CN101119717A

CN101119717A - Substituted phenols as active agents inhibiting vegf production

Info

Publication number: CN101119717A
Application number: CNA200580046708XA
Authority: CN
Inventors: 崔珣奎; 文荣春; 纳达拉贾恩·塔米拉拉苏
Original assignee: PTC Therapeutics Inc
Current assignee: PTC Therapeutics Inc
Priority date: 2004-11-23
Filing date: 2005-11-23
Publication date: 2008-02-06
Also published as: CN101102765A; CN101103000B; CN101103000A

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

Substituted phenol as the activating agent that suppresses the VEGF generation

Relevant application

According to 35U.S.C. § 119, the 60/639th, No. 283 U.S. Provisional Application No. that the application requires that December in 2004 submitted on the 27th and interests, the full text of introducing this application in this article is as a reference.According to 35U.S.C. § 119, the 60/633rd, No. 738 U.S. Provisional Application No. that the 60/629th, No. 889 U.S. Provisional Application that the application requires to submit on November 23rd, 2004 and December in 2004 were submitted on the 6th and interests.

Technical field

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

Background technology

Unusual blood vessel occurs in the morbidity of numerous disease and has played crucial effect, and these diseases comprise virulent, ischemic, struvite and pathological changes immunity (1,2).What the people was known in these pathological changes is cancer, exudative degeneration of macula (exudative macular degeneration) and diabetic retinopathy (DR), and last two kinds is the first cause (3,4) that causes losing one's sight in the U.S..At nearest 10 years, we significantly grew up to the understanding of the molecular basis that blood vessel takes place.The many cytokines and the somatomedin that stimulate blood vessel to take place have been identified, for example VEGF, FGF-2, PDGF, IGF-1, TGF, TNF α, G-CSF (5-7).In these somatomedin, VEGF (VEGF) has played central role (2) in blood vessel takes place.

Identify the VEGF that is also referred to as VEGF-A at first and have the ability (8-10) that causes vascular permeability and strengthen vascular endothelial cell proliferation.VEGF is produced the single-gene coding (11) of four hypotypes by alternative (alternative) montage.Four all hypotypes total same long usually and be rich in GC 5 '-UTR, and comprise 3 of a plurality of rna stability determiners '-UTR.The dimer form (12,13) of receptor VEGFR-2 (being also referred to as KDR or Flk-1) and VEGFR-1 (being called Fltl in the past) identification VEGF.The VEGFR-2 receptor of high degree of specificity is expressed on the epithelial cell.Be attached to the tyrosine kinase activity of the VEGF activation this receptor of VEGFR-2 receptor, cause the formation (14) of epithelial cell proliferation, differentiation and primitive vessel.VEGFR-1 is by acting as a decoy or suppressing growth (15) by the signal transduction path of suppressing by VEGFR-2.

Before 30 years, having proposed to suppress the tumor vessel generation can be the effective way (16) of treatment cancer.Ensuing blood vessel generation actuator and the tumor growth and transfer relevant (17,18) that comprises VEGF, FGFs, PDGF, TGF, EGF, IL-8, IL-6 and blood vessel generation plain (angiopoietin) etc. that studies have shown that.Verified VEGF and receptor thereof have important function in tumor vessel takes place, particularly at the commitment (19) of tumor growth.Really, the growth level of vegf expression with the primary tumor tissue in microvessel density interrelated (20).And, in fact all common solid tumors, all found the growth level (21) of VEGF transcript.Generally speaking, length has the patient of tumor to compare with those tumor free individualities and has higher VEGF level, and the high VEGF level relevant with prognosis mala (22) in blood serum.Consistent with the effect of VEGF in the tumor vessel generation, the ability that the embryonic stem cell that VEGF is invalid in nude mice forms tumor significantly reduces (23).The direct basis that relates to VEGF in tumor takes place is (24,25) that prove by the specific antibody of using anti-VEGF in the human body xenograft in implanting nude mice.In these researchs, reduce positive correlation with vascularization in the tumor that is suppressed at Antybody therapy of tumor growth.Next use the test of soluble recepter to confirm the importance (26) of VEGF activity in tumor growth, and proved by specific antibody treatment and make the VEGF inactivation directly cause the neovascularization (27,28) that has almost completely suppressed relevant with tumor.

In exudative degeneration of macula and diabetic retinopathy, the excessive generation that preclinical experiment and clinical trial have proved VEGF is key to retina superstition (aberrant retinal) or choroidal neovascularization (summary in 3).Obtained evidence, in the patient who suffers from such as the disease of diabetic retinopathy and wet type degeneration of macula, ophthalmic VEGF level and active retina/choroid neovascularization (CNV) has very strong dependency (29,30).In addition, the use transgenic mice studies have shown that the expression of crossing of VEGF has caused choroid or retinal neovascularization to form (31,32) in retinal pigment epithelium or photoreceptor cell.In nearest research, proved neutralizing antibody, soluble recepter, receptor antagonist or siRNA animal model and clinical in reduced effectively the VEGF mediation vascularization (33,34-37).

Vegf expression is comprised the factor of cytokine, somatomedin, steroid hormone and chemicals and the quantity of material, and regulates the adjusting (38,39) as the active variation of oncogene of ras gene or tumor suppressor gene VHL.Yet anoxia is to regulate the most significant physiological signal of vegf expression.By increasing the stability of transcription rate and VEGF transcript, anoxia has produced enhanced vegf expression (40-42).The derivable anoxia factor 1 α (HIF-1 α) is that (hypoxia response element HRE) increases the transcription factor (43,44) that the VEGF gene is expressed in suffering anoxybiotic cell by being attached to the hypoxia response elements that is arranged in the VEGF promoter.Because each factor is attached to 3 '-result of element among the UTR, strengthened the stability (45) of VEGF mRNA greatly.In addition, adjusted the translation initiation of VEGF transcript uniquely.Under anoxia condition, the translation impaired widely (46) of the most cells transcript by medicated cap dependent form rotaring intertranslating start process mediation.Yet the initial of VEGF mRNA translation is unique under anoxia condition, and it is (41,42,47,48) by the internal ribosome entry site in VEGF 5 ' UTR (IRES) mediation.

A large amount of experimental evidences show, can suppress tumor growth (26,49) by preventing that new vessels from forming.Tumor vessel is normally immature, and constantly is subjected to refigure (1,50).The active blood vessel with unusual is that these factors comprise various cytokines, somatomedin and steroid hormone in the ruined result of normal equilibrium of the short angiogenesis factor and the angiogenesis inhibitor factor.Although the adjusting that tumor vessel takes place is very complicated, the evidence of accumulation shows that targeting may be enough to suppress the tumor vessel generation and check tumor growth (24,51,52) in single short angiogenesis factor.In many blood vessel generation targets, VEGF and receptor thereof are the most attracting (1,12).As mentioned above, suppressed to implant the growth of tumor of the human body xenograft in the nude mice with targeting specifically in the mab treatment of VEGF.Then, in tumor model, tested various approach for the VEGF inactivation is designed, and confirmed comprising in cancer, sarcoma and the gliomatous tumor cell line of wide region be highly effectively (21,24,51-53).In addition, suppress VEGF by VEGF antibody and in Rodents of evolving fully and primate, do not produce pronounced side effects (54,55).Generally speaking, these results show that VEGF is the effective target that is used to develop oncotherapy.Really, use many clinical trials underway (17,25) of VEGF inhibitor.

Although multiple short angiogenesis factor is all relevant with the pathology of exudative ageing macular degeneration, VEGF in the pathogeny of these diseases and development, seem the most key (3,56).The data that are derived from preclinical test and clinical trial are verified, separately blocking VEGF just be enough to alleviate or the progress of stable disease (33,34-37).For example, suppressing the conduction of VEGFR signal by the specificity tyrosine kinase inhibitor is enough to stop fully the retinal neovascularization in the muroid retinopathy of premature labor model to form (57).In addition, verified recently in mouse model behind the laser photocoagulation, the new vessels that the siRNA (siRNA) of antagonism muroid VEGF has significantly suppressed eyes forms (58).These results show that the selectivity inhibition of VEGF is attainable and has confirmed that this can be used for treating the neovascular disease of eyes, for example exudative degeneration of macula and diabetic retinopathy.

Used three kinds of approach to suppress the activity of VEGF, comprised that (1) come neutralize VEGF activity (24,26 by using the interactional specific antibody of antagonism VEGF/VEGFR, soluble VEGF-receptor or aptamers oligomer (aptamer oligos), 27,49,51,59,60); (2) suppress VEGFR Mediated Signal Transduction (52,61,62) by specific micromolecule tyrosine kinase inhibitor; And (3) express by using antisense, siRNA or ribozyme to suppress VEGF/VEGFR (58,63-65).Although all these approach have shown the remarkable inhibition that blood vessel is taken place in vivo, they all have great defective.For example, treatment protein (antibody and soluble recepter) or oligomer (antisense, siRNA and ribozyme) are the macromole of poor permeability, need parenteral administration and production cost height usually.Multiple injection forms for the chronic eyes new vessels of treatment, owing to such as the potential complication of detachment of retina and the infection relevant with operation, may be unpractiaca.And the specificity that tyrosine kinase inhibitor is renderd a service is limited.In normal eye and other tissue with low-level formation type ground VEGF expression, therefore it may be deleterious fully suppressing the VEGF function by whole body administration antibody or tyrosine kinase inhibitor, especially for the patient of AMD and RD, the many people among them also are hyperpietic (66-69).

Therefore, need to develop the molecule of special and optimization to develop novel angiogenesis inhibitor medicine.Correspondingly, purpose of the present invention just provides such chemical compound.

Summary of the invention

According to the present invention, confirmed to suppress the chemical compound of transcriptional expression behind the vascular endothelial cell growth factor already, and the using method of this chemical compound was provided.

One embodiment of this invention provides the chemical compound of a kind of formula (I):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

A and B are O or N respectively independently, and condition is: when A is O, and R ³Do not exist, and B is when being O R ²Do not exist;

R ¹And R ²Be independently selected from respectively H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl ,-COR ⁹With-CO ₂R ⁹, R wherein ¹And R ²In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl be respectively replacement or unsubstituted;

R ¹And R ²Can choose wantonly that formation replaces or the unsubstituted 1-3 of containing heterocycle that is selected from the ring hetero atom among N, O and the S with the atom that they connected, comprising R ¹And R ²The hetero atom that is connected; Or

R ¹And R ³Can choose wantonly that formation replaces or the unsubstituted 2-3 of containing heterocycle that is selected from the ring hetero atom among N, O and the S with the atom that they connected, comprising R ¹And R ³The hetero atom that is connected;

R ³Be H, alkyl, aryl or heterocycle, wherein R ³In described alkyl, aryl or heterocyclic group be respectively replacement or unsubstituted;

R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Be independently selected from respectively H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; R wherein ⁴, R ⁵, R ⁶, R ⁷And R ⁸In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulfonyl amino be respectively replacement or unsubstituted; R ¹⁰And R ¹¹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl, wherein R ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl be respectively replacement or unsubstituted;

Below paired each substituent R ⁴With R ⁵, R ⁵With R ⁶, R ⁶With R ⁷, and R ⁷With R ⁸The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 0-2 of having monocyclic heterocycles that is selected from the ring hetero atom among N, O or the S independently, or forms that replace or unsubstituted monocycle aromatic rings, thus formation bicyclo-system;

R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle be respectively replacement or unsubstituted;

Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or its hydrate.

Another embodiment of the present invention provides the chemical compound of a kind of formula (II):

Wherein

R ¹And R ²Be independently selected from H, alkyl, thiazolinyl, aryl and cycloalkyl respectively; R wherein ¹And R ²In described alkyl, thiazolinyl, aryl and cycloalkyl respectively independently for that replace or unsubstituted;

R ¹And R ²The atom that is connected with them can be chosen wantonly and form that 5-7 unit replaces or the unsubstituted 1-3 of containing heterocycle that is selected from the ring hetero atom among N, O and the S, comprising R ¹And R ²The hetero atom that is connected;

R ⁴, R ⁶And R ¹⁵Be independently selected from respectively H, replacement or unsubstituted alkyl and halogen;

Another embodiment of the present invention provides a kind of chemical compound with following structure:

Another embodiment of the present invention provides a kind of formula (I) chemical compound with structure shown in the formula (III):

Wherein

R ¹And R ²Be selected from respectively H, alkyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl ,-COR ⁹With-CO ₂R ⁹R wherein ¹And R ²In described alkyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl respectively independently for that replace or unsubstituted; R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocyclic group respectively independently for that replace or unsubstituted;

Another embodiment of the present invention provides the chemical compound of a kind of formula (IV):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

A and B are O or N respectively independently, and condition is: when B is O, and R ²Do not exist;

R ¹And R ²Be selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; The optional aryl that is replaced by alkyl, alkyl sulfonyl amino or halogen; And cycloalkyl, or

R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of containing heterocycle that is selected from by the ring hetero atom among N, O and the S, comprising R ¹And R ²The hetero atom that is connected;

R ³Be H;

R ⁴For be selected from H ,-COR ⁹, NR ¹⁰R ¹¹And halogen, wherein R ⁹Be alkyl, and R ¹⁰And R ¹¹For being independently selected from H and alkyl sulphonyl respectively;

R ⁵And R ⁶The atom that is connected with them forms optional is had a 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S by what alkyl replaced; Or R ⁵And R ⁶The atom that is connected with them forms the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms a bicyclo-system; Or

R ⁵Be H, and R ⁶Be selected from H, alkyl and halogen,

R ⁷Be H or halogen,

R ⁸Be halogen;

Another embodiment of the present invention provides a kind of selectivity to suppress the method for vascular endothelial cell growth, and it may further comprise the steps: the chemical compound that makes one or more formulas (I) of the cells contacting effective dose that shows vascular endothelial cell growth:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

Another embodiment of the present invention also provides a kind of selectivity to suppress the method for vascular endothelial cell growth, and it may further comprise the steps: one or more that make the cells contacting effective dose that shows vascular endothelial cell growth have the chemical compound of following structure:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of comprising heterocycle that is selected from the ring hetero atom among N, O and the S, and this heterocycle contains R ¹And R ²The hetero atom that is connected;

R ³Be H;

R ⁴Be selected from H ,-COR ⁹,-NR ¹⁰R ¹¹And halogen, wherein R ⁹Be alkyl, and R ¹⁰And R ¹¹Be selected from H and alkyl sulphonyl respectively;

R ⁵And R ⁶The atom that is connected with them forms optional is had a 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S by what alkyl replaced; Or R ⁵And R ⁶The atom that is connected with them forms the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms the bicyclo-system; Or

R ⁵Be H, and R ⁶Be selected from H, alkyl and halogen,

R ⁷Be H or halogen, and

R ⁸Be H or halogen;

Another aspect of the present invention is provided for suppressing VEGF and produces; Being used to suppress blood vessel takes place; And/or be used for the treatment of formula (I), (II), (III) and the chemical compound (IV) of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula.

Another aspect of the present invention provides the pharmaceutical composition that contains formula (I), (II), (III) and chemical compound (IV), and this pharmaceutical composition can be used for suppressing VEGF and produces; Being used to suppress blood vessel takes place; And/or be used for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula.

Another aspect of the present invention provides by using chemical compound described herein to suppress VEGF and produces; Suppressing blood vessel takes place; And/or the method for treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula.

In one embodiment, the present invention relates to suppress the method that VEGF produces, it comprises one or more chemical compounds of the present invention to patient's administration VEGF amount of suppression that these needs are arranged.

In another embodiment, the invention provides and suppress the method that blood vessel takes place, it comprises one or more chemical compounds of the present invention to patient's administration angiogenesis inhibitor amount that these needs are arranged.

In another embodiment, the invention provides the method that is used for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprises one or more chemical compounds of the present invention to patient's drug treatment effective dose that these needs are arranged.

Further understand these and other aspect of the present invention with reference to following preferred embodiment and detailed description.

Some embodiments

Embodiment 1, a kind of method that suppresses patient VEGF generation, it comprises the chemical compound in the chemical compound of the formula that is selected from (I) of VEGF amount of suppression, formula (II), formula (III) and formula (IV), or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 2, a kind of method that suppresses patient vessel's generation, it comprises the chemical compound in the chemical compound of the formula that is selected from (I) of angiogenesis inhibitor amount, formula (II), formula (III) and formula (IV), or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 3, a kind of treatment patient method for cancer, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 4, a kind of method for the treatment of patient's diabetic retinopathy, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 5, a kind of method for the treatment of the exudative degeneration of macula of patient, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 6, a kind of method for the treatment of patient's rheumatoid arthritis, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 7, the psoriasic method of a kind of treatment patient, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 8, the atherosclerotic method of a kind of treatment patient, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 9, a kind of method for the treatment of patient's obesity, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 10, a kind of method for the treatment of patient's chronic inflammatory disease, it comprises the chemical compound in the chemical compound of the formula that is selected from (I), formula (II), formula (III) and the formula (IV) of treatment effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture deliver medicine to the patient that this needs.

Embodiment 11, a kind of method that optionally suppresses VEGF in the cell, it is included in and is enough to optionally suppress the condition of VEGF wherein and under the time, make the chemical compound of at least a formula (I), formula (II), formula (III) and the formula (IV) of described cells contacting effective dose, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture.

Embodiment 12, a kind of method that optionally suppresses VEGF in the cell, it is included in and is enough to optionally suppress the condition of VEGF wherein and under the time, make the chemical compound that comprises the acceptable excipient of materia medica and at least a formula (I), formula (II), formula (III) and formula (IV) of described cells contacting effective dose, or the compositions of its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture.

Embodiment 13, a kind ofly treat or prevent the method that unusual VEGF produces the disease that helps its outbreak and development, it is included in and is enough to optionally suppress the condition of VEGF wherein and under the time, to the chemical compound of at least a formula (I), formula (II), formula (III) and formula (IV) that this patient's drug treatment effective dose that needs is arranged, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture.

Embodiment 14, a kind ofly suppress the method that unusual blood vessel takes place, it is included in and is enough to optionally suppress the condition of VEGF wherein and under the time, to the chemical compound of at least a formula (I), formula (II), formula (III) and formula (IV) that this patient's drug treatment effective dose that needs is arranged, or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture.

Embodiment 15, a kind of pharmaceutical composition, it comprises chemical compound or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or mixture and the acceptable inert matter of materia medica in the chemical compound of the formula of being selected from (I), formula (II), formula (III) and formula (IV).

Embodiment 16, a kind of compositions that suppresses VEGF, it comprises chemical compound or its enantiomer, diastereomer, the acceptable salt of materia medica, prodrug, solvate or the mixture of at least a formula (I), formula (II), formula (III) and formula (IV).The compositions of this inhibition VEGF can contain the acceptable inert matter of materia medica.

The application of chemical compound in pharmaceutical compositions of embodiment 17, formula (I), formula (II), formula (III) and formula (IV).

The specific embodiment

The key factor that blood vessel takes place is that the up regulation of VEGF (VEGF) is the major reason of cancer, diabetic retinopathy and the morbidity of exudative degeneration of macula.According to the present invention, differentiated and transcribed the chemical compound that the back suppresses vegf expression, and the method for using them is provided.Chemical compound of the present invention has the low micromole's activity that suppresses vegf expression.

Term " inhibition VEGF ", " inhibition of VEGF " or the like are meant with untreated cell and compare, and after time enough used compounds for treating of the present invention in the cycle, the back transcriptional expression of VEGF or generation reduced in the cell.For example, the activity of vascular endothelial cell growth factor will reduce, and promote the activity that blood vessel takes place as it.Make us it is desirable in incubation and compare with untreated cell, chemical compound of the present invention can suppress 10% of VEGF cell inner expression amount at least.In one embodiment, compare with untreated cell in incubation, chemical compound of the present invention can suppress about 25% of VEGF cell inner expression amount at least.In another embodiment, compare with untreated cell in incubation, chemical compound of the present invention can suppress about 50% of VEGF cell inner expression amount at least.In a preferred embodiment, compare with untreated cell in incubation, chemical compound of the present invention can suppress about 75% of VEGF cell inner expression amount at least.

Definition

Term used herein " alkyl " is meant optional that replace, side chain or straight chain saturation alkane base.

Term used herein " thiazolinyl " be meant optional replacement with at least one carbon-to-carbon double bond, side chain or straight chain unsaturated alkyl.

Term used herein " alkynyl " be meant optional replacement with at least one carbon-to-carbon triple bond, side chain or straight chain unsaturated alkyl.

Term used herein " aromatic rings " is meant optional replace, mononuclear aromatic ring.Described aromatic rings can be the part of fragrant bicyclo-system, for example naphthyl.Optionally, the aromatic rings of bicyclo-system connection can be cycloaliphatic ring.

Term used herein " aryl " is meant optional 5-7 unit's monocycle alkyl that replace, stable or stable 8-11 unit bicyclo-aryl radical.

Term used herein " cycloalkyl " is meant optional aliphatic hydrocarbon cyclic group that replace, that have 3-10 carbon atom.

Term used herein " cycloalkyl-alkyl " is meant the alkyl with the substituent optional replacement of cycloalkanes.

Term used herein " hetero atom " is meant the arbitrary atom beyond de-carbon or the hydrogen.

Term used herein " heterocycle " is meant optional stable 5-7 unit's monocyclic hydrocarbon ring that replaces or the optional stable 8-11 unit bicyclic hydrocarbons ring that replaces, and the hetero atom that the carbon atom of the 1-4 in this ring is selected among N, O and the S replaces.In the example of bicyclic heterocycles, substituent group can be positioned on each ring.In addition, described heterocycle can be for saturated or unsaturated; With aliphatic or aromatic.

Term used herein " oxime " is meant oximido group=NOR ²⁶, wherein, R ²⁶Be H or C ₁-C ₆Alkyl, oximido be connected to specific atom by be connected two keys with the nitrogen oxime.In the preferred embodiment, R ²⁶Be H.

Term used herein " the acceptable salt of materia medica " is meant organic and the deutero-salt of mineral acid, as acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propanoic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, glycolic, acetone acid, methanesulfonic acid, ethyl sulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid and similar acceptable acid.

Term used herein " amino thiocarbonyl " is meant that amino is connected to the group on the carbon atom of sulfo-carbon back.The sulfo-carbon back is a kind of carbon atom is connected to sulphur atom by two keys a group.Amino thiocarbonyl to shown in the point of contact of atom be the carbon atom of thiocarbonyl part.

Formula used herein (III) comprises the chemical skeleton figure identical with the chemical skeleton figure of formula (I).

Confessed as those skilled in the art, some chemical compound of the present invention can comprise chiral centre, and can be used as racemic mixture or exist as the compositions of enantiomeric pure.For example, in the compositions of enantiomeric pure, this chemical compound can be used as R or the S isomer exists.

Chemical compound of the present invention and compositions

One aspect of the present invention, the chemical compound that provides of the present invention can suppress VEGF generation or the generation of inhibition blood vessel or VEGF generation and the generation of inhibition blood vessel.Another aspect of the present invention, chemical compound provided by the invention can be used for the treatment of cancer, diabetic retinopathy or exudative degeneration of macula, or treat the complication of various cancers, diabetic retinopathy or exudative degeneration of macula.

In one embodiment, compound specificity ground inhibition VEGF of the present invention produces.In another embodiment, chemical compound of the present invention also suppresses for example expression of FGF-2 of other angiogenesis factor except that the expression that suppresses VEGF.When treatment intraocular neovascularization disease (17), preferably use the special inhibitor of vascular endothelial cell growth factor; When suppressing growth of tumor, preferably use angiogenesis inhibitor widely.

Chemical compound of the present invention comprises suc as formula the chemical compound shown in (I):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

R ⁴, R ⁵, R ⁶, R ⁷And R ⁸Be independently selected from respectively H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; Wherein-R ⁴, R ⁵, R ⁶, R ⁷And R ⁸In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulfonyl amino be respectively replacement or unsubstituted; R ¹⁰And R ¹¹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl, wherein R ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl be respectively replacement or unsubstituted;

In one embodiment of formula (I), X is O or S.In another embodiment of formula (I), X is O.In another embodiment of formula (I), X is not O.In one embodiment of formula (I), X is S.In another embodiment of formula (I), X is not S.

In one embodiment of formula (I), X is C or N.In another embodiment of formula (I), Y is C.In another embodiment of formula (I), Y is not C.In one embodiment of formula (I), Y is N.In another embodiment of formula (I), Y is not N.

In one embodiment of formula (I), A and B are respectively O or N.In another embodiment of formula (I), A is O.In another embodiment of formula (I), A is not O.In one embodiment of formula (I), A is N.In another embodiment of formula (I), A is not O.In another embodiment of formula (I), B is O.In another embodiment of formula (I), B is not O.In one embodiment of formula (I), B is N.In another embodiment of formula (I), B is not N.In one embodiment of formula (I), A and B are O.In one embodiment of formula (I), A and B are N.In one embodiment of formula (I), A and B are not O.In one embodiment of formula (I), A and B are not N.

In another embodiment of formula (I), R ¹And R ²Be independently selected from H, alkyl, aryl and cycloalkyl respectively, wherein said alkyl, aryl and cycloalkyl are respectively independently for that replace or unsubstituted.In another embodiment of formula (I), R ¹And R ²Be independently selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; The optional aryl that is replaced by alkyl, alkyl sulfonyl-amino or halogen; And cycloalkyl.

In another embodiment, R ¹And R ²Be independently selected from H and cycloalkyl respectively.

In another embodiment of formula (I), R ¹And R ²Be independently selected from H and the optional alkyl that is substituted by cycloalkyl respectively.In another embodiment of formula (I), R ¹And R ²The alkyl that is independently selected from H respectively and is substituted by cycloalkyl.

In another embodiment of formula (I), R ¹And R ²Be independently selected from H and the optional aryl that is replaced by alkyl respectively.

In another embodiment of formula (I), R ¹And R ²Be independently selected from H and the optional alkyl that is replaced by halogen respectively.In another embodiment of formula (I), R ¹And R ²The alkyl that is independently selected from H respectively and is replaced by halogen.

In another embodiment of formula (I), B is O, R ¹Be the optional aryl that is replaced by halogen.In another embodiment of formula (I), B is O, R ¹Be the aryl that is replaced by halogen.In another embodiment of formula (I), B is O, R ¹Be the aryl that is replaced by bromine.

In another embodiment of formula (I), B is O, R ¹Be the optional aryl that is replaced by halogen.In another embodiment of formula (I), R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of comprising heterocycle that is selected from by the ring hetero atom among N, O and the S, comprising R ¹And R ²The hetero atom that is connected.In another embodiment of formula (I), R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of comprising heterocycle that is selected from the ring hetero atom among N and the O, comprising R ¹And R ²The hetero atom that is connected.

In another embodiment, exemplary and nonrestrictive heterocycle comprises:

。

In one preferred embodiment of formula (I), R ¹And R ²The atom that is connected with them can form unsubstituted heterocycle.R ¹And R ²The exemplary unsubstituting heterocycle that the atom that is connected with them forms comprises following person, but only limits to this:

。

In another preferred embodiment of formula (I), R ¹, R ²Can form the heterocycle of replacement with the atom that is connected with them.In one embodiment, nonrestrictive substituted heterocycle comprises, for example:

In a preferred embodiment, R ¹And R ²The atom that is connected with them forms the heterocycle that is replaced by a substituent group.In another preferred embodiment, R ¹And R ²The atom that is connected with them forms the heterocycle that is replaced by two substituent groups of selecting separately.In another preferred embodiment, R ¹And R ²The atom that is connected with them forms the heterocycle that is replaced by three substituent groups of selecting separately.In another preferred embodiment, R ¹And R ²The atom that is connected with them forms the heterocycle that is replaced by four substituent groups of selecting separately.In another preferred embodiment, R ¹And R ²The atom that is connected with them forms the heterocycle that is replaced by five substituent groups of selecting separately.Exemplarily, R ¹And R ²Non-limiting substituent group on the heterocycle that the atom that is connected with them forms comprises:

。

In a preferred embodiment, R ³Be H.

In another preferred embodiment of formula (I), A is O, R ³Do not exist.

In one embodiment of formula (I), R ⁴Independent be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen.In a preferred embodiment, R ⁴Be selected from-COR ⁹,-NR ¹⁰R ¹¹And halogen.

In one preferred embodiment of formula (I), R ⁴Be H.

In another preferred embodiment of formula (I), R ⁴For-COR ⁹In another preferred embodiment, R ⁴For-the CO-alkyl.In a preferred embodiment, R ⁴For-CO-(C ₁-C ₆Alkyl).In another preferred embodiment, R ⁴For-the CO-methyl.

In one preferred embodiment of formula (I), R ⁴For-C (O) NR ¹⁰R ¹¹In another preferred embodiment, R ⁴For-C (O) NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹In a hydrogen, another is an alkyl sulphonyl.In another preferred embodiment, R ¹⁰And R ¹¹In a hydrogen, another is a methyl sulphonyl.

In one preferred embodiment of formula (I), R ⁴Be halogen.In another preferred embodiment, R ⁴Be bromine or chlorine.In another preferred embodiment, R ⁴Be bromine.In another preferred embodiment, R ⁴Be chlorine.

In one preferred embodiment of formula (I), R ⁵Be H; R ⁵And R ⁶The atom that is connected with them is chosen wantonly that formation replaces or the unsubstituted 0-2 of comprising monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S; Or that replace or unsubstituted monocycle aromatic rings, thereby form the bicyclo-system.

In another preferred embodiment of formula (I), R ⁵Be H.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them form replace or the unsubstituted 0-2 of comprising monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S; Or replacement or unsubstituted monocycle aromatic rings, thereby form a bicyclo-system.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and optional is comprised 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S by what alkyl replaced; Or R ⁵And R ⁶The atom that is connected with them forms the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms a bicyclo-system.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms the unsubstituted 0-2 of comprising monocyclic heterocycles that is selected from by the ring hetero atom among N, O and the S.In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms unsubstituted monocycle aromatic rings, thereby forms a bicyclo-system.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that alkyl replaces.In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from by the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is methyl substituted.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that alkoxy or halogen replaces.In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that alkoxyl replaces.In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that methoxyl group replaces.

In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that halogen replaces.In another preferred embodiment of formula (I), R ⁵And R ⁶The atom that is connected with them forms and comprises 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S, thereby forms a bicyclo-system, and wherein said monocyclic heterocycles is that bromine replaces.

In one preferred embodiment of formula (I), R ⁶Be selected from H, alkyl and halogen.In another preferred embodiment of formula (I), R ⁶Be H.In another preferred embodiment of formula (I), R ⁶Be alkyl.In another preferred embodiment of formula (I), R ⁶Be C ₁-C ₆Alkyl.In another preferred embodiment of formula (I), R ⁶Be methyl.

In one preferred embodiment of formula (I), R ⁷Be hydrogen.In another preferred embodiment of formula (I), R ⁷Be halogen.In another preferred embodiment of formula (I), R ⁷Be chlorine.

In one preferred embodiment of formula (I), R ⁸Be hydrogen.In another preferred embodiment of formula (I), R ⁸Be halogen.In another preferred embodiment of formula (I), R ⁸Be chlorine or bromine.In another preferred embodiment of formula (I), R ⁸Be chlorine.In another preferred embodiment of formula (I), R ⁸Be bromine.

In the one embodiment of this invention, chemical compound comprises chemical compound shown in the formula (Iaa) shown in the formula (I):

Wherein

R ⁸Be hydrogen;

R ¹²Be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; R wherein ¹²In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino respectively independently for that replace or unsubstituted; R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl and heterocycle be respectively replacement or unsubstituted;

R ¹⁰And R ¹¹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl respectively; R wherein ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl be respectively replacement or unsubstituted;

In a preferred embodiment, chemical compound comprises chemical compound shown in the formula (Ia) shown in the formula (I):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

A and B are respectively O or N, and condition is: when A is O, and R ³Do not exist, and B is when being O R ²Do not exist;

R ¹And R ²Be independently selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; By the aryl and the cycloalkyl of alkyl, alkyl sulfonyl-amino or halogen replacement; Or

R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of comprising heterocycle that is selected from the ring hetero atom among N, O and the S, comprising R ¹And R ²The hetero atom that is connected;

R ³Be H;

R ⁴Be selected from H ,-COR ⁹,-NR ¹⁰R ¹¹And halogen, wherein R ⁹Be alkyl, and R ¹⁰And R ¹¹Be independently selected from H and alkyl sulphonyl respectively;

R ⁵And R ⁶The atom that is connected with them can be chosen 0-2 the monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S that comprise that forms the alkyl replacement wantonly, or R ⁵And R ⁶The atom that is connected with them can be chosen the monocycle aromatic rings that forms alkoxy or halogen replacement wantonly, thereby forms the bicyclo-system; Or

R ⁵Be hydrogen, and R ⁶Be selected from H, alkyl and halogen;

R ⁷Be H or halogen; With

R ⁸Be H or halogen;

In another embodiment, the chemical compound of formula (I) comprises the chemical compound shown in (Ib) that has structural formula:

Wherein

R ⁴Be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted alkyl sulfuryl amino and halogen;

R ¹²Be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; R wherein ¹²In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino respectively independently for that replace or unsubstituted;

R ¹⁰And R ¹¹Be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl respectively; R wherein ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl be respectively replacement or unsubstituted;

In a preferred embodiment, chemical compound comprises the chemical compound shown in the structural formula (Ib-2) shown in the formula (Ib):

Wherein

R ¹Be selected from H and alkyl;

R ²Be selected from optional by the alkyl of cycloalkyl or halogen replacement and the optional aryl that is replaced by alkyl;

R ⁴Be selected from H and alkyl; With

R ¹²Be selected from H and halogen;

In one preferred embodiment of formula (Ib-2), R ¹Be hydrogen.In another preferred embodiment of formula (Ib-2), R ¹Be C ₁-C ₆Alkyl.In another preferred embodiment of formula (Ib-2), R ¹Be methyl.

In one preferred embodiment of formula (Ib-2), R ²For choosing wantonly by the alkyl of cycloalkyl or halogen replacement.In one preferred embodiment of formula (Ib-2), R ²Be alkyl.In one preferred embodiment of formula (Ib-2), R ²Be C ₁-C ₆Alkyl.In one preferred embodiment of formula (Ib-2), R ²Be methyl.

In one preferred embodiment of formula (Ib-2), R ²Be the alkyl that is substituted by cycloalkyl.In one preferred embodiment of formula (Ib-2), R ²Be the C that is substituted by cycloalkyl ₁-C ₆Alkyl.In one preferred embodiment of formula (Ib-2), R ²Be the methyl that is substituted by cycloalkyl.In one preferred embodiment of formula (Ib-2), R ²Be the alkyl that is replaced by cyclohexyl.In another preferred embodiment of formula (Ib-2), R ²Be the C that is replaced by cyclohexyl ₁-C ₆Alkyl.In another preferred embodiment of formula (Ib-2), R ²Be the methyl that is replaced by cyclohexyl.

In one preferred embodiment of formula (Ib-2), R ²Be the alkyl that is replaced by halogen.In one preferred embodiment of formula (Ib-2), R ²Be the alkyl that is replaced by one or more fluorine.

In one preferred embodiment of formula (Ib-2), R ²Be the optional aryl that is replaced by alkyl.In one preferred embodiment of formula (Ib-2), R ²Be the aryl that is replaced by alkyl.In one preferred embodiment of formula (Ib-2), R ²Be the C that is replaced by alkyl ₆-C ₈Aryl.In one preferred embodiment of formula (Ib-2), R ²Be the phenyl that is replaced by alkyl.

In one preferred embodiment of formula (Ib-2), R ²For by C ₁-C ₆The aryl that alkyl replaces.In one preferred embodiment of formula (Ib-2), R ²For by C ₁-C ₆The C that alkyl replaces ₆-C ₈Aryl.In one preferred embodiment of formula (Ib-2), R ²For by C ₁-C ₆The phenyl that alkyl replaces.

In one preferred embodiment of formula (Ib-2), R ⁴Be H.In another preferred embodiment of formula (Ib-2), R ⁴Be halogen.In another preferred embodiment of formula (Ib-2), R ⁴Be bromine.

In one preferred embodiment of formula (Ib-2), R ¹²Be H.In another preferred embodiment of formula (Ib-2), R ¹²Be halogen.In another preferred embodiment of formula (Ib-2), R ¹²Be bromine.

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Ic) that has formula:

Wherein

R ¹And R ²Be selected from respectively by alkyl, aryl and cycloalkyl; R wherein ¹And R ²In described alkyl, aryl and cycloalkyl be respectively unsubstituted or unsubstituted independently; R ¹And R ²The atom that is connected with them can be chosen wantonly and form the first monocyclic heterocycles of 5-7 that replace or unsubstituted, or unsubstituted 5-7 unit bicyclic heterocycles, and they contain 1-3 ring hetero atom that is selected from N, O and S, comprising R ¹And R ²The hetero atom that is connected;

R ⁴Be selected from H ,-COR ⁹, replacement or unsubstituted alkyl sulfonamido and halogen, wherein R ⁹For replace or unsubstituted alkyl;

In another embodiment, chemical compound shown in the formula (Ic) comprises the chemical compound of the structure shown in (Ic-2) that has formula:

Wherein

R ¹Be selected from H and alkyl;

R ⁴Be selected from H and halogen;

In one preferred embodiment of formula (Ic-2), R ¹Be hydrogen.In another preferred embodiment of formula (Ic-2), R ¹Be C ₁-C ₆Alkyl.In another preferred embodiment of formula (Ic-2), R ¹Be methyl.

In one preferred embodiment of formula (Ic-2), R ²For choosing wantonly by the alkyl of cycloalkyl or halogen replacement.In one preferred embodiment of formula (Ic-2), R ²Be alkyl.In one preferred embodiment of formula (Ic-2), R ²Be C ₁-C ₆Alkyl.In one preferred embodiment of formula (Ic-2), R ²Be methyl.

In one preferred embodiment of formula (Ic-2), R ²Be the alkyl that is substituted by cycloalkyl.In one preferred embodiment of formula (Ic-2), R ²Be the C that is substituted by cycloalkyl ₁-C ₆Alkyl.In one preferred embodiment of formula (Ic-2), R ²Be the methyl that is substituted by cycloalkyl.In one preferred embodiment of formula (Ic-2), R ²Be the alkyl that is replaced by cyclohexyl.In another preferred embodiment of formula (Ic-2), R ²Be the C that is replaced by cyclohexyl ₁-C ₆Alkyl.In another preferred embodiment of formula (Ic-2), R ²Be the methyl that is replaced by cyclohexyl.

In one preferred embodiment of formula (Ic-2), R ²Be the alkyl that is replaced by halogen.In one preferred embodiment of formula (Ic-2), R ²Be the alkyl that is replaced by one or more fluorine.

In one preferred embodiment of formula (Ic-2), R ²Be the aryl that is replaced by alkyl.In one preferred embodiment of formula (Ic-2), R ²Be the C that is replaced by alkyl ₆-C ₈Aryl.In one preferred embodiment of formula (Ic-2), R ²Be the phenyl that is replaced by alkyl.

In one preferred embodiment of formula (Ic-2), R ²For by C ₁-C ₆The aryl that alkyl replaces.In one preferred embodiment of formula (Ic-2), R ²For by C ₁-C ₆The C that alkyl replaces ₆-C ₈Aryl.In one preferred embodiment of formula (Ic-2), R ²For by C ₁-C ₆The phenyl that alkyl replaces.

In one preferred embodiment of formula (Ic-2), R ⁴Be H.In another preferred embodiment of formula (Ic-2), R ⁴Be halogen.In another preferred embodiment of formula (Ic-2), R ⁴Be bromine.

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Id) that has formula:

Wherein

D be selected from methylene ,-CHNR ¹⁶R ¹⁷,-NR ¹⁶And O, wherein R ¹⁶And R ¹⁷Be selected from replacement or unsubstituted alkyl and replacement or unsubstituted aryl;

R ⁴Be selected from H ,-COR ⁹, replace or unsubstituted alkyl sulfonamido and halogen, wherein R ⁹For replace or unsubstituted alkyl;

R ¹³And R ¹⁴Be independently selected from H, alkyl, aryl, amino carbonyl and heterocycle respectively, wherein R ¹³And R ¹⁴In described alkyl, aryl, amino carbonyl and heterocycle be respectively replacement or unsubstituted; R ¹³And R ¹⁴The atom that is connected with them can be chosen wantonly and form that replace or unsubstituted heterocycle, or that replace or unsubstituted aromatic rings, and they comprise 0-3 ring hetero atom that is selected from N, O and S, comprising R ¹³And R ¹⁴The hetero atom that is connected;

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Ie) that has formula:

Wherein

R ³Be H, alkyl, aryl or heterocycle, wherein R ³In described alkyl, aryl or heterocycle be respectively replacement or unsubstituted;

R ¹³And R ¹⁴Be selected from H, alkyl, aryl, amino carbonyl and heterocycle respectively, it is replacement or unsubstituted that wherein said alkyl, aryl, amino carbonyl and heterocycle are respectively;

In another embodiment, chemical compound shown in the formula (Ie) comprises the chemical compound of the structure shown in (Ie-2) that has formula:

Wherein

D is-NR ¹⁶, R wherein ¹⁶Be the optional aryl that is replaced by halogen;

R ³Be H;

R ⁴Be halogen; With

R ¹³And R ¹⁴Be H;

In one preferred embodiment of formula (Ie-2), R ¹⁶Be aryl.In another preferred embodiment of formula (Ie-2), R ¹⁶Be the aryl that is replaced by one or more halogens.In another preferred embodiment of formula (Ie-2), R ¹⁶Be the aryl that is replaced by one or more chlorine.

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Ih) that has formula:

Wherein

D be selected from by methylene ,-CHNR ¹⁶R ¹⁷,-NR ¹⁶And O, wherein R ¹⁶And R ¹⁷Be selected from replacement or unsubstituted alkyl and replacement or unsubstituted aryl;

R ¹³And R ¹⁴Be selected from H, alkyl, aryl and heterocycle respectively, wherein R ¹³And R ¹⁴In described alkyl, aryl and heterocycle be respectively replacement or unsubstituted;

R ¹⁸For replace or unsubstituted alkyl;

In another embodiment, chemical compound shown in the formula (Ih) comprises the chemical compound of the structure shown in (Ih-2) that has formula:

Wherein,

D be selected from methylene and-NR ¹⁶, R wherein ¹⁶Be aryl;

R ¹³And R ¹⁴Be selected from H and unsubstituted alkyl respectively; With

R ¹⁸Be unsubstituted alkyl;

In one preferred embodiment of formula (Ih-2), D is a methylene.In another preferred embodiment of formula (Ih-2), D is NR ¹⁶, R wherein ¹⁶Be aryl.In another preferred embodiment of formula (Ih-2), D is-NR ¹⁶, R wherein ¹⁶Be C ₆-C ₈Aryl.In another preferred embodiment of formula (Ih-2), D is-NR ¹⁶, R wherein ¹⁶Be phenyl.

In another preferred embodiment of formula (Ih-2), R ¹³And R ¹⁴All be H.In another preferred embodiment of formula (Ih-2), R ¹³And R ¹⁴It all is unsubstituted alkyl.In another preferred embodiment of formula (Ih-2), R ¹³And R ¹⁴It all is methyl.

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (If) that has formula:

Wherein

R ¹³And R ¹⁴Be independently selected from H, alkyl, aryl, aryl alkyl, amino carbonyl and heterocycle respectively, R ¹³And R ¹⁴In described alkyl, aryl, aryl alkyl, amino carbonyl and heterocycle be respectively replacement or unsubstituted;

R ¹³And R ¹⁴The atom that is connected with them can be chosen wantonly and form that replace or unsubstituted heterocycle; Or that replace or unsubstituted aromatic rings, they comprise 0-3 ring hetero atom that is selected from N, O and S, comprising R ¹³And R ¹⁴The hetero atom that is connected;

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Ig) that has formula:

Wherein

A is O or N, and condition is: when A is O, and R ³Do not exist;

R ³Be H; And

R ⁴Be selected from halogen and replacement or the unsubstituted alkyl sulfonamido;

In one preferred embodiment of formula (Ig), A is O, and R ³Do not exist.In another preferred embodiment of formula (Ig), A is N, and R ³Be H.

In another preferred embodiment of formula (Ig), R ⁴Be halogen.In another preferred embodiment of formula (Ig), R ⁴Be chlorine or bromine.In another preferred embodiment of formula (Ig), R ⁴Be chlorine.In another preferred embodiment of formula (Ig), R ⁴Be bromine.

In another preferred embodiment of formula (Ig), R ⁴Be alkyl sulfonyl amino.In another preferred embodiment of formula (Ig), R ⁴Be sulfonyloxy methyl amino.

In another preferred embodiment of formula (Ih-2), R ¹³Be H, and R ¹⁴Be unsubstituted alkyl.In another preferred embodiment of formula (Ih-2), R ¹³Be H, and R ¹⁴Be methyl.In another preferred embodiment of formula (Ih-2), R ¹³And R ¹⁴It all is methyl.In another preferred embodiment of formula (Ih-2), R ¹⁴Be H, and R ¹³Be unsubstituted alkyl.In another preferred embodiment of formula (Ih-2), R ¹⁴Be H, and R ¹³Be methyl.

In another preferred embodiment of formula (Ih-2), R ¹⁸Be methyl.

In another embodiment, chemical compound shown in the formula (I) comprises the chemical compound of the structure shown in (Ii) that has formula:

Wherein

R ¹And R ²For that replace or unsubstituted;

In another embodiment of the present invention, chemical compound is selected from following group shown in the formula (I):

4-(hydroxyl-diphenyl-methyl)-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

3,5-dimethyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

3,4-dihydro-1H-isoquinolin-2-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-(hydroxyl-diphenyl-methyl)-piperidines-1-carboxylic acid (1-bromo-naphthalene-2-yl)-amide;

4-benzyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

Piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-methyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

2-methyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

3,5-dimethyl-piperidines-1-carboxylic acid 1-acetyl group-naphthalene-2-base ester;

4-(hydroxyl-diphenyl-methyl)-piperidines-1-carboxylic acid (1-chloro-naphthalene-2-yl)-amide;

Morpholine-4-carboxylic acid 1-bromo-naphthalene-2-base ester;

1,4-two oxa-s-8-azepine-spiral shell [4.5] certain herbaceous plants with big flowers alkane-8-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-methyl-piperidines-1-carboxylic acid 1-acetyl group-naphthalene-2-base ester;

Diethyl-carbamic acid 1-bromo-naphthalene-2-base ester;

Piperidines-1-carboxylic acid 4-chloro-isoquinolin-3-base ester;

4-benzyl-piperidines-1-carboxylic acid 1-acetyl group-naphthalene-2-base ester;

4-benzyl-piperidines-1-carboxylic acid 2,4,6-three chloro-phenyl esters;

Dimethyl-carbamic acid 1-bromo-naphthalene-2-base ester;

Carbonic acid two-(1-sulfonyloxy methyl amino-naphthalene-2-yl) ester;

4-benzyl-piperidines-1-carboxylic acid naphthalene-2-base amide;

N-(2-hydroxyl-naphthalene-1-yl)-sulfonyloxy methyl amine;

3,5-dimethyl-piperidines-1-carboxylic acid 1-methanesulfonamido-naphthalene-2-base ester;

4-(hydroxyl-diphenyl-methyl)-piperidines-1-carboxylic acid 1-methanesulfonamido-naphthalene-2-base ester;

4-benzyl-piperidines-1-carboxylic acid 1-methanesulfonamido-naphthalene-2-base ester;

4-phenyl-piperidines-1-carboxylic acid 1-methanesulfonamido-naphthalene-2-base ester;

Piperidines-1-carboxylic acid 1-methanesulfonamido-naphthalene-2-base ester; With

Its pharmaceutically acceptable salt, enantiomer, stereoisomer or its hydrate.

In another embodiment, the invention provides the chemical compound of a kind of formula (II):

Wherein

R ¹And R ²Be selected from H, alkyl, thiazolinyl, aryl and cycloalkyl respectively, wherein R ¹And R ²In described alkyl, thiazolinyl, aryl and cycloalkyl respectively independently for that replace or unsubstituted;

R ¹And R ²That the atom that is connected with them can be chosen the replacement that forms 5-7 unit wantonly or the unsubstituted 1-3 of comprising heterocycle that is selected from the ring hetero atom of N, O and S is comprising R ¹And R ²The hetero atom that is connected;

R ⁴, R ⁶And R ¹⁵Be selected from respectively H, replacement or unsubstituted alkyl and halogen;

In another embodiment, the invention provides a kind of chemical compound with following structure:

In another embodiment, the present invention relates to a kind of formula (I) chemical compound with structure shown in the formula (III):

Wherein

R ¹And R ²Be selected from respectively H, alkyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl ,-COR ⁹With-CO ₂R ⁹, R wherein ¹And R ²In described alkyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl respectively independently for that replace or unsubstituted; R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle respectively independently for that replace or unsubstituted;

In another embodiment of the present invention, provide the chemical compound shown in the formula (IV):

Wherein

X is O or S; Condition is: when Y is N, and R ⁸Do not exist;

Z is C or does not exist; Condition is: when Z does not exist, and X, B, R ¹And R ²Do not exist;

A and B are O or N respectively independently; Condition is: when B is O, and R ²Do not exist;

R ¹And R ²Be selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; The optional aryl that is replaced by alkyl, alkyl sulfonyl amino or halogen; And cycloalkyl; Or

R ¹And R ²The atom that is connected with them can be chosen wantonly that formation replaces or the unsubstituted 1-3 of comprising heterocycle that is selected from the ring hetero atom of N, O and S, comprising R ¹And R ²The hetero atom that is connected;

R ³Be H;

R ⁵And R ⁶The atom that is connected with them can form and optional be comprised 0-2 heteroatomic monocyclic heterocycles that is selected from N, O and S by what alkyl replaced; Or R ⁵And R ⁶The atom that is connected with them can form the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms the bicyclo-system; Or

R ⁵Be hydrogen, and R ⁶Be selected from H, alkyl and halogen;

R ⁷Be hydrogen or halogen; With

R ⁸Be halogen;

In one preferred embodiment of formula (IV), Z does not exist.

In another preferred embodiment of formula (IV), Z does not exist, and A is O, and R ³Be hydrogen.

In another preferred embodiment, Z does not exist, and Y is C, R ⁸Do not exist.

In another preferred embodiment of formula (IV), Z does not exist, R ⁴For-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Be selected from H and alkyl sulphonyl respectively.

In another preferred embodiment of formula (IV), Z does not exist, R ⁵And R ⁶The atom that is connected with them can form the monocycle aromatic rings, thereby forms the bicyclo-system.

In another preferred embodiment of formula (IV), Z does not exist, and R ⁷Be hydrogen.

In another preferred embodiment, the present invention relates to a kind of compositions, it comprises one or more chemical compounds of the present invention, and pharmaceutically acceptable carrier.

The method of invention

It is a kind of by using one or more chemical compounds of the present invention to suppress that VEGF produces and/or suppress blood vessel takes place that another aspect of the present invention provides, and/or the method for treatment cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula.

In one embodiment, the present invention relates to the method that a kind of VEGF of inhibition produces, it comprises to patient's administration chemical compound of the present invention that these needs are arranged.

In another embodiment, the present invention relates to a kind of method that blood vessel takes place that suppresses, it comprises to patient's administration chemical compound of the present invention that these needs are arranged.

In another embodiment, the present invention relates to a kind of method of the VEGF of treatment overexpression, it comprises to patient's administration chemical compound of the present invention that these needs are arranged.

In another embodiment, the present invention relates to a kind of treatment method for cancer, it comprises to patient's administration chemical compound of the present invention of suffering from this disease.

In another embodiment, the present invention relates to a kind of method for the treatment of the intraocular neovascularization disease, it comprises to patient's administration chemical compound of the present invention of suffering from this disease.

In one embodiment, the present invention relates to suppress in the cell method of VEGF, it comprises one or more chemical compounds of the present invention that make this cells contacting effective dose.Chemical compound of the present invention can deliver medicine to needs to suppress the patient that VEGF produces.

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprises one or more chemical compounds of the present invention to patient's drug treatment effective dose that these needs are arranged.

The present invention relates to the method that a kind of selectivity suppresses vascular endothelial cell growth on the other hand, and it comprises one or more chemical compounds of the present invention that make the cells contacting effective dose that shows vascular endothelial cell growth.

In another embodiment, the invention provides the method for a kind of treatment or inhibition disease, brought out by unusual vascular endothelial cell growth factor in the morbidity of this disease or the process, this method comprises one or more chemical compounds of the present invention to patient's drug treatment effective dose that these needs are arranged.In some embodiments, described disease is selected from cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula.Do not limit by principle, method of the present invention is by regulating the active machine-processed combinations of VEGF.

Term " inhibition VEGF ", " inhibition of VEGF " or the like, the meaning are transcribing the back expression or producing lower than untreated with VEGF in the cell of The compounds of this invention processing grace time section.Thereby VEGF activity (for example short blood vessel takes place active) also can reduce.It is desirable for when cultivating, chemical compound of the present invention is with respect to the vegf expression in the cell of the amount of untreated cell inhibition at least 10%.In one embodiment, chemical compound of the present invention suppresses at least about the vegf expression in the cell of 25% amount with respect to untreated cell.In another embodiment, this chemical compound suppresses at least about the vegf expression in the cell of 50% amount with respect to untreated cell.In further embodiment, this chemical compound suppresses at least about the vegf expression in the cell of 75% amount with respect to untreated cell.

In one embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (I):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

In another embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (Ia):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

R ¹And R ²Be selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; The optional aryl that is replaced by alkyl, alkyl sulfonyl-amino or halogen; And cycloalkyl, or

R ³Be H;

R ⁴For be selected from H ,-COR ⁹,-NR ¹⁰R ¹¹And halogen, wherein R ⁹Be alkyl, and R ¹⁰And R ¹¹For being selected from H and alkyl sulfonyl respectively;

R ⁵And R ⁶The atom that is connected with them form alkyl optional replacement comprise 0-2 monocyclic heterocycles that is selected from the ring hetero atom of N, O and S; Or R ⁵And R ⁶The atom that is connected with them forms the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms a bicyclo-system; Or

R ⁵Be H, and R6 is selected from by H, alkyl and halogen,

R ⁷For H or halogen and

R ⁸Be H or halogen;

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (I).

In another embodiment, the invention provides a kind of method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (I).

In another embodiment, the invention provides the method that a kind of selectivity suppresses vascular endothelial cell growth, it comprise make the cells contacting effective dose that shows vascular endothelial cell growth one or more suc as formula the chemical compound shown in (I).

In another embodiment, the invention provides a kind of method of the VEGF of treatment overexpression, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (I).

In another embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprises that one or more have the chemical compound of structure shown in the formula (II) to patient's administration that these needs are arranged:

Wherein

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (II).

In another embodiment, the invention provides a kind of method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprise to have this need to patient's administration one or more suc as formula the chemical compound shown in (II).

In another embodiment, the invention provides the method that a kind of selectivity suppresses vascular endothelial cell growth, it comprise make the cells contacting effective dose that shows vascular endothelial cell growth one or more suc as formula the chemical compound shown in (II).

In another embodiment, the invention provides a kind of method of the VEGF of treatment overexpression, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (II).

In another embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (III):

Wherein

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (III).

In another embodiment, the invention provides a kind of method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (III).

In another embodiment, the invention provides the method that a kind of selectivity suppresses vascular endothelial cell growth, it comprise make the cells contacting effective dose that shows vascular endothelial cell growth one or more suc as formula the chemical compound shown in (III).

In another embodiment, the invention provides a kind of method of the VEGF of treatment overexpression, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (III).

In another embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (IV):

Wherein

X is O or S; Condition is: when Y is N, and R ⁸Do not exist;

R ³Be H;

R ⁵Be hydrogen, and R ⁶Be selected from H, alkyl and halogen;

R ⁷Be hydrogen or halogen; With

R ⁸Be halogen;

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (IV).

In another embodiment, the invention provides a kind of method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (IV).

In another embodiment, the invention provides the method that a kind of selectivity suppresses vascular endothelial cell growth, it comprise make the cells contacting effective dose that shows vascular endothelial cell growth one or more suc as formula the chemical compound shown in (IV).

In another embodiment, the invention provides a kind of method of the VEGF of treatment overexpression, it comprise to patient's administration that these needs are arranged one or more suc as formula the chemical compound shown in (IV).

In another embodiment, the invention provides the method that a kind of VEGF of inhibition produces, it comprises the chemical compound 6 that has following structure to patient's administration that these needs are arranged:

In another embodiment, the invention provides a kind of method that blood vessel takes place that suppresses, it comprises to the patient that these needs are arranged gives drug compound 6.

In another embodiment, the invention provides a kind of method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprises to the patient that these needs are arranged gives drug compound 6.

In another embodiment, the invention provides the method that a kind of selectivity suppresses vascular endothelial cell growth, it comprises the chemical compound 6 that makes the cells contacting effective dose that shows vascular endothelial cell growth.

In another embodiment, the invention provides a kind of method of the VEGF of treatment overexpression, it comprises to the patient that these needs are arranged gives drug compound 6.

In embodiments of the present invention, described patient is a mammal.In the preferred embodiment of the inventive method, described patient is human.

Chemical compound of the present invention can cooperate administration with the administration of purified form or with pharmaceutically acceptable excipient.The method according to this invention, can be through any route of administration known in the art with one or more chemical compounds to patient's administration.That concrete exemplary route of administration comprises is oral, eye, rectum, buccal, part, per nasal, eye (opthamalic), subcutaneous, intramuscular, intravenous (inject and pour into), brain are interior, percutaneous and pulmonary.

Term as used herein " treatment effective dose " refers to, and the disease or the disease of treatment, improvement or pre-Radix Stephaniae Tetrandrae identification have perhaps shown the treatment that can survey or the amount that suppresses the medicine of effect.This effect can detect by the disclosed experiment of for example the following example.The accurate effective dose that is used for the patient will depend on patient's body weight, size and health status; The nature and extent of this disease; And the treatment of selection administration or the combination of treatment.Can by in clinician's technical ability and the routine test within judging determine treatment effective dose to stable condition.

For any chemical compound, can at first in cell culture assays, perhaps in animal model, estimate the treatment effective dose such as neoplastic cell, animal model is generally rat, mice, rabbit, Canis familiaris L. or pig.Animal model also can be used for determining the proper concentration and the approach of administration.These information can be used for determining the useful dosage and the approach of human body administration then.

Can determine treatment/prevention effects and toxicity by the standard drug rules in cell culture or experimental animal, for example, ED ₅₀(the treatment effective dose in 50% population) and LD ₅₀(fatal dose in 50% population).The dosage ratio of treatment and toxic action is therapeutic index, and can be expressed as ratio ED ₅₀/ LD ₅₀The exponential pharmaceutical composition of the big treatment of preferred performance.Can be used to prepare the dosage range that is used for the mankind from the data of cell culture assays and zooscopy acquisition.The dosage that is contained in the said composition is preferably comprising having seldom or do not have toxic ED ₅₀The circulation composition scope in.This dosage can sensitivity and the route of administration according to the dosage form that is adopted, patient change in this scope.

Or rather, show that about the observed concentration of The compounds of this invention-biology effect relation initial target plasma concentration scope for about 5-100 μ g/mL, is preferably about 10-50 μ g/mL, more preferably about 10-25 μ g/mL.In order to obtain this plasma concentration, according to route of administration, the dosage of chemical compound of the present invention can be at 0.1 μ g-100, changes in the scope of 000mg.The specific dosage and the guidance of medication are provided in the document, and should have instructed normally obtainable concerning the medical practitioner of this area.Generally, in single dose, fractionated dose or the successive doses of body weight for the patient of about 40-100kg, the scope of dosage is about 1mg/ days-10g/ days, or about 0.1g-3g/ days, or about 0.3g-3g/ days, or about 0.5g-2g/ days (body weight is higher or lower than the patient's of this weight range dosage and can adjusts, and particularly body weight is lower than the child of 40kg).

Definite dosage is with by medical practitioner's each factor decision relevant according to the patient who treats with needs.Adjust dosage and administration so that competent active substance level to be provided, or keep expected effect.The factor that may consider comprises severity of disease, patient's comprehensive health situation, age, body weight and patient's sex, diet, time of administration and frequency, drug combination, reaction sensitivity, the toleration/reaction to treating.According to the half-life and the clearance rate of particular formulations, the depot drug product compositions can every 3-4 days or weekly, or are administered once in per two weeks.

The metabolite of chemical compound of the present invention

The interior metabolism product of chemical compound described herein also within the scope of the invention.Mainly due to enzymatic processes, described product can be by generations such as the oxidation of for example drug compound of giving, reduction, hydrolysis, amidatioon, esterifications.Therefore, the present invention includes by making chemical compound of the present invention contact time enough with mammalian tissues or mammal to produce the chemical compound that method was produced of its metabolite.Typically, these products are following identifies: by preparation radioactive label (for example, C ¹⁴Or H ³) The compounds of this invention, to mammal such as rat, mice, Cavia porcellus, monkey or the detectable dosage of human body administration (for example, greater than about 0.5mg/kg), make it have adequate time and carry out metabolism (being typically about 30 seconds-30 hours), and from urine, blood or other biological sample, separate its converted product.Owing to carried out labelling, these products very easily separate (antibody that remains in the energy conjugated antigen epi-position in the metabolite by use separates other product).Determine the structure of described metabolite by the mode of routine, for example, analyze by MS or NMR.Usually, can carry out the analysis of metabolite by the method identical with conventional medicine metabolite research known in those skilled in the art.As long as this converted product is not present in the body, even itself biologically active not also can be used for the diagnostic analysis of The compounds of this invention therapeutic dose.

Pharmaceutical composition of the present invention

When chemical compound of the present invention can carry out simple administration, chemical compound of the present invention preferably was mixed with pharmaceutical composition.For example, pharmaceutical composition of the present invention can contain can be used in any the method for the invention one or more suc as formula (I), (II), (III) or the chemical compound (IV).Another aspect of the present invention provides the pharmaceutical composition that can be used in the method for the invention.According to specific administering mode and dosage form, pharmaceutical composition of the present invention can be prepared with pharmaceutically acceptable excipient such as carrier, solvent, stabilizing agent, adjuvant, diluent etc.According to preparation and route of administration, described pharmaceutical composition should be formulated as usually has the pH that the physiology is fit to, and the pH scope is about 3-11, is preferably about 3-7.Replace in the embodiment one, preferred pH is adjusted to about 5-8.In another embodiment, pH is adjusted to 4-7.

Or rather, pharmaceutical composition of the present invention contain the treatment or the prevention effective dose one or more, two or more, chemical compound of the present invention more than three kinds or three kinds; With one or more pharmaceutically acceptable excipient.Optionally, pharmaceutical composition of the present invention can contain the association of chemical compound of the present invention; Maybe can contain second active component that is used for the treatment of cancer, diabetic retinopathy or exudative degeneration of macula.

That the dosage form of the present invention that for example is used for parenteral route or oral administration typically is most is solid-state, liquid solution, Emulsion or suspensoid; And the inhalant of pulmonary administration is generally liquid state or powder, preferred powder formulation.Preferred pharmaceutical composition of the present invention also can be mixed with freeze dried solid, and this solid solvent with physiology's compatibility before administration redissolves.The alternative pharmaceutical composition of the present invention can be mixed with syrup, emulsifiable paste, ointment, tablet etc.

Term " the acceptable excipient of materia medica " is meant and is used for for example excipient of the drug substance administration of chemical compound of the present invention.Described term is meant can administration and do not have excessive toxic drug excipient.The acceptable excipient of described materia medica depends in part on the particular composition of administration and is used for the ad hoc approach of administration said composition.Therefore, can there be multiple variation (referring to, Remington ' s PharmaceuticalSciences for example) in the suitable prescription of pharmaceutical composition of the present invention.

The excipient that is fit to can be carrier molecule, and this carrier molecule comprises the big and metabolism of molecular weight macromole such as protein, polysaccharide, polylactic acid, polyglycolic acid, polyamino acid, amino acid copolymer and non-activity virion slowly.Other exemplary excipient comprises antioxidant such as ascorbic acid; Chelating agen such as EDTA; Carbohydrate such as dextrin, hydroxy alkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid; Liquid is as oil, water, normal saline, glycerol and ethanol; Wetting agent or emulsifying agent; PH buffer substance etc.Liposome is also included within the definition of the acceptable excipient of materia medica.

Pharmaceutical composition of the present invention can be mixed with any form that is suitable for required medication.For example; when being intended to be used for oral administration, can be prepared into tablet, buccal tablet (troches), lozenge (lozenges) but, moisture or oil suspension, non-aqueous solution dispersed powders or granule (comprising micronized granule or nanoparticle), Emulsion, hard or soft capsule, syrup or elixir.Can be intended to be used for oral compositions according to the method preparation of any pharmaceutical compositions well known in the art, and, for good to eat preparation is provided, said composition can contain one or more materials that comprises sweeting agent, flavoring agent, coloring agent and antiseptic (preserving agent).

The acceptable excipient of materia medica that is particularly suitable for tablet for example comprises inert diluent such as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; Disintegrating agent such as cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, corn starch or alginic acid; Binding agent such as polyvidone, starch, gelatin or arabic gum; And lubricant such as magnesium stearate, stearic acid or Pulvis Talci.

Described tablet is coating or by the known technology coating not, and this technology comprised by microencapsulation and postpones disintegrate and absorption in the intestines and stomach, thereby provide lasting effect in the time that prolongs.For example, use time-delay material such as glyceryl monostearate or glycerol distearate separately; Or use jointly with wax.

Be used for oral dosage form and can be the form of hard gelatin capsule, wherein active component mixes with inert solid diluent, for example, and cellulose, lactose, calcium phosphate or Kaolin; Or be the form of Perle, wherein, active component mixes with non-water or oily medium, for example, and glycerol, propylene glycol, Polyethylene Glycol, Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil.

In another embodiment, pharmaceutical composition of the present invention can be mixed with suspensoid, and this suspensoid contains the chemical compound of the present invention with the acceptable mixed with excipients of at least a materia medica that is applicable to the preparation suspensoid.In another embodiment, pharmaceutical composition of the present invention can be mixed with and be fit to by adding dispersible powder and the granule that appropriate excipients prepares suspensoid.

The excipient that is applicable to suspensoid comprises suspending agent such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinyl pyrrolidone, Tragacanth, arabic gum; The condensation product of dispersant or wetting agent such as naturally occurring phospholipid (for example lecithin), oxyalkylene and fatty acid (for example, Myrj 45), the condensation product of oxirane and long-chain fatty alcohol (for example, heptadecaethyleneoxycethanol), the condensation product of the partial ester of oxirane and fatty acid derived and hexitan (for example polyoxyethylene sorbitan monooleate dehydration); With thickening agent such as carbomer (carbomer), Cera Flava, hard paraffin or hexadecanol.Described suspensoid also contains one or more antiseptic such as acetic acid, methyl parahydroxybenzoate and/or P-hydroxybenzoic acid n-propyl; One or more coloring agent; One or more flavoring agents; With one or more sweeting agents such as sucrose or glucide.

Pharmaceutical composition of the present invention can also be oil in water emulsion.Oil phase can be vegetable oil, as olive oil or Oleum Arachidis hypogaeae semen; Mineral oil such as liquid paraffin; Or these oily mixture.The emulsifying agent that is fit to comprises naturally occurring natural gum such as arabic gum and Tragacanth; Naturally occurring phospholipid such as soybean lecithin; The ester of fatty acid derived or partial ester; Hexitan such as Arlacel-80; Condensation product such as polyoxyethylene sorbitan monooleate dehydration with these partial esters and oxirane.Described Emulsion can also contain sweeting agent and flavoring agent.Syrup and elixir can be prepared with sweeting agent, for example glycerol, Sorbitol or sucrose.Described dosage form can also contain demulcent, antiseptic, flavoring agent or coloring agent.

In addition, pharmaceutical composition of the present invention can be aseptic injection such as aseptic injection aqueous Emulsion or oily suspensoid.Described Emulsion and suspensoid can use suitable above-mentioned dispersant of mentioning or wetting agent and suspending agent formulated according to method well known in the prior art.Described aseptic injection can also be at nontoxic parenteral route acceptable diluent or aseptic injectable solution or the suspension in the solvent, for example 1,2 propylene glycol solution.Described aseptic injection can also be prepared into freeze dried powder.Adaptable acceptable carrier and solvent are water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil can be used as solvent or suspension medium.In order to reach this purpose, can use the fixed oil of any gentleness, comprise synthetic monoglyceride or diglyceride.In addition, fatty acid such as oleic acid can be used to prepare injection equally.

At large, the The compounds of this invention that is used for the inventive method is water insoluble basically, and is slightly soluble in acceptable proton solvent of most drug and vegetable oil.Yet described chemical compound dissolves in medium-chain fatty acid (for example, sad and capric acid) or triglyceride usually, and has high dissolubility in the propylene glycol ester of medium-chain fatty acid.The present invention also comprises by the replacement of chemistry or biochemical part or addition and for example modifying, by esterification, glycosylation, Pegylation etc., make it be more suitable for transmitting the chemical compound of (for example, improve dissolubility, biological activity, palatability, reduce side effect etc.).

In preferred embodiment, chemical compound of the present invention can be formulated as be suitable for the low solubility chemical compound based on the dosage form of lipid in oral administration.The described oral administration biaavailability that can strengthen this chemical compound based on the dosage form of lipid usually.Therefore, preferred pharmaceutical composition of the present invention contains the The compounds of this invention of treatment or prevention effective dose; With at least a acceptable excipient of materia medica that is selected from following group: medium-chain fatty acid or its propylene glycol ester (for example, the propylene glycol ester of edible fatty acid such as sad fatty acid and capric acid fatty acid) and as the materia medica acceptable surfactant of polyoxy (polyoxyl) 40 castor oil hydrogenated.

In alternative embodiment, can add cyclodextrin as solubility enhancing agent.Preferred cyclodextrin comprise α-, β-and hydroxypropyl, ethoxy, glucosyl group, malt-base and the maltotriose radical derivative of gamma-cyclodextrin.Particularly preferred cyclodextrin solubility reinforcing agent is HP-(HPBC), and it can be added in any above-mentioned composition with the further water solublity feature of improving The compounds of this invention.In one embodiment, described compositions contains the HP-of 0.1-20%, is preferably the HP-of 1-15%, more preferably the HP-of 2.5-10%.The amount of employed solubility enhancing agent depends on the amount of the The compounds of this invention that contains in the compositions.

Therapeutic alliance

Can also be with other active component combination of any chemical compound of the present invention and one or more, described active component can be used for treating cancer, exudative degeneration of macula, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or diabetic retinopathy, and it comprises that the patient who is used for the needs treatment carries out simultaneously or the chemical compound of (sequentially) administration successively with the form of single dose or fractionated dose.When the priority administration, can in twice or twice above administration, use described therapeutic alliance.In alternative embodiment, can be by different one or more The compounds of this invention of administration and one or more extra active component.

It will be appreciated by those skilled in the art that various active components can with chemical compound combination medicine-feeding of the present invention, to strengthen or collaboratively to strengthen the activity that The compounds of this invention suppresses VEGF and/or angiogenesis inhibitor.

The method according to this invention, the combination of active component can be (1) common preparation and administration or transmission in combination preparation simultaneously; (2) alternately or abreast transmit as independent preparation; Or (3) are by any other combined treatment well known in the prior art.When transmitting in alternating treatment, method of the present invention can comprise the priority administration or the transmission of active component, for example in independent solution, Emulsion, suspensoid, tablet, pill or capsule, or by using independent syringe to inject respectively.Usually, during alternating treatment, with each active component administration successively of effective dose, that is, and administration sequentially, and in treating at the same time, two or more active component of co-administered effective dose.Can also use the intermittent therapeutic alliance of different order.

Embodiment

With reference to following non-restrictive example the present invention is carried out more detailed description, embodiment is used for the present invention is further detailed, and is not limited to scope of the present invention.Embodiment is illustrated the preparation of some chemical compound of the present invention, and in vivo or external these chemical compounds are tested.Therefore the technology of operational excellence in the invention process that it should be appreciated by those skilled in the art that the technology of describing among these embodiment represents that the inventor describes has constituted optimal way of the invention process.Yet according to of the present invention open, those skilled in the art should be understood that, under the situation that does not deviate from the spirit and scope of the present invention, can change disclosed ad hoc approach, and still can access same or analogous result.

General synthetic method

Following synthetic route provides the typical synthetic method that is used to prepare chemical compound of the present invention.In the case, except as otherwise noted, substituent group is with above defining.Substituent R and defined substituent R above ⁴, R ⁵, R ⁶, R ⁷And R ⁸Quite, and can represent to comprise any group of those variablees.

Synthetic route A

Synthetic route A is a kind of method that typically is used to prepare aminocarboxylic acid ester of the present invention.By nucleophilic displacement of fluorine, naphthol compound and the reaction of chloro-carbonic acid p-nitrophenyl ester obtain chemical compound of the present invention.

Synthetic route B

Synthetic route B represents to be used to prepare the polytropy of the phosgene synthetic method of chemical compound of the present invention.Shown in this synthetic route, regulate the various variations of aryl by this method.

Synthetic route C

Synthetic route C has described a kind of method that typically is used for synthetic bromo naphthyl aminocarboxylic acid ester of the present invention.The solution of bromonaphthol (0.5mmol) in dichloromethane (2ml) and diisopropyl ethyl amine (0.5mmol) is added in dichloromethane (4ml) solution of the chloro-carbonic acid p-nitrophenyl ester (0.5mmol) that is in the stirring and the state of cooling.At room temperature stirred 30 minutes, and added amine (0.5mmol) then, continue to stir 12 hours.Under reduced pressure, reaction mixture is concentrated and purify by HPLC, obtain product.

Synthetic route D

Be prepared based on following document: Tetrahedron, 1991 (47), 183-188.

Confessed as those skilled in the art, these and other method all can be used for preparing chemical compound of the present invention.The various changes of above-mentioned route and process are significantly to those skilled in the art, and the present invention specifically is not limited to the preparation method of The compounds of this invention.

Usually, synthetic method described here can be used the raw material that known raw material in various marketable material, the document and synthetic method and process by standard obtain easily.The preparation organic molecule and the conversion of functional group and the standard synthetic method of processing can obtain from relevant scientific literature or this area canonical reference book with process.Though be not restricted to any or several sources, generally acknowledged organic synthesis handbook for example comprises: Smith, M.B; March, J.March ' sAdvanced Organic Chemistry:Reactions, Mechanisms, and Structure, the 5th edition; John Wiley﹠amp; Sons:New York, 2001; And Greene, T.W.; Wuts, P.G.M.Protective Groups in OrganicSynthesis, the third edition; John Wiley ﹠amp; Sons:New York, 1999.Above-mentioned description to synthetic method is used to illustrate rather than limit the general process of The compounds of this invention preparation.

Synthesizing of chemical compound

Chemical compound of the present invention can be prepared by any method that well known to a person skilled in the art.For example, can prepare chemical compound of the present invention according to following method.

100ml be equipped with add in the three neck round-bottomed flasks of mechanical agitator the 2-bromophenol (0.5ml, 4.31mmol), pyridine (1.45ml, 18mmol) and dichloromethane (20ml).Flask is positioned in the ice bath, and (2.5ml 4.74mmol) handles more than 30 minutes with phosgene/toluene of 20%.Under 22 ℃ of temperature, stirred 30 minutes.(470 μ l 4.74mmol) are added in the reaction mixture, place at room temperature more than 10 minutes with piperidines.Under reduced pressure, remove and desolvate, by high performance liquid chromatography/mass spectrum purification expection product IA (600mg).

Method II

Under 0 ℃ of temperature, ((1g is in 26ml dichloromethane solution 5.11mmol) 2.14ml) to be added to 1-amino-beta naphthal hydrochlorate for 1.55mg, 15.3mmol with triethylamine.Under 0 ℃ of temperature, (0.57g, 5mmol 0.39ml) slowly handle this solution to use mesyl chloride.This solution at room temperature stirs 1 hour, and at room temperature uses 1N hydrochloric acid to carry out cold shock.Use dichloromethane extraction, at MgSO ₄Last dry, as to use the NMR purification to merge organic layer obtains 1.2g purity and is 95% expection product 21.This product can be directly used in preparation product 19, and need not further purify.By the prepared in reaction product 19 of product 21 with phosgene.

With the test of evaluation to the effect of the endogenous vegf expression of hypoxia inducible

The capability analysis of endogenous vegf expression of chemical compound of the present invention being regulated hypoxia inducible is as follows.By elisa assay (R﹠amp; D system) monitoring vegf protein level.In brief, in the The compounds of this invention existence or not, (1% O under anoxia condition ₂, 5% CO ₂, surplus is a nitrogen) and cultivated the HeLa cell 24-48 hour.Pass through the elisa assay conditioned medium then, and calculate the concentration of VEGF from the standard ELISA curve of each analysis.

Use elisa assay and above-mentioned condition to carry out the dose response analysis.Analyze a series of variable concentrations (for example 7).Concurrently, under the condition identical, carry out the dose response cytotoxicity analysis, to determine that the inhibition to vegf expression is not because cytotoxicity with ELISA with Cell Titer Glo (Promega).Draw dose response curve with suppressing percentage ratio with compound concentrations, and with maximum suppress to be made as 100%, minimum inhibition is made as 0%, thereby produced EC for each chemical compound ₅₀Value and CC ₅₀Value.

The EC of each chemical compound of the present invention ₅₀Be worth as shown in table 1 below.Most preferred of the present invention is 3 or littler chemical compound for μ M value.

Table 1: typical invention chemical compound and effect thereof

Required concentration when reducing the 50%VEGF amount of translating

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Claims

1. chemical compound with structure shown in the formula (I):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

2. chemical compound according to claim 1, it has following structure:

Wherein

R ⁸Be hydrogen;

R ¹²Be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; R wherein ¹²In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulfonyl amino be respectively replacement or unsubstituted;

R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl and heterocycle be respectively replacement or unsubstituted;

R ¹⁰And R ¹¹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl respectively;

R wherein ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl be respectively replacement or unsubstituted;

3. chemical compound according to claim 1, it has following structure:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

R ³Be H;

R ⁵Be H, and R ⁶Be selected from H, alkyl and halogen,

R ⁷Be H or halogen, and

R ⁸Be H or halogen;

4. chemical compound according to claim 1, it has following structure:

Wherein

R ⁴Be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted alkyl sulfonamido and halogen;

R ¹²Be selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino ,-COR ⁹,-OR ⁹,-CO ₂H ,-CO ₂R ⁹,-C (O) NR ¹⁰R ¹¹, SR ⁹,-NR ¹⁰R ¹¹And halogen; R wherein ¹²In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulfonyl amino be respectively replacement or unsubstituted;

R ¹⁰And R ¹¹Be independently selected from H, alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl respectively; R wherein ¹⁰And R ¹¹In described alkyl, thiazolinyl, alkoxyl, alkynyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl be respectively replacement or unsubstituted;

5. chemical compound according to claim 1, it has following structure:

Wherein

R ¹³And R ¹⁴Be independently selected from H, alkyl, aryl, amino carbonyl and heterocycle respectively, wherein R ¹³And R ¹⁴In described alkyl, aryl, amino carbonyl and heterocycle be respectively replacement or unsubstituted;

R ¹³And R ¹⁴The atom that is connected with them can be chosen wantonly and form that replace or unsubstituted heterocycle or replacement or unsubstituted aromatic rings, and it contains 0-3 ring hetero atom that is selected among N, O and the S, comprises R ¹³And R ¹⁴The hetero atom that is connected;

6. chemical compound according to claim 1, it has following structure:

Wherein

R ¹³And R ¹⁴Be independently selected from H, alkyl, aryl, amino carbonyl and heterocycle respectively, it is replacement or unsubstituted that wherein said alkyl, aryl, amino carbonyl and heterocycle are respectively;

7. chemical compound according to claim 1, it has following structure:

Wherein

R ¹³And R ¹⁴Be independently selected from H, alkyl, aryl, aryl alkyl, amino carbonyl and heterocycle respectively, wherein R ¹³And R ¹⁴In described alkyl, aryl, aryl alkyl, amino carbonyl and heterocycle be respectively replacement or unsubstituted;

R ¹³And R ¹⁴The atom that is connected with them can be chosen wantonly and form that replace or unsubstituted heterocycle or replacement or unsubstituted aromatic rings, and it contains 0-3 ring hetero atom that is selected from N, O and the S group, comprises R ¹³And R ¹⁴The hetero atom that is connected;

8. chemical compound according to claim 1, it has following structure:

Wherein

A is O or N; Condition is: when A is O, and R ³Do not exist;

R ³Be H; And

9. chemical compound according to claim 1, it has following structure:

Wherein

R ¹³And R ¹⁴Be independently selected from respectively by H, alkyl, aryl and heterocycle, wherein R ¹³And R ¹⁴In described alkyl, aryl and heterocycle be respectively replacement or unsubstituted;

R ¹⁸For replace or unsubstituted alkyl;

10. one kind suc as formula the chemical compound shown in (II):

Wherein

R ¹And R ²Be independently selected from H, alkyl, thiazolinyl, aryl and cycloalkyl respectively; R wherein ¹And R ²In described alkyl, thiazolinyl, aryl and group of naphthene base be respectively replacement or unsubstituted;

11. chemical compound according to claim 1, it has the structure shown in the formula (III):

Wherein

R ¹And R ²Be independently selected from respectively H, alkyl, aryl, cycloalkyl, heterocycle, alkyl sulphonyl ,-COR ⁹With-CO ₂R ⁹R wherein ¹And R ²In described alkyl, aryl, cycloalkyl, heterocycle and alkyl sulphonyl respectively independently for that replace or unsubstituted;

R ⁹Be selected from H, alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocycle, wherein R ⁹In described alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl and heterocyclic group respectively independently for that replace or unsubstituted;

12. one kind suc as formula the chemical compound shown in (IV):

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

Z is that C or Z do not exist, and condition is: when Z does not exist, and then X, B, R ¹And R ²Do not exist;

R ¹And R ²Be independently selected from H respectively; Optional by the alkyl of cycloalkyl or halogen replacement; The optional aryl that is replaced by alkyl, alkyl sulfonyl amino or halogen; And cycloalkyl, or

R ³Be H;

R ⁵And R ⁶The atom that is connected with them forms and optional is comprised 0-2 monocyclic heterocycles that is selected from the ring hetero atom among N, O and the S by what alkyl replaced; Or R ⁵And R ⁶The atom that is connected with them forms the monocycle aromatic rings of optional alkoxy or halogen replacement, thereby forms a bicyclo-system; Or

R ⁵Be H,

R ⁶Be selected from H, alkyl and halogen,

R ⁷Be H or halogen, and

R ⁸Be halogen.

13. chemical compound with structure as follows:

14. chemical compound according to claim 1, wherein said chemical compound are selected from following group:

3,5-dimethyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

3,4-dihydro-1H-isoquinolin-2-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-benzyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

Piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-methyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

2-methyl-piperidines-1-carboxylic acid 1-bromo-naphthalene-2-base ester;

Morpholine-4-carboxylic acid 1-bromo-naphthalene-2-base ester;

4-methyl-piperidines-1-carboxylic acid 1-acetyl group-naphthalene-2-base ester;

Diethyl-carbamic acid 1-bromo-naphthalene-2-base ester;

Piperidines-1-carboxylic acid 4-chloro-isoquinolin-3-base ester;

4-benzyl-piperidines-1-carboxylic acid 1-acetyl group-naphthalene-2-base ester;

4-benzyl-piperidines-1-carboxylic acid 2,4,6-three chloro-phenyl esters;

Dimethyl-carbamic acid 1-bromo-naphthalene-2-base ester;

Carbonic acid two-(1-sulfonyloxy methyl amino-naphthalene-2-yl) ester;

4-benzyl-piperidines-1-carboxylic acid naphthalene-2-base amide;

N-(2-hydroxyl-naphthalene-1-yl)-sulfonyloxy methyl amine;

Its pharmaceutically acceptable salt, enantiomer, stereoisomer or its hydrate.

15. chemical compound according to claim 1, it has following structure:

Wherein

R ¹And R ²For replace or unsubstituted alkyl;

16. according to any described chemical compound of claim among the claim 1-15, wherein, described chemical compound is that enantiomeric purity is higher than 75% chemical compound, or the pharmaceutically acceptable salt of described chemical compound, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer.

17. according to any described chemical compound of claim among the claim 1-15, wherein, described chemical compound is that enantiomeric purity is higher than 90% chemical compound, or the pharmaceutically acceptable salt of described chemical compound, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer.

18. the application of any described chemical compound of claim in pharmaceutical compositions among the claim 1-17.

19. pharmaceutical composition, it contains one or more as any described chemical compound of claim among the claim 1-17, or the pharmaceutically acceptable salt of described one or more chemical compounds, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer, and pharmaceutically acceptable excipient.

20. one kind is suppressed the method that VEGF produces, it comprises the chemical compound to one or more formulas of patient's administration (I) that these needs are arranged:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

21. one kind is suppressed the method that VEGF produces, this method comprises the chemical compound to one or more formulas of patient's administration (Ia) that these needs are arranged:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;

R ³Be H;

R ⁵Be H, and R ⁶Be selected from H, alkyl and halogen,

R ⁷Be H or halogen, and

R ⁸Be H or halogen;

22. one kind is suppressed the method that VEGF produces, it comprises to the chemical compound of one or more formulas of patient's administration (I) that these needs are arranged to formula (IV).

23. one kind is suppressed the method that blood vessel takes place, it comprises to the chemical compound of one or more formulas of patient's administration (I) that these needs are arranged to formula (IV).

24. a method for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammatory disease or exudative degeneration of macula, it comprises to the chemical compound of one or more formulas of patient's administration (I) that these needs are arranged to formula (IV).

25. a selectivity suppresses the method for vascular endothelial cell growth, it may further comprise the steps: make the chemical compound of one or more formulas (I) of the cells contacting effective dose that shows vascular endothelial cell growth to formula (IV).

26. a method for the treatment of the vascular endothelial cell growth factor overexpression, it comprises to one or more formulas of patient's administration (I) that these needs are arranged to the chemical compound shown in the formula (IV).

27. a treatment method for cancer, it comprises one or more formulas of mammal administration (I) of suffering from this disease chemical compound to formula (IV).

28. a method for the treatment of the intraocular neovascularization disease, it is drawn together to the chemical compound of one or more formulas of patient's administration (I) of suffering from this disease to formula (IV).

29. a selectivity suppresses the method for vascular endothelial cell growth, it may further comprise the steps: one or more that make the cells contacting effective dose that shows vascular endothelial cell growth have the chemical compound of following structure:

Wherein

X is O or S;

Y is C or N, and condition is: when Y is N, and R ⁸Do not exist;