WO2014154723A1 - Nouveaux dérivés de pyrrole pour le traitement du cancer - Google Patents

Nouveaux dérivés de pyrrole pour le traitement du cancer Download PDF

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Publication number
WO2014154723A1
WO2014154723A1 PCT/EP2014/056008 EP2014056008W WO2014154723A1 WO 2014154723 A1 WO2014154723 A1 WO 2014154723A1 EP 2014056008 W EP2014056008 W EP 2014056008W WO 2014154723 A1 WO2014154723 A1 WO 2014154723A1
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Prior art keywords
pyrrole
carboxylic acid
pyridin
hydrogen
methyl
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PCT/EP2014/056008
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English (en)
Inventor
Xingchun Han
Min Jiang
Alexander V. Mayweg
Lisha Wang
Song Yang
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2014154723A1 publication Critical patent/WO2014154723A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to organic compounds useful for therapy in a mammal, and in particular to inhibit cell proliferation and induce cell cycle arrest and apoptosis that overexpress CDK8 or Cyclin C useful for treating cancer.
  • CDK cyclin-dependent kinase
  • Dysregulation of CDKs has been linked to pathological events and both proliferative and non-pro liferative disease, including cancers, Alzhemers disease (AD), parkinson's disease, Stroke/ischemia, pain, traumatic brain injury, kidney disease, inflammation pathologies, type 2 diabetes, viral infection (HSV, HCMV, HPV, HIV).
  • CDK8 is a CyclinC-dependent CDK family kinase and functions as a transcriptional regulator.
  • RNAPII RNA polymerase II
  • CCD C-terminal domain
  • GTFs general transcription factors
  • CDK8 has also been described as a transcriptional coactivator in oncongenic signaling pathways, including the ⁇ -catenin pathway, the serum response network, the Tumor Growth Factor TGFP signaling pathway, the p53 pathway, as well as in thyroid hormone-dependent transcription. Colocalization of CDK8 and Cyclin C was also reported in neurodegenerative disease such as AD. CDK8 was found to be frequently
  • Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I for the treatment of cancer.
  • C h alky alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like.
  • Particular "C h alky! groups are methyl, ethyl, isopropyl and tert-butyl.
  • amino alone or in combination, refers to primary (-NH 2 ), secondary (-NH-) or
  • halogen means fluorine, chlorine, bromine or iodine. Halogen is particularly fluorine or chlorine.
  • hydroxy alone or in combination refers to the group -OH.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular are the sodium salts of the compounds of formula I.
  • Racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • the present invention provides (i) the use of a compound of formula (I)
  • R 1 and R 3 J are independently selected from hydrogen; halogen; and C ⁇ aUcyl, which is unsubstituted or substituted by fluoro;
  • R is hydrogen, C ⁇ aUcyl or phenyl-CH 2 -;
  • R 4 is hydrogen, C ⁇ aUcyl, halogen or phenyl
  • W is nitrogen or -CR 5 ; wherein R 5 is hydrogen, C ⁇ aUcyl, amino, halogen or hydroxy; or a pharmaceutically acceptable salt thereof for the preparation of medicaments for the treatment of cancer, in particular bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • R 1 and R 3 J are independently selected from hydrogen; halogen; and C 1-6 alkyl, which is unsubstituted or substituted by fluoro;
  • R is hydrogen, Ci ⁇ alkyl or phenyl-CH 2 -;
  • R 4 is hydrogen, Ci- 6 alkyl, halogen or phenyl
  • W is nitrogen or -CR 5 ; wherein R 5 is hydrogen, C 1-6 alkyl, amino, halogen or hydroxy; or a pharmaceutically acceptable salt thereof;
  • a further embodiment of the present invention is (iii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is hydrogen, chloro, methyl or ethyl
  • R is hydrogen, methyl or phenyl-CH 2 -;
  • R is hydrogen, chloro, methyl or trifluoromethyl
  • R 4 is hydrogen, methyl, chloro, bromo or phenyl
  • W is nitrogen or -CR 5 ; wherein R 5 is hydrogen, methyl, amino, chloro or hydroxy.
  • Another embodiment of the present invention is (iv) a compound of formulation (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is hydrogen, halogen or C 1-6 alkyl
  • R is hydrogen, Ci ⁇ alkyl or phenyl-CH 2 -;
  • R is hydrogen, Ci- 6 alkyl, halogen or trifluoromethyl
  • R 4 is hydrogen, Ci- 6 alkyl, halogen or phenyl
  • W is -CR 5 ; wherein R 5 is hydrogen, C 1-6 alkyl, amino, halogen or hydroxy.
  • R 1 is hydrogen, chloro, methyl or ethyl
  • R is hydrogen, methyl or phenyl-CH 2 -;
  • R is hydrogen, chloro, methyl or trifluoromethyl
  • R 4 is hydrogen, methyl, chloro, bromo or phenyl; -CR 5 ; wherein R 5 is hydrogen, methyl, amino, chloro or hydroxy.
  • Another embodiment of present invention is (vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is hydrogen
  • R is hydrogen
  • R is C 1-6 alkyl, halogen or trifluoromethyl
  • R 4 is hydrogen or halogen
  • W is -CR 5 ; wherein R 5 is hydrogen, C 1-6 alkyl.
  • R 1 is hydrogen
  • R is hydrogen
  • R is methyl, chloro or trifluoromethyl
  • R 4 is hydrogen or chloro
  • W is -CR 5 ; wherein R 5 is hydrogen or methyl.
  • Another embodiment of present invention is (xiii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is hydrogen, halogen or C 1-6 alkyl
  • R is hydrogen, C 1-6 alkyl or phenyl-CH 2 -;
  • R is hydrogen
  • R 4 is hydrogen, C 1-6 alkyl, halogen or phenyl
  • W is -CR 5 ; wherein R 5 is hydrogen, C 1-6 alkyl, amino, halogen or hydroxy.
  • R 1 is hydrogen, chloro, methyl or ethyl
  • R is hydrogen, methyl or phenyl-CH 2 -;
  • R is hydrogen
  • R 4 is hydrogen, methyl, chloro, bromo or phenyl
  • W is -CR 5 ; wherein R 5 is hydrogen, methyl, amino, chloro or hydroxy.
  • R 5 is hydrogen, methyl, amino, chloro or hydroxy.
  • the compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R 1 , R 2 , R 3 , R 4 and W are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
  • R 2 is C ⁇ g alkyl or phenyl-CH 2 - R 1 1 is C 1 -6 alkyl. Methold 6)
  • II-l reacts with halides in the presence of NaH in in an organic solvent at 0 °C to room temperature.
  • organic solvent for example can be THF, DMF or dioxane.
  • Method 2 coupling reaction between II and bis(pinacolato)diboron affords the bronic ester intermediate III.
  • the reaction can be carried out in the presence of palladium catalyst and a suitable base such as KOAc, in a suitable solvent such as 1,4-dioxane, at 50 °C to 150 °C.
  • II-l reacts with Boc 2 0 at 0 °C to room temperature in an organic solvent such as DCM or THF, to afford intermediate II-2, which undergoes coupling reaction with bis(pinacolato)diboron to give intermediate III-l.
  • the coupling reaction can be carried out in the presence of palladium catalyst and a suitable base such as KOAc, in a suitable solvent such as 1,4-dioxane, at 50 to 150 °C.
  • 3-chloro-lH-pyrrole-2- carboxylic acid methyl ester reacts with NBS at room temperature in an organic solvent such as CH 3 CN or THF to give 4-bromo-3-chloro-lH-pyrrole-2-carboxylic acid methyl ester, which is treated with Boc 2 0 in the presence of DMAP at room temperature in an organic solvent to afford 4-bromo-3-chloro-pyrrole-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.
  • the organic solvent for example can be DCM or THF.
  • the compound of formula I can be prepared according to Scheme 2.
  • Method 8 coupling reaction between compound III and IV affords the intermediate VII.
  • the reaction can be carried out in the presence of Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 , and a suitable base such as Na 2 C0 3 , K 2 C0 or Cs 2 C0 3 , in a suitable solvent such as toluene, EtOH/H 2 0 or l,4-dioxane/H 2 0, at 50 to 150 °C. Hydrolyzation of VII affords VIII.
  • Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2
  • a suitable base such as Na 2 C0 3 , K 2 C0 or Cs 2 C0 3
  • a suitable solvent such as toluene, EtOH/H 2 0 or
  • the hydrolyzation reaction can be carried out in the presence of LiOH or NaOH in a suitable solvent such as EtOH/H 2 0 or MeOH/H 2 0.
  • the hydrolyzation reaction can also be carried out in hydrochloric acid at 60 to 120 °C.
  • VIII undergoes coupling reaction with NH 3 , NH 3 H 2 0 or NH 4 C1 in presence of HATU or EDCI/HOBt, and a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3 , in a suitable solvent such as DMF or THF to give compound I.
  • the intermediate VII can be prepared by Suzuki coupling of material II with bronic acid V or bronic ester VI.
  • the reaction can be carried out in the presence of Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 , and a suitable base such as Na 2 C0 3 , K 2 C0 3 or Cs 2 C0 3 , in a suitable solvent such as toluene, EtOH/H 2 0 or l,4-dioxane/H 2 0, at 50 °C to 150 °C.
  • Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2
  • a suitable base such as Na 2 C0 3 , K 2 C0 3 or Cs 2 C0 3
  • a suitable solvent such as toluene, EtOH/H 2 0 or l,4-dioxane
  • the intermediate VII can be prepared by one-pot reaction.
  • Compound II reacts with bis(pinacolato)diboron in the presence of tris(dibenzylideneacetone) dipalladium and butyldi-l-adamantylphosphine at 60 °C to 130 °C, and a suitable base such as KOAc in a suitable solvent such as DME, then the compound IV, K 2 C0 3 and dioxane/H 2 0 are added and the mixture is stirred at 60 °C to 130 °C for several hours under microwave to afford the intermediate VII.
  • Scheme 3 depicts a general method to prepare compound 1-1. Suzuki coupling reaction of bronic ester III with IV-1 affords intermediate VII-1.
  • the reaction can be carried out in the presence of Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 , and a suitable base such as Na 2 C0 3 or Cs 2 C0 3 , in a suitable solvent such as ⁇ / ⁇ 3 ⁇ 40, toluene or l,4-dioxane/H 2 0, at 50 °C to 150 °C.
  • VII-1 is hydrolyzed by LiOH or NaOH in a suitable solvent such as
  • VIII-1 is treated with HCl in dioxane to afford VIII-2, which undergoes coupling reaction with NH , NH H 2 0 or NH 4 C1 in the presence of HATU or EDCI/HOBt, and a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3 , in a suitable solvent such as DMF or THF to give compound 1-1.
  • a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3
  • R 3 is C h alky!, which is unsubstituted or substituted by fluoro;
  • W is -OR 5 - wherein R 5 is hydrogen, C h alky! or halogen.
  • Scheme 4 describes a general method to prepare compound 1-2.
  • Starting material IX is treated by LDA in an organic solvent such as THF at -78 °C and followed by addition of R 3 COCl or (R 3 CO) 2 0 at -78 °C to room temperature to give intermediate X, which is heated with DMF- DMA to form XI.
  • another method is used to make XI.
  • IX is heated with C-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine in an organic solvent such as DMF at 100 °C to 150 °C to form intermediate XII, which is then treated with (R 3 CO) 2 0 in the presence of TEA in an organic solvent such as DCM to give XI.
  • XI is heated with diethyl aminomalonate hydrochloride in HOAc at 100 °C to 160 °C to form compound VII-2, which is then hydrolyzed to give compound VIII-3.
  • the hydrolyzation reaction can be carried out in the presence of LiOH or NaOH in a suitable solvent such as EtOH/H 2 0, THF/H 2 0 or MeOH/H 2 0.
  • the hydrolyzation reaction can also be carried out in hydrochloric acid at 60 °C to 120 °C.
  • VIII-3 undergoes coupling reaction with NH 3 , NH 3 H 2 0 or NH 4 C1 in the presence of HATU or
  • EDCI/HOBt EDCI/HOBt
  • a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3
  • a suitable solvent such as DMF or THF
  • R 1 is C 2.6 alkyl
  • R 12 is C ⁇ alkyl .
  • Scheme 5 depicts a general method to prepare 1-3. II-3 is treated with (R CO) 2 0 in the presence of BF Et 2 0 in an organic solvent such as DCM at 0°C to room temperature to form the intermediate XIII, which reacts with Boc 2 0 to give XIV.
  • XIV reacts with bronic acid V in the presence of Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh ) 4 or PdCl 2 (PPh ) 2 , and a suitable base such as Na 2 C0 3 or Cs 2 C0 3 , in a suitable solvent such as toluene, EtOH/H 2 0 or l,4-dioxane/H 2 0, at 50 °C to 150 °C to form intermediate XV, which is reduced by TESH with BF 3 Et 2 0 and TFA at 0°C to room temperature to afford compound VII-3.
  • Pd catalyst such as Pd(dppf)Cl 2 , Pd(PPh ) 4 or PdCl 2 (PPh ) 2
  • a suitable base such as Na 2 C0 3 or Cs 2 C0 3
  • a suitable solvent such as toluene, EtOH/H 2 0 or l,4-dioxane/H 2
  • VII-3 is hydrolyzed to give compound VIII-4, which undergoes coupling reaction with NH 3 , NH 3 H 2 0 or NH 4 CI in the presence of HATU or EDCI/HOBt, and a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3 , in a suitable solvent such as DMF or THF to give compound 1-3.
  • a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3
  • a suitable solvent such as DMF or THF
  • Scheme 6 depicts a general method to prepare 1-4. VII-4 undergoes Suzuki
  • Pd catalyst such as Pd(dppf)Cl 2 or Pd(PPh ) 4 and a suitable base such as Na 2 C0 3 or Cs 2 C0 3 in a suitable solvent such as
  • VIII-5 undergoes coupling reaction with NH , NH 3 H 2 0 or NH 4 C1 in the presence of HATU or EDCI/HOBt, and a suitable base such as TEA, DIPEA, Na 2 C0 3 or NaHC0 3 , in a suitable solvent such as DMF or
  • This invention also relates to a process for the preparation of a compound of formula I comprising the reaction of
  • R 1 , R 2 , R 3 , R 4 and W are defined above unless otherwise indicated.
  • the coupling agent can be for example HATU or EDCI/HOBt.
  • the base can be for example TEA, DIPEA, Na 2 C0 3 or NaHC0 3 .
  • a compound of formula I when manufactured according to the above process is also an object of the invention.
  • the invention also relates to a compound of formula I for use as therapeutically active substance.
  • compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but particularly ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compounds of formula I are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aque
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit CDK8 activity. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 50 mg/kg of patient body weight per day, with the typical initial range of compound used being about 0.3 to about 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 5 mg to about 500 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or exeipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 5 mg to 500 mg of the compound of the invention compounded with about 90 mg to 30 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5mg to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment includes a pharmaceutical composition comprising a compound of Formula I for use in the treatment of a hyperproliferative disease. Another embodiment includes a pharmaceutical composition comprising a compound of Formula I for use in the treatment of cancer.
  • the compounds of the invention inhibit the kinase activity of protein. Accordingly, the compounds of the invention are useful for inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in particular cancer cells.
  • Compounds of the invention are useful for inhibiting cell proliferation, inducing cell cycle arrest and apoptosis in cells that overexpress CDK8 or Cyclin C.
  • compounds of the invention are useful for inhibiting cell proliferation, inducing cell cycle arrest and apoptosis in cells in which the apoptotic pathway is disrupted or proliferation pathway is overexpressed/or immortalized, for example by deregulation of CDK8 or Cyclin C.
  • the compounds of inventions are useful as inhibitors of CDK8 or Cyclin C.
  • An embodiment of this invention includes the use of a compound for the treatment of cancer, in particular bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • a further embodiment of this invention includes the use of a compound for the treatment of gastric cancer or colorectal cancer.
  • Another embodiment of this invention includes the use of a compound for the preparation of a medicament for the treatment of cancer, in particular bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • a compound for the preparation of a medicament for the treatment of cancer in particular bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • a further embodiment of this invention includes the use of a compound for the preparation of a medicament for the treatment of gastric cancer or colorectal cancer.
  • Another embodiment of this invention relates to a compound of formula I for the treatment of cancer, in particular bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • a further embodiment of this invention relates to a compound of formula I for the treatment of gastric cancer or colorectal cancer.
  • Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof include bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, liver, skin, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancers.
  • the invention relates to a method of treating or preventing gastric cancer or colorectal cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • Another embodiment includes a method of treating or preventing neurodegenerative disease in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • Particular neurodegenerative disease for treatment includes Alzhemers disease, parkinson's disease, Huntington's dsease and Amyotrophic lateral sclerosis (ALS).
  • the compounds of the invention can be used in combination with small molecule inhibitors such as tyrosine kinase inhibitors, Serine/Threonine kinase inhibitors, lipid kinase inhibitors, protein-protein inhibitors, etc., cytotoxic agents, radiotherapy, antibodies and cancer vaccines for the treatment of cancer.
  • small molecule inhibitors such as tyrosine kinase inhibitors, Serine/Threonine kinase inhibitors, lipid kinase inhibitors, protein-protein inhibitors, etc.
  • cytotoxic agents such as tyrosine kinase inhibitors, Serine/Threonine kinase inhibitors, lipid kinase inhibitors, protein-protein inhibitors, etc.
  • BSA bovine serum albumin
  • DIPEA N,N-diisopropylethylamine
  • EGTA ethylene glycol tetraacetic acid
  • HATU 2-(7-aza- IH-benzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate
  • HCMV human cytomegalovirus
  • HIV human immunodeficiency virus
  • HSV herpes simplex virus
  • HPV human papillomavirus
  • nM nanomoles per liter
  • PdCl 2 (PPh 3 ) 2 bis(triphenylphosphine)palladium(II) chloride
  • TR-FRET time resolved-fluorescence resonance energy transfer
  • LC/MS spectra were obtained using a MicroMass Plateform LC (WatersTM alliance 2795- ZQ2000). Standard LC/MS conditions were as follows (running time 6 minutes): Acidic condition: A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) + .
  • the microwave assisted reactions were carried out in a Biotage Initiator Sixty.
  • Step 1 Preparation of (4-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester
  • Step 3 Preparation of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrrole-l,2- dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • Step 4 Preparation of 4-(2-tert-butoxycarbonylamino-pyridin-4-yl)-lH-pyrrole-2- carboxylic acid methyl ester
  • Step 7 Preparation of 4-(2-amino-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Example 2 Preparation of l-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 4-bromo-l-methyl-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 2 Preparation of l-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 3 Preparation of l-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid
  • Step 4 Preparation of l-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • HATU 467 mg, 1.2 mmol
  • TEA 124 mg, 1.2 mmol
  • NH 4 C1 59 mg, 1.1 mmol
  • Step 1 Preparation of l-benzy -4-bromo-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 2 Preparation of l-benzyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 3 Preparation of l-benzy -4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid
  • Step 4 Preparation of l-benzyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrrole-2- carboxylic acid methyl ester
  • Step 4 Preparation of 4-(3-methyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 4 Preparation of 5-chloro-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • DMF dimethyl methoxysulfoxide
  • HOBt 72 mg, 0.53 mmol
  • EDCI 102 mg, 0.53 mmol
  • the mixture was stirred at room temperature for 30 minutes, and then aqueous ammonia (4 mL) was added.
  • the resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with water (10 mL), and then extracted with EtOAc (20 mLx5).
  • Step 1 Preparation of 4-bromo- -methyl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 2 Preparation of 5-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 4 Preparation of 5-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • DMF dimethyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid
  • HOBt 70 mg, 0.52 mmol
  • EDCI 100 mg, 0.52 mmol
  • the mixture was stirred at room temperature for 30 min, and then aqueous ammonia (4 mL) was added.
  • the resulting mixture was stirred at room temperature for 1 h, and then poured into water (30 mL). The precipitate was collected by filtering and washed with EtOAc (1 mL) to give 5- methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide (81 mg).
  • Step 3 Preparation of 5-acetyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 4 Preparation of 5-ethyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 7 Preparation of 3-chloro-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • DMF dimethyl methoxysulfoxide
  • HOBt 73 mg, 0.54 mmol
  • EDCI 104 mg, 0.54 mmol
  • the mixture was stirred at room temperature for 30 minutes, and then aqueous ammonia (4 mL) was added. The resulting mixture was stirred at room temperature and was completed as monitored by HPLC.
  • Step 1 Preparation of 4-(3-chloro-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 2 Preparation of 4-(3-chlor -pyridin-4-yl)-lH-pyrrole-2-carboxylic acid
  • Step 3 Preparation of 4-(3-chloro-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • HOBt 109 mg, 0.81 mmol
  • EDCI 156 mg, 0.81 mmol
  • the mixture was stirred at room temperature for 30 minutes, and then aqueous ammonia (4 mL) was added.
  • the resulting mixture was stirred at room temperature for 5 h and then poured into water (20 mL).
  • Step 1 Preparation of 4-(3-bromo-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 3 Preparation of 4-(3-bromo-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 4-(3-phenyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 3 Preparation of 4-(3-phenyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of l-pyridazin-4-yl-propan-2-one
  • Step 3 Preparation of 3-methyl-4-pyridazin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 5 Preparation of 3-methyl-4-pyridazin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • DMF 3 mL
  • HOBt 159 mg, 1.18 mmol
  • EDCI 227 mg, 1.18 mmol
  • the mixture was stirred at room temperature for 30 min, and then ammonia (5 mL) was added.
  • the resulting mixture was stirred at room temperature. When the reaction was complete, the mixture was concentrated.
  • Step 1 Preparation of dimethyl-((E -2-pyridin-4-yl-vinyl)-amine
  • Step 2 Preparation of (E)-4-dimethylamino-l,l,l-trifluoro-3-pyridin-4-yl-but-3-en-2- one
  • Step 3 Preparation of 4-pyridin-4-yl-3-trifluoromethyl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 4 Preparation of 4-pyridin-4- -3-trifluoromethyl-lH-pyrrole-2-carboxylic acid
  • Step 5 Preparation of 4-pyridin-4-yl-3-trifluoromethyl-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 4-(2-hydroxy-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 2 Preparation of 4-(2-hydrox -pyridin-4-yl)-lH-pyrrole-2-carboxylic acid
  • Step 3 Preparation of 4-(2-hydroxy-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • a mixture of 4-(2-hydroxy-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid (100 mg, 0.49 mmol), EDCI (113 mg, 0.59 mmol) and HOBt (80 mg, 0.59 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. Then aqueous ammonia (6 mL) was added. The resulting mixture was stirred for 30 minutes and purified by prep-HPLC to give 4-(2-hydroxy-pyridin-4-yl)-lH- pyrrole-2-carboxylic acid amide (14.0 mg).
  • Step 1 Preparation of 4-bromo-3-methyl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 4 Preparation of 4-(3-chloro-pyridin-4-yl)-3-methyl-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 4-(2-methyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester
  • Step 3 Preparation of 4-(2-methyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 3 Preparation of 4-(2-chloro-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 1 Preparation of 3-methyl-4-(2-methyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 3 Preparation of 3-methyl-4-(2-methyl-pyridin-4-yl)-lH-pyrrole-2-carboxylic acid amide
  • Step 2 Preparation of 3-methyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 1 Preparation of l-pyridin-4-yl-butan-2-one
  • Step 3 Preparation of 3-ethyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid ethyl ester
  • Step 5 Preparation of 3-ethyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • DMF dimethyl methyl-N-(2-aminoethyl)-2-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl-4-pyridin-4-yl-lH-pyrrole-2-carboxylic acid amide
  • HOBt 112 mg, 0.83 mmol
  • EDCI 159 mg, 0.83 mmol
  • the mixture was stirred at room temperature for 30 minutes, and then aqueous ammonia (5 mL) was added.
  • the resulting mixture was stirred at room temperature for 5 hours and then poured into water (20 mL).
  • the aqueous layer was extracted with EtOAc (20 mL x 5).
  • the biological activity of the compounds of the invention can be determined using the assay described below.
  • CDK8/Cyclin C protein was obtained from Invitrogen, cat# PV4402.
  • ULight-Glycogen Synthase (Ulight-GS) peptide with sequence PASVPPSPSLSRHSSPHQ(pS)ED, and Europium- anti-phospho Glycogen Synthase (Ser641) [Eu-anti-P-GS (Ser641)] were obtained from Perkin Elmer, cat# TRF0131-M and cat# TRF0220.
  • Adenosine-5 '-triphosphate (ATP) was obtained from Invitrogen, cat# PV3227.
  • Example 23 In vitro cell proliferation assay:
  • the compounds of the present invention were tested for their capacity to inhibit a CDK8 activity and activation as described herein.
  • the Examples were tested in the above assay and found to have IC 50 of about 0.0001 ⁇ to about 30 ⁇ .
  • Particular compounds of formula I were found to have IC 50 of about 0.0001 ⁇ to about 1 ⁇ .
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
  • Example B A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

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Abstract

L'invention concerne une méthode de traitement d'un cancer, cette méthode utilise des composés représentés par la formule générale (I) dans laquelle R1, R2, R3, R4 et W sont tels que décrits ici dans la description.
PCT/EP2014/056008 2013-03-29 2014-03-26 Nouveaux dérivés de pyrrole pour le traitement du cancer WO2014154723A1 (fr)

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WO2017076968A1 (fr) 2015-11-03 2017-05-11 Lu License Ab Composés destinés au traitement de désordres hyperprolifératifs
WO2018139660A1 (fr) 2017-01-30 2018-08-02 国立大学法人京都大学 Nouveau composé, et procédé de production de lymphocytes t régulateurs
WO2019068613A1 (fr) 2017-10-02 2019-04-11 Boehringer Ingelheim International Gmbh Nouveaux composés de [1,6]naphthyridine et dérivés utilisés en tant qu'inhibiteurs de cdk8/cdk19
EP3607944A4 (fr) * 2017-04-03 2020-11-18 Kyoto Pharmaceutical Industries, Ltd. Nouvel inhibiteur de kinase dépendante de la cycline 8 et/ou 19
WO2023048275A1 (fr) 2021-09-27 2023-03-30 国立大学法人京都大学 Procédé de production de lymphocyte t
WO2023095801A1 (fr) 2021-11-24 2023-06-01 レグセル株式会社 Lymphocyte t humain contrôlable par inductibilité et son procédé de préparation
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US10208056B2 (en) 2015-08-26 2019-02-19 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Condensed tricyclic compounds as protein kinase inhibitors
WO2017076968A1 (fr) 2015-11-03 2017-05-11 Lu License Ab Composés destinés au traitement de désordres hyperprolifératifs
US11471446B2 (en) 2015-11-03 2022-10-18 Lu License Ab Compounds for treatment of hypoproliferative disorders
WO2018139660A1 (fr) 2017-01-30 2018-08-02 国立大学法人京都大学 Nouveau composé, et procédé de production de lymphocytes t régulateurs
US11013728B2 (en) 2017-04-03 2021-05-25 Kyoto Pharmaceutical Industries, Ltd. Cyclin-dependent kinase 8 and/or 19 inhibitor
EP3607944A4 (fr) * 2017-04-03 2020-11-18 Kyoto Pharmaceutical Industries, Ltd. Nouvel inhibiteur de kinase dépendante de la cycline 8 et/ou 19
WO2019068613A1 (fr) 2017-10-02 2019-04-11 Boehringer Ingelheim International Gmbh Nouveaux composés de [1,6]naphthyridine et dérivés utilisés en tant qu'inhibiteurs de cdk8/cdk19
WO2023048275A1 (fr) 2021-09-27 2023-03-30 国立大学法人京都大学 Procédé de production de lymphocyte t
WO2023095801A1 (fr) 2021-11-24 2023-06-01 レグセル株式会社 Lymphocyte t humain contrôlable par inductibilité et son procédé de préparation
WO2023095802A1 (fr) 2021-11-24 2023-06-01 レグセル株式会社 Composition pharmaceutique de traitement ou de prévention de troubles liés aux lymphocytes t

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