (1mL) and water (8mL) and wash gained solution with methylene dichloride (5mL, 2mL then).Under nitrogen gas stream dry solvent and by the preparation HPLC carry out purifying.Collect final compound 86, it is glassiness yellow solid (2mg, 2%).LC/MS?RT＝4.17min；M/Z+385，33％；383，100％。

Compound 40,57,58,59,62,63,64,87,88 can synthesize in a similar way.

O.8-bromo-2,3-dihydro-1H-dibenzofuran-4-ketone (compound 47):

With K ₂CO ₃(4.15g, (2.595g, 15.0mmol) (1.93ml is 15.0mmol) in the solution in DMF (50mL) with 3-bromine tetrahydrobenzene 30mmol) to join the 4-bromophenol.After at room temperature stirring was spent the night, enriched mixture was dissolved in it among EtOAc, and water and salt water washing.Concentrate organism, obtain ether, 3.80g, 100% into brown oil.

Under 200 ℃, (1.8g, 7.1mmol) at N, the solution in the N-Diethyl Aniline (10ml) heated 7 hours with described ether.Mixture is cooled to room temperature, among the cold 6N HCl (50ml) of impouring, and extracts with ether (2 *).With the organism that 1N HCl and salt water washing merge, concentrate and carry out chromatographic separation (10%EtOAc in hexane), obtain 4-bromo-2-hexamethylene-2-thiazolinyl phenol, 1.70g, 94.4% into clarified oil.

Solution in benzene refluxes and spends the night with this phenol and MCPBA (metachloroperbenzoic acid, 3-chlorine peroxybenzoic acid).Be settled out solid and filter it.Concentrated filtrate and carry out chromatographic separation (10%EtOAc in hexane) obtains the 8-bromo-1,2,3 into clarified oil, 4-tetrahydrochysene-dibenzofuran-4-alcohol, 0.66g, 39%.

With DDQ (2,3-two chloro-5, the 6-dicyano p-benzoquinone, 100mg, (70mg is 0.26mmol) in the solution in dimethylbenzene (3.0ml) 0.44mmol) to join this alcohol.Solution becomes garnet, and it was refluxed 6 hours.Described garnet disappears, and is settled out light brown solid.Filtering mixt.Go forward side by side circumstances in which people get things ready for a trip spectrum of concentrated filtrate is separated, and obtains the compound 47 into white solid, 50mg, 72%.

P.1-(5-chloro-3,8-dihydro-2 h-pyrrole be [2,3-b] indoles-1-yl also)-ethyl ketone (compound 48,49):

With TEA (0.84ml, 6.0mmol) and diacetyl oxide (0.24ml, (0.531g is 2.3mmol) in the suspension in THF (20ml) 2.5mmol) to join 5-chlorine tryptamine hydrochloride.After at room temperature stirring was spent the night, enriched mixture on Rotary Evaporators was dissolved in it among EtOAc, and water and salt water washing.Dry and concentrated gained organism obtains being 49 of oil, 0.539g, 99%.

Q. (5-bromo-1H-indoles-2-ylmethyl)-phenyl-amine (compound 28,29):

Under 0 ℃, with DMAP (22mg, 0.2mmol) and DCC (0.535mg, 2.6mmol) join 5-bromo-1H-Indoline-2-carboxylic acid (0.48g, 2.0mmol) and aniline (0.20ml is 2.2mmol) in the mixture in DCM (10ml).At room temperature mixture was stirred 2 hours, concentrate it by Rotary Evaporators then.Resistates is carried out chromatographic separation (5%EtOAc in hexane), obtain being 28 of light yellow solid, 0.44g, 70%.

Under 0 ℃, the solution of acid amides 28 in THF (10ml) is joined LAH, and (lithium aluminum hydride, 83mg is 2.2mmol) in the suspension in ether (10ml).Under 50 ℃, mixture heating up is spent the night.The reaction of order water (0.08ml), 20%NaOH (0.06ml) and water (0.28ml) termination reaction mixture.Filter and wash white solid with THF.Concentrated filtrate.Resistates is carried out chromatographic separation (10%EtOAc in hexane), obtain being yellowish brown solid 29,0.181g, 54%.

R.2-[(5-chloro-1H-indol-3-yl methyl)-amino]-1-phenyl-ethanol (compound 43,45)

In the Dean-Stark device, (0.568g is 3.16mmol) with 2-amino-1-phenylethyl alcohol (0.442g, 3.22mmol) mixture in toluene (70ml) for backflow 5-chloro-1H-3-formaldehyde.By heating, the solid dissolving.After 16 hours, concentrated reaction mixture obtains being 43 of light yellow solid, 0.93g, 99%.

Under 0 ℃, with NaBH ₄(1.50g, 40mmol) portions joins imines 43 (0.596g is 2.0mmol) in the suspension in MeOH (25ml).At room temperature stir spend the night after, the reaction of water termination reaction mixture concentrates on Rotary Evaporators removing most of methyl alcohol, and with EtOAc extraction (3 *).Concentrate the organism that merges, obtain solid, wash it, obtain being 45 of white solid, 0.209g, 94% with ether (3 *).

Embodiment 2: estimate the mensuration to the influence that can induce anoxybiotic endogenous vegf expression

Compound of the present invention is regulated and can be induced the ability of anoxybiotic endogenous vegf expression followingly to analyze.Measure (R ﹠amp by ELISA; D System) monitoring vegf protein level.Concise and to the point, at hypoxia condition (1%O ₂, 5%CO ₂, surplus is a nitrogen) under, compound of the present invention exist or not in the presence of, with HeLa cell cultures 24-48 hour.By ELISA conditioned medium is measured, and by the standard ELISA curve calculation VEGF concentration of each mensuration.

Utilize ELISA mensuration and aforesaid condition to carry out the dose-response analysis.The condition of dose-response ELISA is similar to aforesaid condition.Can analyze a series of, seven kinds of concentration for example.Abreast, can utilize CellTiter Gio (Promega) to carry out the dose-response cytotoxic assay under the condition identical with ELISA, be not because due to the cytotoxicity with the inhibition of guaranteeing vegf expression.Can utilize and suppress percentage ratio compound concentration is drawn dose response curve, and maximum suppress to be set to 100% and minimum suppress to be set to 0%, can produce the EC of each compound ₅₀And CC ₅₀Value.The EC of preferred compound of the present invention ₅₀Can preferably less than 10, be more preferably less than 2 less than 50, be more preferably less than 1, and more preferably less than 0.5.

The EC of a series of preferred compounds of the present invention ₅₀Be provided in the table 1.

Table 1

Embodiment 3: compound of the present invention suppresses tumor growth in vivo in the PD model

In the pharmacophore model of VEGF level, compound of the present invention also shows activity in following evaluation tumour.Concise and to the point, can be with in the subcutaneous implantation nude mice of HT1080 cell (human fibrosarcoma cell system).After seven days, with the dosage range of expectation, for example 200mg/kg/ days to this mouse oral administration compound, continues seven days.Then, tumour is excised from mouse, and in containing the Tris-HCl damping fluid of proteinase inhibitor with its homogenization (98).Subsequently, end user VEGF ELISA test kit (R ﹠amp; D System) measures VEGF level in the tumour.Measure the protein concn that test kit is measured homogenate with Bio-Rad Protein, and VEGF level standard in the tumour is turned to protein concn.

When at 100mm ³When using a week on the tumour, compare with vehicle treatment control group (data not shown), preferred compound of the present invention can suppress tumor growth at least 50% usually.

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Claims

1, the compound of formula (I)

Wherein:

R ₂Be hydrogen; C ₁～C ₄Alkyl; Perhaps can with R ₃Altogether;

R ₄And R ₅Can be hydrogen independently of one another; C ₁～C ₆Alkyl; Perhaps R ₄And R ₅Can form altogether=the CH-cycloalkyl ,=CH-amino or=the CH-0 aryl, wherein said cycloalkyl and aryl are optional by at least one halogen group, C ₁～C ₄Alkyl, C ₁～C ₅Alkoxyl group ,-CF ₃,-OCF ₃,-NO ₂,-CN or-N (CH ₃) ₂Replace, and described amino is optional by at least one C ₁～C ₄Alkyl replaces;

R _bBe hydroxyl or pyrryl; And

N is 0,1,2,3 or 4;

2, the compound of claim 1, wherein X be selected from F, Cl, Br ,-CH ₃,-CH ₂-CH ₃,-CF ₃With-O-CF ₃, and n is 1.

3, the compound of claim 1, wherein X is selected from Cl and Br, and n is 1.

4, the compound of claim 1, wherein R ₂And R ₃Be selected from altogether:

5, the compound of claim 1, wherein R ₂Be hydrogen.

6, the compound of claim 1, wherein R ₂And R ₃Form altogether:

7, the compound of claim 1, wherein R ₄And R ₅Be selected from altogether:

8, the compound of claim 1, wherein R ₄And R ₅All be H.

9, the compound of claim 1, wherein R ₄And R ₅Be independently selected from hydrogen and C ₁～C ₆Alkyl.

10, the compound of claim 1, wherein said compound are the compound of formula (Ia)

11, the compound of claim 1, wherein said compound are the compound of formula (Ib)

12, the compound of formula (II)

X wherein ₁Be halogen; And

R ₂Be 5～6 yuan of heteroaryls;

13, the compound of formula (III):

Wherein

R ₀For H or-C (O) O-(C ₁-C ₆Alkyl);

R ₂Be hydrogen; C ₁～C ₄Alkyl; Perhaps can with R ₃Altogether;

R _bBe hydroxyl or pyrryl;

N is 0,1,2,3 or 4;

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl;

14, the compound of claim 13, wherein X is selected from Br and Cl, and n is 1.

15, the compound of claim 13, wherein n is 0.

16, the compound of claim 13, wherein R ₂And R ₃Be selected from altogether:

17, the compound of claim 13, wherein R ₂And R ₃Be independently selected from C ₁～C ₄Alkyl.

18, the compound of claim 13, wherein R ₂And R ₃All be hydrogen.

19, the compound of claim 13, wherein R ₂And R ₃It all is methyl.

20, the compound of claim 13, wherein R ₀For:

21, the compound of claim 13, wherein R ₀Be hydrogen.

22, the compound of claim 13, wherein R ₂And R ₃Form cyclohexyl altogether, wherein said cyclohexyl is optional to be substituted, thus the compound of the formula of formation (IIIa)

R wherein ₇Be hydrogen, phenyl or benzyl;

23, according to the compound of claim 22, R wherein ₇Be hydrogen.

24, according to the compound of claim 22, R wherein ₇Be phenyl.

25, the compound of claim 13, wherein R ₂And R ₃The cyclization that is connected with them gets up to form carbonyl, and wherein said compound is the compound of formula (IIIb)

26, the compound of formula (IV)

Wherein

X ₁Be halogen; And

27, the compound of claim 26, wherein R ₈Be the phenyl that is replaced by at least one alkoxyl group.

28, the compound of claim 26, wherein R ₈Be the phenyl that is replaced by at least one halogen.

29, the compound of formula V

Wherein

X ₁Be halogen;

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl; And

R _qFor hydrogen, phenyl or-OH;

30, the compound of claim 29, wherein R ₁Be hydrogen.

31, the compound of claim 29, wherein R _qBe phenyl.

32, the compound of claim 29, wherein R _qFor-OH.

33, the compound of claim 29, wherein R ₆For-C (O) O-alkyl.

34, the compound of formula (VI)

Wherein

X ₁Be halogen;

R _bBe hydroxyl or pyrryl,

R _cBe C ₁～C ₆Alkyl or C ₅～C ₆Cycloalkyl;

35, the compound of claim 34, wherein R ₁Be hydrogen and R ₆For-C (O)-R _a, R wherein _aBe C ₁～C ₆Alkyl or phenyl.

36, the compound of formula (VII)

Wherein

X ₁Be halogen;

37, the compound of formula (VIII)

Wherein

X ₁Be halogen;

R ₉For hydrogen or-C (O)-alkyl;

R ₁₀Be hydrogen;-CH ₂-R _d-C (O)-NH-R _dPerhaps-CH ₂-NH-R _d

R _eFor-C (O)-R _fPerhaps-(CH ₂) _p-CH (OH)-R _Ff

M is 1,2 or 3;

N is 0,1 or 2; And

P is 1,2 or 3;

38, the compound of claim 37, wherein X ₁Be chlorine or bromine.

39, the compound of claim 37, wherein R ₉For hydrogen or

Group.

40, the compound of claim 37, wherein R ₁₁For-(CH ₂) _m-NH-R _e

41, the compound of claim 40, wherein R ₉For

Group.

42, the compound of claim 37, wherein R ₁₀For-CH ₂-R _d

43, the compound of claim 37, wherein R ₁₀For-C (O)-NH-R _d

44, the compound of claim 37, wherein R ₁₀For-CH ₂-NH-R _d

45, the compound of claim 37, wherein R ₁₁Be C ₁～C ₆Alkyl.

46, the compound of claim 37, wherein R ₁₁For-CH=N-CH ₂-CH (OH)-R _dGroup.

47, the compound of claim 37, wherein R ₁₁For-(CH ₂) _m-NH-R _eGroup.

48, be selected from the compound of compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24, perhaps the pharmacy acceptable salt of any described compound, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer.

49, each compound of claim 1～48, wherein said compound is greater than about 75% enantiomeric pure, the perhaps pharmacy acceptable salt of described compound, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer.

50, each compound of claim 1～48, wherein said compound is greater than about 90% enantiomeric pure, the perhaps pharmacy acceptable salt of described compound, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer.

51, a kind of pharmaceutical composition, it comprises one or more compounds of claim 1～50 or pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer and the pharmaceutically acceptable vehicle of described one or more compounds.

52, a kind of pharmaceutical composition, it comprises pharmacy acceptable salt, hydrate, solvate, inclusion compound, polymorphic form, racemoid or steric isomer and the pharmaceutically acceptable vehicle of one or more compounds that are selected from compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 or described one or more compounds.

53, the purposes that is used for pharmaceutical compositions according to each compound of claim 1～50.

54, according to the purposes of claim 53, wherein said pharmaceutical composition suppresses the VEGF generation or blood vessel takes place.

55, according to the purposes of claim 53, wherein said pharmaceutical composition is used for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriatic, atherosclerosis, obesity, chronic inflammatory diseases or exudative macular degeneration.

56, according to the purposes of claim 55, wherein said pharmaceutical composition is used for the treatment of cancer, diabetic retinopathy or exudative macular degeneration.

57, according to the purposes of claim 56, wherein said pharmaceutical composition is used for the treatment of cancer.

58, according to the purposes of claim 56, wherein said pharmaceutical composition is used for the treatment of diabetic retinopathy.

59, according to the purposes of claim 56, wherein said pharmaceutical composition is used for the treatment of exudative macular degeneration.

60, a kind ofly suppress the method that VEGF in the individuality generates, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual administration VEGF amount of suppression.

61, a kind ofly suppress the method that individual medium vessels takes place, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual administration angiogenesis inhibitor amount.

62, method for cancer in a kind of treatment individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

63, a kind of method for the treatment of diabetic retinopathy in the individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

64, a kind of method for the treatment of exudative macular degeneration in the individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

65, a kind of method for the treatment of rheumatoid arthritis in the individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

66, psoriatic method in a kind of treatment individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

67, a kind of atherosis method of individual medium sized artery for the treatment of, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

68, a kind of method for the treatment of obesity in the individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

69, a kind of method for the treatment of chronic inflammatory diseases in the individuality, it comprises to each compound or each pharmaceutical composition of claim 51～52 of the claim 1～50 of described individual drug treatment significant quantity.

70, according to each method of claim 60～69, wherein the described compound of administration is sent at least a compound that is selected from compound number 2,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 to described individuality.