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WO2005081997A2 - Inhibiteurs des proteine kinases a base d'isothiazole - Google Patents

Inhibiteurs des proteine kinases a base d'isothiazole Download PDF

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Publication number
WO2005081997A2
WO2005081997A2 PCT/US2005/005859 US2005005859W WO2005081997A2 WO 2005081997 A2 WO2005081997 A2 WO 2005081997A2 US 2005005859 W US2005005859 W US 2005005859W WO 2005081997 A2 WO2005081997 A2 WO 2005081997A2
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compound
tautomer
prodrug
salt
cla
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PCT/US2005/005859
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English (en)
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WO2005081997A3 (fr
Inventor
Congxin Liang
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Scripps Research Institute
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Scripps Research Institute
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Publication of WO2005081997A2 publication Critical patent/WO2005081997A2/fr
Publication of WO2005081997A3 publication Critical patent/WO2005081997A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to isothiazole based compounds and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins.
  • Many aspects of cell life for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities.
  • abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors.
  • Isothiazole based derivatives having activity as protein kinase inhibitors have been disclosed in Intemational Patent Application WO 09962890 and in US Patent No. 6235764. What is needed is a class of modified isothiazole based derivatives having both activity as protein kinase inhibitors and enhanced drug properties.
  • the invention is directed to hydroxy containing isothiazole derivatives and to their use as inhibitors of protein kinases. It is disclosed herein that hydroxy containing isothiazole derivatives have enhanced and unexpected drug properties that advantageously distinguish this class of compounds over known isothiazole derivatives having protein kinase inhibition activity. It is also disclosed herein that hydroxy containing isothiazole derivatives are useful in treating disorders related to abnormal protein kinase activities such as cancer.
  • hydroxy compounds may have advantageous and unexpected properties that distinguish them from known compounds. They are therefore useful in treating disorders related to abnormal protein kinase activities such as cancer.
  • One aspect of the invention is directed to a compound represented by Formula (I):
  • X is O or S;
  • R 1 is selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C6-C10) arylalkyl, (C5-C9) heteroarylalkyl, substituted (C6-C10) arylalkyl, and substituted (C5-C9) heteroarylalkyl;
  • R 2 and R 3 are independently hydrogen or (C1-C6) alkyl;
  • R 4 is selected from the group consisting of hydrogen, (C1-C6) alkyl, and hydroxyl;
  • n and m are independently 0, 1 , 2, or 3;
  • p is independently 1 , 2, or 3;
  • R 5 is selected from the group consisting of hydroxyl, (C1- C6) alkoxy, (C3-C8) cycloalkoxy, substituted or unsubstituted O-(C6-C10) aryl, and NR 6 R 7 ;
  • R 6 and R 7
  • a compound of Formula (I) where R 5 is OH may exist in its open-acid form or its cyclic-lactone form or the two forms may co-exist in solution or in vivo as illustrated in Figure I.
  • all compounds of Formula (I) have at least one asymmetric center and the stereochemistry at the asymmetric center(s) is(are) either RS, R, or S.
  • Preferred acid species of this embodiment are represented in Figure 2.
  • Preferred amide species of this embodiment are represented in Figure 3.
  • the compound, salt, tautomer, or prodrug is represented by Formula (II):
  • R 5a is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, and substituted or unsubstituted (C6-C10) aryl.
  • X is O;
  • R 1 is selected from the group consisting of optionally substituted (C6-C10) arylmethylene and (C5-C9) heteroarylmethylene;
  • R 2 and R 3 are hydrogen;
  • R 4 is selected from the group consisting of hydrogen and hydroxyl.
  • Preferred species within this first embodiment are represented by the following structures:
  • R 5 of Formula I is NR 6 R 7 .
  • X is O;
  • R 1 is selected from the group consisting of optionally substituted (C6-C10) arylmethylene and (C5-C9) heteroarylmethylene;
  • R 2 and R 3 are hydrogen;
  • R 4 is selected from the group consisting of hydrogen and hydroxyl.
  • a first group of preferred species is represented by the following structures:
  • a second group of preferred species is represented by the following structures:
  • a third group of preferred species is represented by the following structures:
  • a fourth group of preferred species is represented by the following structures:
  • a fifth group of preferred species is represented by the following structures:
  • a sixth group of preferred species is represented by the following structures:
  • a seventh group of preferred species is represented by the following structures:
  • a ninth group of preferred species is represented by the following structures:
  • a tenth group of preferred species is represented by the following core structures:
  • R is selected from the group consisting of radical represented by the following structures:
  • Provisios may apply to any of the above subgroups or embodiments wherein any one or more of the other above described embodiments or species may be excluded from such subgroups or embodiments.
  • Another aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of the first aspect of the invention.
  • the protein kinase is selected from the group consisting of VEGF receptors and PDGF receptors.
  • Figure 1 illustrates that the hydroxyl containing portion of the isothiazole based compound of the invention, and illustrates that this portion of the compound may exist in its open-acid form or its cyclic-lactone form or the two forms may co-exist in solution or in vivo.
  • Figure 2 illustrates preferred compounds of the invention in acid or open-chain form.
  • Figure 3 illustrates preferred compounds of the invention which are amides.
  • Figure 4 illustrates a scheme used to synthesize the acid compounds in Figure 2.
  • Figure 5 illustrates a method for completion of the synthesis of 1-10 which is representative of the acid compounds.
  • Figure 6 illustrates a scheme used for the synthesis of compounds like 2-3.
  • the present invention provides compounds capable of regulating and/or modulating protein kinase activities of, but not limited to, VEGFR (Vascular Endothelial Growth Factor Receptor) and/or FGFR (Fibroblast Growth Factor Receptor).
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptor
  • the present invention provides a therapeutic approach to the treatment of disorders related to the abnormal functioning of these kinases.
  • disorders include, but not limited to, solid tumors such as glioblastoma, melanoma, and Kaposi's sarcoma, and ovarian, lung, prostate, pancreatic, colon and epidermoid carcinoma.
  • VEGFR/FGFR inhibitors may also be used in the treatment of restenosis and diabetic retinopathy.
  • this invention relates to the inhibition of vasculogenesis and angiogenesis by receptor-mediated pathways, including the pathways comprising VEGF receptors, and/or FGF receptors.
  • receptor-mediated pathways including the pathways comprising VEGF receptors, and/or FGF receptors.
  • the compounds of this invention can be synthesized by following the published general procedures. But the following intermediates are specific to compounds of this invention and may be used in place of their respective counterparts in the published general procedures: (4 : ?,6R)-t-butyl-6-(2-aminoethyl)- 2,2-dimethyl-1 ,3-dioxane-4-acetate; 4-amino-3-hydroxy-butanoic acid; 2-hydroxy-4- aminobutyric acid; and isoserine. These intermediates may be purchased from commercial sources (e.g. Fisher Scientific, Fairlawn, New Jersey and Sigma Aldrich, Milwaukee, Wisconsin).
  • Example 1 (3 ,5 ?)-7- ⁇ 3-[3-(4-bromo-2,6-difluorobenzyloxy)-4- carbamoylisothiazol-5-yl]ureido ⁇ -3,5-dihydroxyheptanoic acid, sodium salt
  • Solid (3-benzyloxy-4-cyanoisothiazol-5-yl)-carbamic acid phenyl ester (1-4, 38.7g, 0.1 1 mol) was added slowly to concentrated sulfuric acid (75 mL) over 1 h and the mixture was stirred for additional 3 h.
  • the viscous solution was diluted by slow addition of ice (150 g) followed by vigorous stirring for an additional 1 h.
  • the precipitate was filtered and pressed on the filter without washing with water.
  • the wet solid was dissolved in DMF (250 mL) under heating to 120 °C. The mixture was then cooled to room temperature and kept at ca. 5 °C for 3 h.
  • Example 2 (3R,5S)-6- ⁇ 3-[3-(4-Bromo-2,6-difiuoro-benzyloxy)-4-carbamoyl- isothiazol-5-yl]-ureido ⁇ -3,5-dihydroxy-hexanoic acid tert-butyl ester.
  • Triflic anhydride 1.4mL (2.36g, 8.345mmol) was dropwise added at -78 °C to a solution of 2,6-lutidine 1.35mL (11.63mmol) and f-Butyl (3R,5S)-6-hydroxy-3,5-O- isopropylidene-3,5-dihydroxyhexanoate 1.981g (7.609 mmol, obtained from Kaneka Corp.) in dichloromethane (anh., 50mL) over 3 minutes. The mixture was stirred at - 78 °C for 10 min, then placed on ice-slush bath and stirred at 0 °C for 45 min.
  • the resulting pink mixture was transferred into ice-cooled solution of ammonia in methanol (7M solution, 200mL). The mixture was placed on ambient water bath and stirred at RT for 6 hours. The reaction mix was evaporated to dryness, the residue partitioned between ether (200mL) and aqueous potassium carbonate (6g in 200 mL of water), the aqueous phase re-extracted with ether (150mL). Combined organic extracts were dried (magnesium sulfate) and evaporated. The crude product was purified on a column of silica (125g) eluting with a mixture of chloroform-methanol- conc. aq.
  • 3-hydroxy-butyric acid derivatives 4a-d can be made using the commercially available 4-amino-3-hydroxy-butyric acid (e.g. Fisher Scientific, Fairlawn, New Jersey).
  • Example 8 Amide derivatives of Example 4.
  • Example 9 further amide derivatives of Example 4.
  • Example A 4- ⁇ 3-[3-(4-Bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5- yl]-ureido ⁇ -2-hydroxy-butyric acid
  • Example C Amide examples of Example A.
  • Example D Amide examples of Example B
  • Example E Amide examples of Example 3:
  • Example 8 Amide derivatives of Example 4.
  • Example 9 further amide derivatives of Example 4.
  • R is selected from the following radicals:
  • the compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure.
  • KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and [ ⁇ - 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required).
  • the reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 10 ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
  • HUVEC VEGF induced proliferation
  • HUVEC cells (Cambrex, CC-2517) were maintained in EGM (Cambrex, CC-3124) at 37°C and 5% CO 2 . HUVEC cells were plated at a density 5000 cells/well (96 well plate) in EGM. Following cell attachment (1 hour) the EGM- medium was replaced by EBM (Cambrex, CC-3129) + 0.1% FBS (ATTC , 30-2020) and the cells were incubated for 20 hours at 37°C.
  • the medium was replaced by EBM +1% FBS, the compounds were serial diluted in DMSO and added to the cells to a final concentration of 0 - 5,000 nM and 1% DMSO.
  • VEGF 10ng/ml VEGF (Sigma, V7259) and incubated for 45 hours at 37°C.
  • Cell proliferation was measured by BrdU DNA incorporation for 4 hours and BrdU label was quantitated by ELISA (Roche kit, 16472229) using 1 M H 2 SO 4 to stop the reaction. Absorbance was measured at 450nm using a reference wavelength at 690nm.
  • Figure 1 shows that a compound like the first structure may exist in its open- acid form or its cyclic- lactone form or the two forms may co-exist in solution or in vivo.
  • Figure 2 shows the preferred compounds of the invention in acid or open- chain form. There are two variable regions on these compounds. The first variable region is found on the "left end" of the molecule, as shown, which is the substitution on the phenyl ring of the 3-benzyl ether. The second variable region is the side chain on the 5-urea functionality.
  • Figure 3 shows the preferred compounds of the invention which are all amides. Both these structures and those from Figure 2 show the same core isothiazole ring with its 3-benzyl ether, 4- carboxamide and 5-urea functionality. The three variable regions on the amide compounds are found in the substitution of the phenyl ring of the benzyl ether, the length of the side chain on the 5- urea functionality and the type of substitution on the amide of the side chain.
  • Figure 4 shows the scheme used to synthesize the acid compounds in Figure 2.
  • the intermediates until isothiazole 1-6 were obtained according literature methods (Larson, E. R.; Noe, M. O; Gant, T. G. Isothiazole Derivatives Useful As Anticancer Agents. International publication number WO 99/62890; international publication date 12/03/1999. Larson, E. R.; Noe, M. C; Gant, T. G. Isothiazole Derivatives Useful As Anticancer Agents. United States patent US 6,235,764. Date of patent 5/22/2001) and are not further described in this report.
  • the purification method for 1-5 was changed significantly and this process is therefore detailed in the experimental section. Accordingly, crude 1-5 was purified by crystallization from hot DMF, which proved more convenient than the tedious, repeated centrifugation procedure given in the patents cited above.
  • Figure 5 shows the completion of the synthesis of 1-10 which is representative of the acid compounds. Simple deprotection of the acetonide group is followed by neutralizing the carboxylic acid to give the desired sodium salt 1-10.
  • Figure 6 shows the scheme used for the synthesis of compounds like 2-3. This starts from compound 1-6 and substitutes a different primary amine for the urea formation than the earlier scheme in Figures 4 and 5.

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  • Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des dérivés à base d'isothiazole contenant un hydroxy qui présentent des propriétés thérapeutiques améliorées et inattendues en tant qu'inhibiteurs de protéine kinases et qui sont utilisés dans le traitement de troubles associés à des activités anormales des protéine kinases, tels que le cancer.
PCT/US2005/005859 2004-02-20 2005-02-22 Inhibiteurs des proteine kinases a base d'isothiazole Ceased WO2005081997A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54653804P 2004-02-20 2004-02-20
US60/546,538 2004-02-20

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WO2005081997A2 true WO2005081997A2 (fr) 2005-09-09
WO2005081997A3 WO2005081997A3 (fr) 2006-05-11

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PCT/US2005/005875 Ceased WO2005082001A2 (fr) 2004-02-20 2005-02-22 Inhibiteurs ameliores de proteine kinase a base d'isothiazole

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013101954A1 (fr) * 2011-12-28 2013-07-04 Allergan, Inc. Dérivés de 3-phényl-5-uréidoisothiazole-4-carboximide et de 3-amino-5-phénylisothiazole en tant qu'inhibiteurs de la kinase
WO2024140850A1 (fr) * 2022-12-28 2024-07-04 苏州必扬医药科技有限公司 Inhibiteur de protéine tyrosine kinase et son utilisation médicale
US12083114B2 (en) 2018-12-19 2024-09-10 Disarm Therapeutics, Inc. Inhibitors of SARM1 in combination with neuro-protective agents

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9353093B2 (en) 2014-10-07 2016-05-31 Allergan, Inc. Indole-1-carboxamides as kinase inhibitors
US9403803B2 (en) 2014-10-08 2016-08-02 Allergan, Inc. Indole-3-carboxamides as kinase inhibitors
US9371314B2 (en) 2014-10-09 2016-06-21 Allergan, Inc. Pyridyl benzothiophenes as kinase inhibitors
US9359336B2 (en) 2014-10-09 2016-06-07 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4057416A (en) * 1976-06-18 1977-11-08 Fmc Corporation 3-Alkylthio-, 3-alkylsulfinyl-, and 3-alkylsulfonylisothiazole derivatives as herbicides
UA60365C2 (uk) * 1998-06-04 2003-10-15 Пфайзер Продактс Інк. Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013101954A1 (fr) * 2011-12-28 2013-07-04 Allergan, Inc. Dérivés de 3-phényl-5-uréidoisothiazole-4-carboximide et de 3-amino-5-phénylisothiazole en tant qu'inhibiteurs de la kinase
US8969583B2 (en) 2011-12-28 2015-03-03 Allergan, Inc. 3-phenyl-5-ureidoisothiazole-4-carboximide and 3-amino-5-phenylisothiazole derivatives as kinase inhibitors
EP3184525A1 (fr) * 2011-12-28 2017-06-28 Allergan, Inc. Dérivés de 3-phényl-5-ureidoisothiazole-4-caboximide et de 3-amino-5-phénylisothiazole en tant qu'inhibiteurs de kinase
US12083114B2 (en) 2018-12-19 2024-09-10 Disarm Therapeutics, Inc. Inhibitors of SARM1 in combination with neuro-protective agents
WO2024140850A1 (fr) * 2022-12-28 2024-07-04 苏州必扬医药科技有限公司 Inhibiteur de protéine tyrosine kinase et son utilisation médicale
TWI894754B (zh) * 2022-12-28 2025-08-21 大陸商蘇州必揚醫藥科技有限公司 一種蛋白酪胺酸激酶抑制劑及其醫藥用途

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WO2005082001A3 (fr) 2006-03-02
WO2005082001A2 (fr) 2005-09-09

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