[go: up one dir, main page]

CN101027283A - 3,4-disubstituted maleimides for use as vascular damaging agents - Google Patents

3,4-disubstituted maleimides for use as vascular damaging agents Download PDF

Info

Publication number
CN101027283A
CN101027283A CNA2005800212199A CN200580021219A CN101027283A CN 101027283 A CN101027283 A CN 101027283A CN A2005800212199 A CNA2005800212199 A CN A2005800212199A CN 200580021219 A CN200580021219 A CN 200580021219A CN 101027283 A CN101027283 A CN 101027283A
Authority
CN
China
Prior art keywords
compound
formula
group
amino
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2005800212199A
Other languages
Chinese (zh)
Inventor
J·-C·阿诺尔德
C·S·哈里斯
F·T·博伊勒
K·H·吉布森
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of CN101027283A publication Critical patent/CN101027283A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

This invention relates to novel compounds of Formula (I) for use as vascular damaging agents: Formula (I) wherein R<l>, R<7>, R<8>, R<9>, AR , AR<2>, AR<3>, p, q and r are as described in the specification. The invention also relates to methods for preparing compounds of Formula (I), to their use as medicaments (including methods for the treatment of angiogenesis or disease states associated with angiogenesis) and to pharmaceutical compositions containing compounds of Formula (I).

Description

As 3 of vascular damaging agents, 4-disubstituted maleimides
The present invention relates to vascular damaging agents and uses thereof.The invention particularly relates to some compound that can have the vascular damaging agents purposes, the method for preparing these compounds, they are as the purposes of medicine (comprise treatment vasculogenesis or with the method for the disease of associated angiogenesis) and comprise their medicinal compositions.The invention still further relates to the purposes of this compounds in the preparation medicine, described medicine is used to produce angiogenesis inhibitor and/or anti-angiogenic effect.
Normal blood vessels is created in many processes of comprising fetal development, wound healing and some the female reproduction assembly functions and plays an important role.Unwanted or pathologic vessels generates relevant with disease, described disease comprises diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, sebaceous cyst, Kaposi sarcoma and vascular tumor (Fan etc., 1995, Trends Pharmacol.Sci.16:57-66; Folkman, 1995, Nature Medicine 1:27-31).Form the crucial pathological characters that new vascular system is several diseases (J.Folkman, NewEngland Journal of Medicine 333,1757-1763 (1995)) by vasculogenesis.For example, for the solid tumor growth, it must grow its blood supply, and it highly relies on this supply and obtains oxygen and nutrition; If this blood supply mechanicalness is closed, then tumour experience gangrenosum acne death.Neovascularization also is the Clinical symptoms of invasive pannus and atherosclerotic patch in psoriatic skin infringement, the patient with rheumatoid arthritis joint.The retina neovascularization is the pathological characters of macular degeneration and diabetic retinopathy.
Therefore, expectation makes the neovascularization counter-rotating by the blood vessel endothelium that destroys new formation, and has useful curative effect.This vascular damaging activity obviously has the following value with the associated angiogenesis disease of treatment: as cancer, diabetes, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disorder, acute inflammation, endometriosis, dysfunctional uterine bleeding with the outgrowth illness in eye of retinal vessel.
It is reported, external and under non-cell toxicity concentration, some known compound that causes the selective destruction tumor vascular system is to endothelial cell proliferation, be cellular segregation [the Blakey D C etc. that exert an influence, Proceedings, of the American Association for CancerResearch, 41,329,2000, summary 2086], with make cell shape change [Davis P D etc., Proceedings of the American Association for Cancer Research, 41,329,2000 summaries 2085; Chaplin D J ﹠amp; Dougherty G J, Br J Cancer, 80, Suppl 1,57-64,1999].Therefore, can expect the vascular system of these compounds to new formation, for example tumor vascular system has destruction.For example, can predict reasonably that they can cause the selective destruction tumor vascular system in vitro and in vivo.Because the hungry osmium of oxygen and nutrition destroys tumor vascular system and causes the tumor blood flow minimizing again and cause death of neoplastic cells, promptly has anti-tumor activity [Davis P D etc.; Chaplin D J ﹠amp; Dougherty G J; Blakey D C etc., all the same].
Have this active compound please WO 00/40529 (AngiogenePharmaceuticals) in International Patent Application WO 99/02166 (AngiogenePharmaceuticals), international monopoly and International Patent Application WO 00/41669 (AngiogenePharmaceuticals) in description is also arranged.
We determine to have a class maleimide compound of vascular damaging activity.Therefore, in accordance with a first feature of the invention, provide formula (I) compound or its salt:
Figure A20058002121900081
Formula (I)
Wherein:
Ar 1Be selected from phenyl, heteroaryl or heterocyclic radical;
Ar 2Be selected from phenyl or heteroaryl;
Ar 3Be selected from phenyl or monocycle hetero-aromatic ring, this monocycle hetero-aromatic ring comprises 1-3 heteroatoms that is selected from N, O or S;
R 1Be selected from hydrogen ,-C (O)-R 2,-C (O)-O-R 2,-C (O) N (R 4)-R 2With-CH 2-R 2, group N (R wherein 4)-R 2Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 2Be selected from: hydrogen, halogen, cyano group, amino, hydroxyl ,-SO 3, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyloyl oxygen base, phosphonato, C 2-6Thiazolinyl, cycloalkyl, cycloalkyl C 1-4Alkyl-, heterocyclic radical, heterocyclic radical C 1-4Alkyl-, aryl and aryl C 1-4Alkyl-, R wherein 2Middle alkyl or alkenyl chain or carbocylic radical, heterocyclic radical or heteroaryl ring are optional by one or more R that are selected from 3Group replace;
R 3Be selected from C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkyloyl, hydroxyl, amino, formamyl ,-SO 3, phosphonato ,-C (O)-O-R 4With-N (R 4) R 5, group-N (R wherein 4) R 5Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 4And R 5Independently be selected from: hydrogen, C 1-4Alkyl and C (O)-R 6
R 6For choosing wantonly by carboxyl or the amino C that replaces 1-4Alkyl;
R 7Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 8Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 9Be selected from: cyano group, halogen and nitro;
R 10Be selected from hydrogen or C 1-4Alkyl;
P is the integer of 0-3;
Q is the integer of 0-3;
R is the integer of 1-3.
For avoiding feeling uncertain, when p is 0, Ar 1All positions on the ring are all replaced by hydrogen, and when q was 0, similarly regulation was applicable to Ar 2And Ar 3
For avoiding feeling uncertain, when p is 1-3, term (R 7) pUse be illustrated in Ar 11,2 or 3 R is arranged on the ring 7Substituting group, when p was 2 or 3, they can be identical or different groups.For example, (R 7) pBe 3, during the 4-dichloro, then p is 2, and with respect to Ar 1Group and pyrroles-2,5-diketo group bonded position, Ar 13 of ring have chloro, and 4 have chloro.
Although the pharmacy acceptable salt of preferred The compounds of this invention, the non-pharmacy acceptable salt of other of The compounds of this invention also may be useful, for example in the pharmacy acceptable salt of preparation The compounds of this invention.
One side again according to the present invention's first feature provides the medicinal compositions that contains formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable vehicle.
According to the present invention's first feature more on the one hand, medicinal compositions is provided, said composition contains formula (I) compound or its pharmacy acceptable salt, and the pharmaceutically acceptable diluent or carrier of blended with it.
Because their vascular damaging activity, formula (I) compound has anti-angiogenesis activity.Therefore, according to second feature of the present invention, provide formula (I) compound or its pharmacy acceptable salt, prodrug or solvate in the purposes of preparation in the medicine, this medicine be used to suppress and/or counter-rotating and/or alleviating vascular generates and/or with the symptom of any disease of associated angiogenesis.
One side again according to the present invention's second feature, be provided at that inhibition in the warm-blooded animal and/or counter-rotating and/or alleviating vascular generate and/or with the methods of treatment of any disease symptoms of associated angiogenesis, this method comprises formula (I) compound or its pharmacy acceptable salt, prodrug or the solvate that gives described warm-blooded animal treatment (comprising prevention) significant quantity.
It is believed that formula (I) compound suppresses tubulin polymerization, this causes their vascular damaging activity.Therefore, according to the one side again of the present invention's second feature, provide formula (I) compound or its pharmacy acceptable salt, prodrug or the solvate purposes in the preparation medicine, this medicine is used to suppress tubulin polymerization.
One side again according to the present invention's second feature, provide by suppressing the method for tubulin polymerization treatment warm-blooded animal, this method comprises formula (I) compound or its pharmacy acceptable salt, prodrug or the solvate that gives described warm-blooded animal treatment (comprising prevention) significant quantity.
Preferred warm-blooded animal is behaved.
With the disease example of associated angiogenesis be solid tumor, diabetes, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disorder, acute inflammation, endometriosis, dysfunctional uterine bleeding and with the outgrowth illness in eye of retinal vessel.Disease preferred and associated angiogenesis is a solid tumor.Preferred solid tumor comprises colon, lung, mammary gland, brain, ovary, prostate gland, skin and metastatic tumo(u)r, for example hepatic metastases knurl.
According to the 3rd feature of the present invention, provide the purposes of formula (I) compound as medicine.
Term " heteroaryl " is meant 4 yuan of-10 yuan of aromatic monocyclic or dicyclos, contain the most nearly 5 heteroatomss that independently are selected from nitrogen, oxygen or sulphur, and by ring carbon atom or theheterocyclic nitrogen atom connection, wherein allow nitrogen-key, for example the key that is connected with the nitrogen of pyridine ring cannot be arranged, but the key by the 1-nitrogen connection of pyrazoles ring can be arranged.Preferred term " heteroaryl " is meant 5 yuan of-10 yuan of aromatic monocyclic or dicyclos, contain the most nearly 5 heteroatomss that independently are selected from nitrogen, oxygen or sulphur, and by ring carbon atom or theheterocyclic nitrogen atom connection, wherein allow nitrogen-key, for example the key that is connected with the nitrogen of pyridine ring cannot be arranged, but the key by the 1-nitrogen connection of pyrazoles ring can be arranged.More preferably term " heteroaryl " is meant 5 yuan or 6 yuan of aromatic monocyclic or dicyclo, contain the most nearly 5 heteroatomss that independently are selected from nitrogen, oxygen or sulphur, and by ring carbon atom or theheterocyclic nitrogen atom connection, wherein allow nitrogen-key, for example the key that is connected with the nitrogen of pyridine ring cannot be arranged, but the key by the 1-nitrogen connection of pyrazoles ring can be arranged.The example of 5 yuan or 6 yuan heteroaromatic ring systems comprises pyrroles, furans, imidazoles, triazole, tetrazolium, pyrazine, pyrimidine, pyridazine, pyridine, different  azoles,  azoles, 1,2,4- diazole, isothiazole, thiazole, 1,2,4-triazole and thiophene.The special example of 5 yuan or 6 yuan heteroaromatic ring systems comprises pyrroles, furans, imidazoles, triazole, pyrazine, pyrimidine, pyridazine, pyridine, different  azoles,  azoles, 1,2,4- diazole, isothiazole, thiazole and thiophene.More particularly, term " heteroaryl " is meant 9 yuan or 10 yuan of aromatic monocyclic or dicyclo, contain the most nearly 5 heteroatomss that independently are selected from nitrogen, oxygen or sulphur, and by ring carbon atom or theheterocyclic nitrogen atom connection, wherein allow nitrogen-key, for example the key that is connected with the nitrogen of pyridine ring cannot be arranged, but the key by the 1-nitrogen connection of pyrazoles ring can be arranged.9 yuan or 10 yuan of dicyclo heteroaromatic ring systems are to contain and the aromatics dicyclo loop systems of 5 yuan of rings or 6 yuan of rings of another 6 yuan ring condensed.The example of 5/6 and 6/6 dicyclo loop systems comprises cumarone, benzoglyoxaline, thionaphthene, benzothiazole, benzisothiazole, benzoxazol, benzisoxa  azoles, 1,3-benzo dioxole, indoles, pyridine-imidazole, Mi Dingbing imidazoles, quinoline, isoquinoline 99.9, quinoxaline, quinazoline, phthalazines, cinnoline and naphthyridines.The special example of 5/6 and 6/6 dicyclo loop systems comprises cumarone, benzoglyoxaline, thionaphthene, benzothiazole, benzisothiazole, benzoxazol, benzisoxa  azoles, indoles, pyridine-imidazole, Mi Dingbing imidazoles, quinoline, isoquinoline 99.9, quinoxaline, quinazoline, phthalazines, cinnoline and naphthyridines.
Term " heterocyclic radical " is meant the monocycle or the dicyclo of 5 yuan-10 yuan saturated or fractional saturations, contains the most nearly 5 heteroatomss that are selected from nitrogen, oxygen or sulphur, and connects by ring carbon atom or theheterocyclic nitrogen atom.' heterocyclic radical ' example comprise tetrahydrofuran base, 2,3-dihydro-4H-pyranyl, pyrrolinyl, pyrrolidyl, 1,3-thiazoles alkyl, morpholinyl, piperidyl, piperazinyl, dihydropyridine base, dihydro-pyrimidin base and azepan base.' heterocyclic radical ' special example comprise pyrrolinyl, pyrrolidyl, morpholinyl, piperidyl, piperazinyl, dihydropyridine base and dihydro-pyrimidin base.
Term " carbocylic radical " is meant 3 yuan of-10 yuan of monocycles, dicyclo or the three ring carbocyclic rings of saturated fully or fractional saturation.The isocyclic example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo-octane, adamantyl or 2,3-dihydro indenes.
Term aryl is meant phenyl or naphthyl.
Term halogen is meant fluorine, chlorine, bromine or iodine.
The term formamyl is meant group-CONH 2
Amino-acid residue is defined as derived from L-amino acid by amido linkage and amino coupling.Can form this key by the carboxylate group on the amino acid backbone or by the pendant carboxylic acid ester group, preferably form by the carboxylate group on the amino acid backbone.Amino-acid residue comprises that by natural and alpha-non-natural amino acid preferred those residues of natural amino acid deutero-comprise a-amino acid, beta-amino acids and gamma-amino acid.For avoiding feeling uncertain, amino acid comprises those with following universal architecture:
Figure A20058002121900131
Wherein R is an amino acid side chain.Amino acid whose definition also comprises the amino acid analogue that has other methylene radical in the amino acid backbone, for example Beta-alanine; With the amino acid of non-natural existence, for example Cyclohexylalanine.
Preferred amino acids comprises glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, methionine(Met), proline(Pro), phenylalanine, tryptophane, Serine, Threonine, halfcystine, tyrosine, l-asparagine (asparaginine), glutamine, aspartic acid, L-glutamic acid, Methionin, arginine, Histidine, Beta-alanine and ornithine.More preferably, amino acid comprises L-glutamic acid, Serine, Threonine, arginine, glycine, L-Ala, Beta-alanine and Methionin.Especially preferred, amino acid comprises L-glutamic acid, Serine and glycine.
R 7Esterified group be when the about pH=7 of pH, increase the esterified group of macromolecule water-solubility.This type of group comprises the group that contains ionogen, for example acidic functionality or basic functionality; With the group that contains the hydrophilic functional group.Basic functionality comprises: amino, morpholino, piperidino-(1-position only), piperazine-1-base, tetramethyleneimine-1-base, amino acid and tetrahydroglyoxaline-1-base.Acidic functionality comprises: carboxyl, sulfonic acid, phosphoric acid ester, sulfuric ester and acid-like substance be tetrazyl for example.Hydrophilic radical comprises hydroxyl.
The esterified suitable R of hydroxyl wherein 7Group comprises: C 1-6Alkyloyl oxygen base, aryl carbonyl oxygen base, heterocyclic radical ketonic oxygen base, heteroaryl ketonic oxygen base, wherein R 1Group is chosen wantonly and is selected from following 1-3 group replacement: C 1-4Alkyl, C 1-4Alkyloyl, C 1-4Alkyloyl C 1-4Alkyl, C 1-4Alkyloyl heterocyclic radical, hydroxyl, hydroxyl C 1-4Alkyl, carboxyl, carboxyl phenyl, phosphono, phosphono C 1-4Alkyl, amino, amino C 1-4Alkyl, N-C 1-4Alkylamino, N, N-two C 1-4Alkylamino, formamyl, formamyl C 1-4Alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic radical carbonyl, heterocyclic radical C 1-4Alkanoylamino, formamyl heterocyclic radical [wherein, contain that the optional substituting group of heterocyclic radical is optional further to be replaced by following group: C 1-4Alkyl, hydroxyl C 1-4Alkyl, C 1-4Alkoxy C 1-4Alkyl, C 1-4Alkyloyl and formyl radical, wherein formamyl and amino optional substituting group are optional further by following group N-replacement: C 1-4Alkyl, two-C 1-4Alkyl, hydroxyl C 1-4Alkyl, two-(hydroxyl C 1-4Alkyl), carboxyl C 1-4Alkyl, wherein amino choosing wantonly replaced by amino-acid residue], condition is to work as R 1Be C 1-6When alkyloyl oxygen base or aryl carbonyl oxygen base, R 1Be substituted, and R 1Not by C 1-4Alkyl replaces.
The more preferably esterified R of hydroxyl wherein 7Group comprises:
1) carboxyl pentanoyl oxygen base,
2) 4-carboxyl phenyl propionyloxy,
3) 4-(N methyl piperazine-1-base ethyl) phenylcarbonyl group oxygen base,
4) 4-(piperazine-1-base ethyl) phenylcarbonyl group oxygen base,
5) 4-[N-two-(hydroxyethyl) amino methyl] phenylcarbonyl group oxygen base,
6) 3-(N-ethanoyl piperazine-1-base ethyl) phenylcarbonyl group oxygen base,
7) 3-[N-two-(hydroxyethyl) amino methyl] phenylcarbonyl group oxygen base,
8) 4-(N methyl piperazine-1-base propionamido) phenylcarbonyl group oxygen base,
9) N methyl piperazine-1-base carbonyl propionyloxy,
10) N-two-(hydroxyethyl) aminocarboxyl propionyloxy,
11) piperazine-1-base carbonyl propionyloxy,
12) (N-ethanoyl piperazine-1-yl) carbonyl propionyloxy,
13) (N-two-(hydroxyethyl) aminocarboxyl propionyloxy and
14) 4-(piperazine-1-ylmethyl) phenylcarbonyl group oxygen base.
The further preferred esterified R of hydroxyl wherein 7Group comprises:
4-(N methyl piperazine-1-base propionamido) phenylcarbonyl group oxygen base,
N methyl piperazine-1-base carbonyl propionyloxy and
N-two-(hydroxyethyl) aminocarboxyl propionyloxy.
In this manual, be used for term C 1-4Alkyl and C 1-6The generic term of alkyl " alkyl " comprises straight chain and branched-chain alkyl.But relate to concrete alkyl, for example " propyl group ' " only specifically refers to linear form, relates to concrete branched-chain alkyl, for example ' sec.-propyl ' only specifically refer to the side chain form.Rule of similarity is applicable to other generic term.C 1-6The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, sec-butyl and the tertiary butyl; Amino C 1-4The example of alkyl comprises amino methyl, amino-ethyl or aminopropyl; Hydroxyl C 1-4The example of alkyl comprises methylol, hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methyl-propyl group; Aryl C 1-4The example of alkyl comprises benzyl and styroyl; Cycloalkyl C 1-4The example of alkyl comprises cyclopropyl ethyl, cyclobutylmethyl and cyclohexyl propyl group; Heterocyclic radical C 1-4The example of alkyl comprises piperazinyl methyl, piperazinyl ethyl, morpholinyl methyl or morpholinyl ethyl; C 2-6The example of thiazolinyl comprises allyl group and crotyl; C 1-4The example of alkoxyl group comprises methoxyl group, oxyethyl group and propoxy-; C 1-4The example of alkyloyl comprises formyl radical or propionyl; C 1-6The example of alkyloyl oxygen base comprises propionyloxy or butyryl acyloxy.
Should understand, in some compound of different characteristics of the present invention, owing to there are one or more unsymmetrical carbons, may there be optical activity form or racemic form, therefore in its definition, the present invention includes any this optical activity or racemic form, this optical activity or racemic form have inhibition and/or counter-rotating and/or alleviating vascular generates and/or with the character of any disease symptoms of associated angiogenesis.Can carry out the synthetic of optical activity form by the standard technique of organic chemistry of knowing in this area, for example synthetic by the optical activity raw material, or by the resolution of racemic form.Equally, the activity of available these compounds of standard laboratory technological assessment of hereinafter mentioning.
The invention still further relates to any of different characteristics compound of the present invention and all tautomeric forms, this type of tautomeric form have that inhibition and/or counter-rotating and/or alleviating vascular generate and/or with the character of any disease symptoms of associated angiogenesis.
It can also be appreciated that may there be solvation in some The compounds of this invention, for example hydrated form and not solvation form.Should be understood that the present invention includes have inhibition and/or counter-rotating and/or alleviating vascular generates and/or with all these type of solvation forms of the character of any disease symptoms of associated angiogenesis.
Formula (I) compound can the prodrug forms administration, and described prodrug decomposes in human or animal body, obtains formula (I) compound.The example of prodrug comprises the ester of hydrolyzable formula (I) compound in the body.
Known various forms of prodrugs in this area.The example of relevant this type of prodrug derivant, referring to:
A) Design of Prodrugs, H.Bundgaard edits, (Elsevier, 1985) and Methods in Enzymology, the 42nd volume, the 309-396 page or leaf, K.Widder etc. compile (Academic Press, 1985);
B) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard edit, the 5th chapter " Design and Application ofProdrugs ", H.Bundgaard compiles, 113-191 page or leaf (1991);
c)H.Bundgaard，Advanced?Drug?Delivery?Reviews，8，1-38(1992)；
D) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77,285 (1988); And
E) N.Kakeya etc., Chem Pharm Bull, 32,692 (1984).
Hydroxyl formula (I) but the vivo hydrolysable ester of compound is for example pharmaceutically acceptable ester, the hydrolysis in human or animal body of this pharmaceutically acceptable ester produces parent acid or alcohol.The suitable pharmaceutically acceptable ester of carboxyl comprises C 1-6Alkoxy methyl ester, for example methoxymethyl ester; C 1-6Alkyloyl oxygen ylmethyl ester, for example oxy acid methyl neopentyl ester; The phthalidyl ester; C 3-8Cyclo alkoxy carbonyl oxygen base C 1-6Alkyl ester, for example 1-cyclohexyl-carbonyl oxygen base ethyl; 1,3-dioxole-2-ketone group methyl ester, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester; And C 1-6The alkoxy-carbonyl oxy ethyl ester.
Hydroxyl formula (I) but the vivo hydrolysable ester of compound comprises inorganic ester, for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester), alpha-acyloxy alkyl oxide and because the related compound that produces parent hydroxy is decomposed in the hydrolysis of body lactone.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.But the group that is used for hydroxyl formation vivo hydrolysable ester selects to comprise benzoyl and phenyl acetyl, alkoxy carbonyl (obtaining alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl) N-alkyl-carbamoyl (obtaining carbamate), dialkyl amido ethanoyl and the carboxyl ethanoyl of alkyloyl, benzoyl, phenyl acetyl and replacement.
The pharmacy acceptable salt of suitable The compounds of this invention is, the acid salt that the The compounds of this invention of enough alkalescence is for example arranged, for example with as mineral acid or organic acid, the acid salt that becomes of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acid for example.In addition, it is an alkali metal salt that the suitable pharmacy acceptable salt of enough tart benzoxazine ketone derivatives of the present invention is arranged, for example sodium or sylvite; Alkaline earth salt, for example calcium or magnesium salts; Ammonium salt or provide and to accept cationic organic alkali salt on the physiology, for example salt that becomes with following amine: methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.
In each feature of the present invention, preferred Ar 1Group or value comprise phenyl, 5 yuan of-6 yuan of heteroaryls or 5 yuan of-6 yuan of heterocyclic radicals.In each feature of the present invention, further preferred Ar 1Group or value comprise: phenyl, 6 yuan of heteroaryls or 6 yuan of heterocyclic radicals.In each feature of the present invention, also further preferred Ar 1Group or value comprise: phenyl, 6 yuan of heteroaryls or 6 yuan of heterocyclic radicals, wherein heteroaryl or heterocyclic ring contain 1-2 the heteroatoms that is selected from nitrogen.In each feature of the present invention, also further preferred Ar 1Group or value comprise: phenyl, pyridyl and piperidyl.In each feature of the present invention, most preferred Ar 1Value is a phenyl.
In each feature of the present invention, preferred Ar 2Group or value comprise phenyl or 5 yuan of-6 yuan of heteroaryls.In each feature of the present invention, further preferred Ar 2Group or value comprise: phenyl or 6 yuan of heteroaryls.In each feature of the present invention, also further preferred Ar 1Group or value comprise: phenyl or 5 yuan of-6 yuan of heteroaryls, wherein this hetero-aromatic ring contains 1-2 the heteroatoms that is selected from nitrogen.In each feature of the present invention, also further preferred Ar 2Group or value comprise: phenyl and pyridyl.Most preferred Ar 2Value is a phenyl.
In each feature of the present invention, preferred Ar 3Group or value comprise phenyl or 6 yuan of bicyclic heteroaryls.In each feature of the present invention, further preferred Ar 3Group or value comprise phenyl, pyridyl and pyrimidyl.In each feature of the present invention, most preferred Ar 3Value is a phenyl.
In each feature of the present invention, preferred R 1Group or value comprise hydrogen ,-C (O) N (R 4)-R 2,-CH 2-R 2With-C (O)-O-R 2In each feature of the present invention, preferred R 1Group or value comprise hydrogen and-CH 2-R 2R most preferably 1Be hydrogen.
In each feature of the present invention, preferred R 2Group or value are hydrogen, optional by one or more R that are selected from 3The C that replaces of group 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-4Alkyl.In each feature of the present invention, further preferred R 2Group or value are hydrogen, optional by one or more R that are selected from 3The C that replaces of group 1-6Alkyl, 6 yuan of heterocyclic radicals and 6 yuan of heterocyclic radical C 1-4Alkyl.In each feature of the present invention, also further preferred R 2Group or value are hydrogen, optional by R 3The C that replaces 1-4Alkyl or heterocyclic radical C 1-4Alkyl.In each feature of the present invention, most preferred R 2Group or value are for hydrogen, by a R 3Methyl, the tertiary butyl or piperidines-1-ylmethyl that group replaces.
In each feature of the present invention, preferred R 3Group or value are amino, hydroxyl and phosphonato.Most preferred R 3Value is a phosphonato.
In each feature of the present invention, preferred R 4Group or value are hydrogen or methyl, most preferably hydrogen.
In each feature of the present invention, preferred R 5Group or value are hydrogen or methyl, most preferably hydrogen.
In each feature of the present invention, preferred R 6Group or value are hydrogen or methyl, most preferably hydrogen.
In each feature of the present invention, preferred R 7Group or value are hydroxyl, nitro, amino, halogen, phosphonato, C 1-4Alkyl, C 1-4Alkoxyl group, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified.In each feature of the present invention, further preferred R 7Group or value are hydroxyl, nitro, amino, halogen, C 1-4Alkoxyl group, wherein amino choosing wantonly replaced by amino-acid residue.In each feature of the present invention, also further preferred R 7Group or value are hydroxyl, nitro, amino, glutamyl-NH-, seryl-NH-, alanyl-NH-or glycyl-NH-.In each feature of the present invention, also further preferred R 7Group or value are hydroxyl, nitro, amino or glutamyl-NH-.R most preferably 7Be hydrogen.
In each feature of the present invention, work as R 7For replaced by amino-acid residue amino the time, the preferred amino acids group comprises: L-glutamic acid, Serine, Threonine, arginine, glycine, L-Ala, Beta-alanine and Methionin.
In each feature of the present invention, preferred R 8Group or value are selected from hydrogen or methyl, preferred hydrogen.
In each feature of the present invention, preferred R 9Group or value are selected from hydrogen or methyl, preferred hydrogen.
In each feature of the present invention, preferred R 10Group or value are selected from hydrogen or C 1-4Alkyl.In each feature of the present invention, further preferred R 10Group or value are selected from hydrogen or methyl.In each feature of the present invention, most preferred R 10Value is a hydrogen.
In each feature of the present invention, preferred p value is 0,1 or 2, and further preferred p is 1 or 2, and most preferably p is 1.
In each feature of the present invention, preferred q value is 0 or 1, and most preferably q is 0.
In each feature of the present invention, preferred r value is 1 or 2, and most preferably r is 1.
In each feature of described invention, preferred one group of compound comprises formula (II) compound or its salt in this article
Figure A20058002121900191
Formula (II)
Ar 1Be selected from phenyl, heteroaryl or heterocyclic radical;
Ar 2Be selected from phenyl or heteroaryl;
Ar 3Be selected from phenyl or monocycle hetero-aromatic ring, this monocycle hetero-aromatic ring contains 1-3 the heteroatoms that is selected from N, O or S;
R 1Be selected from hydrogen ,-C (O)-R 2,-C (O)-O-R 2,-C (O) N (R 4)-R 2With-CH 2-R 2, group N (R wherein 4)-R 2Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 2Be selected from: hydrogen, halogen, cyano group, amino, hydroxyl ,-SO 3, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyloyl oxygen base, phosphonato, C 2-6Thiazolinyl, cycloalkyl, cycloalkyl C 1-4Alkyl-, heterocyclic radical, heterocyclic radical C 1-4Alkyl-, aryl and aryl C 1-4Alkyl-, R wherein 2The optional R that is selected from of middle alkyl or alkenyl chain or carbocylic radical, heterocyclic radical or heteroaryl ring 3One or more groups replace;
R 3Be selected from C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkyloyl, hydroxyl, amino, formamyl ,-SO 3, phosphonato ,-C (O)-O-R 4With-N (R 4) R 5, group-N (R wherein 4) R 5Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 4And R 5Independently be selected from: hydrogen, C 1-4Alkyl and C (O)-R 6,
R 6For choosing wantonly by carboxyl or the amino C that replaces 1-4Alkyl;
R 7Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 8Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4 alkaneOxygen base and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 9Be selected from: cyano group, halogen and nitro;
R 10Be selected from hydrogen or C 1-4Alkyl;
X is selected from-N (R 10)-;
Y is-O-,
P is the integer of 0-3;
Q is the integer of 0-3;
R is 0,1 or 2 integer.
In each feature of described invention, preferred one group of compound comprises formula (III) compound or its salt in this article
Figure A20058002121900211
Ar 1Be selected from phenyl, 5 yuan of-6 yuan of heteroaryls or 5 yuan of-6 yuan of heterocyclic radicals;
Ar 2Be selected from phenyl or 5 yuan of-6 yuan of heteroaryls;
R 1Be selected from hydrogen, C 1-6Alkyl, C 1-6Alkoxy carbonyl, hydroxyl C 1-6Alkyl, amino C 1-6Alkyl, heterocyclic radical C 1-6Alkyl and phosphonato C 1-6Alkyl;
R 7Be selected from halogen, hydroxyl, nitro, amino, phosphonato and C 1-4Alkoxyl group, wherein amino choosing wantonly replaced by amino-acid residue;
R 10Be hydrogen or C 1-4Alkyl;
X is selected from-N (R 10)-;
Y is selected from-O-,
P is the integer of 0-3.
According to a feature more of the present invention, medicinal compositions is provided, said composition contains formula (II) or formula (III) compound or its pharmacy acceptable salt and pharmaceutically acceptable vehicle.
According to a feature more of the present invention, medicinal compositions is provided, said composition contains and pharmaceutically acceptable diluent or carrier blended formula (II) or formula (III) compound, or its pharmacy acceptable salt.
According to a feature more of the present invention, provide formula (II) or formula (III) compound or its pharmacy acceptable salt in the purposes of preparation in the medicine, this medicine inhibition and/or counter-rotating and/or alleviating vascular generate and/or with any disease symptoms of associated angiogenesis.
According to a feature more of the present invention, be provided at that inhibition in the warm-blooded animal and/or counter-rotating and/or alleviating vascular generate and/or with the methods of treatment of any disease symptoms of associated angiogenesis, this method comprises formula (II) or formula (III) compound that gives described warm-blooded animal treatment (comprising prevention) significant quantity, or its pharmacy acceptable salt.
According to a feature more of the present invention, formula (II) or formula (III) compound or its pharmacy acceptable salt purposes in the preparation medicine is provided, this medicine suppresses tubulin polymerization.
According to a feature more of the present invention, provide by suppressing the method for tubulin polymerization treatment warm-blooded animal, this method comprises formula (II) or formula (III) compound that gives described warm-blooded animal treatment (comprising prevention) significant quantity, or its pharmacy acceptable salt.
In each feature of the present invention, preferred one group of compound comprises following compound or its salt:
1) 3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles;
2) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-hydroxy phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
3) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-phosphonato phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
4) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
5) 3-[4-(2-cyano-benzene oxygen) anilino]-4-[3-(α-Gu Anxianji amino) phenyl]-2,5-dioxo-2,5-dihydro-1H-pyrroles;
6) 1-hydroxyethyl-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles;
7) 1-(phosphonato ethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles.
Can be by the known any method that is applicable to preparation chemofacies related compounds, preparation The compounds of this invention or its pharmacy acceptable salt.When being used to prepare The compounds of this invention or its salt, these class methods as the present invention again a feature provide, and illustrate, wherein Ar by following representative embodiment 1, Ar 2, Ar 3, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, X, Y, p, q and r implication and preamble definition identical.About the general guideline of reaction conditions and reagent, the reader can consult the Advanced Organic Chemistry of Jerry March, the 4th edition, John Wiley ﹠amp; Sons 1992 publishes.The general guideline of relevant blocking group, the reader can consult the Protective Groups in Organic Synthesis the 2nd edition of Green etc., John Wiley ﹠amp; Sons publishes.
Therefore,, provide the method for preparation formula (I) compound or its salt, this method (unless otherwise indicated, Ar wherein according to the 4th feature of the present invention 1, Ar 2, Ar 3, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, X, Y, p, q and r definition be the same) comprising:
A) make the reaction of formula (A) compound and formula (B) compound, wherein Z 1Be leavings group;
Figure A20058002121900231
Formula (A) formula (B)
B) for R wherein 1Not formula (I) compound of hydrogen, make wherein R 1Formula (I) compound and formula R for hydrogen 1-Z 2Compound reaction, wherein Z 2Be leavings group;
C) make the reaction of formula (C) compound and formula (D) compound, wherein:
(i) Z 3For-Y-H, Z 4Be leavings group; Or
(ii) Z 3Be leavings group, Z 4Be formula H-Y-compound;
Figure A20058002121900233
Figure A20058002121900234
Formula (C) formula (D)
D) for R wherein 7Group reacts the amino acid of formula (E) compound and amino acid or protection for formula (I) compound of the amino that replaced by amino-acid residue;
Figure A20058002121900241
Formula (E)
E) for R wherein 7Group is formula (I) compound of phosphonato, makes the activation phosphate derivative reaction of formula (F) compound and protection;
Figure A20058002121900242
Formula (F)
F) for R wherein 7Group is formula (I) compound of esterified hydroxy groups, makes formula (F) compound and carboxylic acid or activated carboxylic acid derivatives reaction;
G) make the reaction of formula (G) compound and formula (H) compound, wherein;
(i) Z 5Be hydrogen, Z 6Be leavings group; Or
(ii) Z 5Be leavings group, Z 4Be hydrogen;
Figure A20058002121900251
Figure A20058002121900252
Formula (G) formula (H)
Then, if desired:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any blocking group;
Iii) form salt.
More than Fan Ying concrete reaction conditions is as follows:
Method a) can be at suitable solvent, and for example alcohol, DMF, DMSO or methylene dichloride exist down, under 0-150 ℃, carry out the reaction of formula (A) compound and formula (B) compound.
Method b) R wherein 1Formula (I) compound and formula R for hydrogen 1-Z 2The reaction of compound can be carried out under arbitrary following condition:
(i) by Mitsunobu reaction, for example in the presence of triphenyl phosphine and DEAD or DTAD, at suitable solvent for example in the methylene dichloride, at room temperature; Or
(ii) Z wherein 2During for halogen, alkali for example sodium hydride or salt of wormwood in the presence of, at suitable solvent for example among methylene dichloride or the DMF, in room temperature to 80 ℃ reaction down.
Method c) can be for example in the presence of methylene dichloride, DMF or the DMA at suitable solvent, under room temperature to 150 ℃, make the reaction of formula (C) compound and formula (D) compound.
Method d) available suitable amide key forms reaction, makes the amino acid reaction of formula (E) compound and amino acid or protection.Know amido linkage in this area and form reaction, for example can be in the presence of DMAP, for example among methylene dichloride, chloroform or the DMF, at room temperature, make EDCl and carbodiimide carry out coupled reaction at suitable solvent.
Method e) can be for example in the methylene dichloride at suitable solvent, in the presence of MCBDA ,-60 ℃ to room temperature, the activation phosphate derivative of formula (F) compound and protection was reacted about 2 hours.The example of the activation phosphate derivative of protection comprises diethylamino phosphorous acid di-t-butyl ester (di-tert-butyl diethylphosphoramidite).
Method f) knows the method that forms ester between hydroxyl and carboxylic acid or the activating carboxy acid in this area.For example, can alkali for example triethylamine in the presence of, make this reaction of acyl chlorides and alcohol reaction.Carboxylic acid derivative is under suitable condition, can form any carboxylic acid derivative of ester bond with hydroxyl reaction.The example of carboxylic acid derivative comprises acyl chlorides.
Method g) at suitable solvent for example in the presence of the DMF, 0 ℃ under 100 ℃, can make the reaction of formula (G) compound and formula (H) compound.
Can be by the general introduction in the flow process 1, the preparation method a), b), c), d), e), f) and intermediate g):
Reaction conditions (i) is at suitable solvent for example in the presence of DMF or the DMSO, ℃ uses ammonia down in room temperature to 100.
Reaction conditions is (ii) at suitable solvent for example in the presence of DMF, DMA or the DMSO, at-10 ℃ to 60 ℃.
Reaction conditions is (iii) in the presence of SULPHURYL CHLORIDE, at suitable solvent for example among methylene dichloride/DMF, at room temperature.
Figure A20058002121900271
Flow process 1
Have commercially availablely as the compound of above-mentioned reaction starting raw material, or they are known compounds, maybe can prepare them by methods known in the art.
Also can recognize, in described herein some reaction, any sensitive group in the possible essential/compound that needs protection.Known situation about wherein must or need protection of those skilled in the art and suitable guard method.Can use GPF (General Protection False group (illustrating referring to T.W.Green Protective Groups in Organic Synthesis, John Wileyand Sons, 1991) by standard practices.Therefore, if reactant comprises group for example amino, carboxyl or hydroxyl, in some reaction of mentioning in this article, this group may need protection.
The appropriate protection group of amino or alkylamino is for example acyl group, for example alkyloyl, for example ethanoyl; Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Or aroyl, for example benzoyl.The deprotection condition of above blocking group must change with the blocking group of selecting.Therefore, for example can be by with suitable alkali alkali metal hydroxide for example, for example lithium hydroxide or sodium hydroxide hydrolysis are for example removed for example alkyloyl of acyl group, or alkoxy carbonyl or aroyl.Perhaps, for example can remove for example tert-butoxycarbonyl of acyl group by handling with suitable sour example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid; Can by catalyzer for example for example palladium on carbon hydrogenation or by with Lewis acid for example three (trifluoroacetic acid) boron handle, remove for example benzyloxycarbonyl of aryl methoxy carbonyl.The suitable alternative blocking group of primary amino is a phthaloyl for example, and this phthaloyl can be by use alkylamine, for example dimethylamino propylamine or remove with the hydrazine processing.
The appropriate protection group of hydroxyl is for example acyl group, for example alkyloyl, for example ethanoyl; Aroyl, for example benzoyl; Or arylmethyl, for example benzyl.The deprotection condition of above blocking group must change with the blocking group of selecting.Therefore, for example can be by with suitable alkali, for example for example lithium hydroxide or sodium hydroxide hydrolysis of alkali metal hydroxide removed for example acyl group, for example alkyloyl or aroyl.Perhaps, can pass through for example for example palladium on carbon hydrogenation of catalyzer, remove arylmethyl, for example benzyl.
The appropriate protection group of carboxyl is an esterified group for example; for example can be by for example with alkali methyl or the ethyl removed of sodium hydroxide hydrolysis for example; maybe can be by with acid organic acid for example; for example trifluoroacetic acid is handled for example tertiary butyl remove, maybe can be by for example benzyl removed of palladium on carbon hydrogenation for example of catalyzer for example.
Can remove blocking group with the routine techniques of knowing in the chemical field in any appropriate to the occasion stage in synthetic.
Comprise in people's the Mammals at therapeutic treatment (comprising prophylactic treatment), be use formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt, according to the standard pharmaceutical practice, it is formulated as medicinal compositions usually.
The present composition can be the form that is fit to orally use (for example tablet, lozenge, hard or soft capsule, water-based or oiliness suspensoid, emulsion, can disperse powder or granule, syrup or elixir); Be fit to the local form of using (for example ointment, ointment, gelifying agent or water-based or oily solution or suspension), be fit to by inhalation form (for example micro mist powder or liquid aerosol), be fit to the form (for example intravenously, subcutaneous, intramuscular or intramuscular administration be with aseptic aqueous solution or oil solution, or the suppository of rectal administration) of form (for example micro mist powder) by being blown into administration or administered parenterally.
Can pass through ordinary method, obtain the present composition with the conventional pharmaceutical excipient of knowing in this area.Therefore, predetermined composition for oral administration can contain for example one or more tinting materials, sweeting agent, correctives and/or sanitas.
The pharmaceutically acceptable appropriate excipients of tablet comprises for example inert diluent, for example lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch; Lubricant, for example Magnesium Stearate, stearic acid or talcum powder; Sanitas, for example ethyl p-hydroxybenzoate or propylparaben; And antioxidant, for example xitix.Tablet is dressing or dressing not, with the disintegration that improves them and subsequently activeconstituents or improve their stability and/or outward appearance in GI absorption, in either case, use conventional Drug coating and the method known in this area.
Composition for oral administration can be the hard-gelatin capsules form, and wherein for example lime carbonate, calcium phosphate or kaolin mix activeconstituents with inert solid diluent; Or Gelseal form, wherein for example peanut oil, whiteruss or mixed with olive oil of activeconstituents and water or oil.
Aqueous suspension contains activeconstituents fine powder and one or more suspension agents, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth and gum arabic usually; Dispersion agent or wetting agent, the condensation product of Yelkin TTS or alkylene oxide and lipid acid (for example polyoxyethylene stearic acid ester) for example, or the condensation product of oxyethane and long chain aliphatic, 17 carbon ethyleneoxy group hexadecanols (heptadecaethyleneoxycetanol) for example, or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitol, octadecanoic acid ester of polyethylene glycol for example, or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitol dehydrate, for example polyethylene polyoxyethylene-sorbitan mono-oleate.Aqueous suspension also can contain one or more sanitass (for example ethyl p-hydroxybenzoate or propylparaben; Antioxidant (for example xitix); Tinting material; Correctives and/or sweeting agent (as sucrose, asccharin or aspartame).
Can be suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (for example whiteruss) by making activeconstituents, suspension makes up oil.Oil suspension also can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add those sweeting agents for example described above and correctives, agreeable to the taste oral preparations is provided.Can preserve these compositions by adding for example xitix of antioxidant.
Be applicable to by adding disperseed powder and the granule that entry prepares aqueous suspension, contain activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass usually.Suitable dispersion agent or wetting agent and suspension agent can illustrate by above-mentioned those.Also can there be other vehicle, for example sweeting agent, correctives and tinting material.
Medicinal compositions of the present invention also can be the oil-in-water emulsion form.Oil phase can be for example sweet oil or a peanut oil of vegetables oil, or mineral oil whiteruss for example, or the mixture of any of these oil.Suitable emulsifying agent can be for example naturally occurring glue, for example gum arabic or tragacanth; Naturally occurring phosphatide for example soybean, Yelkin TTS, derived from the ester of lipid acid and hexitol dehydrate or the condensation product of part ester (for example polyoxyethylene-sorbitan mono-oleate) and described part ester and oxyethane, for example polyoxyethylene sorbitan monooleate.Emulsion also can contain sweeting agent, correctives and sanitas.
Syrup and elixir can be used sweeting agent, for example glycerine, propylene glycol, sorbyl alcohol, aspartame or sucrose preparation, and can contain negative catalyst, sanitas, correctives and/or tinting material.
Medicinal compositions also can be aseptic injection water-based or oil-based suspension form, can be by currently known methods, with one or more suitable above-mentioned dispersion agents or wetting agent and suspension agent preparation.Aseptic injection preparation also can be the aseptic injectable solution or the suspension of nontoxic parenteral acceptable diluent or solvent, for example 1,3 butylene glycol solution.
Can be mixed with suppository by making activeconstituents and suitable non-irritating excipient, it is a solid under usual temperature, but is liquid under rectal temperature, therefore dissolves and discharge medicine in rectum.Suitable vehicle comprises for example theobroma oil and polyoxyethylene glycol.
By using ordinary method well known in the art, activeconstituents and local acceptable conventional solvent or thinner are prepared together, can obtain topical formulations usually, for example ointment, ointment, gelifying agent and water-based or oily solution or suspension.
By the composition that is blown into administration can be the micro mist powder type, this micro mist powder contains mean diameter and is for example 30 μ m or littler particle, and powder itself contains independent activeconstituents or with one or more physiologically acceptable carriers activeconstituents of diluting of lactose for example.The powder that will be used for being blown into aptly places and contains for example capsule of 1-50mg activeconstituents then, with the turbine type inhaler device, for example is used for the device that the known drug Sodium Cromoglicate is blown into and uses together.
Composition by inhalation can be the aerosol form of conventional pressurization, and this aerosol arrangement distributes activeconstituents with the aerosol that contains solid micro-powder or drop.Can use conventional aerosol propellent for example volatility fluorinated hydrocarbons or hydrocarbon, and can arrange the aerosol device to distribute quantitative activeconstituents aptly.
The further information of relevant preparation, the reader can be with reference to Comprehensive MedicinalChemistry the 5th volume the 25.2nd chapter (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990.
Produce the amount of the activeconstituents of single formulation with one or more mixed with excipients, need change according to host who is treated and concrete route of administration.For example, the preparation that is used for the per os administration of human for example contain usually with suitably and the 0.5mg-2g promoting agent of sufficient quantity mixed with excipients, this vehicle can account for total composition about 5% to about 98% (weight).Dosage unit form contains the 1mg that has an appointment usually to about 500mg activeconstituents.About route of administration and the further information of dosage, the reader can be with reference to Comprehensive Medicinal Chemistry the 5th volume the 25.3rd chapter (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.
According to the medical principle of knowing, be used for the treatment of or prevent the dosage size of formula (I), formula (II) or formula (III) compound of purpose, nature will change according to the character of illness and seriousness, animal or patient's age and sex, route of administration.
When the formula (I) of using treatment or prevention purpose, formula (II) or formula (III) compound, divided dose gives if desired, and the per daily dose scope that then gives usually for example is the 0.5mg-75mg/kg body weight.Generally speaking, when adopting parenteral route, dosage is less.Therefore, for example when intravenous administration, use for example dosage of 0.5mg-20mg/kg body weight usually.But the preferred vein dosage of intravenous administration is usually: every about 10mg-500mg The compounds of this invention of patient.
The compounds of this invention can be united use with other medicines and therapy, these other medicines and therapy be used to suppress and/or counter-rotating and/or alleviating vascular generates and/or with any disease symptoms of associated angiogenesis.The example of this type of disease comprises: cancer, diabetes, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disorder, acute inflammation, endometriosis, dysfunctional uterine bleeding and with the outgrowth illness in eye of retinal vessel.
If press the fixed dosage preparation, this type of joint product uses The compounds of this invention and other active medicine in its approval dosage range in the described dosage range herein.When combined preparation is improper, expect sequential use.
The anticancer therapy of preamble definition can use by monotherapy, or can comprise conventional surgical or radiotherapy or chemotherapy except that The compounds of this invention.This chemotherapy can comprise one or more antitumor drugs with lower class:
(i) antiproliferative/antitumor drug and the combination thereof as being used for the medical science oncology, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Antimetabolite (for example antifol, for example fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; Antitumor antibiotics (for example anthracycline, as Dx, bleomycin, Dx, daunomycin, epirubicin, idarubicin, Mitomycin-C, dactinomycin and Plicamycin); Antimitotic drug (for example vinca alkaloids such as vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine and taxanes medicine (taxoids) are as safe element and taxotere); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin such as Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);
(ii) cytostatics, antiestrogen (tamoxifen for example for example, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor downward modulation conditioning agent (for example fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogens (for example Magace), aromatase inhibitor (Anastrozole for example, letrozole, vorazole and Exemestane) and 5 inhibitor, for example finasteride;
The (iii) medicine (for example inhibitors of metalloproteinase such as Marimastat and urokinase plasmin activator receptor depressant of functions) of anticancer invasion and attack;
(iv) somatomedin depressant of functions, for example this type of inhibitor comprises: growth factor antibodies, growth factor receptor antibody (anti--erbb2 antibody trastuzumab [Herceptin for example TM] and anti--erbb1 antibody Cetuximab [C225]), farnesyl transferase inhibitor, mek inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, epidermal growth factor family inhibitor (EGFR family tyrosine kinase inhibitor for example for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib (gefitinib) for example, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib (erlotinib), OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), Thr6 PDGF BB man group inhibitor for example; PHGF man group inhibitor for example;
(v) anti-angiogenic formation medicine for example suppresses those medicines (anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin for example of vascular endothelial growth factor effect TM], for example at International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO98/13354) disclosed compound and the compound (for example linomide, beta 2 integrin alpha v β 3 depressant of functions and angiostatin) that works by other mechanism;
(vi) vascular damaging agents, for example combretastatin A4 and in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 disclosed compound;
(vii) antisense therapy for example at above-mentioned listed target those, for example resists-ras antisense drug ISIS 2503;
(viii) gene therapy method, comprise and for example replace the distortion gene, p53 or distortion BRCA1 or BRCA2, GDEPT (the enzyme prodrug therapy of gene-guiding) method for example distort, for example use those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, with the method for increase patient to chemotherapy or radiotherapy tolerance, for example multidrug resistance gene therapy; With
(ix) immunotherapy comprises for example increasing exsomatizing and the interior method of body of patient tumors cell immunogenicity, for example with for example interleukin-2, interleukin-4 or granulocyte-macrophage colony stimutaing factor transfection of cytokine; Reduce the method for T-cell anergy; Use the method for the immunocyte of transfection, for example the dendritic cell of cytokine transfection; Use the method and the method for using antiidiotypic antibody of the tumor cell line of cytokine transfection.
(x) cell cycle inhibitor comprises for example CDK inhibitor (for example flavones pyrrole alcohol (flavopiridol)) and other cell cycle chechpoint inhibitor (for example checkpoint kinase); Aurora kinase inhibitor and other kinases (for example mitotic kinesins) that relates to mitotic division and division of cytoplasm adjusting; And histone deacetylase inhibitors.
Can realize this type of combination therapy by while, each composition sequential or that treat respectively.This type of joint product uses The compounds of this invention and other active medicine in its approval dosage range in the described dosage range of preamble.
The compounds of this invention also can be united use with surgery or radiotherapy.
According to the 5th feature of the present invention, formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt are provided, the form of preferred medicinal compositions when with divided dose (being called branch dosage again) administration, produces the antitumor action bigger than single dose administration.
Antitumor action includes but not limited to that tumor growth inhibition, tumor growth delay, tumor regression, tumour dwindle, increase treatment and stop the long time of back tumor regrowth, delay disease progression.Expectation is when needing treatment to comprise the warm-blooded animal of the cancer of solid tumor, for example during people's The compounds of this invention, described methods of treatment will produce the effect of arriving by for example following one or more index measurements: the time of the degree of antitumor action, reactivity, disease progression and survival rate.
One side again according to the present invention's the 5th feature, be provided at for example method of philtrum generation angiolysis effect of warm-blooded animal, this method comprises formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt that gives described animal effective dose with divided dose, the form of preferred medicinal compositions.
One side again according to the present invention's the 5th feature, be provided at warm-blooded animal for example philtrum treatment comprise the method for cancer of solid tumor, this method comprises formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt that gives described animal effective dose with divided dose, the form of preferred medicinal compositions.
One side again according to the present invention's the 5th feature, medicine with the divided dose administration is provided, this medicine contains formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt of two or more dosage parts, the form of preferred medicinal compositions, these dosage are partly added up and are reached total per daily dose, and this medicine is used for the method by the therapy for treating human or animal body.
One side again according to the present invention's the 5th feature, kit with the divided dose administration is provided, this kit contains formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt of two or more dosage parts, the form of preferred medicinal compositions, these dosage are partly added up and are reached total per daily dose.
One side again according to the present invention's the 5th feature provides kit, and this kit comprises:
A) be formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt of two or more dosage parts of unit dosage, these dosage are partly added up and are reached total per daily dose, and this unit dosage is used for the divided dose administration; With
B) contain the container of described formulation.
One side again according to the present invention's the 5th feature provides kit, and this kit comprises:
A) be formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt of two or more dosage parts of unit dosage, and vehicle or carrier, these dosage are partly added up and are reached total per daily dose; With
B) contain the container of described formulation.
One side again according to the present invention's the 5th feature, formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt purposes in the preparation medicine is provided, this medicine is used in for example people's generation angiolysis effect of warm-blooded animal with the divided dose administration.
According to the present invention's the 5th feature more on the one hand, formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt purposes in the preparation medicine is provided, this medicine is with the divided dose administration, be used for warm-blooded animal for example the people produce antitumous effect.
One side again according to the present invention's the 5th feature, formula (I), formula (II) or formula (III) compound or its pharmacy acceptable salt purposes in the preparation medicine is provided, this medicine is with the divided dose administration, be used for warm-blooded animal for example the people produce antitumor action.
Divided dose is called branch dosage again, expression will be in arbitrary Time of Day (for example 1 from the midnight to the midnight 24 hours) gives for example people's total dose of warm-blooded animal, the two or more parts that are divided into total dose, press timed interval between the each several part approximately greater than 0 hour to about 10 hours, preferred about 1 hour to about 6 hours, more preferably from about 2 hours to about 4 hours, give these parts.The each several part of total dose is reducible to be equated or does not wait.
Preferred total dose is divided into reducible two portions that equate or do not wait.
For example, the timed interval between the dosage can be selected from: about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours and about 6 hours.
The timed interval between the dosage can preferred 45-375 minute, contain 45 and 375 minutes for greater than any the number of minutes (comprising non-integer) between 0 minute-600 minutes.If give the dosage greater than two in the timed interval between each dosage, then each dosage is reducible equates or does not wait.
Preferably, more than or equal to 1 hour and less than the timed interval between two dosage of 6 hours in, give this two dosage.
More preferably, more than or equal to 2 hours and less than the timed interval between two dosage of 5 hours in, give this two dosage.
Also more preferably, more than or equal to 2 hours and be less than or equal in timed interval between two dosage of 4 hours, give this two dosage.
Especially, total dose is divided into reducible two portions that equate or do not wait, between the dosage interval greater than or equal about 2 hours, and be less than or equal to about 4 hours.
More particularly, total dose is divided into reducible equal two portions, between the dosage interval greater than or equal about 2 hours, and be less than or equal to about 4 hours.
For avoiding feeling uncertain, term ' pact ' expression provides time ± 15 minute in describing in the time, therefore, represents 45-75 minute in for example about 1 hour, represents 75-105 minute in about 1.5 hours.In other place, its common dictionary meanings of term ' pact ' have.
Although formula (I), formula (II) or formula (III) compound mainly have the value of the medicine that is used for warm-blooded animal (comprising the people), but when needing inhibition and/or counter-rotating and/or alleviating vascular to generate and/or during with any disease symptoms of associated angiogenesis, they are also useful.Therefore, they can be used as pharmacological tool, are used for the development of true tumor method of testing and seek new pharmacological reagent.
Biological assay
Colchicine combining site competitive assay test kit
The ligand specificity is the index of vascular damaging activity in conjunction with colchicine ability of combining site on tubulin, with " Cytoskeleton " (1650 Fillmore St.#240, Denver, CO80206, U.S.A.) size exclusion chromatography of test kit catalog number: BK023 is measured test kit, estimates.Use following reagent:
The tubulin damping fluid obtains 0.1mM GTP, 0.5mM MgCl 2, 0.5mM EGTA, 40mM PIPES damping fluid, end reaction mixture pH6.9;
By the tubulin of ox brain purifying, 1mg/ml tubulin damping fluid;
0.02mM fluorescence colchicine tubulin damping fluid [FITC (Fluorescein Isothiocyanate)-mark];
2mM colchicine tubulin damping fluid;
0.2mM vinealeucoblastine(VLB) tubulin damping fluid; With
G-25 Sephadex TMFine-granularity 34-138 μ m.
The following reaction:
8 μ l test compounds (being dissolved in DMSO) are leniently mixed with 150 μ l tubulins.Then with this mixture 37 ℃ of following incubations 30 minutes.Add 4 μ l fluorescence colchicine then, with incubation mixture vortex 5 seconds, incubation 30 minutes again under 37 ℃ then.
When the reactant incubation finishes, carry out size exclusion chromatography, make with tubulin bonded fluorescent colchicine and do not separate in conjunction with colchicine with free.If test compounds suppresses the combination of fluorescent colchicine, then measure the signal of decay, can be used as colchicine position bound fraction and confirm compound.
The following size exclusion chromatography that carries out uses and fills 3ml G-25 Sephadex TMThe chromatography column of Fine slurry.The incubation mixture is moved on the post with transfer pipet, collect the most nearly 12 parts of elutriants, every part 160 μ l.On spectrophotometer, detect and to contain the tubulin component and excite and at the fluorescent of 535nm emission at 485nm.
Also contrast incubation, in the incubation mixture, replace 8 μ l test compounds with 8 μ l DMSO (negative control) and 8 μ l colchicine storing solutions (positive competitive contrast).
Calculating is with respect to the DMSO negative control, and unmarked colchicine or test compounds combine the degree of competition with colchicine.
For example, in above mensuration, 10 μ M embodiment, 1 compound suppresses 80% colchicine combination, and 10 μ M embodiment, 9 compounds suppress 85% colchicine combination.
Formula (I), formula (II) or formula (III) compound comprise the prodrug of vascular damaging agents and vascular damaging agents.Think that the vascular damaging agents prodrug dissociates in vivo.Do not accept the constraint that opinion is considered, the activity of these prodrugs in external colchicine combining site competitive assay may be than little when what expect based on the mensuration of cell or these compound activities of in-vivo measurement the time.
Now, illustrate the present invention with following indefiniteness embodiment, except as otherwise noted, wherein:
(i) evaporate by rotary evaporation in vacuo,, carry out aftertreatment by removing by filter residual solid for example behind the siccative;
(ii) under 18-25 ℃ envrionment temperature, for example under argon or the nitrogen atmosphere, operate at rare gas element;
The yield that (iii) provides only is used to illustrate, and unnecessary be available maximum yield;
(iv) by nuclear (proton usually) mr (NMR) and mass-spectrometric technique conclusive evidence formula (I) end product structure; Press the δ scale and measure the proton resonance chemical displacement value, the peak multiplicity is as follows: s, and unimodal; D, doublet; T, triplet; M, multiplet; Br, broad peak; Q, quartet, quin, quintet;
(v) all do not characterize intermediate usually, by thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), infrared (IR) or NMR assay purity;
(vi) on silica gel (Merck Keiselgel:Art.9385), dodge the formula chromatography;
(vii) OASIS TMFor being used for the macroporous copolymer of purifying hydrophilic compounds, make by the lipotropy Vinylstyrene and the wetting ability N-vinyl pyrrolidone of balanced proportions.OASIS TMFollowing patent is seen in description: U.S. Patent number 5882521, U.S. Patent number 5976376 and U.S. Patent number 6106721.OASIS TMThe sample extraction product derive from Waters Corporation (Milford, Massachusetts, USA).
(viii) diatomite (celite) is meant diatomite.
Abbreviation
Metachloroperbenzoic acid mCPBA
Methylene dichloride DCM
N,N-DIMETHYLACETAMIDE DMA
4-dimethylaminopyridine DMAP
2,3-two chloro-5,6-dicyano-1,4-benzoquinones DDQ
Dimethyl formamide DMF
Azo-group dicarboxylate DTAD
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride EDCI
Dimethyl sulfoxide (DMSO) DMSO
N-(9-fluorenyl methoxy carbonyl) N-FMOC
N-crassitude NMP
Tetrahydrofuran THF
Embodiment 1
3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900401
2 embodiment 1
Stir down, to 2 (1.84g; 8.90mmol) hexalin (5ml) soup compound in add 3-chloro-4-phenylpyrrole-2,5-diketone (1.80g; 8.90mmol).Under 120 ℃, with the suspension heated overnight that obtains.Reaction mixture is cooled to room temperature, grinds with ether (10ml).With sedimentation and filtration, collect, with ether (30ml) washing, be dried to constant weight, obtain embodiment 1 compound.
Yield: 91%
1HNMR (DMSOd 6): 6.64 (d, 1H); 6.85 (2x merges d, 4H); 6.99 (m, 2H); 7.19 (m, 3H); 7.25 (s, 1H); 7.67 (t, 1H); 7.87 (dd, 1H); 9.56 (bs, 1H); 10.76 (bs, 1H)
MS-ESI：380[M-H] -
Be prepared as follows raw material:
Figure A20058002121900402
Stir down, to 1-fluoro-4-oil of mirbane (11.9g; 85.0mmol) and 2-cyanophenol (10.0g; 84.0mmol) DMF (100ml) soup compound in add K 2CO 3(15.1g; 109mmol).Under 90 ℃, mixture heating up is spent the night.Suspension is cooled to room temperature, and product precipitates in water (250ml) separates out.With solid filtering, collect, with cold diethyl ether (20ml) washing, be dried to constant weight, obtain 1.
Yield: 93%
1HNMR(DMSOd 6)：7.34(d，2H)；7.37(d，1H)；7.49(t，1H）；7.85(t，1H)；8.03(dd，1H)；8.34(d，2H).
MS-ESI：241[M+H] +
Stir down, to 1 (22.3g; 92.9mmol) EtOAc-EtOH (150ml, 10: 1) solution in add 10% palladium on carbon (2.23g).The suspension that obtains is exposed in the 1 normal atmosphere hydrogen, keeps 2.5h.Catalyzer is removed by filter by Celite pad,, obtain 2, be white solid the filtrate evaporation.
Yield: 74%
1HNMR(DMSOd 6)：5.14(bs，2H)；6.65(d，2H)；6.86(d，1H)；6.89(d，2H)；7.19(t，1H)；7.61(t，1H)；7.83(dd，1H).
MS-ESI：211[M+H] +
Embodiment 2
1-methyl-3-[4-(2-cyano-benzene oxygen) phenylamino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900411
Embodiment 1 embodiment 2
Stir down, to embodiment 1 (0.100g; 0.25mmol) DMF (0.200ml) solution in add 60%NaH oil dispersion liquid (0.011g; 0.28mmol).After immersion is disappeared, add MeI (0.035g; 0.28mmol), reaction mixture was at room temperature stirred 1 hour.Solution is through dodging the formula chromatography purification, with 80/20 pentane/CH 2Cl 2Wash-out obtains embodiment 2 compounds.
Yield: 37%
1HNMR (DMSOd 6): 3.01 (s, 3H); 6.63 (d, 1H); 6.80 (2 merge d, 4H); 6.97 (m, 2H); 7.18 (m, 3H); 7.27 (t, 1H); 7.69 (t, 1H); 7.87 (dd, 1H): 9.73 (bs, 1H).
MS-ESI：394[M-H] -
Embodiment 3
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-p-methoxy-phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900421
5 embodiment 3
Stir down, to 5 (0.20g; 0.84mmol) hexalin (0.50ml) suspension in add 2 (0.19g; 0.93mmol) [referring to embodiment 1].Under 120 ℃, with the reaction mixture heated overnight.Solution is used 95/5 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 3 compounds, is orange solids.
Yield: 35%
1HNMR(DMSOd 6)：3.53(s，3H)；6.40(s，1H)；6.61(d，1H)；6.68(d，1H)；6.76(dd，1H)；6.84(m，4H)；7.13(t，1H)；7.27(t，1H)；7.67(t，1H)；7.84(dd，1H)；9.76(bs，1H)；10.34(bs，1H).
MS-ESI：410[M+H] -
Be prepared as follows raw material:
Under 0 ℃, stir down, to 3-p-methoxy-phenyl Acetyl Chloride 98Min. (3.00g; 16.2mmol) ether (20ml) solution in bubbling feed ammonia, continue 10 minutes.With the solid filtering that forms, to collect, recrystallization in hot water (100ml) obtains 3, is white crystalline solid.
Yield: 44%
1HNMR(DMSOd 6)：3.34(s，3H)；3.74(s，2H)；6.85(m，3H)；7.21(t，1H)；7.43(bs，2H).
MS-ESI：166[M+H] +
Under-10 ℃, stir down, to 3 (1.00g; 6.10mmol) and oxalic acid diethyl ester (0.97g; 6.70mmol) DMF (10ml) solution in add solid potassium tert-butoxide (0.82g; 6.70mmol).Under-10 ℃, the orange solution that obtains was stirred 30 minutes, add again solid potassium tert-butoxide (0.82g, 6.70mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (100ml), reduce pH value of solution to 1 with concentrated hydrochloric acid.With the sedimentation and filtration that obtains, to collect, water (50ml), ether (50ml) washing are dried to constant weight, obtain 4.
Yield: 77%
1HNMR(DMSOd 6)：3.78(s，1H)；6.89(dd，1H)；7.35(t，1H)；7.57(m，2H)；10.67(bs，1H).
MS-ESI：218[M+H] +
Stir down, to 4 (1.00g; 4.50mmol) and CCl 4Add in MeCN (2.00ml) (10ml) suspension triphenyl phosphine (3.59g, 13.7mmol).With solid dissolving 1 hour, with the orange solution that obtains restir 2 hours at room temperature.Solvent is removed, and residual residue is through dodging the formula chromatography purification, with 50/50 pentane/CH 2Cl 2Wash-out obtains 5, is yellow solid.
Yield: 49%
1HNMR(DMSOd 6)：3.78(s，3H)；7.14(dd，1H)；7.36(m，2H)；7.75(t，1H)；11.53(bs，1H).
MS-ESI：236[M-H] -
Embodiment 4
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-hydroxy phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900431
Stir down, to 11 (1.00g; 2.10mmol) EtOAc-EtOH (50ml, 10: 1) solution in add PearlmanShi catalyzer (0.50g) suspension be exposed in the 1 normal atmosphere hydrogen, kept 5 hours.Catalyzer is removed by diatomite filtration, filtrate is concentrated on Rotary Evaporators, residue is used 95/5 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 4, is orange solids.
Yield: 65%
1HNMR (DMSOd 6): 6.39 (d, 1H); 6.44 (s, 1H); 6.56 (d, 1H); 6.67 (d, 1H); 6.89 (2x merges d, 4H); 6.95 (t, 1H); 7.26 (t, 1H); 7.67 (t, 1H); 7.86 (dd, 1H); 9.25 (bs, 1H); 9.50 (bs, 1H); 10.72 (bs, 1H).
MS-ESI：398[M+H] +
Be prepared as follows raw material:
Figure A20058002121900441
Stir down, to 4-hydroxyl phenylacetic acid (25.0g; Add the vitriol oil (1ml) in MeOH 164mmol) (300ml) solution.With vlil 5 hours.With solvent evaporation, residue is dissolved in CH 2C1 2(300ml), water (5 * 50ml) washings.Organic layer is through dried over mgso, is evaporated to driedly, obtains 6, is dark-brown oily matter.
Yield: 85%
1HNMR(DMSOd 6)：3.58(s，2H)；3.62(s，3H)；6.68(m，3H)；7.11(t，1H)；9.39(bs，1H).
MS-ESI：166[M+H] +
Under 0 ℃, to 6 (23.1g; 139mmol) add dense NH 4The OH aqueous solution (150ml).Reaction mixture at room temperature stirred spend the night.With the solution evaporation that obtains, use among the AcOH and residue.Solid recrystallization in hot ro-butyl acetate (100ml) with obtaining obtains 7, is pale solid.
Yield: 60%
1HNMR(DMSO)3.35(s，2H)；6.68(m，3H)；6.85(bs，1H)；7.10(t，1H)；7.41(bs，1H)；9.29(bs，1H)
MS-ESI：152[M+H] +
Stir down, to 7 (5.00g; 33.0mmol) and bromotoluene (5.93g; 34.7mmol) DMF (50ml) solution in add solid carbonic acid potassium (6.84g; 49.5mmol).Suspension at room temperature stirred spend the night.Suspension water (100ml) is ground, with the sedimentation and filtration that obtains, collect, water (100ml) and cold diethyl ether (10ml) washing obtain 8, are white solid.
Yield: 99%
1HNMR(DMSO)5.09(s，2H)；6.89(m，2H)；6.95(m，1H)；7.35(t，1H)；7.50-7.36(m，5H)；9.29(bs，1H)
MS-ESI：242[M+H] +
Under-10 ℃, stir down, to 8 (6.00g; 24.9mmol) and oxalic acid diethyl ester (4.00g; 27.4mmol) DMF (50ml) solution in add solid potassium tert-butoxide (3.35g; 24.7mmol).Under-10 ℃, the orange solution that obtains was stirred 30 minutes, add again solid potassium tert-butoxide (3.35g, 27.4mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (300ml), pH value of solution is reduced to 1 with concentrated hydrochloric acid.With the sedimentation and filtration that obtains, collect, water (3 * 50ml), ether (50ml) washing, be dried to constant weight, obtain 9.
Yield: 83%
1HNMR(DMSO)：5.11(s，2H)；6.97(dd，1H)；7.36(m，2H)；7.43(t，2H)；7.49(m，2H)；7.58(d，1H)；7.66(m，1H)；10.65(bs，1H).
MS-ESI：294[M-H] -
Stir down, to 9 (5.00g; 16.9mmol) and SOCl 2(10.1g; 84.7mmol) CH 2Cl 2(20ml) add DMF (1ml) in the suspension.With solid dissolving 1 hour, at room temperature, again the orange solution that obtains was stirred 2 hours.Solvent is removed, residue is dissolved in MeOH (25ml), grind with ether (100ml).With solid filtering, collect, with cold diethyl ether (20ml) washing, be dried to constant weight, obtain 10.
Yield: 63%
1HNMR(DMSO)：5.17(s，2H)；7.21(dd，1H)；7.36-7.50(m，8H)；11.53(bs，1H).
MS-ESI：312[M-H] -
Stir down, to 10 (2.00g; 6.40mmol) hexalin (5ml) suspension in add 2 (1.48g; 7.00mmol).With reaction mixture 120 ℃ of following heated overnight.Solution is used 95/5 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 11, is orange solids.
Yield: 74%
1HNMR (DMSOd 6): 4.80 (s, 2H); 6.53 (s, 1H); 6.62 (d, 1H); 6.68 (d, 1H); 6.84 (2x merges d, 4H); 7.10 (t, 1H); 7.21 (t, 1H); 7.32 (m, 1H); 7.36 (m, 3H); 7.57 (t, 1H); 7.84 (dd, 1H); 9.53 (bs, 1H); 11.22 (bs, 1H).
MS-ESI：488[M+H] +
Embodiment 5
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-phosphonato phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900461
12 embodiment 5
Under-10 ℃, stir down, to 12 (0.47g; 0.80mmol) DCM (10ml) solution in add pure TFA (10ml).Allow the darkorange solution that obtains be warming up to room temperature, stirred 1 hour.Solvent evaporation to doing, is dissolved in MeCN (2.00ml) with residue, uses the OASIS resin purification, use 30/70 MeCN/H 2The O wash-out.Solvent is removed on Rotary Evaporators, the pH of remaining aqueous solution is transferred to 7.With the solution freeze-drying, obtain embodiment 5 compounds, be yellow solid.
Yield: 49%
1HNMR (DMSOd 6-TFA): 6.66 (d, 1H); 6.68 (s, 1H); 6.78 (t, 1H); 6.83 (2x merges d, 4H); 6.95 (d, 1H); 7.14 (t, 1H); 7.23 (t, 1H); 7.68 (t, 1H); 7.83 (dd, 1H); 13.12 (bs, 1H).
MS-ESI：478[M+H] +
Be prepared as follows raw material:
Figure A20058002121900471
Embodiment 4 12
Stir down, to embodiment 4 (0.55g; 1.40mmol) THF (10ml) solution in add diethylamino phosphorous acid di-t-butyl ester (0.66g; 2.63mmol).Solution was at room temperature stirred 2 hours.Orange solution is cooled to-60 ℃, in 30 minutes, adds mCPBA (0.63g; 3.60mmol) CH 2Cl 2(50ml) solution.Allow reaction mixture be warming up to room temperature, use CH 2Cl 2(50ml) dilution is with 10% (w/v) Na 2S 2O 5(2 * 10ml) washings of the aqueous solution (10ml) and water.Organic layer is through MgSO 4Drying is concentrated into about 2ml, through dodging the formula chromatography purification, uses 98/3 CH 2Cl 2/ MeOH wash-out obtains 12, is orange solids.
Yield: 57%
1HNMR (DMSOd 6): 1.43 (s, 18H); 6.67. (m, 3H); 6.83 (2x merges d, 4H); 6.87 (d, 1H); 7.15 (s, 1H); 7.26 (t, 1H); 7.69 (t, 1H); 7.87 (dd, 1H); 9.67 (bs, 1H); 10.82 (bs, 1H).
MS-ESI：588[M-H] -
Embodiment 6
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-nitrophenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900481
Stir down, to 15 (1.00g; 3.90mmol) hexalin (3ml) suspension in add 2 (0.83g; 3.90mmol) [referring to embodiment 1].With reaction mixture 120 ℃ of following heated overnight.Solution is cooled to room temperature, grinds with ether (10ml).The precipitation that obtains is washed with ether (10ml), be dried to constant weight, obtain embodiment 6 compounds, be dark brown solid.
Yield: 74%
1HNMR (DMSOd 6): 6.53 (d, 1H); 6.84 (2x merges d, 4H); 7.25 (t, 1H); 7.40 (m, 1H); 7.47 (t, 1H); 7.65 (t, 1H); 7.72 (m, 1H); 7.88 (dd, 1H); 8.04 (dd, 1H); 9.91 (bs, 1H); 10.94 (bs, 1H).
MS-ESI：427[M+H] +
Be prepared as follows raw material:
Figure A20058002121900482
Stir down, to 3-nitrophenyl ethyl acetate (6.00g; 28.7mmol) add dense NH in the soup compound 4The OH aqueous solution (100ml).The suspension that obtains at room temperature stirred spend the night.The crystalline solid that forms is filtered, collect, water (100ml), ether (20ml) washing are dried to constant weight in vacuum drying oven, obtain 13.
Yield: 52%
1HNMR(DMSO)：3.36(s，2H)；7.02(bs，2H)；7.64(t，1H)；7.74(d，1H)；8.14(dd，1H)；8.17(s，1H).
MS-ESI：179[M-H] -
Under-10 ℃, stir down, to 13 (2.00g; 11.0mmol) and oxalic acid diethyl ester (1.78g adds solid potassium tert-butoxide (1.48g in DMF 12.2mmol) (20ml) solution; 12.1mmol).The orange solution that obtains was stirred 30 minutes down at-10 ℃, add again solid potassium tert-butoxide (1.48g, 12.1mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (200ml), pH value of solution is reduced to 1 with concentrated hydrochloric acid.With the sedimentation and filtration that obtains, collect, water (3 * 50ml), ether (50ml) washing, be dried to constant weight, obtain 14.
Yield: 78%
1HNMR(DMSO)：7.71(t，1H)；8.10(dd，1H)；8.45(d，1H)；8.89(s，1H)；10.71(bs，1H).
MS-ESI：233[M+H] -
Stir down, to 14 (2.00g; 8.50mmol) and SOCl 2(5.08g; 42.7mmol) CH 2Cl 2(10ml) add DMF (1.00ml) in the suspension.With solid dissolving 1 hour, with the orange solution that obtains restir 2 hours at room temperature.Solvent is removed, residue is dissolved in MeOH (25ml), water (100ml) grinds.With solid filtering, collect, with cold diethyl ether (20ml) washing, be dried to constant weight, obtain 15.
Yield: 63%
1HNMR(DMSO)：7.90(t，1H)；8.26(d，1H)；8.41(dd，1H)；8.63(s，1H)；11.70(bs，1H).
MS-ESI：251[M-H] -
Embodiment 7
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900491
Embodiment 6 embodiment 7
Stir down, to embodiment 6 (1.00g; 2.30mmol) EtOAc-EtOH (33ml, 10: 1) solution in add 10% palladium on carbon (0.100g).The suspension that obtains is exposed in the 1 normal atmosphere hydrogen, kept 1 hour.Catalyzer is removed by diatomite filtration, filtrate is concentrated into about 10ml on Rotary Evaporators.Solution is ground with ether (30ml),, collect,, be dried to constant weight, obtain embodiment 7 with ether (10ml) washing with solid filtering.
Yield: 69%
1HNMR(DMSOd 6)：4.93(bs，2H)；6.26(d，1H)；6.38(dd，1H)；6.81(m，7H)；7.24(t，1H)；7.71(t，1H)；7.85(dd，1H)；9.43(bs，1H)；10.72(bs，1H).
MS-ESI：397[M+H] +
Embodiment 8
3-[4-(2-cyano-benzene oxygen) anilino]-4-[3-(α-Gu Anxianji amino) phenyl]-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900501
At room temperature, stir down, to 17 (0.36g; 0.52mmol) CH 2Cl 2(150ml) bubbling feeds HCl gas in the solution, continues 4 hours.With reaction terminating, add the two  alkane solution (20ml) of 4.0M HCl, suspension is kept spending the night down at 0 ℃.With solid filtering, collect, use CH 2Cl 2(150ml) thorough washing.With solid water-soluble (5ml), solution OASIS resin purification is used 30/70 MeCN/H 2The O wash-out.Organic solvent is removed on Rotary Evaporators, the pH of remaining aqueous solution is transferred to 2.With the solution freeze-drying, obtain embodiment 8 compounds, be orange solids.
Yield: 30%.
1HNMR(DMSOd 6)：1.97(m，2H)；2.31(m，2H)；3.90(t，1H)；6.53(d，1H)；6.56(d，1H)；6.79(d，2H)；6.82(d，2H)；7.08(t，1H)；7.21(t，1H)；7.39(s，1H)；7.52(d，1H)；7.67(t，1H)；7.82(dd，1H)；9.37(bs，1H)；10.45(bs，1H)；10.76(bs，1H).
MS-ESI：524[M-H] -
Be prepared as follows raw material:
Figure A20058002121900511
Stir down, to embodiment 7 (0.30g; 0.76mmol) DMF (0.50ml) solution in add DMAP (0.05g; 0.38mmol) and Boc-Glu (OtBu) OH (0.25g; 0.84mmol).The solution that obtains is cooled to 0 ℃, adds solid EDCI (0.19g; 0.99mmol).The red solution that obtains was at room temperature stirred 2 hours.Reaction mixture is used 98/2 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 17 compounds, is yellow foam.
Yield: 80%
1HNMR (DMSOd 6): 1.37 (s, 18H); 1.72-1.91 (m, 2H); 2.21 (m, 2H); 4.07 (m, 1H); 6.54 (d, 1H); 6.84 (2x merges d, 4H); 6.97 (d, 1H); 7.08 (t, 1H); 7.22 (t, 1H); 7.35 (s, 1H); 7.52 (d, 1H); 7.67 (t, 1H); 7.84 (dd, 1H); 9.54 (bs, 1H); 9.86 (bs, 1H); 10.45 (bs, 1H).
MS-ESI：682[M+H] +
Embodiment 9
1-(1-hydroxyethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900521
18 embodiment 9
Stir down, to 18 (0.50g; 0.98mmol) MeOH (30ml) solution in add tosic acid pyridine  (0.25g; 0.98mmol).The solution that obtains was heated 2 hours down at 60 ℃.Solvent is removed, and residue is used 95/5 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 9 compounds, is orange solids.
Yield: 96%
1HNMR (DMSOd 6): 3.59 (m, 4H); 4.87 (t, 1H); 6.66 (d, 1H); 6.83 (2x merges d, 4H); 6.96 (m, 2H); 7.18 (m, 3H); 7.27 (t, 1H); 7.69 (t, 1H); 7.87 (dd, 1H); 9.72 (bs, 1H).
MS-ESI：426[M+H] +
Be prepared as follows raw material:
Figure A20058002121900522
Embodiment 1 18
Stir down, to embodiment 1 (0.50g; 1.30mmol) DCM (5ml) suspension in add triphenyl phosphine (0.38g; 1.44mmol) and 2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethanol (0.19g; 1.30mmol).Solution is cooled to 0 ℃, in 10 minutes, adds azido-formic acid di tert butyl carbonate (0.33g; 1.44mmol) DCM (5.00ml) solution.Allow the dark-brown solution that obtains be warming up to room temperature, stirred 2 hours.Reaction mixture is concentrated into about 5ml,, uses 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 18, is orange solids.
Yield: 86%
1HNMR (DMSOd 6): 1.46-1.73 (m, 6H); 3.61-3.80 (m, 6H); 4.63 (m, 1H); 6.65 (d, 1H); 6.81 (2x merges d, 4H); 6.96 (m, 2H); 7.19 (m, 3H); 7.27 (t, 1H); 7.71 (t, 1H); 7.87 (dd, 1H); 9.76 (bs, 1H).
MS-ESI：508[M-H] -
Embodiment 10
1-(1-phosphonato ethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
19 embodiment 10
Under-10 ℃, stir down, to 19 (0.49g; 0.79mmol) DCM (50ml) solution in add pure TFA (50ml).Allow the darkorange solution that obtains be warming up to room temperature, stirred 1 hour.Solvent evaporation to doing, is dissolved in MeCN (2ml) with residue, uses the OASIS resin purification, use 45/55 MeCN/H 2The O wash-out.Organic solvent is removed on Rotary Evaporators, the pH of remaining aqueous solution is transferred to 7.With the solution freeze-drying, obtain embodiment 10 compounds, be yellow solid.Yield: 28%
1HNMR (DMSOd 6-TFA): 3.76 (t, 2H); 4.05 (m, 2H); 6.65 (d, 1H); 6.83 (2x merges d, 4H); 6.95 (m, 2H); 7.17 (m, 3H); 7.22 (t, 1H); 7.66 (t, 1H); 7.82 (dd, 1H).
MS-ESI：504[M-H] -
Be prepared as follows raw material:
Figure A20058002121900541
Stir down, to embodiment 9 (0.40g; 0.94mmol) THF (10ml) solution in add diethylamino phosphorous acid di-t-butyl ester (0.22g; 0.85mmol).Solution was at room temperature stirred 2 hours.Orange solution is cooled to-60 ℃, in 30 minutes, adds mCPBA (0.21g; 1.22mmol) CH 2Cl 2(10ml) solution.Allow reaction mixture be warming up to room temperature, use CH 2Cl 2(50ml) dilution is with 10% (w/v) Na 2S 2O 5(2 * 10ml) washings of the aqueous solution (10ml) and water.Organic layer is through MgSO 4Drying is concentrated into about 2ml, through dodging the formula chromatography purification, uses 98/3 CH 2Cl 2/ MeOH wash-out obtains 19, is orange solids.
Yield: 84%
1HNMR (DMSOd 6): 1.39 (s, 18H); 3.78 (t, 2H); 4.09 (m, 2H); 6.66 (d, 1H); 6.8l (2x merges d, 4H); 6.95 (m, 2H); 7.18 (m, 3H); 7.27 (t, 1H); 7.68 (t, 1H); 7.88 (dd, 1H); 9.76 (bs, 1H).
MS-ESI：616[M-H] -
Embodiment 11
3-[4-(2-cyano-benzene oxygen) anilino]-4-pyridin-3-yl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900542
22 embodiment 11
Stir down, to 22 (0.20g; 0.82mmol) methyl alcohol (5ml) suspension in add 2 (0.17g; 0.82mmol).With reaction mixture 70 ℃ of following heated overnight.The orange suspension that obtains is cooled to room temperature, is evaporated to driedly,, use 96/4CH by dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 11 compounds, is orange crystalline solid.
Yield: 43%
1HNMR (DMSOd 6): 6.84 (dd, 1H); 6.93 (2x merges d, 4H); 7.28 (t, 1H); 7.69-7.78 (m, 3H); 7.88 (dd, 1H); 8.29 (s, 1H); 8.60 (d, 1H); 10.18 (bs, 1H); 11.10 (bs, 1H).
MS-ESI：383[M+H] +
Be prepared as follows raw material:
Figure A20058002121900551
Stir down, to 3-Pyridineacetic Acid ethyl ester (5.00g; 30.2mmol) add dense NH in the soup compound 4OH (50ml) at room temperature stirs the suspension that obtains and to spend the night.Solution evaporation to doing, is obtained solid, it with MeCN-ether (100ml, 3: 1) washing, is dried to constant weight in vacuum drying oven, obtain 20, be white solid.
Yield: 76%
1HNMR(DMSOd 6)：3.43(s，2H)；6.98(bs，1H)；7.33(m，1H)；7.52(bs，1H)；7.69(d，1H)；8.46(m，2H).
MS-ESI：137[M+H] +
Under-10 ℃, stir down, to 20 (3.00g; 22.1mmol) oxalic acid diethyl ester (3.55g; 24.0mmol) DMF (50ml) solution in add solid potassium tert-butoxide (2.97g; 24.3mmol).The orange solution that obtains was stirred 30 minutes down at-10 ℃, add again solid potassium tert-butoxide (2.97g, 24.3mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (300ml), pH value of solution is reduced to 1 with concentrated hydrochloric acid.With the sedimentation and filtration that obtains, collect, water (5 * 50ml), ether (50ml) washing, be dried to constant weight, obtain 21 hydrochloride.
Yield: 78%
MS-ESI：189[M+H] +
Stir down, to 21 (1.00g; 4.40mmol) and SOCl 2(2.63g; 22.1mmol) CH 2Cl 2(5ml) add DMF (2ml) in the suspension.With solid dissolving 2 hours, with the orange solution that obtains restir 2 hours at room temperature.Solvent is removed, residue is ground with MeOH (50ml).With solid filtering, collect, with cold MeOH (10ml) washing, be dried to constant weight, obtain 22.
Yield: 87%
1HNMR(DMSO)：7.84(m，1H)；8.42(d，1H)；8.84(dd，1H)；9.03(s，1H)；11.75(bs，1H).
MS-ESI：209[M+H] +
Embodiment 12
3-[4-(2-cyano-benzene oxygen) anilino]-4-piperidines-1-base-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900561
25 embodiment 12
Stir down, to 25 (0.10g; 0.26mmol) DMF (0.20ml) solution in add piperidines (0.07g; 0.78mmol).Solution was stirred 1 hour down at 40 ℃.Reaction mixture is used 80/20 CH through dodging the formula chromatography purification 2Cl 2/ MeCN wash-out obtains free alkali, is red oil.This oily matter is dissolved in ether (10ml), adds the two  alkane solution (1ml) of 4.0M HCl.With sedimentation and filtration, collect, with ether (10ml) washing, be dried to constant weight, obtain the HCl salt of embodiment 12.
Yield: 42%
1HNMR(DMSOd 6)：1.39(m，4H)；1.46(m，2H)；3.38(m，4H)；6.79(m，3H)；7.03(d，2H)；7.19(t，1H)；7.60(t，1H)；7.62(bs，1H)；7.85(dd，1H)；10.24(bs，1H).
MS-ESI：389[M+H] +
Be prepared as follows raw material:
Figure A20058002121900571
Stir down, to maleimide (1.00g; 10.3mmol) NMP (1ml) solution in add 2 (2.16g; 10.3mmol) [referring to embodiment 1].With solution 110 ℃ of following heated overnight.Reaction mixture is cooled to room temperature,, uses 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 23, is pale solid.
Yield: 90%
1HNMR(DMSOd 6)：4.59(m，1H)；6.20(d，1H)；6.75(d，2H)；6.81(d，1H)；7.00(d，2H)；7.21(t，1H)；7.63(t，1H)；7.85(dd，1H)；11.32(bs，1H).
MS-ESI：307[M+H] +
Stir down, to 23 (1.00g; 3.30mmol) DCM (50ml) solution in add DDQ (0.74g; 3.30mmol).Solution at room temperature stirred spend the night.By diatomite filtration, filtrate is used 96/4 CH through dodging the formula chromatography purification with reaction mixture 2Cl 2/ MeOH wash-out obtains 24, is light yellow solid.
Yield: 35%
1HNMR(DMSOd 6)：5.62(s，1H)；6.95(d，1H)；7.17(d，2H)；7.31(t，1H)；7.57(d，2H)；7.69(t，1H)；7.91(dd，1H)；9.64(bs，1H)；11.32(bs，1H).
MS-ESI：306[M+H] +
Stir down, to 24 (1.18g; 3.90mmol) DMF (10ml) solution in add N-bromine succinimide (0.62g; 3.50mmol).Solution at room temperature stirred spend the night.Reaction mixture is used 98/2 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 25, is the rust solid.
Yield: 82%
1HNMR(DMSOd 6)：6.96(d，1H)；7.14(d，2H)；7.25-7.29(m，3H)；7.68(t，1H)；7.89(dd，1H)；9.68(bs，1H)；11.12(bs，1H).
MS-ESI：386[M+H] +
Embodiment 13
3-[6-(2-cyano-benzene oxygen) pyridin-3-yl amino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900581
27 embodiment 13
Stir down, to 27 (0.20g; 0.94mmol) hexalin (2ml) soup compound in add 3-chloro-4-phenylpyrrole-2,5-diketone (0.19g; 0.94mmol).With the suspension that obtains 120 ℃ of following heated overnight.Reaction mixture is cooled to room temperature,, uses 80/20CH through dodging the formula chromatography purification 2Cl 2/ MeCN wash-out obtains embodiment 13 compounds, is orange solids.
Yield: 37%
1HNMR(DMSOd 6)：6.83(d，1H)；6.91(d，2H)；7.05(dd，1H)；7.16(m，3H)；7.26(dd，1H)；7.34(t，1H)；7.56(m，1H)；7.74(t，1H)；7.89(dd，1H)；9.55(bs，1H)；10.34(bs，1H).
MS-ESI：383[M+H] +
Be prepared as follows raw material:
Figure A20058002121900591
Stir down, to 2-chloro-5-nitropyridine (2.00g; 12.6mmol) and 2-cyanophenol (1.50g; 12.6mmol) DMF (5ml) soup compound in add K 2CO 3(2.21g; 16.4mmol).With mixture heating up to 80 ℃ maintenance 4 hours.Suspension is cooled to room temperature, and product precipitates in water (100ml) separates out.With solid filtering, with cold diethyl ether (30ml) washing, be dried to constant weight, obtain 26.
Yield: 82%
1HNMR(DMSOd 6)：7.51-7.56(m，3H)；7.84(t，1H)；8.01(dd，1H)；8.74(dd，1H)；9.07(d，1H).
MS-ESI：242[M+H] +
Stir down, to 26 (2.50g; 10.4mmol) EtOAc-EtOH (100ml, 10: 1) solution in add 10% palladium on carbon.The suspension that obtains is exposed under the 1 normal atmosphere hydrogen, keeps 1.5h.Catalyzer is removed by filter by Celite pad,, obtain 27, be white solid the filtrate evaporation.
Yield: 83%
1HNMR(DMSOd 6)：5.26(bs，2H)；6.96(d，1H)；7.07(d，1H)；7.16(dd，1H)；7.30(t，1H)；7.57(d，1H)；7.69(t，1H)；7.87(dd，1H).
MS-ESI：212[M+H] +
Embodiment 14
1-(1-amino-ethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900601
28 embodiment 14
Under-10 ℃, stir down, to 28 (0.25g; 0.48mmol) DCM (20ml) solution in add pure TFA (20ml).Allow the deep yellow solution that obtains be warming up to room temperature, stirred 1 hour.To doing, residue is used 95/5CH through dodging the formula chromatography purification with solvent evaporation 2Cl 2/ MeOH-NH 3Wash-out obtains free alkali, is yellow oil.Oily matter is dissolved in ether (10ml), adds the two  alkane solution (1.00ml) of 4.0M HCl.With the sedimentation and filtration that obtains, collect, be dried to constant weight, obtain the HCl salt of embodiment 14 compounds.
Yield: 92%
1HNMR (DMSOd 6): 3.09 (t, 2H); 3.79 (t, 2H); 6.64 (d, 1H); 6.83 (2x merges d, 4H); 6.97 (m, 2H); 7.20 (m, 3H); 7.28 (t, 1H); 7.72 (t, 1H); 7.86 (bs, 1H); 7.88 (dd, 1H).
MS-ESI：423[M-H] -
Be prepared as follows raw material:
Figure A20058002121900602
Embodiment 1 28
Stir down, to embodiment 1 (0.40g; 1.04mmol) DCM (4ml) suspension in add triphenyl phosphine (0.30g; 1.16mmol) and N-(2-hydroxyethyl) t-butyl carbamate (0.17g; 1.04mmol).Solution is cooled to-10 ℃, in 10 minutes, adds DTAD (0.27g; 1.16mmol) DCM (5ml) solution.Allow the dark-brown solution that obtains be warming up to room temperature, stirred 2 hours.Reaction mixture is concentrated into about 5ml,, uses 97/3CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 28, is the deep yellow solid.
Yield: 73%
1HNMR (DMSOd 6): 1.39 (m, 9H); 3.17 (q, 2H); 3.57 (t, 2H); 6.66 (d, 1H); 6.83 (2x merges d, 4H); 6.97 (m, 2H); 7.18 (m, 3H); 7.27 (t, 1H); 7.72 (t, 1H); 7.87 (dd, 1H); 9.70 (bs, 1H).
MS-ESI：525[M+H] +
Embodiment 15
1-(1-piperidines-1-base ethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900611
Embodiment 1 embodiment 15
Stir down, to embodiment 1 (0.20g; 0.52mmol) DCM (2ml) suspension in add triphenyl phosphine (0.153g; 0.58mmol) and 1-piperidines ethanol (0.07g; 0.52mmol).Solution is cooled to-10 ℃, in 10 minutes, adds DTAD (0.13g; 0.58mmol) DCM (1ml) solution.Allow the dark-brown solution that obtains be warming up to room temperature, stirred 2 hours.Reaction mixture is concentrated into about 1.00ml,, uses 97/3CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 15 compounds, is yellow solid.
Yield: 52%
1HNMR(DMSOd 6)：1.39(m，2H)；1.47?(m，4H)；2.47(m，4H)；2.50(m，2H)；3.62(t，2H)；6.64(d，1H)；6.85(d，2H)；6.98(m，1H)；7.18(m，2H)；7.25(t，1H)；7.56-7.69(m，4H)；7.71(t，1H)；7.88(dd，1H)；9.72(bs，1H).
MS-ESI：491[M-H] -
Embodiment 16
3-[4-(2-cyano-benzene oxygen) anilino]-4-(4-hydroxy phenyl)-2,5-dioxo-2,5-dihydro-1H-gives a tongue-lashing and coughs up
Figure A20058002121900621
32 embodiment 16
Stir down, to 32 (0.50g; 1.00mmol) EtOAc-EtOH (20ml, 10: 1) solution in add PearlmanShi catalyzer (0.10g).Suspension is exposed under the 1 normal atmosphere hydrogen, kept 2.5 hours.Catalyzer is removed by diatomite filtration, filtrate is concentrated on Rotary Evaporators, residue CH 2Cl 2(30ml) grind.With solid filtering, collect, in vacuum drying oven, be dried to constant weight, obtain embodiment 16 compounds, be orange solids.
Yield: 76%
1HNMR(DMSOd 6)：6.53(d，2H)；6.63(d，1H)；6.82(m，6H)；7.22(t，1H)；7.73(t，1H)；7.81(d，1H)；9.29(bs，1H)；9.44(bs，1H)；10.34?(bs，1H).
MS-ESI：398?[M+H] +
Be prepared as follows raw material:
Stir down, to 4-hydroxybenzene ethanamide (5.00g; 33.0mmol) and bromotoluene (5.93g; 34.7mmol) DMF (30ml) solution in add solid carbonic acid potassium (3.86g; 36.3mmol).Suspension at room temperature stirred spend the night.Suspension water (100ml) is ground, with the sedimentation and filtration that obtains, collect, water (100ml) and cold diethyl ether (10ml) washing obtain 29, are white solid.
Yield: 91%
1HNMR(DMSO)3.30(s，2H)；5.09(s，2H)；6.82(bs，2H)；6.96(d，2H)；7.19(d，2H)；7.45(m，5H).
MS-ESI：242[M+H] +
Under-10 ℃, stir down, to 29 (5.70g; 23.7mmol) and oxalic acid diethyl ester (3.80g adds solid potassium tert-butoxide (2.93g in DMF 26.0mmol) (50ml) solution; 26.0mmol).To obtain orange solution and stir 30 minutes down at-10 ℃, add again solid potassium tert-butoxide (2.93g, 26.0mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (300ml), the pH of solution is reduced to 1 with concentrated hydrochloric acid.With the sedimentation and filtration that obtains, collect, water (3 * 50ml), ether (50ml) washing, be dried to constant weight, obtain 30.
Yield: 82%
1HNMR(DMSO)：5.14(s，2H)；7.09(d，2H)；7.34-7.48(m，5H)；7.97(d，2H)；10.57(bs，1H).
MS-ESI：295[M-H] -
Stir down, to 30 (4.14g; 14.0mmol) and CCl 4Add solid triphenyl phosphine (11.0g in MeCN (20ml) (200ml) suspension; 42.0mmol).With solid dissolving 1 hour, with the orange solution that obtains restir 2 hours at room temperature.Solvent is removed, and residue is used 50/50 CH through dodging the formula chromatography purification 2Cl 2/ pentane wash-out obtains 31, is yellow solid.
Yield: 70%
1HNMR(DMSO)：5.21(s，2H)；7.19(d，2H)；7.38(m，1H)；7.43(m，2H)；7.49(d，2H)；7.88(d，2H)；11.40(bs，1H).
MS-ESI：313?[M-H] -
Stir down, to 31 (1.00g; 3.20mmol) hexalin (5ml) suspension in add 2 (0.67g; 3.20mmol).With reaction mixture 120 ℃ of following heated overnight.Solution is used 99/1 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 32, is orange solids.
Yield: 48%
1HNMR(DMSOd 6)：5.04(s，2H)；6.71(d，2H)；6.81(m，5H)；6.84(d，2H)；7.19(t，1H)；7.35(m，5H)；7.61(t，1H)；7.84(dd，1H)；9.03(bs，1H)；11.05(bs，1H).
MS-ESI：488[M+H] +
Embodiment 17
3-[4-(4-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900641
34 embodiment 17
Stir down, to 3-chloro-4-phenylpyrrole-2,5-diketone (0.20g; 0.97mmol) hexalin (5ml) suspension in add 34 (0.22g; 1.06mmol).With reaction mixture 120 ℃ of following heated overnight.Solution is used 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 17 compounds, is orange solids.
Yield: 57%
1HNMR(DMSOd 6)：6.82(d，2H)；6.84(d，2H)；6.96(m，4H)；7.19(m，3H)；7.87(d，2H)；9.57(bs，1H)；10.62(bs，1H).
MS-ESI：382[M+H] +
Be prepared as follows raw material:
Figure A20058002121900642
Stir down, to 1-fluoro-4-oil of mirbane (3.93g; 27.7mmol) and 4-cyanophenol (3.00g; 25.2mmol) DMF (10ml) soup compound in add K 2CO 3(4.53g; 32.8mmol).Mixture heating up to 90 ℃ is spent the night.Suspension is cooled to room temperature, and product precipitates in water (50ml) separates out.With solid filtering,, obtain 33 with cold diethyl ether (10ml) washing.
Yield: 93%
1HNMR(DMSOd 6)：7.35(m，4H)；7.98(d，2H)；8.33(d，2H).
MS-ESI：241[M+H] +
Stir down, to 33 (5.00g; 92.9mmol) EtOAc-EtOH (55ml, 10: 1) solution in add 10% palladium on carbon (0.50g).The suspension that obtains is exposed under the 1 normal atmosphere hydrogen, kept 1.5 hours.Catalyzer is removed by filter by Celite pad,, obtain 34, be white solid the filtrate evaporation.
Yield: 74%
1HNMR(DMSOd 6)：5.13(bs，2H)；6.65(d，2H)；6.84(d，2H)；7.00(d，2H)；7.79(d，2H).
MS-ESI：211[M+H] +
Embodiment 18
3-[4-(3-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
36 embodiment 18
Stir down, to 3-chloro-4-phenylpyrrole-2,5-diketone (0.20g; 0.97mmol) hexalin (5ml) suspension in add 36 (0.22g; 1.06mmol).With reaction mixture 120 ℃ of following heated overnight.Solution is used 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 18 compounds, is orange solids.
Yield: 67%
1HNMR(DMSOd 6)：6.72(d，2H)；6.82(d，H)；6.96(m，2H)；7.22(m，5H)；7.61(m，2H)；9.54(bs，1H)；10.75(bs，1H).
MS-ESI：382[M+H] +
Be prepared as follows raw material:
Figure A20058002121900661
Feedstock production is as follows:
Stir down, to 1-fluoro-4-oil of mirbane (3.93g; 27.7mmol) and 3-cyanophenol (3.00g; 25.2mmol) DMF (10ml) soup compound in add K 2CO 3(4.53g; 32.8mmol).Mixture heating up to 90 ℃ is spent the night.Suspension is cooled to room temperature, and product precipitates in water (50ml) separates out.With solid filtering,, obtain 35 with cold diethyl ether (10ml) washing.
Yield: 96%
1HMR(DMSOd 6)：7.26(d，2H)；7.59(dd，1H)；7.71(t，1H)；7.79(m，2H)；8.31(d，2H).
MS-ESI：241[M+H] +
Stir down, to 35 (5.00g; 92.9mmol) EtOAc-EtOH (55ml, 10: 1) solution in add 10% palladium on carbon.The suspension that obtains is exposed under the 1 normal atmosphere hydrogen, kept 1.5 hours.Catalyzer is removed by filter by Celite pad, and with the filtrate evaporation, residue is used 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 36, is white solid.
Yield: 85%
1HNMR(DMSOd 6)：5.10(bs，2H)；6.81(d，2H)；6.84(d，2H)；7.21(dd，1H)；7.27(s，1H)；7.559(m，2H).
MS-ESI：211[M+H] +
Embodiment 19
1-tert-butoxycarbonyl-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900671
Embodiment 1 embodiment 19
Stir down, to embodiment 1 (1.00g; 2.62mmol) MeCN (10ml) solution in add DMAP (0.016g, 0.13mmol) and tert-Butyl dicarbonate (0.58g; 2.67mmol).Reaction mixture was at room temperature stirred 1 hour.Solution is through dodging the formula chromatography purification, with 50/50 pentane/CH 2Cl 2Wash-out obtains embodiment 19 compounds.
Yield: 67%
1HNMR(DMSOd 6)1.56(s，9H)；6.62(d，1H)；6.79(d，2H)；6.86(d，2H)；6.97(m，1H)；7.239(m，3H)；7.289(t，1H)；7.68(t，1H)；7.88(dd，1H)：9.90(bs，1H).
MS-ESI：480[M-H] -
Embodiment 20
3-[N-methyl-4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900672
37 embodiment 20
Stir down, to 37 (0.12g; 0.24mmol) DCM (10ml) solution in add TFA (10ml).The orange solution that obtains was at room temperature stirred 1 hour.With solvent evaporation, residue is used 99/1 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 20 compounds, is dark red solid.
Yield: 43%
1HNMR(DMSOd 6)3.52(s，3H)；6.53(d，1H)；6.88(d，2H)；7.12(m，4H)；7.25(m，4H)；7.65(t，1H)；7.85(dd，1H)：10.34(bs，1H).
MS-ESI：394[M-H] -
Be prepared as follows raw material:
Figure A20058002121900681
Embodiment 19 37
Under-10 ℃, stir down, to embodiment 19 (0.20g; 0.42mmol) THF (1ml) solution in add the mineral oil dispersion liquid (0.017g of 60%NaH; 0.42mmol).Add methyl-sulfate (0.064g; 0.54mmol), reaction mixture was at room temperature stirred 1 hour.Solution is used 99/1 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains 37.
Yield: 59%
1HNMR(DMSOd 6)1.52(s，9H)；3.52(s，3H)；6.48(d，1H)；6.88(d，2H)；7.11(d，2H)；7.12-7.29(m，6H)；7.71(t，1H)；7.88(dd，1H).
MS-ESI：396[M(-Boc)+H] +
Embodiment 21
3-[4-(2-cyano-benzene oxygen) anilino]-4-(3, the 4-dichlorophenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles
Figure A20058002121900691
42 embodiment 22
Stir down, to 42 (0.05g; 0.18mmol) hexalin (0.20ml) suspension in add 2 (0.04g; 0.18mmol).With reaction mixture 120 ℃ of following heated overnight.Solution is used 97/3 CH through dodging the formula chromatography purification 2Cl 2/ MeOH wash-out obtains embodiment 22 compounds, is yellow solid.
Yield: 42%
1HNMR(DMSOd 6)：6.67(d，1H)；6.87-6.95(m，5H)；7.08(s，1H)；7.2g(t，1H)；7.44(d，1H)；7.69(t，1H)；7.87(dd，1H)；9.79(bs，1H)；10.79(bs，1H).
MS-ESI：450[M+H] +
Be prepared as follows raw material:
Figure A20058002121900692
Stir down, to 3,4-dichlorophenylacetic acid (0.50g; 2.40mmol) DMF (0.50ml) suspension in add K 2CO 3(0.41g; 2.97mmol) and methyl-sulfate (0.38g; 2.97mmol).Reaction mixture was at room temperature stirred 2 hours.Add dense NH 4The OH aqueous solution (20ml) at room temperature stirs the suspension that obtains and to spend the night.With sedimentation and filtration, to collect, water (10ml) washing is dried to constant weight in vacuum drying oven, obtain 40, is white solid.
Yield: 48%
1HNMR(DMSOd 6)：3.42(s，2H)；6.98(bs，1H)；7.26(dd，1H)；7.53(bs，2H)；7.58(d，1H).
MS-ESI：202[M-H] -
Under-10 ℃, stir down, to 40 (0.15g; 0.74mmol) and oxalic acid diethyl ester (0.12g; 0.81mmol) DMF (2ml) solution in add solid potassium tert-butoxide (0.10g; 0.81mmol).The orange solution that obtains was stirred 30 minutes down at-10 ℃, add again solid potassium tert-butoxide (0.10g, 0.81mmol).Allow the suspension that obtains be warming up to room temperature, restir 30 minutes.Add entry (10ml), the pH of solution is reduced to 1 with concentrated hydrochloric acid.With the gained sedimentation and filtration, collect, water (3 * 5ml), cold diethyl ether (1ml) washing, be dried to constant weight, obtain 41.
Yield: 82%
1HNMR(DMSO)：7.58(d，1H)；8.06(d，1H)；8.30(s，1H)；10.23(bs，1H).
MS-ESI：256[M-H] -
Stir down, to 41 (0.14g; 0.56mmol) and SOCl 2(0.18g; 2.80mmol) CH 2Cl 2(2ml) add DMF (0.5ml) in the suspension.With solid dissolving 2 hours, with the yellow solution that obtains restir 2 hours at room temperature.Solvent is removed, residue is dissolved in MeOH (0.50ml).Add entry (5ml), with the sedimentation and filtration that obtains, collect, water (10ml) washing is dried to constant weight, obtains 42.
Yield: 59%
1HNMR(DMSO)：7.79(d，1H)；7.88(d，1H)；8.02(s，1H)；11.70(bs，1H).
MS-ESI：274[M-H] -

Claims (11)

1. a formula (I) compound or its salt:
Wherein:
Ar 1Be selected from phenyl, heteroaryl or heterocyclic radical;
Ar 2Be selected from phenyl or heteroaryl;
Ar 3Be selected from phenyl or monocycle hetero-aromatic ring, this monocycle hetero-aromatic ring comprises 1-3 heteroatoms that is selected from N, O or S;
R 1Be selected from hydrogen ,-C (O)-R 2,-C (O)-O-R 2,-C (O) N (R 4)-R 2With-CH 2-R 2, group N (R wherein 4)-R 2Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 2Be selected from: hydrogen, halogen, cyano group, amino, hydroxyl ,-SO 3, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyloyl oxygen base, phosphonato, C 2-6Thiazolinyl, cycloalkyl, cycloalkyl C 1-4Alkyl-, heterocyclic radical, heterocyclic radical C 1-4Alkyl-, aryl and aryl C 1-4Alkyl-, R wherein 2In alkyl or alkenyl chain or carbocylic radical, heterocyclic radical or heteroaryl ring optional by one or more R that are selected from 3Group replace;
R 3Be selected from C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkyloyl, hydroxyl, amino, formamyl ,-SO 3, phosphonato ,-C (O)-O-R 4With-N (R 4) R 5, group-N (R wherein 4) R 5Can choose wantonly and form 4 yuan of-6 yuan of heterocycles;
R 4And R 5Independently be selected from: hydrogen, C 1-4Alkyl and C (O)-R 6,
R 6For choosing wantonly by carboxyl or the amino C that replaces 1-4Alkyl;
R 7Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 8Be selected from halogen, hydroxyl, nitro, amino, cyano group, phosphonato, C 1-4Alkyl, hydroxyl C 1-4Alkyl, amino C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkyloyl, wherein amino choosing wantonly replaced by amino-acid residue, and hydroxyl is optional esterified;
R 9Be selected from: cyano group, halogen and nitro;
R 10Be selected from hydrogen or C 1-4Alkyl;
P is the integer of 0-3;
Q is the integer of 0-3;
R is the integer of 1-3.
2. the compound of claim 1, wherein Ar 1Be selected from: phenyl, pyridyl and piperidyl.
3. the compound of claim 1 or claim 2, wherein Ar 2Be selected from: phenyl and pyridyl.
4. each compound, wherein Ar in the aforementioned claim 3Be selected from: phenyl, pyridyl and pyrimidyl.
5. each compound, wherein R in the aforementioned claim 7Be amino, C 1-4Alkoxyl group, hydroxyl or phosphonato, wherein said amino is optional to be replaced by amino-acid residue, and described hydroxyl is optional esterified.
6. the compound of claim 5, wherein said amino-acid residue is independent of L-glutamic acid, Serine, Threonine, arginine, glycine, L-Ala, Beta-alanine or Methionin.
7. compound, described compound is selected from:
1) 3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles;
2) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-hydroxy phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
3) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-phosphonato phenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
4) 3-[4-(2-cyano-benzene oxygen) anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-1H-pyrroles;
5) 3-[4-(2-cyano-benzene oxygen) anilino]-4-[3-(α-Gu Anxianji amino) phenyl]-2,5-dioxo-2,5-dihydro-1H-pyrroles;
6) 1-hydroxyethyl-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles;
7) 1-(phosphonato ethyl)-3-[4-(2-cyano-benzene oxygen) anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-1H-pyrroles;
Or its salt.
8. medicinal compositions, described composition comprise among the claim 1-7 each compound.
Among the claim 1-7 each compound or its pharmacy acceptable salt in the purposes of preparation in the medicine, wherein said medicine inhibition and/or counter-rotating and/or alleviating vascular generate and/or with any disease symptoms of associated angiogenesis.
10. each compound or its pharmacy acceptable salt are in the purposes of preparation in the medicine among the claim 1-7, and wherein said medicine is used to suppress tubulin polymerization.
11. the method for preparation formula (I) compound or salt, described method (unless otherwise indicated, Ar wherein 1, Ar 2, Ar 3, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, X, Y, p, q and r definition be with claim 1) comprising:
A) make the reaction of formula (A) compound and formula (B) compound, wherein Z 1Be leavings group;
Figure A2005800212190005C1
B) for R wherein 1Be not formula (I) compound of hydrogen, make wherein R 1Formula (I) compound and formula R for hydrogen 1-Z 2Compound reaction, wherein Z 2Be leavings group;
C) make the reaction of formula (C) compound and formula (D) compound, wherein:
(i) Z 3For-Y-H, and Z 4Be leavings group; Or
(ii) Z 3Be leavings group, and Z 4Be formula H-Y-compound;
Figure A2005800212190005C2
D) for R wherein 7Group reacts the amino acid of formula (E) compound and amino acid or protection for formula (I) compound of the amino that replaced by amino-acid residue;
Figure A2005800212190005C3
E) for R wherein 7Group is formula (I) compound of phosphonato, makes the activation phosphate derivative reaction of formula (F) compound and protection;
F) for R wherein 7Group is formula (I) compound of esterified hydroxy groups, makes formula (F) compound and carboxylic acid or activated carboxylic acid derivatives reaction;
G) make the reaction of formula (G) compound and formula (H) compound, wherein:
(i) Z 5Be hydrogen, and Z 6Be leavings group; Or
(ii) Z 5Be leavings group, and Z 4Be hydrogen;
Figure A2005800212190006C2
Then, if desired:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any blocking group;
Iii) form salt.
CNA2005800212199A 2004-04-26 2005-04-22 3,4-disubstituted maleimides for use as vascular damaging agents Pending CN101027283A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04291074 2004-04-26
EP04291074.5 2004-04-26

Publications (1)

Publication Number Publication Date
CN101027283A true CN101027283A (en) 2007-08-29

Family

ID=34966765

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2005800212199A Pending CN101027283A (en) 2004-04-26 2005-04-22 3,4-disubstituted maleimides for use as vascular damaging agents

Country Status (4)

Country Link
EP (1) EP1742911A1 (en)
JP (1) JP2007534733A (en)
CN (1) CN101027283A (en)
WO (1) WO2005102997A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104010501A (en) * 2011-08-03 2014-08-27 萧崇玮 SRC homology region 2-containing protein tyrosine phosphatase-1 potentiator and therapeutic method thereof
CN110698380A (en) * 2019-10-24 2020-01-17 华东理工大学 Lactam derivative and preparation method and application thereof
CN112661690A (en) * 2020-12-24 2021-04-16 温州医科大学 Preparation method of 3-chloro-4-amino maleimide compound
CN115433115A (en) * 2022-10-17 2022-12-06 聊城大学 A kind of 3,4-disubstituted maleimide compound and its synthesis method

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5475643B2 (en) 2007-05-04 2014-04-16 マリーナ バイオテック，インコーポレイテッド Amino acid lipids and uses thereof
ITTO20110667A1 (en) * 2011-07-25 2013-01-26 Congenia Srl USE OF PHARMACEUTICAL COMPOUNDS

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1119548B1 (en) * 1998-10-08 2004-12-08 SmithKline Beecham plc 3-(3-chloro-4-hydroxyphenylamino)-4-(2-nitrophenyl)-1h-pyrrole-2,5-dione as glycogen synthase kinase-3 inhibitor (gsk-3)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104010501A (en) * 2011-08-03 2014-08-27 萧崇玮 SRC homology region 2-containing protein tyrosine phosphatase-1 potentiator and therapeutic method thereof
CN110698380A (en) * 2019-10-24 2020-01-17 华东理工大学 Lactam derivative and preparation method and application thereof
CN112661690A (en) * 2020-12-24 2021-04-16 温州医科大学 Preparation method of 3-chloro-4-amino maleimide compound
CN112661690B (en) * 2020-12-24 2022-04-19 温州医科大学 Preparation method of 3-chloro-4-amino maleimide compound
CN115433115A (en) * 2022-10-17 2022-12-06 聊城大学 A kind of 3,4-disubstituted maleimide compound and its synthesis method

Also Published As

Publication number Publication date
WO2005102997A1 (en) 2005-11-03
WO2005102997A8 (en) 2006-11-23
JP2007534733A (en) 2007-11-29
EP1742911A1 (en) 2007-01-17

Similar Documents

Publication Publication Date Title
RU2153495C2 (en) Quinazoline derivatives, method of preparation thereof, pharmaceutical composition, and a method for reaching antiproliferative effects
JP6141568B1 (en) Novel pyrazolo [3,4-d] pyrimidine compound or salt thereof
TWI221470B (en) Pyrimidine derivatives and pharmaceutical compositions containing the same
CZ265193A3 (en) Quinazoline derivatives
CN106883213A (en) A novel dual inhibitor of EGFR and ALK kinases
CN103298814A (en) 2-Anilinopurin-8-ones as TTK/MPS1 inhibitors for the treatment of proliferative diseases
CN102153543B (en) Maleate salts of a quinazoline derivative useful as an antiangiogenic agent
JPH11504031A (en) Quinazoline derivatives
CN102260263A (en) Diphenylamine purine derivatives, and preparation method and medicinal application thereof
JP6704422B2 (en) Quinazoline derivative salt and method for producing the same
JP2010533700A (en) Pyrimidine derivatives
EP2269994B1 (en) The polymorphs of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof
US7125906B2 (en) Indole derivatives having anti-angiogenetic activity
WO2018159613A1 (en) Antitumor-effect enhancer using pyrazolo[3,4-d]pyrimidine compound
CN101128456A (en) Quinazoline derivatives as tyrosine kinase inhibitors
Fan et al. Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites
CN101027283A (en) 3,4-disubstituted maleimides for use as vascular damaging agents
CN116102575B (en) Cyclic 2-aminopyrimidine compounds and uses thereof
CN111440177B (en) A kind of substituted pyrazolo[1,5-a]pyrimidine compound and its preparation method and application
CN113880814B (en) Pyrimidine amine compound and application thereof
Hu et al. Design, synthesis and pharmacological evaluation of novel 4-phenoxyquinoline derivatives as potential antitumor agents
US10745380B2 (en) Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies
Sun et al. Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor
CN118724907B (en) A macrocyclic polyamine-derived quinazoline compound and its preparation method and application
WO2012169785A9 (en) Symmetrically structured quinazoline derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20070829