EP0984692A1 - Novel angiogenesis inhibitors - Google Patents
Novel angiogenesis inhibitorsInfo
- Publication number
- EP0984692A1 EP0984692A1 EP98923719A EP98923719A EP0984692A1 EP 0984692 A1 EP0984692 A1 EP 0984692A1 EP 98923719 A EP98923719 A EP 98923719A EP 98923719 A EP98923719 A EP 98923719A EP 0984692 A1 EP0984692 A1 EP 0984692A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyrimidine
- pyrazolo
- pyridyl
- compound
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- 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
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Definitions
- the present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
- Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes.
- Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
- VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
- KDR mediates the mitogenic function of VEGF
- Flt-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
- VEGF vascular growth in the retina leads to visual degeneration culminating in blindness.
- Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p0 2 levels in mice that lead to neovascularization.
- Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor iinmunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
- VEGF vascular endothelial growth factor
- monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
- These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
- VEGF-binding construct of Flk-1 Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors.
- Embryonic stem cells which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
- KDR or Flt-1 are implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
- Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression.
- cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
- Raf-activating oncogenes e.g., K-ras, erb-B
- R j is H, C 0 alkyl, C 3 . 6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 .
- heterocyclyl or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
- R 2 &R 3 are independently H, C j _ 6 alkyl, C 5 . 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
- R 4 is H, C M0 alkyl, C3-6 cycloalkyl, C ⁇ _ 6 alkoxy C 2 . ⁇ 0 alkenyl, C 2 - ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, Cj- 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
- R 5 is H, or C ⁇ . 6 alkyl, OR, halo, NH 2 or N0 2 ;
- Ra is H, C 0 alkyl, halogen, N0 2 , OR, -NR NR 7 R 8 , R 7 R 8 ,
- R is H, or C 6 alkyl
- R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR, COOR, COO-, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
- composition which is comprised of a compound represented by the formula I:
- R l 5 R 2 , R 3 , R 4 and R 5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
- Also included is a method of treating a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
- Also included in the present invention is a method of treating diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
- a method of treating ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
- a method of treating retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
- Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology. Also included is a method of treating age-related macular degeneration.
- alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
- Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
- alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
- substituted alkyl this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1 -3 groups of R a , described herein.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non- aromatic (non-resonating) carbon-carbon double bonds may be present.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a , when a substituted alkenyl group is provided.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a , when a substituted alkynyl group is provided.
- Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
- Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
- the preferred aryl groups are phenyl and naphthyl.
- Aryl groups may likewise be substituted with 1 -3 groups of R a as defined herein.
- Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
- heterocycle, heteroaryl or heterocyclic represents a stable 5- to 7- membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a .
- heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
- alkoxy refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
- alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
- halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
- prodrug refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process.
- exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of amides of aryl acids (e.g., benzoic acid) and alkane(C ! . 6 )dioic acids.
- Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
- R ! is H, C M0 alkyl, C 3 . 6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 .
- heterocyclyl or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
- R 2 &R 3 are independently H, C N6 alkyl, C 5 . 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
- R 4 is H, C 0 alkyl, C3-6 cycloalkyl, Cj. 6 alkoxy C 2 . 10 alkenyl, C 2 - ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ - 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
- R 5 is H, or Cj_ 6 alkyl, OR, halo, NH 2 or N0 2 ;
- R a is H, C M0 alkyl, halogen, N0 2 , OR, -NR, NR 7 R 8 , R 7 R 8j
- R is H, or Cj. 6 alkyl
- R7&R8 are independently H, Cj. 10 alkyl, C3-6 cycloalkyl, COR, COOR, COO-, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
- Rj is H, C J . JO alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
- R 2 &R 3 are independently H, Cj_ 6 alkyl, C 3 - 6 cycloalkyl, OH, or halogen;
- R 4 is H, Cj.io a] ky ⁇ , C 3 - 6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, C ⁇ - 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
- Schemes 1-3 for preparing the novel compounds of this invention are presented below.
- the examples which follow the schemes illustrate the compounds that can be synthesized by Schemes 1-3, but Schemes 1-3 are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative pu ⁇ oses.
- the examples specifically illustrate the application of the following schemes to specific compounds.
- a method for the preparation of 3,6-diaryl pyrazolo(l,5-A)pyrimidines comprises mixing a commercially available malondialdehyde compound (1), with commercially available aminopyrazole (2) in an alcohol, such as ethanol, methanol, isopropanol, butanol and the like, said alcohol containing catalytic quantities of an acid, such as acetic acid, to yield (3), wherein Arl and r2, respectively, are R4 and Rl 5 as described above.
- Scheme 2 depicts a means for making 3,6-diaryl pyrazolo(l,5-A)pyrimidines when the desired aminopyrazole is not commercially available.
- compound (8) is obtained.
- Treatment of (8) with a boronic acid derivative in the presence of a palladium catalyst provides after workup the desired material (9).
- Arl and Ar2 are as described above.
- Scheme 3 illustrateates another method for the preparation of 3,7 diarylpyrazolo(l,5-A)pyrimidines.
- the commercially available ketone (15) and nitrile (18) are treated seperately with dimethylformamidedimethyl acetal (16) in refluxing toluene to give products (17) and (19) respectively.
- Compound (19) is then treated with hydrazinehydrochloride in refluxing ethanol to give the aminopyrazole (20).
- Arl and Ar2 are as described above.
- the invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier.
- pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, abso ⁇ tion, distribution, metabolism and excretion.
- Other factors, more practical in nature, which are also important in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
- a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.
- a counterion e.g., an alkali metal cation such as sodium or potassium.
- suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
- An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
- an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
- Pharmaceutically acceptable salts also include acid addition salts.
- the compound can be used in the form of salts derived from inorganic or organic acids or bases.
- examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,
- Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
- Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
- any variable e.g., aryl, heterocyle, Rl, etc
- its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated.
- the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
- the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
- the carrier employed may be, for example, either a solid or liquid.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- liquid carriers include syrup, peanut oil, olive oil, water and the like.
- the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
- Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
- Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
- Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like.
- the size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.
- Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
- Examples of injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions.
- Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
- the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
- various buffering agents, preservatives and the like can be included.
- dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
- An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
- An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
- An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
- An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
- the compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.
- Step 2 A suspension of (10) (250 mg, 0.82 mmol), thiophene-3-boronic acid (11) (158 mg, 1.24 mmol), and aqueous sodium carbonate (2 M, 1 mL) in dioxane (5 mL) was de-gassed by evacuating and backflushing with argon (3x). Tetrakis(triphenyl-phosphine) palladium (20 mg, 0.017 mmol) was added and the reaction mixture was de-gassed again. The argon filled flask was then submerged in an oil bath pre-heated to 90°C and was heated at that temperature for 16 h.
- Ethanethiol (30 mg, 36 uL) was added drop wise over 1 min to a suspension of sodium hydride (23 mg, 0.98 mmol) in dry DMF (2 mL) under argon. After 15 min, the compound of example 2 (50 mg, 0.16 mmol) was added and the reaction mixture was heated at 150°C for 1.5 h. The resulting brown solution was cooled, poured into water (25 mL) and washed with ethyl acetate (2 x 25 mL). The combined organics were dried (Na 2 S0 4 ), concentrated, and purified by flash chromatography (40%
- Step 2 A solution of 25 (2.0 g, 8.3 mmol) in dry THF (30 mL) at
- 0°C was treated with lithium aluminum hydride (1.0 M in THF, 16.5 mL, 16.5 mmol) over a 5 min period.
- the reaction mixture was warmed gradually to 15°C over 20 min and then was re- cooled to 0°C and quenched sequentially with water (630 uL), aqueous sodium hydroxide (I N, 630 uL), and then water (3 x 630 uL).
- the resulting white suspension was stirred for 15 min, dried (Na2S04), and filtered washing with THF (100 mL) and ethyl acetate (100 mL).
- VEGF receptor kinase activity is measured by inco ⁇ oration of radio-labeled phosphate into polyglutamic acid, tyrosine, 4: 1 (pEY) substrate.
- the phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radio- labeled phosphate quantified by scintillation counting.
- VEGF receptor kinase The intracellular tyrosine kinase domains of human
- KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519- 524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene.
- GST glutathione S-transferase
- Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).
- Sf21 cells were infected with recombinant virus at a multiplicity of infection of 5 virus particles/ cell and grown at
- VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
- Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
- quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF).
- the mitogenic response to VEGF or bFGF is determined by measuring the inco ⁇ oration of [ 3 H]thymidine into cellular DNA.
- HUVECs frozen as primary culture isolates are obtained from Clonetics Co ⁇ . Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages 3-7.
- EGM Endothelial Growth Medium
- NUNC #167008 NUNCLON 96-well polystyrene tissue culture plates
- IPX [ 3 HlThymidine [Methyl- 3 H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 uCi/ml in low-glucose DMEM.
- HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth- arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C0 2 .
- Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37°C/5% C0 2 for 2 hours to allow test compounds to enter cells.
- [ 3 H]Thymidine (10 ul/well) is added. 5. Three days after addition of [ 3 H]thymidine, medium is removed by aspiration, and cells are washed twice with Cell Wash Medium (400 ul/well followed by 200 ul/well). The washed, adherent cells are then solubilized by addition of Cell Lysis Solution (100 ul/well) and warming to 37°C for 30 minutes. Cell lysates are transferred to 7-ml glass scintillation vials containing 150 ul of water. Scintillation cocktail (5 ml/vial) is added, and cell-associated radioactivity is determined by liquid scintillation spectroscopy.
- the compounds of formula I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
- the instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC 50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFRl and the Src family).
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4807697P | 1997-05-30 | 1997-05-30 | |
US48076P | 1997-05-30 | ||
GBGB9800681.0A GB9800681D0 (en) | 1998-01-14 | 1998-01-14 | Novel angiogenesis inhibitors |
GB9800681 | 1998-01-14 | ||
PCT/US1998/010590 WO1998054093A1 (en) | 1997-05-30 | 1998-05-26 | Novel angiogenesis inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0984692A1 true EP0984692A1 (en) | 2000-03-15 |
EP0984692A4 EP0984692A4 (en) | 2001-02-21 |
Family
ID=26312935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98923719A Withdrawn EP0984692A4 (en) | 1997-05-30 | 1998-05-26 | Novel angiogenesis inhibitors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0984692A4 (en) |
JP (1) | JP2002501532A (en) |
AU (1) | AU734009B2 (en) |
CA (1) | CA2291709A1 (en) |
WO (1) | WO1998054093A1 (en) |
Families Citing this family (160)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002523497A (en) | 1998-08-29 | 2002-07-30 | アストラゼネカ・アクチエボラーグ | Pyrimidine compounds |
EP1107958B1 (en) | 1998-08-29 | 2006-08-16 | AstraZeneca AB | Pyrimidine compounds |
CA2341409A1 (en) * | 1998-08-31 | 2000-03-09 | Merck And Co., Inc. | Novel angiogenesis inhibitors |
GB9828511D0 (en) | 1998-12-24 | 1999-02-17 | Zeneca Ltd | Chemical compounds |
US6265403B1 (en) * | 1999-01-20 | 2001-07-24 | Merck & Co., Inc. | Angiogenesis inhibitors |
IL144745A0 (en) | 1999-02-10 | 2002-06-30 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
US6245759B1 (en) * | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
EP1188244B1 (en) * | 1999-03-26 | 2004-11-10 | Microsoft Corporation | Lossless adaptive encoding of finite alphabet data |
GB9907658D0 (en) | 1999-04-06 | 1999-05-26 | Zeneca Ltd | Chemical compounds |
GB9919778D0 (en) | 1999-08-21 | 1999-10-27 | Zeneca Ltd | Chemical compounds |
UA74803C2 (en) | 1999-11-11 | 2006-02-15 | Осі Фармасьютікалз, Інк. | A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use |
GB0004887D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004886D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004888D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0007371D0 (en) | 2000-03-28 | 2000-05-17 | Astrazeneca Uk Ltd | Chemical compounds |
US20020061897A1 (en) | 2000-03-30 | 2002-05-23 | Elliott Richard L. | Neuropeptide Y antagonists |
GB0016877D0 (en) | 2000-07-11 | 2000-08-30 | Astrazeneca Ab | Chemical compounds |
BR0113056A (en) | 2000-08-09 | 2003-07-08 | Astrazeneca Ab | Compound, process for preparation thereof, pharmaceutical composition, and method for producing an antiangiogenic and / or vascular permeability reducing effect in a warm-blooded animal, and use of a compound |
AU7652101A (en) | 2000-08-09 | 2002-02-18 | Astrazeneca Ab | Cinnoline compounds |
GB0021726D0 (en) | 2000-09-05 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
US7067520B2 (en) | 2000-11-17 | 2006-06-27 | Ishihara Sangyo Kaisha, Ltd. | Preventive or therapeutic medicines for diabetes containing fused-heterocyclic compounds or their salts |
CN1307173C (en) | 2000-12-21 | 2007-03-28 | 葛兰素集团有限公司 | Pyrimidineamines as angiogenesis modulators |
KR100830082B1 (en) | 2001-01-05 | 2008-05-20 | 화이자 인크. | Antibodies to insulin-like growth factor i receptor |
GB0103926D0 (en) | 2001-02-17 | 2001-04-04 | Astrazeneca Ab | Chemical compounds |
GB0113041D0 (en) | 2001-05-30 | 2001-07-18 | Astrazeneca Ab | Chemical compounds |
US6995171B2 (en) | 2001-06-21 | 2006-02-07 | Agouron Pharmaceuticals, Inc. | Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents |
AR039067A1 (en) | 2001-11-09 | 2005-02-09 | Pfizer Prod Inc | ANTIBODIES FOR CD40 |
US7279473B2 (en) | 2001-12-17 | 2007-10-09 | Smithkline Beecham Corporation | Pyrazolopyridazine derivatives |
PL371486A1 (en) | 2002-02-01 | 2005-06-13 | Astrazeneca Ab | Quinazoline compounds |
JP2005527511A (en) | 2002-03-01 | 2005-09-15 | ファイザー インコーポレイテッド | Indolyl-urea derivatives of thienopyridine useful as anti-angiogenic agents and methods of use thereof |
EP1490354A1 (en) | 2002-03-09 | 2004-12-29 | Astrazeneca AB | 4-imidazolyl substituted pyrimidine derivatives with cdk inhibitory activity |
GB0205690D0 (en) | 2002-03-09 | 2002-04-24 | Astrazeneca Ab | Chemical compounds |
GB0205688D0 (en) | 2002-03-09 | 2002-04-24 | Astrazeneca Ab | Chemical compounds |
GB0205693D0 (en) | 2002-03-09 | 2002-04-24 | Astrazeneca Ab | Chemical compounds |
ES2287476T3 (en) | 2002-05-10 | 2007-12-16 | Smithkline Beecham Corporation | REPLACED PIRAZOLOPIRIMIDINAS. |
US7449488B2 (en) * | 2002-06-04 | 2008-11-11 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
UA77303C2 (en) | 2002-06-14 | 2006-11-15 | Pfizer | Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use |
CZ20023575A3 (en) * | 2002-10-25 | 2004-01-14 | Léčiva, A.S. | Process for preparing N-ethyl-N-[3-(3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-acetamide (zaleplon) |
CN1747950A (en) | 2002-12-19 | 2006-03-15 | 美国辉瑞有限公司 | 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases |
EA010727B1 (en) | 2003-02-26 | 2008-10-30 | Суджен, Инк. | Aminoheteroaryl compounds as protein kinase inhibitors |
CA2516824A1 (en) | 2003-02-28 | 2004-09-10 | Teijin Pharma Limited | Pyrazolo[1,5-a]pyrimidine derivatives |
WO2004087707A1 (en) * | 2003-03-31 | 2004-10-14 | Vernalis (Cambridge) Limited | Pyrazolopyrimidine compounds and their use in medicine |
GB0311274D0 (en) | 2003-05-16 | 2003-06-18 | Astrazeneca Ab | Chemical compounds |
GB0311276D0 (en) | 2003-05-16 | 2003-06-18 | Astrazeneca Ab | Chemical compounds |
GB0314262D0 (en) | 2003-06-19 | 2003-07-23 | Univ Nottingham Trent | Novel compounds and methods of using the same |
DE602004017479D1 (en) | 2003-08-29 | 2008-12-11 | Pfizer | THIENOPYRIDINPHENYLACETAMIDES SUITED AS NEW ANTIANGIOGENIC AGENTS AND DERIVATIVES THEREOF |
AR045563A1 (en) | 2003-09-10 | 2005-11-02 | Warner Lambert Co | ANTIBODIES DIRECTED TO M-CSF |
DE10356579A1 (en) | 2003-12-04 | 2005-07-07 | Merck Patent Gmbh | amine derivatives |
JP2007515474A (en) * | 2003-12-22 | 2007-06-14 | エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド | CRF receptor antagonists and methods related thereto |
NZ547009A (en) | 2003-12-23 | 2009-09-25 | Pfizer | Novel quinoline derivatives |
GB0330002D0 (en) | 2003-12-24 | 2004-01-28 | Astrazeneca Ab | Quinazoline derivatives |
TW200528101A (en) | 2004-02-03 | 2005-09-01 | Astrazeneca Ab | Chemical compounds |
CA2578066C (en) | 2004-08-26 | 2011-10-11 | Pfizer Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
WO2006033795A2 (en) * | 2004-09-17 | 2006-03-30 | Wyeth | Substituted pyrazolo [1, 5-a] pyrimidines for inhibiting abnormal cell growth |
DK1812440T3 (en) | 2004-11-04 | 2011-01-31 | Vertex Pharma | Pyrazolo [1,5-a] pyrimidines which can be used as inhibitors of protein kinases |
EP1863848A4 (en) | 2005-03-31 | 2009-09-23 | Agensys Inc | Antibodies and related molecules that bind to 161p2f10b proteins |
EP2444419A1 (en) | 2005-04-26 | 2012-04-25 | Pfizer Inc. | P-Cadherin antibodies |
JP5161777B2 (en) | 2005-09-07 | 2013-03-13 | アムジェン フレモント インク. | Human monoclonal antibody against activin receptor-like kinase-1 |
WO2007035744A1 (en) | 2005-09-20 | 2007-03-29 | Osi Pharmaceuticals, Inc. | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
CN101277956A (en) | 2005-09-30 | 2008-10-01 | 阿斯利康(瑞典)有限公司 | Imidazo [1,2-A] pyridine having anti-cell-proliferation activity |
RU2008117298A (en) | 2005-10-06 | 2009-11-20 | Шеринг Корпорейшн (US) | Pyrazolopyrimidines as Protein Kinase Inhibitors |
UA91129C2 (en) | 2006-05-09 | 2010-06-25 | Пфайзер Продактс Инк. | Cycloalkylamino acid derivatives and pharmaceutical compositions thereof |
EP1900739A1 (en) * | 2006-08-30 | 2008-03-19 | Cellzome Ag | Diazolodiazine derivatives as kinase inhibitors |
US20100093760A1 (en) * | 2006-09-12 | 2010-04-15 | The General Hospital Corporation | Methods for identifying compounds that modulate cell signaling and methods employing such compounds |
BRPI0718029A2 (en) * | 2006-11-06 | 2013-11-26 | Supergen Inc | IMIDAZO (1,2-B) PYRIDAZINE AND PIRAZOLE (1,5-A) PYRIMIDINE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS |
US8131527B1 (en) | 2006-12-22 | 2012-03-06 | Astex Therapeutics Ltd. | FGFR pharmacophore compounds |
WO2008078091A1 (en) | 2006-12-22 | 2008-07-03 | Astex Therapeutics Limited | Bicyclic heterocyclic compounds as fgfr inhibitors |
AU2007337895C1 (en) | 2006-12-22 | 2014-07-31 | Astex Therapeutics Limited | Tricyclic amine derivatives as protein tyrosine kinase inhibitors |
CA2693915A1 (en) | 2007-07-20 | 2009-01-29 | Merck & Co., Inc. | Pyrazolo[1,5-a]pyrimidine derivatives |
WO2009033094A2 (en) | 2007-09-07 | 2009-03-12 | Agensys, Inc. | Antibodies and related molecules that bind to 24p4c12 proteins |
EP2206714B1 (en) * | 2007-09-28 | 2015-01-21 | Kyowa Hakko Kirin Co., Ltd. | Agent for prevention and/or treatment of skin diseases |
GB0720041D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New Compounds |
GB0720038D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New compounds |
WO2009077334A1 (en) * | 2007-12-14 | 2009-06-25 | F. Hoffmann-La Roche Ag | Novel imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives |
WO2009085913A1 (en) | 2007-12-19 | 2009-07-09 | Vertex Pharmaceuticals Incorporated | PYRAZOLO [1,5-a] PYRIMIDINES USEFUL AS JAK2 INHIBITORS |
CA2718403A1 (en) * | 2008-03-13 | 2009-09-17 | The General Hospital Corporation | Inhibitors of the bmp signaling pathway |
GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
CA2737597C (en) | 2008-10-16 | 2017-03-14 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Fully human antibodies to high molecular weight-melanoma associated antigen and uses thereof |
CN102307875A (en) | 2009-02-09 | 2012-01-04 | 苏伯俭股份有限公司 | Pyrrolopyrimidinyl axl kinase inhibitors |
US20120189641A1 (en) | 2009-02-25 | 2012-07-26 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
JP2012519170A (en) | 2009-02-26 | 2012-08-23 | オーエスアイ・ファーマシューティカルズ,エルエルシー | INSITU method for monitoring EMT status of tumor cells in vivo |
WO2010099138A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
WO2010099363A1 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
US8465912B2 (en) | 2009-02-27 | 2013-06-18 | OSI Pharmaceuticals, LLC | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
TW201035088A (en) | 2009-02-27 | 2010-10-01 | Supergen Inc | Cyclopentathiophene/cyclohexathiophene DNA methyltransferase inhibitors |
GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
GB0906470D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
CA2766403A1 (en) | 2009-07-13 | 2011-01-20 | Genentech, Inc. | Diagnostic methods and compositions for treatment of cancer |
JP2013500991A (en) | 2009-07-31 | 2013-01-10 | オーエスアイ・ファーマシューティカルズ,エルエルシー | mTOR inhibitor and angiogenesis inhibitor combination therapy |
US20120157471A1 (en) | 2009-09-01 | 2012-06-21 | Pfizer Inc. | Benzimidazole derivatives |
EP2475996A1 (en) | 2009-09-11 | 2012-07-18 | F. Hoffmann-La Roche AG | Method to identify a patient with an increased likelihood of responding to an anti-cancer agent |
AU2010297344A1 (en) | 2009-09-17 | 2012-02-23 | F. Hoffmann-La Roche Ag | Methods and compositions for diagnostics use in cancer patients |
WO2011073521A1 (en) | 2009-12-15 | 2011-06-23 | Petri Salven | Methods for enriching adult-derived endothelial progenitor cells and uses thereof |
ES2607806T3 (en) | 2010-02-12 | 2017-04-04 | Pfizer Inc | Salts and polymorphs of 8-fluoro-2- {4 - [(methylamino} methyl] phenyl} -1,3,4,5-tetrahydro-6H-azepino [5,4,3-cd] indole-6-one |
US20110275644A1 (en) | 2010-03-03 | 2011-11-10 | Buck Elizabeth A | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
EP2542893A2 (en) | 2010-03-03 | 2013-01-09 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
CN102791712B (en) | 2010-03-05 | 2015-07-01 | 协和发酵麒麟株式会社 | Pyrazolopyrimidine derivative |
WO2011153224A2 (en) | 2010-06-02 | 2011-12-08 | Genentech, Inc. | Diagnostic methods and compositions for treatment of cancer |
CA2802857C (en) | 2010-06-16 | 2018-09-11 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Antibodies to endoplasmin and their use |
EP2848940A1 (en) | 2010-07-19 | 2015-03-18 | F. Hoffmann-La Roche AG | Method to identify a patient with an increased likelihood of responding to an anti-cancer therapy |
MX2013000676A (en) | 2010-07-19 | 2013-02-27 | Hoffmann La Roche | Method to identify a patient with an increased likelihood of responding to an anti-cancer therapy. |
WO2012012750A1 (en) | 2010-07-23 | 2012-01-26 | Trustees Of Boston University | ANTI-DEsupR INHIBITORS AS THERAPEUTICS FOR INHIBITION OF PATHOLOGICAL ANGIOGENESIS AND TUMOR CELL INVASIVENESS AND FOR MOLECULAR IMAGING AND TARGETED DELIVERY |
EP2621928A1 (en) | 2010-09-27 | 2013-08-07 | Proximagen Limited | 7-hydroxy-pyrazolo[1,5-a]pyrimidine compounds and their use as ccr2 receptor antagonists |
WO2012042421A1 (en) | 2010-09-29 | 2012-04-05 | Pfizer Inc. | Method of treating abnormal cell growth |
JP5802756B2 (en) | 2010-10-20 | 2015-11-04 | ファイザー・インク | Pyridine-2-derivatives as smoothened receptor modulators |
WO2012116040A1 (en) | 2011-02-22 | 2012-08-30 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma |
US8748435B2 (en) | 2011-04-01 | 2014-06-10 | Novartis Ag | Pyrazolo pyrimidine derivatives |
US9150644B2 (en) | 2011-04-12 | 2015-10-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies that bind insulin-like growth factor (IGF) I and II |
ES2724801T3 (en) | 2011-04-19 | 2019-09-16 | Pfizer | Combinations of anti-4-1BB antibodies and ADCC inducing antibodies for cancer treatment |
WO2012149014A1 (en) | 2011-04-25 | 2012-11-01 | OSI Pharmaceuticals, LLC | Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment |
JP2014517079A (en) | 2011-06-22 | 2014-07-17 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compounds useful as ATR kinase inhibitors |
EP3812387A1 (en) | 2011-07-21 | 2021-04-28 | Sumitomo Dainippon Pharma Oncology, Inc. | Heterocyclic protein kinase inhibitors |
EP2781216A4 (en) | 2011-09-02 | 2015-05-27 | Kyowa Hakko Kirin Co Ltd | Chemokine receptor activity regulator |
CN103814030A (en) | 2011-09-22 | 2014-05-21 | 辉瑞大药厂 | Pyrrolopyrimidine and purine derivatives |
AU2011378675B2 (en) | 2011-10-04 | 2017-10-05 | Epsilogen Ltd | IgE anti -HMW-MAA antibody |
AU2012335247A1 (en) | 2011-11-08 | 2014-05-29 | Pfizer Inc. | Methods of treating inflammatory disorders using anti-M-CSF antibodies |
WO2013152252A1 (en) | 2012-04-06 | 2013-10-10 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
JP6243918B2 (en) | 2012-10-16 | 2017-12-06 | トレロ ファーマシューティカルズ, インコーポレイテッド | PKM2 modulators and methods for their use |
CN107629059B (en) | 2012-12-07 | 2020-07-28 | 沃泰克斯药物股份有限公司 | Compounds useful as inhibitors of ATR kinase |
US9260426B2 (en) | 2012-12-14 | 2016-02-16 | Arrien Pharmaceuticals Llc | Substituted 1H-pyrrolo [2, 3-b] pyridine and 1H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors |
CA2905993C (en) | 2013-03-14 | 2022-12-06 | Tolero Pharmaceuticals, Inc. | Substituted 4-amino-pyrimidinyl-2-amino-phenyl derivatives and pharmaceutical compositions thereof for use as jak2 and alk2 inhibitors |
JP6542192B2 (en) * | 2013-03-14 | 2019-07-10 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドThe Brigham and Women’s Hospital, Inc. | BMP inhibitors and methods of use thereof |
EP2970288A1 (en) | 2013-03-15 | 2016-01-20 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
EP2970289A1 (en) | 2013-03-15 | 2016-01-20 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
US9663519B2 (en) | 2013-03-15 | 2017-05-30 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
US9206188B2 (en) | 2013-04-18 | 2015-12-08 | Arrien Pharmaceuticals Llc | Substituted pyrrolo[2,3-b]pyridines as ITK and JAK inhibitors |
KR20160058960A (en) | 2013-10-04 | 2016-05-25 | 압토스 바이오사이언시스 인코포레이티드 | Compositions and methods for treating cancers |
UA115388C2 (en) | 2013-11-21 | 2017-10-25 | Пфайзер Інк. | 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders |
WO2015085132A1 (en) | 2013-12-06 | 2015-06-11 | Vertex Pharmaceuticals Incorporated | 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof |
EP3126528B1 (en) | 2014-04-04 | 2021-08-18 | Crown Bioscience, Inc. (Taicang) | Methods for determining responsiveness to mek/erk inhibitors |
WO2015155624A1 (en) | 2014-04-10 | 2015-10-15 | Pfizer Inc. | Dihydropyrrolopyrimidine derivatives |
NZ725496A (en) | 2014-04-30 | 2019-11-29 | Pfizer | Cycloalkyl-linked diheterocycle derivatives |
LT3152212T (en) | 2014-06-05 | 2020-05-11 | Vertex Pharmaceuticals Inc. | Radiolabelled derivatives of a 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]- pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof |
HUE044280T2 (en) | 2014-06-17 | 2019-10-28 | Vertex Pharma | Method for treating cancer using a combination of chk1 and atr inhibitors |
WO2016001789A1 (en) | 2014-06-30 | 2016-01-07 | Pfizer Inc. | Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer |
US10513521B2 (en) | 2014-07-15 | 2019-12-24 | The Brigham And Women's Hospital, Inc. | Compositions and methods for inhibiting BMP |
EP3177320B1 (en) | 2014-07-31 | 2021-01-06 | The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services | Human monoclonal antibodies against epha4 and their use |
WO2016097918A1 (en) | 2014-12-18 | 2016-06-23 | Pfizer Inc. | Pyrimidine and triazine derivatives and their use as axl inhibitors |
EP3611506B1 (en) | 2015-04-20 | 2021-11-17 | Sumitomo Dainippon Pharma Oncology, Inc. | Predicting response to alvocidib by mitochondrial profiling |
WO2016178876A2 (en) | 2015-05-01 | 2016-11-10 | Cocrystal Pharma, Inc. | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
CA2985804A1 (en) | 2015-05-18 | 2016-11-24 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs having increased bioavailability |
WO2017009751A1 (en) | 2015-07-15 | 2017-01-19 | Pfizer Inc. | Pyrimidine derivatives |
US10568887B2 (en) | 2015-08-03 | 2020-02-25 | Tolero Pharmaceuticals, Inc. | Combination therapies for treatment of cancer |
EP3355926A4 (en) | 2015-09-30 | 2019-08-21 | Vertex Pharmaceuticals Inc. | Method for treating cancer using a combination of dna damaging agents and atr inhibitors |
US20180371551A1 (en) | 2015-12-03 | 2018-12-27 | Agios Pharmaceuticals, Inc. | Mat2a inhibitors for treating mtap null cancer |
CN106632260B (en) * | 2016-09-29 | 2019-04-26 | 上海天慈生物谷生物工程有限公司 | A kind of preparation method of small molecule kinase inhibitors |
WO2018094275A1 (en) | 2016-11-18 | 2018-05-24 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
CA3047557A1 (en) | 2016-12-19 | 2018-06-28 | Tolero Pharmaceuticals, Inc. | Profiling peptides and methods for sensitivity profiling |
US11497756B2 (en) | 2017-09-12 | 2022-11-15 | Sumitomo Pharma Oncology, Inc. | Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib |
WO2019075367A1 (en) | 2017-10-13 | 2019-04-18 | Tolero Pharmaceuticals, Inc. | Pkm2 activators in combination with reactive oxygen species for treatment of cancer |
CN112512597A (en) | 2018-07-26 | 2021-03-16 | 大日本住友制药肿瘤公司 | Methods for treating diseases associated with aberrant ACVR1 expression and ACVR1 inhibitors useful therefor |
AU2019391097A1 (en) | 2018-12-04 | 2021-05-20 | Sumitomo Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
KR20210146290A (en) | 2019-02-12 | 2021-12-03 | 스미토모 다이니폰 파마 온콜로지, 인크. | Formulations comprising heterocyclic protein kinase inhibitors |
JP2022525149A (en) | 2019-03-20 | 2022-05-11 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | Treatment of Acute Myeloid Leukemia (AML) with Venetoclax Failure |
US11712433B2 (en) | 2019-03-22 | 2023-08-01 | Sumitomo Pharma Oncology, Inc. | Compositions comprising PKM2 modulators and methods of treatment using the same |
US20220315581A1 (en) * | 2019-06-14 | 2022-10-06 | Medshine Discovery Inc. | Fused ring compound as fgfr and vegfr dual inhibitor |
WO2021155006A1 (en) | 2020-01-31 | 2021-08-05 | Les Laboratoires Servier Sas | Inhibitors of cyclin-dependent kinases and uses thereof |
GR1010096B (en) * | 2020-07-02 | 2021-10-08 | Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε, | Pyrazolo[1,5-a]pyrimidines as autotaxin inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997029109A1 (en) * | 1996-02-07 | 1997-08-14 | Janssen Pharmaceutica N.V. | Pyrazolopyrimidines as crf receptor antagonists |
EP0795555A1 (en) * | 1995-09-28 | 1997-09-17 | Otsuka Pharmaceutical Factory, Inc. | Analgesics |
-
1998
- 1998-05-26 AU AU75944/98A patent/AU734009B2/en not_active Ceased
- 1998-05-26 WO PCT/US1998/010590 patent/WO1998054093A1/en not_active Application Discontinuation
- 1998-05-26 EP EP98923719A patent/EP0984692A4/en not_active Withdrawn
- 1998-05-26 JP JP50079099A patent/JP2002501532A/en active Pending
- 1998-05-26 CA CA002291709A patent/CA2291709A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0795555A1 (en) * | 1995-09-28 | 1997-09-17 | Otsuka Pharmaceutical Factory, Inc. | Analgesics |
WO1997029109A1 (en) * | 1996-02-07 | 1997-08-14 | Janssen Pharmaceutica N.V. | Pyrazolopyrimidines as crf receptor antagonists |
Non-Patent Citations (2)
Title |
---|
KIRKPATRICK W E ET AL: "3-HALO-5,7-DIMETHYLPYRAZOLO U1,5-APYRIMIDINES, A NONBENZODIAZEPINOID CLASS OF ANTIANXIETY AGENTS DEVOID OF POTENTIATION OF CENTRAL NERVOUS SYSTEM DEPRESSANT EFFECTS OF ETHANOL OR BARBITURATES" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 20, no. 3, 1 March 1977 (1977-03-01), pages 386-393, XP000670076 ISSN: 0022-2623 * |
See also references of WO9854093A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU7594498A (en) | 1998-12-30 |
WO1998054093A1 (en) | 1998-12-03 |
EP0984692A4 (en) | 2001-02-21 |
JP2002501532A (en) | 2002-01-15 |
CA2291709A1 (en) | 1998-12-03 |
AU734009B2 (en) | 2001-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6235741B1 (en) | Angiogenesis inhibitors | |
EP0984692A1 (en) | Novel angiogenesis inhibitors | |
AU760020B2 (en) | Novel angiogenesis inhibitors | |
US6465484B1 (en) | Angiogenesis inhibitors | |
AU744939B2 (en) | Novel angiogenesis inhibitors | |
US6162804A (en) | Tyrosine kinase inhibitors | |
AU747427B2 (en) | Novel angiogenesis inhibitors | |
US6265403B1 (en) | Angiogenesis inhibitors | |
EP2170823B1 (en) | N-(2-(hetaryl)aryl)arylsulfonamides and n-(2-(hetaryl)hetaryl)arylsulfonamides | |
US6380203B1 (en) | Angiogenesis inhibitors | |
JP2009536617A (en) | Thiazoles, imidazoles, and pyrazoles useful as inhibitors of protein kinases | |
US20140221336A1 (en) | Compounds useful as inhibitors of janus kinases | |
JP2002534385A (en) | New compound | |
JP2010510216A (en) | Compounds useful as inhibitors of protein kinases | |
JP2002544272A (en) | Substituted 3-pyridyl-4-arylpyrroles and related treatments and prophylaxis | |
US6228871B1 (en) | Angiogenesis inhibitors | |
WO2004089930A1 (en) | 4-fluoroquinolone derivatives and their use as kinase inhibitors | |
US20230312583A1 (en) | 1h-imidazo [4,5-h] quinazoline compound as novel selective flt3 inhibitors | |
KR20240028959A (en) | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same | |
MXPA03010535A (en) | Inhibitors of src and other protein kinases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19991230 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20010108 |
|
AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7A 01N 43/54 A, 7C 07D 487/04 B, 7A 61K 31/305 B, 7C 07D 487/04 J, 7C 07D 239:00 J, 7C 07D 231:00 J |
|
17Q | First examination report despatched |
Effective date: 20021022 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20040224 |