WO2012143879A1 - A crystalline form of a salt of a morpholino sulfonyl indole derivative and a process for its preparation - Google Patents

A crystalline form of a salt of a morpholino sulfonyl indole derivative and a process for its preparation Download PDF

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Publication number
WO2012143879A1
WO2012143879A1 PCT/IB2012/051967 IB2012051967W WO2012143879A1 WO 2012143879 A1 WO2012143879 A1 WO 2012143879A1 IB 2012051967 W IB2012051967 W IB 2012051967W WO 2012143879 A1 WO2012143879 A1 WO 2012143879A1
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Prior art keywords
compound
cancer
crystalline form
solvent
process according
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PCT/IB2012/051967
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English (en)
French (fr)
Inventor
Suneel Manohar Babu CHENNAMSETTY
Kishor JOSHI
Yogesh CHINCHWADE
Yogesh HULAWALE
Selvam PARAMASIVAN
Meenakshi Sivakumar
Sivaramakrishnan Hariharan
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Piramal Healthcare Limited
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Application filed by Piramal Healthcare Limited filed Critical Piramal Healthcare Limited
Priority to AU2012245971A priority Critical patent/AU2012245971A1/en
Priority to CA2831730A priority patent/CA2831730A1/en
Priority to US14/112,671 priority patent/US20140045847A1/en
Priority to EP12723912.7A priority patent/EP2699568A1/en
Publication of WO2012143879A1 publication Critical patent/WO2012143879A1/en
Priority to IL228810A priority patent/IL228810A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a crystalline form of a pharmaceutically acceptable salt of a morpholino sulfonyl indole derivative (as described herein) that is capable of inhibiting, modulating and/or regulating Insulin-Like-Growth Factor I Receptor (IGF-1R) and Insulin Receptor (IR); and a process for its preparation.
  • IGF-1R Insulin-Like-Growth Factor I Receptor
  • IR Insulin Receptor
  • PKs Protein kinases
  • PTKs protein tyrosine kinases
  • STKs serine-threonine kinases
  • RTKs receptor tyrosine kinases
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor related receptor
  • IGF-1R Insulin-like Growth Factor-1 Receptor
  • IGF-1 and IGF-2 are abnormally expressed in numerous tumors, including, but not limited to, breast, prostate, thyroid, lung, hepatoma, colon, brain, neuroendocrine, and others.
  • IGF-1R small molecule inhibitors have been found to inhibit cancer growth in vitro, in vivo and in clinical trials.
  • BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epothelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines.
  • mesenchymal Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma
  • epothelial breast, lung, pancreatic, colon, gastric
  • hematopoietic multiple myeloma and leukemia
  • RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. Defects in Insulin-R and IGF-1R are indicated in type-II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman et al., DN&P, 1994, 7:334-339.
  • amorphous or non-crystalline form of a pharmaceutically acceptable salt in particular, methane sulfonate salt of the morpholino sulfonyl indole derivative, (S)-ethyl 4- (2-carbamoyl-5-chloro-3-(2-(phenoxymethyl) morpholinosulfonyl)-lH-indol-7-ylamino) piperidine-l-carboxylate, that is capable of inhibiting, modulating and/or regulating Insulin- Like-Growth Factor I Receptor and Insulin Receptor has been disclosed in the applicant's copending PCT patent application.
  • the amorphous or non-crystalline form had relatively inadequate shelf-life due to stability problems under stress conditions, which caused difficulty in reproducing its the pharmacological activity. Therefore, there was a need for developing a process for the preparation of a stable crystalline form of said derivative for overcoming the problems associated with the instability of the amorphous or non-crystalline form of the specified compound, which problems have been addressed by the applicant in the current patent application by providing a stable crystalline form of the compound, designated herein as the Compound I.
  • the present invention relates to a crystalline form of a pharmaceutically acceptable salt of a morpholino sulfonyl indole derivative, particularly, (S)-ethyl 4-(2- carbamoyl-5-chloro-3-(2-(phenoxymethyl) morpholinosulfonyl) -lH-indol-7-ylamino) piperidine-l-carboxylate methane sulfonate (herein after referred to as Compound I).
  • a pharmaceutically acceptable salt of a morpholino sulfonyl indole derivative particularly, (S)-ethyl 4-(2- carbamoyl-5-chloro-3-(2-(phenoxymethyl) morpholinosulfonyl) -lH-indol-7-ylamino) piperidine-l-carboxylate methane sulfonate (herein after referred to as Compound I).
  • the present invention relates to a process for the preparation of the crystalline form of Compound I.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of Compound I and one or more pharmaceutically acceptable excipients or carriers.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of Compound I, and a pharmaceutically acceptable carrier and optionally other therapeutic agents.
  • the present invention relates to a crystalline form of the Compound I for use in the treatment of an Insulin- Like-Growth Factor I Receptor (IGF-1R) or Insulin Receptor (IR) mediated disease or disorder by administering to a subject in need thereof, a therapeutically effective amount of the crystalline form of Compound I.
  • IGF-1R Insulin- Like-Growth Factor I Receptor
  • IR Insulin Receptor
  • the present invention relates to a crystalline form of the Compound I for use in the treatment of cancer, by administering to a subject in need thereof, a therapeutically effective amount of the crystalline form of Compound I.
  • the present invention relates to a method for the treatment of an Insulin- Like-Growth Factor I Receptor (IGF-1R) or Insulin Receptor (IR) mediated disease or disorder by administering to a subject in need thereof, a therapeutically effective amount of the crystalline form of Compound I.
  • IGF-1R Insulin- Like-Growth Factor I Receptor
  • IR Insulin Receptor
  • the present invention relates to a method of treatment of cancer by administering to a subject in need thereof, a therapeutically effective amount of the crystalline form of Compound I.
  • the present invention relates to use of the crystalline form of Compound I for the treatment of an Insulin-Like-Growth Factor I Receptor (IGF-1R) or Insulin Receptor (IR) mediated disease or disorder.
  • IGF-1R Insulin-Like-Growth Factor I Receptor
  • IR Insulin Receptor
  • the present invention relates to use of the crystalline form of Compound I for the treatment of cancer.
  • the present invention relates to use of the crystalline form of Compound I for the manufacture of a medicament for use in the treatment of an Insulin-Like- Growth Factor I Receptor (IGF-1R) or Insulin Receptor (IR) mediated disease or disorder.
  • IGF-1R Insulin-Like- Growth Factor I Receptor
  • IR Insulin Receptor
  • the present invention relates to use of the crystalline form of Compound I for the manufacture of a medicament for use in the treatment of cancer.
  • Figure 1 shows characteristic X-Ray powder diffraction spectrum (diffractogram) of the crystalline form of Compound I obtained when solvent used for crystallization is isopropyl acetate.
  • FIG. 2 shows characteristic differential scanning calorimetric (DSC) thermogram for the crystalline form of Compound I obtained when solvent used for crystallization is isopropyl acetate.
  • the present invention provides a crystalline form of a pharmaceutically acceptable salt of a morpholino sulfonyl indole derivative, particularly, (S)-ethyl 4-(2- carbamoyl-5-chloro-3-(2-(phenoxymethyl)morpholinosulfonyl)-lH-indol-7- ylamino)piperidine-l-carboxylate methane sulfonate (Compound I) and a process for its preparation.
  • a pharmaceutically acceptable salt of a morpholino sulfonyl indole derivative particularly, (S)-ethyl 4-(2- carbamoyl-5-chloro-3-(2-(phenoxymethyl)morpholinosulfonyl)-lH-indol-7- ylamino)piperidine-l-carboxylate methane sulfonate (Compound I) and a process for its preparation.
  • the crystalline form of compound I is useful in the inhibition of Insulin-Like-Growth Factor I Receptor (IGF-1R) and Insuli
  • compound I refers to, (S)-ethyl 4-(2-carbamoyl-5-chloro-3-(2-(phenoxymethyl) morpholinosulf onyl)- 1 H-indol-7-ylamino)piperidine- 1 -carboxylate methane sulfonate.
  • the free base namely (S)-ethyl 4-(2-carbamoyl-5-chloro-3-(2- (phenoxymethyl)morpholinosulfonyl)- 1 H-indol-7-ylamino)piperidine- 1 -carboxylic acid is referred to herein as the free base of compound I or compound I free base.
  • amorphous form of compound I encompasses within its scope, the amorphous form of compound I or its mixture with one or more crystalline form(s) of compound I.
  • Many pharmaceutically active compounds have been found to exist in more than one polymorphic form, such as one or more crystalline forms, an amorphous form, and/or sometimes one or more solvated forms. Frequently it is found that the different forms have different physical or chemical properties, such as solubility, hygroscopicity, etc., or have properties that render some form easier to formulate into a pharmaceutical product. In addition, certain forms can have a greater stability than the other forms, as shown by a decreased tendency to spontaneously convert into a different polymorphic form or to entrap impurity causing instability. Unfortunately, predicting the potential number, or even the existence, of polymorphs for a given molecule is not possible. However, regulatory agencies desire that the various polymorphic forms of a compound be identified before a pharmaceutical product is approved for marketing, because it is essential that a product will remain stable and have predictable properties during its entire shelf life.
  • the preparation of the amorphous form of Compound I has been described in a copending patent application of the applicant.
  • the amorphous form of Compound I ((S)-ethyl 4-(2-carbamoyl-5-chloro-3-(2-(phenoxymethyl)mo holinosulfonyl)-lH-indol-7- ylamino)piperidine-l-carboxylate methane sulfonate) was found to be unstable under stress conditions, due to its tendency to entrap methane sulfonic acid used for the salt preparation.
  • the said compound I in its amorphous form was found to have a relatively inadequate shelf life due to a slow rate of degradation caused by an entrapped acid, which caused difficulty in reproducing its pharmacological activity. Therefore, there was a need for developing a process for preparation of a stable form of the Compound I with a view to obtain reproducibility of the compound's pharmacological activity.
  • the synthesis provided in the current invention affords a crystalline form of Compound I, which is stable with reproducible pharmacological activity even under stress conditions or after elapse of long duration of time.
  • the current synthesis facilitates a large-scale or commercial synthesis by incorporating a sequence of techniques known in the art, as well as the methods set forth below, from readily available starting materials.
  • Polymorphs of compounds are generally prepared by crystallization of the compounds under different conditions.
  • the different conditions are, for example, using different commonly used solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention relates to a process for the preparation of the crystalline form of Compound I, comprising:
  • Step 1) purifying the free base of Compound I by treating a solution of said free base in a solvent selected from isopropyl acetate, THF, 2-methyl tetrahydrofuran, toluene, heptane, methylethylketone, ethyl acetate, isopropyl acetate or combinations thereof; with activated charcoal and Si-thiol (silicycle), filtering the resulting mixture through a celite bed, repeatedly washing the celite bed with the same solvent and evaporation of the filtrate; and Step 2) reacting the purified free base of compound I with methanesulfonic acid in said solvent at a temperature range of 70-80 °C for about 4-5 h to initiate crystallization of the Compound I as methane sulfonate salt, followed by cooling the resulting reaction mixture to room temperature and further to a temperature range of 0-5 °C to afford a crystalline mass, which is optionally washed with the same chilled solvent to obtain the required crystalline
  • the solvent used in step 1) and step 2) above may be selected from THF, 2-methyl tetrahydrofuran, a mixture of 2-methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate.
  • the solvent used in step 1) and step 2) above is isopropyl acetate.
  • the present invention relates to a process for the preparation of the crystalline form of Compound I, comprising crystallizing the amorphous form of the compound I( (S)-ethyl 4-(2-carbamoyl-5-chloro-3-(2-(phenoxymethyl) morpholinosulfonyl)- lH-indol-7-ylamino)piperidine-l-carboxylate methane sulfonate) with a solvent selected from isopropyl acetate, THF, 2-methyl tetrahydrofuran, toluene, heptane, methylethylketone, ethyl acetate, isopropyl acetate or combinations thereof.
  • a solvent selected from isopropyl acetate, THF, 2-methyl tetrahydrofuran, toluene, heptane, methylethylketone, ethyl acetate, isopropyl a
  • the amorphous form of the compound I is obtained by reacting the free base of Compound I with methanesulphonic acid in THF as the solvent at room temperature for about 30 min. to 2 h, according to the process for preparation of the amorphous form of compound I, as disclosed by the applicant in a copending PCT patent application.
  • the solvent used for crystallization of the amorphous form of the compound I may be selected from THF, 2-methyl tetrahydrofuran, a mixture of 2-methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate.
  • the solvent used for crystallization of the amorphous form of the compound I is isopropyl acetate.
  • the crystalline form of the Compound I of the present invention is characterized by X-Ray diffraction peaks at an angle of refraction 2-theta of 9.22, 11.92, 13.58, 15.74, 18.37, 18.65, 18.95, 19.37, 19.59, 20.33, 20.92, 22.48, 22.79, 23.97, 24.19,
  • the crystalline form of the Compound I of the present invention is characterized by the melting temperature onset of the crystalline form of Compound I was determined by differential scanning calorimetry (DSC) which is found to be 224.08 ⁇ 0.5 °C at 20 deg/min under nitrogen, with a peak melting temperature of 226.83+ 0.5 °C.
  • DSC differential scanning calorimetry
  • process for the preparation of the free base of the compound I from which the crystalline form of Compound I (as methane sulfonate salt) is prepared employs reaction steps as shown in the following scheme 1.
  • Step la Diazotising compound 1 (which is commercially available or may be prepared by methods, well-known in the art): by reacting it with NaNC> 2 and HC1 at a temperature range of -10 to 5 °C, followed by a dropwise addition of the diazotized mixture to an alkaline solution of the reagent, ethyl 2- methyl-3-oxobutanoate in a base selected from NaOEt, KOH or NaOH in a solvent selected from methanol or ethanol at a to -15 °C to obtain compound 2.
  • the step la is carried out using NaOEt as the base in ethanol as the solvent.
  • Step lb Cyclising compound 2 obtained in step la by reaction with a Lewis acid such as ZnCl 2 , AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid at a temperature range of 80 - 120 °C for 5- 12 h to obtain compound 3.
  • a Lewis acid such as ZnCl 2 , AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid
  • cyclization of the compound 2 is carried out using polyphosphoric acid in o-phosphoric acid as the Lewis acid at a temperature range of 80 - 85 °C for 2-3 h.
  • Step lc Sulphonating compound 3 obtained in step lb by reaction with sulphuric acid and acetic anhydride at a temperature range of 0-30 °C for 10-20 h to obtain compound 4.
  • Step Id Reacting compound 4 as obtained in step lc with oxalyl chloride or thionyl chloride in the presence of an organic base selected from triethylamine or pyridine in a solvent selected from DMF, methylene dichloride or a mixture thereof at a temperature range of 25 - 50 °C for 2-4 h to obtain the corre oride 4A:
  • step Id compound 4A is isolated prior to reaction with the reagent E.
  • the crude compound 5 obtained in step Id is purified with an alcohol selected from methanol, ethanol, n-propanol, isopropanol or n-butanol to obtain substantially pure compound 5.
  • the crude compound 5 obtained in step Id is purified with methanol.
  • Step le Reducing compound 5 obtained in step Id by reacting it with a reducing agent selected from Fe and NH 4 C1, Zn and HC1 or SnCk, for 2-8 h in a solvent selected from methanol, ethanol, THF, water or a mixture thereof, to obtain compound 6.
  • a reducing agent selected from Fe and NH 4 C1, Zn and HC1 or SnCk
  • step le reduction of compound 5 is carried out using Fe and NH 4 CI as the reducing agent in a mixture of THF, water and ethanol as solvent at a temperature range of 70-80 °C for 2-4 h.
  • the residual iron and iron oxides obtained during reduction using Fe and NH 4 C1 as reducing agent were removed by using EDTA and chloroform.
  • the residual iron and iron oxides obtained during reduction using Fe and NH 4 CI as reducing agent were removed by filtration.
  • the crude compound 6 obtained is purified with an alcohol selected from methanol, ethanol, n-propanol, isopropanol or n-butanol to obtain substantially pure compound 6.
  • the crude compound 6 obtained is purified with isopropanol. Step If: Reacting compound 6 obtained in step le with isopropyl alcohol and ammonia at a temperature range of 80 - 120 °C at a pressure of 0.5 - 10 kg/cm 2 for 10-18 h in an autoclave or in a microwave for 10-15 min to obtain compound 7:
  • the crude compound 7 is purified with an alcohol selected from methanol, ethanol, n-propanol, isopropanol or n-butanol to obtain substantially pure compound 7.
  • the crude compound 7 is purified with isopropanol. Step lg: Reacting compound 7 obtaine If with compound F:
  • a process for the preparation of Compound E used in step Id above comprises the following steps:
  • this present invention relates to a method of modulating the catalytic activity of PKs (protein kinases) in a subject in need thereof comprising contacting the PK with the crystalline form of compound I.
  • PKs protein kinases
  • modulation refers to the alteration of the catalytic activity of receptor tyrosine kinases (RTKs), cellular tyrosine kinases (CTKs) and serine-threonine kinases (STKs).
  • RTKs receptor tyrosine kinases
  • CTKs cellular tyrosine kinases
  • STKs serine-threonine kinases
  • modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTKs, CTKs or STKs is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
  • catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
  • contacting refers to bringing the crystalline form of compound 1 and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly; i.e., by interacting with the kinase itself, or indirectly; i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent.
  • Such “contacting” can be accomplished “in vitro,” i.e., in a test tube, a petri dish or the like.
  • contacting may involve only a compound and a PK of interest or it may involve whole cells.
  • Cells may also be maintained or grown in cell culture dishes and contacted with the compound in that environment.
  • the ability of the compound to affect a PK related disorder i.e., the IC50 of the compound, defined below, can be determined before use of the compound in vivo with more complex living organisms is attempted.
  • multiple methods exist, and are well known to those skilled in the art, to get the PKs in contact with the compound including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
  • the above -referenced PK is selected from the group comprising an RTK, a CTK or an STK in another aspect of this invention.
  • the PK is an RTK.
  • the receptor tyrosine kinase (RTK) whose catalytic activity is modulated by the crystalline form of compound I is selected from the group comprising EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR , PDGFRp, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk- 1 , Flt-1, FGFR-1R, FGFR-1R, FGFR-3R and FGFR-4R.
  • the receptor protein kinase is selected from IR, IGF-1R, or IRR.
  • the cellular tyrosine kinase whose catalytic activity is modulated by the crystalline form of compound I is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • serine-threonine protein kinase whose catalytic activity is modulated by the crystalline form of compound I is selected from the group consisting of CDK2 and Raf .
  • this invention relates to a method for treating or preventing a PK- related disorder in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of the crystalline form of compound I.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.
  • PK-related disorder As used herein, "PK-related disorder,” “PK driven disorder,” and “abnormal PK activity” all refer to a condition characterized by inappropriate (i.e., diminished or, more commonly, exessive) PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases).
  • Treating refers to alleviating or abrogating the cause and/or the effects of a PK-related disorder.
  • the terms “prevent”, “preventing” and “prevention” refer to a method for barring a mammal from acquiring a PK-related disorder in the first place.
  • administration and variants thereof (e.g., “administering” a compound) in reference to the crystalline form of compound I means introducing the compound into the system of the animal in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent (i.e. the crystalline form of Compound I) that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • the protein kinase -related disorder may be selected from the group comprising an RTK, a CTK or an STK-related disorder in a further aspect of this invention.
  • the protein kinase-related disorder is an RTK-related disorder.
  • the above referenced PK-related disorder may be selected from the group consisting of an EGFR-related disorder, a PDGFR-related disorder, an IGFR-related disorder and a flk-related disorder.
  • the above referenced PK-related disorder may be a cancer selected from, but not limited to astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colon carcinoma, colorectal cancer, chrondro sarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyona, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thymona, thyroid cancer, testicular cancer or osteosarcoma in a further aspect of this invention.
  • the PK-related disorder is a cancer selected from breast cancer, colon carcinoma, colorectal cancer, Ewing's sarcoma or rhabdosarcoma.
  • the present invention therefore relates to a crystalline form of Compound I for use in the treatment of diseases or disorders mediated by Insulin-Like-Growth Factor I Receptors (IGF -IR) or Insulin Receptors (IR) comprising administering to a subject in need thereof, a therapeutically effective amount of the crystalline form of Compound I.
  • IGF -IR Insulin-Like-Growth Factor I Receptors
  • IR Insulin Receptors
  • the present invention relates to the crystalline form of Compound I for use in the treatment of diseases or disorders mediated by Insulin-Like-Growth Factor I Receptors or Insulin Receptors, wherein the Insulin-Like-Growth Factor I Receptor and Insulin Receptor mediated disease or disorder is cancer.
  • the present invention relates to the crystalline form of Compound I for use in the treatment of cancer.
  • the present invention also encompasses a method of treating or preventing cancer in a mammal in need of such treatment which comprises administering to said mammal a therapeutically effective amount of the crystalline form of the compound I.
  • the present invention relates to a use of the crystalline form of Compound I for the manufacture of a medicament for the treatment of diseases or disorders mediated by Insulin-Like-Growth Factor I Receptor (IGF-IR) and Insulin Receptor (IR).
  • IGF-IR Insulin-Like-Growth Factor I Receptor
  • IR Insulin Receptor
  • the present invention relates to the use of the crystalline form of Compound I for the manufacture of a medicament for the treatment of diseases or disorders mediated by Insulin— Like-Growth Factor I Receptor and Insulin Receptor, wherein the Insulin-Like-Growth Factor I Receptor and Insulin Receptor mediated disease or disorder is cancer.
  • the present invention relates to the use of the crystalline form of Compound I for the manufacture of a medicament for the treatment of cancer.
  • Types of cancers which may be treated using the crystalline form of the compound I include, but are not limited to astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colon carcinoma, colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyona, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thymona, thyroid cancer, testicular cancer or osteosarcoma.
  • the cancer being treated is selected from breast cancer, colon carcinoma, colorectal cancer, Ewing
  • the above -referenced PK-related disorder may be an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hyperproliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hyperproliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • a method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of the crystalline form of the compound I is also encompassed by the present invention.
  • Methods of treating or preventing ocular diseases such as diabetic retinopathy and age- related macular degeneration, are also part of the invention.
  • Also included within the scope of the present invention is a method of treating or preventing inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions, as well as treatment or prevention of bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets.
  • inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions
  • bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets.
  • disorders which might be treated with the compound of this invention include, without limitation, immunological and cardiovascular disorders such as atherosclerosis.
  • a method of treating cancer comprises administering a therapeutically effective amount of the crystalline form of compound I in combination with radiation therapy and/or in combination with a second compound which is a therapeutically effective compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxiccytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ⁇ agonists, PPAR- ⁇ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ - secretase inhibitors, agents
  • the instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of the crystalline form of the compound I along with said second compound.
  • the PKs whose catalytic activity is modulated by the compound of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs).
  • RTK- mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization (or conformational changes in the case of IR, IGF-1R or IRR), transient stimulation of the intrinsic protein tyrosine kinase activity, autophosphorylation and subsequent phosphorylation of other substrate proteins.
  • the protein kinase (PK), the catalytic activity of which is modulated by contact with the crystalline form of the compound I is a protein tyrosine kinase (PTK), more particularly, a receptor protein tyrosine kinase (RTK).
  • PTK protein tyrosine kinase
  • RTK receptor protein tyrosine kinase
  • RTKs whose catalytic activity can be modulated with the compound of this invention, or salt thereof, are, without limitation, EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR , PDGFRp, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR- 2R, FGFR-3R and FGFR-4R.
  • the RTK is selected from IGF-1R.
  • the protein tyrosine kinase whose catalytic activity is modulated by contact with the crystalline form of the compound I can also be a non-receptor or cellular protein tyrosine kinase (CTK).
  • CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with the crystalline form of the compound I .
  • Still another group of PKs which may have their catalytic activity modulated by contact with crystalline form of the compound I are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf.
  • the present invention is directed to crystalline form of the compound I which modulates RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including, but not limited to, carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melonoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreatic cancers, colon cancers, blood cancers, breast cancers, prostrate cancers, renal cell carcinomas, lung cancer and bone cancers.
  • PK activity that the compound described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders.
  • compositions of the compound of the present invention are a further aspect of this invention.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • active ingredient refers to any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product, which substance(s) are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.
  • active ingredient refers to Compound I.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the crystalline form of the compound I, with or without pharmaceutically acceptable carriers or diluents.
  • Suitable compositions of this invention include aqueous solutions comprising the crystalline form of the compound I and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • the solutions may be introduced into a patient's bloodstream by local bolus injection.
  • the crystalline form of the compound I may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the crystalline form of the compound I can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and/or topical routes of administration.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydro xypropyl-cellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, lactose or dried cornstarch, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin, lactose or dried cornstarch
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the compound may be administered, for example, in the form of a tablet or a capsule, or as an aqueous solution or suspension.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.
  • sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p- hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form ofan oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injec tables.
  • the compound of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compound of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compound of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of the compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • FBS Fetal bovine serum (Gibco, USA);
  • Colo205 Human colon adenocarcinoma cell-line
  • MCF-7 Human breast adenocarcinoma cell-line A673 Ewing tumor cell-line
  • a cold diazonium salt solution was prepared by addition of sodium nitrite (Spectrochem, 27.9 g, 0.405 mol) to a solution of 2-nitro-4-chloro aniline (Aldrich, 50 g, 0.289 mol) in a mixture of cone. HC1 (100 mL) and water (225 mL) at -10 °C to -5 °C.
  • the diazonium salt mixture was then added into the ethanol solution of ethyl-2-methyl acetoacetate with constant stirring, maintaining the temperature below -10 °C.
  • the solid was then filtered by suction filtration to yield crude compound 2, which is washed with water (150 mL) and again filtered by suction filtration.
  • the compound is dried at 12-16 h at 45- 50 °C to afford pure compound 2.
  • the filtrate was concentrated to reduce the volume, which was chased with EtOH (Commercial grade, 54 mL), water (540 mL) was added and stirred at room temperature for 30-45 min.
  • EtOH Common grade, 54 mL
  • water 540 mL
  • the solid obtained was suction-filtered, washed with water (54 mL) and dried at 45-50 °C for 12 - 16 h to afford the title compound 6.
  • the compound 6 obtained may be optionally purified further by treatment with isopropyl alcohol (Commercial grade, 130 mL) followed by filtration and drying.
  • X-Ray diffractograms of the crystalline form of Compound I was recorded on a X-Ray difractometer, Bruker, D8 Advance, LynxEye detector, X-Ray tube with Cu target anode, slit 0.3, antiscatter slit 1°, Power 40 kV, 40 mA, Scanning speed 0.25 sec/step, 0.02 deg, Wave length: 1.5406 A
  • the X-Ray diffractograms were recorded for the crystalline form of Compound I, obtained using solvent of crystallisation selected from THF, 2-methyl tetrahydrofuran, a mixture of 2- methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate and were found to be identical, indicating that an identical crystalline form of Compound I was obtained with each of the above-mentioned solvents.
  • solvent of crystallisation selected from THF, 2-methyl tetrahydrofuran, a mixture of 2- methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate and were found to be identical, indicating that an identical crystalline
  • Table 1 indicates the main peaks of % intensity greater than 10, at an angle of refraction 2- theta of 9.22, 11.92, 13.58, 15.74, 18.37, 18.65, 18.95, 19.37, 19.59, 20.33, 20.92, 22.48, 22.79, 23.97, 24.19, 24.59, 28.48 ⁇ 0.2°, obtained for the crystalline form of Compound I, obtained using isopropyl acetate as crystallization solvent.
  • Melting point was measured by differential scanning calorimetry (DSC) using a Parkin Elmer, Diamond DSC, the temperature gradient program is 50 °C to 260 °C at a ramp of 20 °C per min and sample mass of 1-2 mg.
  • the melting points were recorded for the crystalline form of Compound I, obtained using solvent of crystallisation selected from THF, 2-methyl tetrahydrofuran, a mixture of 2- methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate, and the melting points recorded were found to be identical, indicating that an identical crystalline form of Compound I was obtained with each of the above-mentioned solvents.
  • solvent of crystallisation selected from THF, 2-methyl tetrahydrofuran, a mixture of 2- methyl tetrahydrofuran and toluene, a mixture of 2-methyl tetrahydrofuran and heptane, methylethylketone, ethyl acetate or isopropyl acetate
  • the organic layer was extracted with 10 % aqueous HCl (3.5 L) twice.
  • the combined aqueous layers were basified to pH of 9-10 with 10 % NaOH solution (Merck, 3 L) and extracted with EtOAc (Commercial grade, 5.25 + 3.5 L).
  • the combined organic layers were washed with water (3.5 L), 10 % brine (3.5 L) and dried over anhydrous Na 2 S0 4 (100 g). The solvent was removed completely by distillation below 50 °C to afford the title compound D as an oil.
  • the in vitro kinase assays using IGF-1R kinase GST fusion proteins were conducted using a homogeneous time -resolved fluorescence (HTRF) format.
  • Kinase reactions were carried out in a 384-well plate format in a final volume of 20 ⁇ .
  • the standard enzyme reaction buffer consisted of 50mM Tris HCL (pH: 7.4), 1 mM EGTA, 10 mM MgCl 2 , 2 mM DTT, 0.01 % Tween-20, IGF-1R/ IR kinase enzyme, poly GT peptide substrate (Perkin Elmer [Ulight Glu-Tyr (4:l)]n) and ATP [concentration equivalent to KmJ.
  • IGFRK enzyme used for the assay was intracellular kinase domain of human IGF-1R and expressed as GST fusion proteins using the baculovirus expression system and purified using glutathione - Sepharose column. IGFRK was used at a final concentration of 0.25 nM.
  • Cells were grown and maintained in a medium containing 10 % FBS. Cells grown as subconfluent monolayer, were subjected to serum starvation by replacing the respective culture medium with plain medium (containing no serum) and incubated for about 16 h at 37 °C in 5 % CO 2 incubator. Serum starved cells were treated with compound I at different concentrations for 1 h at 37 °C in 5 % CO 2 incubator and stimulated with IGF-1 (50 ng/mL) for the last 5 minutes of treatment with Compound I. After stimulation cells were washed twice with cold lx PBS, pH 7.2 and cell lysates were prepared using CelLytic M cell lysis reagent (Sigma) containing protease and phosphatase inhibitors.
  • the cancer cell lines were seeded in triplicate (at density, from 3000-5000 cells/well depending on cell type) with 10 % FCS in 180 of culture medium in tissue culture grade 96 well plates and allowed to recover for 24 h in humidified 5 % CO 2 incubator at 37 ⁇ 1 °C. After 24 h, media was replaced from the plate completely and 180 of fresh media containing 100 ng/mL IGF-1 without FCS was added followed with addition of 20 ⁇ of 10X crystalline form of Compound I (dissolved first in DMSO and then in cell medium, final DMSO concentration did not exceed 0.5 %) in wells.
  • Compound I in crystalline form was used at concentration range of 0.1, 1, 3 and 10 ⁇ and the plates were incubated for 72 h in humidified 5 % CO 2 incubator at 37 ⁇ 1 °C. Control wells were treated with vehicle (DMSO). At the end of the incubation periods, the plates were assayed by the CellTiter-Glo® Luminescent Cell Viability assay protocol. Percent cytoxicity was calculated at the various drug concentrations. Graph for cytotoxicity vs. concentration of Compound I was plotted, and the IC5 0 values were determined. CellTiter-Glo® Luminescent Cell Viability Assay
  • the CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.
  • the amount of ATP is directly proportional to the number of cells present in culture Protocol
  • the plate is equilibrated and its contents are maintained at room temperature for approximately 30 minutes.
  • a volume of CellTiter-Glo® Reagent was added in a volume equal to the volume of cell culture medium present in each well (e.g., 100 ⁇ ⁇ of reagent to 100 ⁇ ⁇ of medium containing cells for a 96-well plate).
  • the contents are mixed for 2 minutes on an orbital shaker to induce cell lysis.
  • the plate is allowed to incubate at room temperature for 10 minutes to stabilize the luminescent signal.
  • the luminescence is recorded using the POLARstar optima plate reader at excitation 536 nm and emission 590 nm.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218475A (zh) * 2015-10-15 2016-01-06 湖南华腾制药有限公司 1,2-吗啉盐酸盐的合成方法

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140046059A1 (en) * 2011-04-21 2014-02-13 Piramal Enterprises Limited Process for the preparation of morpholino sulfonyl indole derivatives
WO2014002007A1 (en) * 2012-06-26 2014-01-03 Piramal Enterprises Limited Method of predicting or monitoring response to igf-1r and ir inhibitors using biomarkers
CN105189484B (zh) 2012-11-29 2018-05-04 凯莫森特里克斯股份有限公司 Cxcr7拮抗剂
WO2014177915A1 (en) 2013-05-01 2014-11-06 Piramal Enterprises Limited Cancer combination therapy using imidazo[4,5-c]quinoline derivatives
CN104098498A (zh) * 2014-07-30 2014-10-15 天津市斯芬克司药物研发有限公司 一种吲唑类化合物及其制备方法
US10375382B2 (en) 2014-09-15 2019-08-06 Dmitry Gorilovsky System comprising multiple digital cameras viewing a large scene
SG11202005365WA (en) 2017-12-15 2020-07-29 Inthera Bioscience AG 1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer
US11464786B2 (en) 2018-12-12 2022-10-11 Chemocentryx, Inc. CXCR7 inhibitors for the treatment of cancer
CN113149941A (zh) * 2020-01-22 2021-07-23 中国科学院上海药物研究所 醚类化合物及其在防治糖尿病及代谢综合征中的药学用途
WO2025014774A1 (en) 2023-07-07 2025-01-16 Viridian Therapeutics, Inc. Methods of treating active and chronic thyroid eye disease

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014851A2 (en) * 2002-08-09 2004-02-19 Merck & Co., Inc. Tyrosine kinase inhibitors

Family Cites Families (308)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3126375A (en) 1964-03-24 Chioacyl
US2789118A (en) 1956-03-30 1957-04-16 American Cyanamid Co 16-alpha oxy-belta1, 4-pregnadienes
US2990401A (en) 1958-06-18 1961-06-27 American Cyanamid Co 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids
US3048581A (en) 1960-04-25 1962-08-07 Olin Mathieson Acetals and ketals of 16, 17-dihydroxy steroids
US3749712A (en) 1970-09-25 1973-07-31 Sigma Tau Ind Farmaceuti Triamcinolone acetonide esters and process for their preparation
US3996359A (en) 1972-05-19 1976-12-07 Ab Bofors Novel stereoisomeric component A of stereoisomeric mixtures of 2'-unsymmetrical 16,17-methylenedioxy steroid 21-acylates, compositions thereof, and method of treating therewith
SE378110B (en:Method) 1972-05-19 1975-08-18 Bofors Ab
SE378109B (en:Method) 1972-05-19 1975-08-18 Bofors Ab
US4319039A (en) 1979-06-15 1982-03-09 Merck & Co., Inc. Preparation of ammonium salt of hypocholesteremic fermentation product
US4231938A (en) 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
US4294926A (en) 1979-06-15 1981-10-13 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
US4444784A (en) 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
MX7065E (es) 1980-06-06 1987-04-10 Sankyo Co Un procedimiento microbiologico para preparar derivados de ml-236b
JPS5889191A (ja) 1981-11-20 1983-05-27 Sankyo Co Ltd ３−ヒドロキシ−ｍｌ−２３６ｂ誘導体の製造法
US5354772A (en) 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
US4911165A (en) 1983-01-12 1990-03-27 Ethicon, Inc. Pliabilized polypropylene surgical filaments
US4681893A (en) 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
US4885314A (en) 1987-06-29 1989-12-05 Merck & Co., Inc. Novel HMG-CoA reductase inhibitors
US4782084A (en) 1987-06-29 1988-11-01 Merck & Co., Inc. HMG-COA reductase inhibitors
US4820850A (en) 1987-07-10 1989-04-11 Merck & Co., Inc. Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
US5180589A (en) 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5030447A (en) 1988-03-31 1991-07-09 E. R. Squibb & Sons, Inc. Pharmaceutical compositions having good stability
US4916239A (en) 1988-07-19 1990-04-10 Merck & Co., Inc. Process for the lactonization of mevinic acids and analogs thereof
EP0360390A1 (en) 1988-07-25 1990-03-28 Glaxo Group Limited Spirolactam derivatives
US5118853A (en) 1988-10-13 1992-06-02 Sandoz Ltd. Processes for the synthesis of 3-disubstituted aminoacroleins
US5290946A (en) 1988-10-13 1994-03-01 Sandoz Ltd. Processes for the synthesis of 3-(substituted indolyl-2-yl)propenaldehydes
WO1990005525A1 (en) 1988-11-23 1990-05-31 Pfizer Inc. Quinuclidine derivatives as substance p antagonists
US4929437A (en) 1989-02-02 1990-05-29 Merck & Co., Inc. Coenzyme Q10 with HMG-CoA reductase inhibitors
US5164372A (en) 1989-04-28 1992-11-17 Fujisawa Pharmaceutical Company, Ltd. Peptide compounds having substance p antagonism, processes for preparation thereof and pharmaceutical composition comprising the same
US5189164A (en) 1989-05-22 1993-02-23 Sandoz Ltd. Processes for the synthesis of syn-(E)-3,5-dihydroxy-7-substituted hept-6-enoic and heptanoic acids and derivatives and intermediates thereof
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
PH27357A (en) 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
IE903957A1 (en) 1989-11-06 1991-05-08 Sanofi Sa Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present
FR2654725B1 (fr) 1989-11-23 1992-02-14 Rhone Poulenc Sante Nouveaux derives de l'isoindolone, leur preparation et les compositions pharmaceutiques qui les contiennent.
FR2654726B1 (fr) 1989-11-23 1992-02-14 Rhone Poulenc Sante Nouveaux derives de l'isoindolone et leur preparation.
GB8929070D0 (en) 1989-12-22 1990-02-28 Fujisawa Pharmaceutical Co Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same
WO1991009844A1 (en) 1990-01-04 1991-07-11 Pfizer Inc. Substance p antagonists
US5232929A (en) 1990-11-28 1993-08-03 Pfizer Inc. 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use
US5321032A (en) 1990-02-15 1994-06-14 Fujisawa Pharmaceutical Co., Ltd. Peptide compounds and pharmaceutical compositions thereof
US5420245A (en) 1990-04-18 1995-05-30 Board Of Regents, The University Of Texas Tetrapeptide-based inhibitors of farnesyl transferase
CA2084193C (en) 1990-06-01 1998-04-07 John A. Lowe, Iii 3-amino-2-aryl quinuclidines
ATE116317T1 (de) 1990-07-23 1995-01-15 Pfizer Chinuclidinderivate.
CA2089736A1 (en) 1990-09-28 1992-03-29 Manoj C. Desai Fused ring analogs of nitrogen containing nonaromatic heterocycles
GB9023116D0 (en) 1990-10-24 1990-12-05 Fujisawa Pharmaceutical Co Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same
DE69114117T2 (de) 1990-12-21 1996-03-21 Fujisawa Pharmaceutical Co Neue Verwendung von Peptidderivat.
EP0566589A1 (en) 1991-01-10 1993-10-27 Pfizer Inc. N-alkyl quinuclidinium salts as substance p antagonists
ATE154354T1 (de) 1991-02-11 1997-06-15 Merck Sharp & Dohme Azabicyclische verbindungen, diese enthaltende pharmazeutische zubereitungen und ihre therapeutische verwendung
JPH082901B2 (ja) 1991-03-01 1996-01-17 ファイザー・インコーポレーテッド １−アザビシクロ［３．２．２ノナン−３−アミン誘導体類
US5747469A (en) 1991-03-06 1998-05-05 Board Of Regents, The University Of Texas System Methods and compositions comprising DNA damaging agents and p53
WO1992017449A1 (en) 1991-03-26 1992-10-15 Pfizer Inc. Stereoselective preparation of substituted piperidines
FR2677361A1 (fr) 1991-06-04 1992-12-11 Adir Nouveaux peptides et pseudopeptides, derives de tachykinines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
FR2676053B1 (fr) 1991-05-03 1993-08-27 Sanofi Elf Nouveaux composes dialkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2676055B1 (fr) 1991-05-03 1993-09-03 Sanofi Elf Composes polycycliques amines et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2676442B1 (fr) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa Nouveau derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent.
FR2676447B1 (fr) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa Nouveaux derives du thiopyranopyrrole et leur preparation.
FR2676443B1 (fr) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa Nouveaux derives de perhydroisoindole et leur preparation.
FR2676446B1 (fr) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa Nouveaux derives du thiopyranopyrrole, leur preparation et les compositions pharmaceutiques qui les contiennent.
US5292726A (en) 1991-05-22 1994-03-08 Merck & Co., Inc. N,N-diacylpiperazines
DE9290057U1 (de) 1991-05-22 1994-01-05 Pfizer Inc., New York, N.Y. Substituierte 3-Aminochinuclidine
WO1992021677A1 (en) 1991-05-31 1992-12-10 Pfizer Inc. bibNUCLIDINE DERIVATIVES
GB9113219D0 (en) 1991-06-19 1991-08-07 Fujisawa Pharmaceutical Co Peptide compound,processes for preparation thereof and pharmaceutical composition comprising the same
PL172054B1 (pl) 1991-06-20 1997-07-31 Pfizer Sposób wytwarzania nowych pochodnych fluoroalkoksybenzyloaminowych zwiazków heterocyklicznych zawierajacych azot PL PL PL PL PL PL
TW202432B (en:Method) 1991-06-21 1993-03-21 Pfizer
US5288730A (en) 1991-06-24 1994-02-22 Merck Sharp & Dohme Limited Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
ATE133657T1 (de) 1991-07-05 1996-02-15 Merck Sharp & Dohme Aromatische verbindungen, diese enthaltende pharmazeutische zusammensetzungen und ihre therapeutische anwendung
WO1993001169A2 (en) 1991-07-05 1993-01-21 Merck Sharp & Dohme Limited Aromatic compounds, pharmaceutical compositions containing them and their use in therapy
EP0536817A1 (en) 1991-07-05 1993-04-14 MERCK SHARP & DOHME LTD. Azabicyclic compounds as tachykinin antagonists
JPH06509090A (ja) 1991-07-10 1994-10-13 メルク　シヤープ　エンド　ドーム　リミテツド 芳香族化合物、それらを含む組成物、及び治療におけるそれらの使用
WO1993001159A1 (en) 1991-07-10 1993-01-21 Merck Sharp & Dohme Limited Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy
MY110227A (en) 1991-08-12 1998-03-31 Ciba Geigy Ag 1-acylpiperindine compounds.
US5459270A (en) 1991-08-20 1995-10-17 Merck Sharp & Dohme Limited Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them
ATE195867T1 (de) 1991-09-20 2000-09-15 Glaxo Group Ltd Neue medizinische indikation für tachykinin- antagonisten
US5527808A (en) 1991-09-26 1996-06-18 Pfizer Inc. Fused tricyclic nitrogen containing heterocycles
WO1993009116A1 (en) 1991-11-07 1993-05-13 Yoshitomi Pharmaceutical Industries, Ltd. Quinuclidine compound and medicinal use thereof
EP0613458B1 (en) 1991-11-12 1998-01-07 Pfizer Inc. Acyclic ethylenediamine derivatives as substance p receptor antagonists
CA2083891A1 (en) 1991-12-03 1993-06-04 Angus Murray Macleod Heterocyclic compounds, compositions containing them and their use in therapy
HU217629B (hu) 1991-12-12 2000-03-28 Novartis Ag. Eljárás fluvasztatint tartalmazó stabilizált gyógyszerkészítmények előállítására
GB9200535D0 (en) 1992-01-10 1992-02-26 Fujisawa Pharmaceutical Co New compound
GB9201179D0 (en) 1992-01-21 1992-03-11 Glaxo Group Ltd Chemical compounds
US5328927A (en) 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
JP2656702B2 (ja) 1992-03-23 1997-09-24 ファイザー製薬株式会社 ペプチド性キヌクリジン
FR2689888B1 (fr) 1992-04-10 1994-06-10 Rhone Poulenc Rorer Sa Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent.
JPH07505648A (ja) 1992-04-15 1995-06-22 メルク　シヤープ　エンド　ドーム　リミテツド アザサイクリック化合物
GB2266529A (en) 1992-05-01 1993-11-03 Merck Sharp & Dohme Tetrahydroisoquinoline derivatives
WO1993023380A1 (en) 1992-05-18 1993-11-25 Pfizer Inc. Bridged aza-bicyclic derivatives as substance p antagonists
GB9211193D0 (en) 1992-05-27 1992-07-08 Merck Sharp & Dohme Therapeutic agents
US5719147A (en) 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
CA2099233A1 (en) 1992-06-29 1993-12-30 Conrad P. Dorn Morpholine and thiomorpholine tachykinin receptor antagonists
US5637699A (en) 1992-06-29 1997-06-10 Merck & Co., Inc. Process for preparing morpholine tachykinin receptor antagonists
US5612336A (en) 1992-07-13 1997-03-18 Merck, Sharp & Dohme Ltd. Heterocyclic amide derivatives as tachykinin antagonists
CA2140343A1 (en) 1992-07-17 1994-02-03 Sean M. Sullivan Method and reagent for treatment of animal diseases
GB2268931A (en) 1992-07-22 1994-01-26 Merck Sharp & Dohme Azabicyclic tachykinin-receptor antagonists
AU675447B2 (en) 1992-07-28 1997-02-06 Merck Sharp & Dohme Limited Carboxamidomethyl piperidine and analogues
GB2269170A (en) 1992-07-29 1994-02-02 Merck Sharp & Dohme Azatricyclic tachykinin antagonists
WO1994003429A1 (en) 1992-07-31 1994-02-17 Merck Sharp & Dohme Limited Substituted amines as tachykinin receptor antagonists
JPH07506379A (ja) 1992-08-04 1995-07-13 ファイザー・インコーポレーテッド 物質ｐ受容体アンタゴニストとしての３−ベンジルアミノ−２−フェニル−ピペリジン
GB9216911D0 (en) 1992-08-10 1992-09-23 Merck Sharp & Dohme Therapeutic agents
ATE197793T1 (de) 1992-08-13 2000-12-15 Warner Lambert Co Tachykinin antagonistes
JP2909214B2 (ja) 1992-08-19 1999-06-23 フアイザー・インコーポレイテツド 置換ベンジルアミノ窒素含有非芳香族複素環化合物
US5387595A (en) 1992-08-26 1995-02-07 Merck & Co., Inc. Alicyclic compounds as tachykinin receptor antagonists
ATE161530T1 (de) 1992-09-04 1998-01-15 Takeda Chemical Industries Ltd Kondensierte heterozyklische verbindungen, deren herstellung und verwendung
US5563161A (en) 1992-09-10 1996-10-08 Merck Sharp & Dohme Ltd. Alcohols and ethers with aromatic substituents as tachykinin-antagonists
GB9220286D0 (en) 1992-09-25 1992-11-11 Merck Sharp & Dohme Therapeutic agents
JP2656699B2 (ja) 1992-10-21 1997-09-24 ファイザー製薬株式会社 置換ベンジルアミノキヌクリジン
GB9222262D0 (en) 1992-10-23 1992-12-09 Merck Sharp & Dohme Therapeutic agents
GB9222486D0 (en) 1992-10-26 1992-12-09 Merck Sharp & Dohme Therapeutic agents
JPH08502510A (ja) 1992-10-28 1996-03-19 メルク シヤープ エンド ドーム リミテツド タキキニン拮抗剤としてのアリールメチルオキシメチルピペリジン
JP2656700B2 (ja) 1992-10-28 1997-09-24 ファイザー製薬株式会社 置換キヌクリジン誘導体
US5554627A (en) 1992-10-30 1996-09-10 Merck, Sharp & Dohme Ltd. Tachykinin antagonists
NZ254604A (en) 1992-11-12 1997-06-24 Pfizer Quinuclidine derivative and pharmaceutical compositions thereof
US5261188A (en) 1992-11-23 1993-11-16 The Standard Products Company Belt weatherstrip with bulb
JP2722279B2 (ja) 1992-12-10 1998-03-04 ファイザー・インク． アミノメチレンで置換した非芳香族複素環式化合物及びサブスタンスｐのアンタゴニストとしての使用
US5604260A (en) 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US5661162A (en) 1992-12-14 1997-08-26 Merck Sharp & Dohme Limited 4-aminomethyl/thiomethyl/sulfonylmethyl-4-phenylpiperdines as tachykinin receptor antagonists
GB9226581D0 (en) 1992-12-21 1993-02-17 Merck Sharp & Dohme Therapeutic agents
EP0604181A1 (en) 1992-12-21 1994-06-29 Eli Lilly And Company Antitumor compositions and method of treatment
GB9300051D0 (en) 1993-01-04 1993-03-03 Merck Sharp & Dohme Therapeutic agents
ES2111288T3 (es) 1993-01-15 1998-03-01 Searle & Co Nuevos 3,4-diaril tiofenos y analogos de los mismos utiles como agentes antiinflamatorios.
EP0610793A1 (en) 1993-02-08 1994-08-17 Takeda Chemical Industries, Ltd. Tetracyclic morpholine derivatives and their use or analgesics
WO1994019323A1 (en) 1993-02-18 1994-09-01 Merck Sharp & Dohme Limited Azacyclic compounds, compositions containing them and their use as tachykinin antagonists
AU6140694A (en) 1993-02-22 1994-09-14 Merck Sharp & Dohme Limited Aromatic compounds, compositions containing them and their use in therapy
WO1994019357A1 (en) 1993-02-23 1994-09-01 Merrell Dow Pharmaceuticals Inc. Farnesyl:protein transferase inhibitors as anticancer agents
US5298627A (en) 1993-03-03 1994-03-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
CA2157117C (en) 1993-03-04 1999-01-05 Manoj C. Desai Spirocyclic piperidine derivatives
US5409944A (en) 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
CA2118985A1 (en) 1993-04-02 1994-10-03 Dinesh V. Patel Heterocyclic inhibitors of farnesyl protein transferase
US5496833A (en) 1993-04-13 1996-03-05 Merck Sharp & Dohme Limited Piperidine tachykinin receptor antagonists
ATE158580T1 (de) 1993-05-06 1997-10-15 Merrell Pharma Inc Substituierte pyrrolidin-3-alkyl-piperidine verwendbar als tachykinin-antagonisten
EP0698015A1 (en) 1993-05-14 1996-02-28 Genentech, Inc. Preparation of n-cyanodithioimino-carbonates and 3-mercapto-5-amino-1h-1,2,4-triazole
US5602098A (en) 1993-05-18 1997-02-11 University Of Pittsburgh Inhibition of farnesyltransferase
IL109646A0 (en) 1993-05-19 1994-08-26 Pfizer Heteroatom substituted alkyl benzylamino-quinuclidines
US5380738A (en) 1993-05-21 1995-01-10 Monsanto Company 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents
EP0702681A1 (en) 1993-06-07 1996-03-27 Merck & Co. Inc. Spiro-substituted azacycles as neurokinin antagonists
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
US5436265A (en) 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
GB9602877D0 (en) 1996-02-13 1996-04-10 Merck Frosst Canada Inc 3,4-Diaryl-2-hydroxy-2,5- dihydrofurans as prodrugs to cox-2 inhibitors
EP0634402A1 (en) 1993-07-14 1995-01-18 Takeda Chemical Industries, Ltd. Isochinolinone derivatives, their production and use
DE69413822T2 (de) 1993-07-15 1999-02-25 Pfizer Inc., New York, N.Y. Benzyloxychinuclidine als substanz p antagonisten
TW365603B (en) 1993-07-30 1999-08-01 Rhone Poulenc Rorer Sa Novel perhydroisoindole derivatives, their preparation and pharmaceutical compositions which contain them
GB9315808D0 (en) 1993-07-30 1993-09-15 Merck Sharp & Dohme Therapeutic agents
GB9317987D0 (en) 1993-08-26 1993-10-13 Glaxo Group Ltd Chemical compounds
JP2963200B2 (ja) 1993-09-17 1999-10-12 ファイザー・インク． ヘテロアリールアミノおよびヘテロアリールスルホンアミド置換３−ベンジルアミノメチルピペリジン類および関連化合物
DK0719253T3 (da) 1993-09-17 2004-07-26 Pfizer 3-amino-5-carboxy-substituerede piperidiner og 3-amino-4-carboxy-substituerede pyrrolidiner som tachykininantagonister
IL111002A (en) 1993-09-22 1998-09-24 Glaxo Group Ltd Piperidine derivatives their preparation and pharmaceutical compositions containing them
US5728830A (en) 1993-09-22 1998-03-17 Kyowa Hakko Kogyo Co., Ltd. Farnesyltransferase inhibitor
IL111235A (en) 1993-10-15 2001-03-19 Schering Plough Corp Medicinal preparations for inhibiting protein G activity and for the treatment of malignant diseases, containing tricyclic compounds, some such new compounds and a process for the preparation of some of them
US5719148A (en) 1993-10-15 1998-02-17 Schering Corporation Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
SG43768A1 (en) 1993-10-15 1997-11-14 Schering Corp Tricyclic sulfonamide compounds useful for inhibition of g-protein function and for treatment of proliferative dieases
IL111258A0 (en) 1993-10-15 1994-12-29 Schering Corp Tricyclic carbamate compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
US5661152A (en) 1993-10-15 1997-08-26 Schering Corporation Tricyclic sulfonamide compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
US5721236A (en) 1993-10-15 1998-02-24 Schering Corporation Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
NZ275037A (en) 1993-10-25 1998-01-26 Parke Davis & Co Substituted tetra- and pentapeptide inhibitors of protein as farnesyl transferase inhibitors
WO1995011880A1 (en) 1993-10-27 1995-05-04 Merck Sharp & Dohme Limited Substituted amides as tachykinin antagonists
US5344991A (en) 1993-10-29 1994-09-06 G.D. Searle & Co. 1,2 diarylcyclopentenyl compounds for the treatment of inflammation
CA2152822A1 (en) 1993-11-04 1995-05-11 William R. Baker Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase
US5783593A (en) 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase
WO1995012612A1 (en) 1993-11-05 1995-05-11 Warner-Lambert Company Substituted di- and tripeptide inhibitors of protein:farnesyl transferase
US6403577B1 (en) 1993-11-17 2002-06-11 Eli Lilly And Company Hexamethyleneiminyl tachykinin receptor antagonists
US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
IT1271462B (it) 1993-12-03 1997-05-28 Menarini Farma Ind Antagonisti delle tachichinine,procedimento per la loro preparazione e loro impiego in formulazioni farmaceutiche.
US5484799A (en) 1993-12-09 1996-01-16 Abbott Laboratories Antifungal dorrigocin derivatives
IL111960A (en) 1993-12-17 1999-12-22 Merck & Co Inc Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them
EP0736007A4 (en) 1993-12-21 1997-03-19 Lilly Co Eli NON-PEPTIDE ANTAGONISTS OF TACHYKININ RECEPTORS
ATE177099T1 (de) 1993-12-29 1999-03-15 Pfizer Diazabicyclische neurokinin antagonisten
CA2178219C (en) 1993-12-29 2005-03-22 Raymond Baker Substituted morpholine derivatives and their use as therapeutic agents
JPH09507500A (ja) 1994-01-13 1997-07-29 メルク シヤープ エンド ドーム リミテツド ｇｅｍ二置換アザシクロ系のタキキニン拮抗薬
US5728716A (en) 1994-01-28 1998-03-17 Merck Sharp & Dohme Limited Aralkylamino substituted azacyclic therapeutic agents
US5393790A (en) 1994-02-10 1995-02-28 G.D. Searle & Co. Substituted spiro compounds for the treatment of inflammation
GB9402688D0 (en) 1994-02-11 1994-04-06 Merck Sharp & Dohme Therapeutic agents
US5610165A (en) 1994-02-17 1997-03-11 Merck & Co., Inc. N-acylpiperidine tachykinin antagonists
IL112778A0 (en) 1994-03-04 1995-05-26 Merck & Co Inc Substituted heterocycles, their preparation and pharmaceutical compositions containing them
WO1995024612A1 (de) 1994-03-07 1995-09-14 International Business Machines Corporation Verfahren und vorrichtung zur schnellen interpolation von zwischenwerten aus periodischen phasenverschobenen signalen und zur erkennung von defekten in einem drehkörper
CA2185441A1 (en) 1994-03-15 1995-09-21 Michael D. Lewis Isoprenyl transferase inhibitors
FR2718136B1 (fr) 1994-03-29 1996-06-21 Sanofi Sa Composés aromatiques aminés, procédé pour leur obtention et compositions pharmaceutiques les contenant.
AU1615895A (en) 1994-03-31 1995-10-12 Bristol-Myers Squibb Company Imidazole-containing inhibitors of farnesyl protein transferase
US5523430A (en) 1994-04-14 1996-06-04 Bristol-Myers Squibb Company Protein farnesyl transferase inhibitors
US5610145A (en) 1994-04-15 1997-03-11 Warner-Lambert Company Tachykinin antagonists
US5362718A (en) 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
IL113472A0 (en) 1994-04-29 1995-07-31 Lilly Co Eli Non-peptidyl tachykinin receptor antogonists
AU690682B2 (en) 1994-05-05 1998-04-30 Merck Sharp & Dohme Limited Morpholine derivatives and their use as antagonists of tachikinins
CZ325496A3 (en) 1994-05-07 1997-09-17 Boehringer Ingelheim Kg Amino acid derivatives, process for preparing and pharmaceutical compositions containing thereof
US5510510A (en) 1994-05-10 1996-04-23 Bristol-Meyers Squibb Company Inhibitors of farnesyl protein transferase
US5563255A (en) 1994-05-31 1996-10-08 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of raf gene expression
AU693898B2 (en) 1994-06-06 1998-07-09 Warner-Lambert Company Tachykinin (NK1) receptor antagonists
CA2192389A1 (fr) 1994-06-10 1995-12-21 Bernard Baudoin Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
EP0686629A3 (en) 1994-06-10 1999-02-10 Eli Lilly And Company Cyclohexyl tachykinine receptor antagonists
US5571792A (en) 1994-06-30 1996-11-05 Warner-Lambert Company Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase
MX9700271A (es) 1994-07-12 1997-05-31 Lilly Co Eli Antagonistas heterociclicos del receptor de taquinicina.
CA2154116A1 (en) 1994-07-22 1996-01-23 Philip Arthur Hipskind 1-aryl-2-acetamidopentanone derivatives for use as tachykinin receptor antagonists
GB9415996D0 (en) 1994-08-08 1994-09-28 Merck Sharp & Dohme Therapeutic agents
GB9415997D0 (en) 1994-08-08 1994-09-28 Merck Sharp & Dohme Therapeutic agents
TW432061B (en) 1994-08-09 2001-05-01 Pfizer Res & Dev Lactams
WO1996005529A1 (en) 1994-08-09 1996-02-22 Micron Optics, Inc. Temperature compensated fiber fabry-perot filters
CA2155448A1 (en) 1994-08-11 1996-02-12 Katerina Leftheris Inhibitors of farnesyl protein transferase
DE69514367T2 (de) 1994-08-11 2000-07-27 Banyu Pharmaceutical Co., Ltd. Substituierte amidderivate
EP0805154A1 (en) 1994-08-12 1997-11-05 Banyu Pharmaceutical Co., Ltd. N,n-disubstituted amic acid derivative
EP0777659B1 (en) 1994-08-15 2001-06-06 MERCK SHARP & DOHME LTD. Morpholine derivatives and their use as therapeutic agents
DE4429506B4 (de) 1994-08-19 2007-09-13 Degussa Gmbh Verfahren zur Extraktion natürlicher Carotinoid-Farbstoffe
DE4429653C2 (de) 1994-08-20 1997-04-03 Anton Dr More Konverter und Verfahren zum Frischen von Metallschmelzen insbesondere von Roheisen zu Stahl
JPH10504580A (ja) 1994-08-25 1998-05-06 メレルファーマスーティカルズ インコーポレイテッド アレルギー病の処置に有用な新規な置換ピペリジン類
DE69405864T2 (de) 1994-08-29 1998-03-26 Akzo Nobel Nv Verfahren zur Herstellung von quaternären Diestern
GB9417956D0 (en) 1994-09-02 1994-10-26 Merck Sharp & Dohme Therapeutic agents
GB9418545D0 (en) 1994-09-15 1994-11-02 Merck Sharp & Dohme Therapeutic agents
US5457107A (en) 1994-09-16 1995-10-10 Merck & Co., Inc. Polymorphic form of a tachykinin receptor antagonist
EP0783490B1 (en) 1994-09-30 2002-02-06 Novartis AG 1-acyl-4-aliphatic aminopiperidine compounds
TW397825B (en) 1994-10-14 2000-07-11 Novartis Ag Aroyl-piperidine derivatives
FR2725986B1 (fr) 1994-10-21 1996-11-29 Adir Nouveaux derives de piperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
DE69534213T2 (de) 1994-10-25 2006-01-12 Astrazeneca Ab Therapeutisch wirksame Heterocyclen
GB9421709D0 (en) 1994-10-27 1994-12-14 Zeneca Ltd Therapeutic compounds
EP0714891A1 (en) 1994-11-22 1996-06-05 Eli Lilly And Company Heterocyclic tachykinin receptor antagonists
JP4319251B2 (ja) 1994-11-22 2009-08-26 エヌエックスピー ビー ヴィ 半導体素子を有し導体トラックが形成されている基板が接着層により結合されている支持本体を有する半導体装置
FR2727411B1 (fr) 1994-11-30 1997-01-03 Rhone Poulenc Rorer Sa Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent
AU3971295A (en) 1994-12-09 1996-06-26 Warner-Lambert Company Substituted tetra- and pentapeptide inhibitors of protein:farnesyl transferase
IL116323A0 (en) 1994-12-13 1996-03-31 Sandoz Ag Tachykinin antagonists their preparation and pharmaceutical compositions containing them
GB9426103D0 (en) 1994-12-23 1995-02-22 Merck Sharp & Dohme Therapeutic agents
EA000164B1 (ru) 1995-01-09 1998-10-29 Магла Интернэшнл Лтд. Состав для печати изображения на поверхности изделия из каучукового латекса, способ печати изображения и изделия из каучукового латекса
ES2229259T3 (es) 1995-01-12 2005-04-16 Glaxo Group Limited Derivados de piperidina con actividad antagonista de taquiquinina.
AU4915796A (en) 1995-01-12 1996-07-31 University Of Pittsburgh Inhibitors of prenyl transferases
FR2729390A1 (fr) 1995-01-18 1996-07-19 Rhone Poulenc Rorer Sa Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2729951B1 (fr) 1995-01-30 1997-04-18 Sanofi Sa Nouveaux composes heterocycliques, procede pour leur preparation et compositions pharmaceutiques en contenant
FR2730492B1 (fr) 1995-02-09 1997-03-14 Rhone Poulenc Rorer Sa Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2730491B1 (fr) 1995-02-09 1997-03-14 Rhone Poulenc Rorer Sa Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
US5633272A (en) 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
GB9505492D0 (en) 1995-03-18 1995-05-03 Merck Sharp & Dohme Therapeutic agents
GB9505491D0 (en) 1995-03-18 1995-05-03 Merck Sharp & Dohme Therapeutic agents
US5554641A (en) 1995-03-20 1996-09-10 Horwell; David C. Nonpeptides as tachykinin antagonists
GB9505692D0 (en) 1995-03-21 1995-05-10 Glaxo Group Ltd Chemical compounds
US5700806A (en) 1995-03-24 1997-12-23 Schering Corporation Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
US5684013A (en) 1995-03-24 1997-11-04 Schering Corporation Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
EP0733632B1 (en) 1995-03-24 2003-06-04 Takeda Chemical Industries, Ltd. Cyclic compounds, their production and use as tachykinin receptor antagonists
IL117580A0 (en) 1995-03-29 1996-07-23 Merck & Co Inc Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
US5565568A (en) 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists
US5712280A (en) 1995-04-07 1998-01-27 Schering Corporation Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
IL117798A (en) 1995-04-07 2001-11-25 Schering Plough Corp Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them
DE69628559T2 (de) 1995-04-07 2004-04-29 Schering Corp. Carbonyl-piperaznyl und piperidinyl derivate zur hemmung farnesyl protein transferase
US5891872A (en) 1995-04-07 1999-04-06 Schering Corporation Tricyclic compounds
AU700693B2 (en) 1995-04-13 1999-01-14 Aventis Pharmaceuticals Inc. Novel substituted piperazine derivatives having tachykinin receptor antagonists activity
US5831115A (en) 1995-04-21 1998-11-03 Abbott Laboratories Inhibitors of squalene synthase and protein farnesyltransferase
IL118101A0 (en) 1995-05-03 1996-09-12 Abbott Lab Inhibitors of farnesyltransferase
EA000669B1 (ru) 1995-05-25 2000-02-28 Фудзисава Фармасьютикал Ко., Лтд. Производные пиперазина
US5919780A (en) 1995-06-16 1999-07-06 Warner Lambert Company Tricyclic inhibitors of protein farnesyltransferase
GB9513118D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
GB9513117D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
GB9513121D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
ATE199552T1 (de) 1995-07-07 2001-03-15 Pfizer Substituierte benzolaktamverbindungen als substanz-p-antagonisten
FR2736641B1 (fr) 1995-07-10 1997-08-22 Rhone Poulenc Rorer Sa Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
AT402617B (de) 1995-07-11 1997-07-25 Datacon Schweitzer & Zeindl Gm Anlage zum automatisierten, hermetischen anlage zum automatisierten, hermetischen verschliessen von gehäusen verschliessen von gehäusen
FR2736638B1 (fr) 1995-07-12 1997-08-22 Rhone Poulenc Rorer Sa Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
CH690163A5 (fr) 1995-07-28 2000-05-31 Symphar Sa Dérivés gem-diphosphonates substitués utiles en tant qu'agents anti-cancers.
TW340842B (en) 1995-08-24 1998-09-21 Pfizer Substituted benzylaminopiperidine compounds
US6020343A (en) 1995-10-13 2000-02-01 Merck Frosst Canada, Inc. (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
EP0858444A4 (en) 1995-10-18 1999-12-01 Merck & Co Inc CYCLOPENTYL-TACHYKININ RECEPTOR ANTAGONISTS
WO1997017070A1 (en) 1995-11-06 1997-05-15 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
DE19541283A1 (de) 1995-11-06 1997-05-07 Boehringer Ingelheim Kg Neue Aminosäurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
GB9523244D0 (en) 1995-11-14 1996-01-17 Merck Sharp & Dohme Therapeutic agents
PT1186606E (pt) 1995-11-17 2004-08-31 Biotechnolog Forschung Mbh Gbf Derivados do epotilone sua preparacao e utilizacao
EP0862435A4 (en) 1995-11-22 1999-02-03 Merck & Co Inc INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
JP2000500760A (ja) 1995-11-23 2000-01-25 メルク シヤープ エンド ドーム リミテツド スピロピペリジン誘導体およびタキキニン拮抗薬としてのその使用
GB9524157D0 (en) 1995-11-25 1996-01-24 Pfizer Ltd Therapeutic agents
HU224225B1 (hu) 1995-12-01 2005-06-28 Sankyo Co. Ltd. Tachikinin receptor antagonista hatású heterociklusos vegyületek, ezek előállítási eljárása és alkalmazásuk gyógyszerkészítmények előállítására
DK0865440T3 (da) 1995-12-08 2002-07-22 Janssen Pharmaceutica Nv Farnesylproteinfransferaseinhiberende (imidazol-5-yl)-2-quinolinonderivater
GB9525296D0 (en) 1995-12-11 1996-02-07 Merck Sharp & Dohme Therapeutic agents
DK1019392T3 (da) 1995-12-22 2006-03-20 Schering Corp Tricykliske amider anvendelige til inhibering af G-proteinfunktion og til behandling af proliferative sygdomme
WO1997026246A1 (en) 1996-01-16 1997-07-24 Warner-Lambert Company Substituted histidine inhibitors of protein farnesyltransferase
US6673927B2 (en) 1996-02-16 2004-01-06 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Farnesyl transferase inhibitors
AU715202B2 (en) 1996-04-03 2000-01-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
SI9720035B (sl) 1996-04-12 2009-10-31 Searle & Co Substituirani benzensulfonamidni derivati kot predzdravila COX-2 inhibitorjev
CZ376498A3 (cs) 1996-05-22 1999-02-17 Warner-Lambert Company Inhibitory proteinové farnesyl fransferázy
CA2260216A1 (en) 1996-07-15 1998-01-22 Bristol-Myers Squibb Company Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase
US5861419A (en) 1996-07-18 1999-01-19 Merck Frosst Canad, Inc. Substituted pyridines as selective cyclooxygenase-2 inhibitors
WO1999001124A1 (en) 1996-12-03 1999-01-14 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
EP0951285A1 (en) 1996-12-30 1999-10-27 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
CA2276081A1 (en) 1996-12-30 1998-07-09 Lekhanh O. Tran Inhibitors of farnesyl-protein transferase
CN1345334A (zh) 1999-01-29 2002-04-17 伊姆克罗尼系统公司 对kdr特异的抗体及其应用
GB9904387D0 (en) 1999-02-25 1999-04-21 Pharmacia & Upjohn Spa Antitumour synergistic composition
EP1187633A4 (en) 1999-04-08 2005-05-11 Arch Dev Corp USE OF ANTI-VEGF ANTIBODIES TO ENHANCE RADIATION IN ANTICANCER THERAPY
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
KR20050049562A (ko) 1999-10-27 2005-05-25 싸이토키네틱스, 인코포레이티드 퀴나졸리논을 사용하는 방법 및 조성물
JP4361276B2 (ja) 2001-04-10 2009-11-11 メルク エンド カムパニー インコーポレーテッド Ａｋｔ活性の阻害物質
US6960584B2 (en) 2001-04-10 2005-11-01 Merck & Co., Inc. Inhibitors of Akt activity
WO2002083140A1 (en) 2001-04-10 2002-10-24 Merck & Co., Inc. Inhibitors of akt activity
WO2002083139A1 (en) 2001-04-10 2002-10-24 Merck & Co., Inc. Inhibitors of akt activity
WO2003013526A1 (en) 2001-08-08 2003-02-20 Merck & Co. Inc. Anticoagulant compounds
US7060705B2 (en) 2001-11-07 2006-06-13 Merck & Co., Inc. Mitotic kinesin inhibitors
WO2003050064A2 (en) 2001-12-06 2003-06-19 Merck & Co., Inc. Mitotic kinesin inhibitors
CA2468266A1 (en) 2001-12-06 2003-06-19 Merck & Co., Inc. Substituted bicyclic pyrimidinones as a mitotic kinesin ksp inhibitors
DE60234278D1 (de) 2001-12-06 2009-12-17 Merck & Co Inc Mitotische kinesin-hemmer
US7244723B2 (en) 2001-12-06 2007-07-17 Merck & Co., Inc. Substituted furopyrimidinones as a mitotic kinesin inhibitors
EP1458726B1 (en) 2001-12-06 2009-07-15 Merck & Co., Inc. Mitotic kinesin inhibitors
WO2003105855A1 (en) 2002-01-11 2003-12-24 Merck & Co., Inc. Mitotic kinesin inhibitors
MXPA04007402A (es) 2002-02-01 2005-06-17 Ariad Gene Therapeutics Inc Compuestos que contienen fosforo y usos de los mismos.
EP1492487B1 (en) 2002-03-08 2009-11-11 Merck & Co., Inc. Mitotic kinesin inhibitors
AU2003223467B2 (en) 2002-04-08 2007-10-04 Merck Sharp & Dohme Corp. Inhibitors of Akt activity
EP1494676B1 (en) 2002-04-08 2013-05-08 Merck Sharp & Dohme Corp. Fused quinoxaline derivatives as inhibitors of akt activity
CA2481229C (en) 2002-04-08 2010-09-21 Merck & Co., Inc. Substituted pyrazine inhibitors of akt
JP4451136B2 (ja) 2002-04-08 2010-04-14 メルク エンド カムパニー インコーポレーテッド Ａｋｔ活性阻害薬
AU2003299517A1 (en) 2002-05-23 2004-05-25 Merck & Co., Inc. Mitotic kinesin inhibitors
EP1509507A4 (en) 2002-05-23 2006-09-13 Merck & Co Inc INHIBITORS OF MITOTIC KINESIN
ATE356804T1 (de) 2002-06-14 2007-04-15 Merck & Co Inc Inhibitoren von mitotischem kinesin
AR046639A1 (es) 2003-11-21 2005-12-14 Schering Corp Combinaciones terapeuticas de anticuerpo anti- igfr1
MX2007010972A (es) 2005-03-09 2007-09-19 Schering Corp Compuestos tieno[2,3-b]piridina y tiazolo[5,4-b]piridina para inhibir la actividad de quinesina de proteina de quinesina del huso acromatico.
EP1863571A1 (en) 2005-03-09 2007-12-12 Shering Corporation Compounds for inhibiting ksp kinesin activity
BRPI0616731A2 (pt) * 2005-09-09 2016-08-23 Analytecon Sa derivados de isoquinolina como inibidores do igf-1r
CN101258130B (zh) * 2005-09-09 2012-11-28 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉
MY149430A (en) 2005-12-13 2013-08-30 Merck Sharp & Dohme Polycyclic indazole derivatives that are erk inhibitors
KR20080103996A (ko) 2006-02-16 2008-11-28 쉐링 코포레이션 Ｅｒｋ 억제제로서 피롤리딘 유도체
CA2691417A1 (en) 2007-06-18 2008-12-24 Schering Corporation Heterocyclic compounds and use thereof as erk inhibitors
US20140046059A1 (en) * 2011-04-21 2014-02-13 Piramal Enterprises Limited Process for the preparation of morpholino sulfonyl indole derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014851A2 (en) * 2002-08-09 2004-02-19 Merck & Co., Inc. Tyrosine kinase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARBONI ET AL., MOL CANCER THER, vol. 8, no. 12, 2009
PLOWMAN ET AL., DN&P, vol. 7, 1994, pages 334 - 339

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218475A (zh) * 2015-10-15 2016-01-06 湖南华腾制药有限公司 1,2-吗啉盐酸盐的合成方法

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