[go: up one dir, main page]

WO2003051877A1 - 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer - Google Patents

2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer Download PDF

Info

Publication number
WO2003051877A1
WO2003051877A1 PCT/US2002/040328 US0240328W WO03051877A1 WO 2003051877 A1 WO2003051877 A1 WO 2003051877A1 US 0240328 W US0240328 W US 0240328W WO 03051877 A1 WO03051877 A1 WO 03051877A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally
alkyl
group
alkoxy
substituents selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2002/040328
Other languages
English (en)
Inventor
Chengzhi Zhang
Dongping Fan
Yamin Wang
Tindy Li
Stephen J. Boyer
Jennifer Burke
Brian C. Raudenbush
Wai C. Wong
Shihong Ying
Ming Wang
Qian Zhao
Christopher A. Carter
Nils Burkhardt
Josef Pernerstorfer
Maria Niewoehner
Elizabeth CARLSON-SULLIVAN
Ulrich Niewoehner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Bayer Corp
Original Assignee
Bayer AG
Bayer Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG, Bayer Corp filed Critical Bayer AG
Priority to AU2002366362A priority Critical patent/AU2002366362A1/en
Publication of WO2003051877A1 publication Critical patent/WO2003051877A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 present invention relates to 2-substituted pyrrolo[2.1-a]isoquinoline derivatives which are inhibitors of phosphodiesterase 10a, a process for preparing these compounds and a method of treating cancer by administering these compounds.
  • Cyclic AMP metabolism is regulated by the opposing activities of adenylyl cyclase, which generates cAMP in response to extracellular stimuli (e.g. engagement of G-protein coupled receptors by their cognate ligands), and 3 ',5 '-cyclic nucleotide phosphodiesterases (PDEs), which hydrolyze cAMP to 5 '-AMP.
  • PDEs 3 ',5 '-cyclic nucleotide phosphodiesterases
  • Signal transduction via cAMP is associated with transcriptional events that can result in the inhibition of cellular proliferation (T. J. Shaw et al, Exp. Cell Res. 273, 95 (2002); T.W. Moody et al., Ann. N.Y Acad. Sci. 921, 26 (2000); W.L.
  • the ICAST (Inhibitor of Cyclic AMP Signal Transduction) gene encodes a specific 3',5'- cyclic nucleotide phosphodiesterase. Compared to corresponding normal tissues, ICAST mRNA is overexpressed in breast carcinoma specimens, liver metastases of colorectal carcinoma and non-small cell lung carcinomas.
  • the ICAST cDNA was also recently cloned by other groups and named PDE 10a (K. Fujishige et al., J. Biol. Chem. 274, 18 438 (1999); S.H. Soderling et al., Proc. Natl. Acad. Sci. USA 96, 7071 (1999); K.
  • R"", R"' Me, Et, i-Pr, C ⁇ H ⁇
  • the compounds (B) are described as having anti-tumor activity due to their ability to intercalate into DNA. It is not mentioned that they have any PDE 10a inhibitory activity.
  • R H, OCH 3
  • R" CH 3
  • R'" C 6 H 5
  • R'" OR , CH 3 , NH 2
  • R 1 and R 2 independently from each other denote hydrogen, C ⁇ - -alkyl or trifluoromethyl or
  • R 1 and R 2 together form a C ⁇ - -alkylene bridge
  • R 3 and R 4 independently from each other denote C ⁇ - 6 -alkyl optionally further substituted with halogen up to perhalo;
  • R 5 denotes a radical of the formula
  • R 6 denotes Ci- 6 -alkyl, trifluoromethyl, trifluoromethoxy, halogen, hydrogen, hydroxy or C ⁇ - 6 -alkoxy; X and Y independently from each other denote
  • C 6 -C 10 -aryl optionally having from 1 to 3 substituents selected from the group consisting of C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkyl, C 3 - 8 -cycloalkyl, trifluoromethyl, trifluoromethoxy and halogen, or
  • heteroaryl or heterocyclyl may optionally have from 1 to 3 substituents selected from the group consisting of i) C 3 . 8 -cycloalkyl; ii) C ⁇ - 6 -alkyl, optionally having from 1 to 3 substituents selected from the group consisting of C 3 - 8 -cycloalkyl, hydroxy, C ⁇ _ 6 -alkoxy, halogen, phenylamino, morpholinyl, (C ⁇ - 6 -alkyl)-aminocarbonyl, benzo[2,3]dioxolyl and C 6 -C 10 -aryl, wherein said aryl is optionally substituted with C ⁇ _ 6 -alkyl or C ⁇ - 6 -alkoxy; iii) C 6 -C ⁇ o-aryl, optionally having from 1 to 3 substituents selected from the group consisting of
  • X and Y together with the nitrogen atom to which they are attached form heterocyclyl fused to C 6 -C 10 -aryl, optionally having from 1 to 3 substituents selected from the group consisting of halogen, Ci- 6 - alkyl, C 3 . 8 -cycloalkyl, C ⁇ . 6 -alkoxy and hydroxymethyl;
  • Y denotes -NR 9 R 10 ; wherein R 9 and R 10 independently from each other denote 1) hydrogen,
  • C 6 -C ⁇ o-aryl optionally having from 1 to 3 substituents selected from the group consisting of halogen, C ⁇ - 6 -alkyl, C 3 . 8 -cycloalkyl, C ⁇ - 6 -alkoxy, trifluoromethoxy and trifluoromethyl, 3) heterocyclyl,
  • R 9 and R 10 together with the nitrogen atom to which they are attached form heterocyclyl or heteroaryl, wherein said heteroaryl or heterocyclyl may optionally have from 1 to 3 substituents selected from the group consisting of Ci- 6 -alkyl, C ⁇ - 6 -alkoxy, halogen and methoxymethyl;
  • R and R independently from each other denote hydrogen, C ⁇ - 4 -alkyl or trifluoromethyl;
  • R 3 and R 4 independently from each other denote Ci- 6 -alkyl optionally further substituted with halogen up to perhalo;
  • R 5 denotes a radical of the formula
  • R 6 denotes halogen, hydrogen, hydroxy or Ci- 6 -alkoxy
  • X and Y together with the nitrogen atom to which they are attached form heterocyclyl fused to C 6 -C ⁇ o-aryl, optionally having from 1 to 3 substituents selected from the group consisting of halogen, C ⁇ - 6 - alkyl, C ⁇ - 6 -alkoxy and hydroxymethyl; or
  • X denotes hydrogen and Y denotes -NR 9 R 10 ; wherein R 9 and R 10 independently from each other denote
  • R 9 and R 10 together with the nitrogen atom to which they are attached form heterocyclyl or heteroaryl, wherein said heterocyclyl or heteroaryl optionally have from 1 to 3 substituents selected from the group consisting of C ⁇ _ 6 -alkyl and methoxymethyl;
  • a further alternative embodiment of the present invention relates to a compound of the formula (I), wherein
  • R 1 and R 2 independently from each other denote hydrogen or C ⁇ _ 4 -alkyl;
  • R j denotes C ⁇ - 6 -alkyl or trifluoromethyl;
  • R 4 denotes C ⁇ - -alkyl
  • R 5 denotes a radical of the formula selected from the group consisting of:
  • X and Y together with the nitrogen atom to which they are attached form i) morpholino, optionally further subsituted with 1 to 2 substituents Ci- 6 -alkyl; ii) piperidinyl, optionally having from 1 to 2 substituents selected from the group consisting of hydroxyl, hydroxymethyl and C ⁇ _ 6 -alkyl; iii) pyrrolidinyl, optionally having from 1 to 2 substituents selected from the group consisting of C ⁇ - 6 -dialkylamino, pyridyl, carboxamido, Ci- 6 -alkoxy, phenylaminomethyl, methoxymethyl and methoxyphenyl; or iv) piperazinyl, optionally having from 1 to 2 substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, benzyl, morpholinoe
  • X and Y together with the nitrogen atom to which they are attached fomi dimethoxytetrahydroisoquinolinyl, 2-methyl-6- fluorotetrahydroquinolinyl, indolinyl, isoindolinyl or
  • X denotes hydrogen and Y denotes a) phenylamino, having from 1 to 2 substituents selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl and Ci-e-alkyl; b) piperidinyl, optionally further substituted with 1 to 2 - ⁇ - alkyl; c) triazolyl; d) pyrrolidinyl, optionally further substituted with 1 to 2 methoxymethyl; e) morpholino; f) imidazoyl; g) C 3 _ 8 -cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; h) Ci- 6 -dialkylamino; or i) azepanyl;
  • a further alternative embodiment of the present invention relates to a compound of the formula (T): wherein R >3 to R are defined as described above.
  • a further alternative embodiment of the present invention relates to a compound of the formula (I), wherein
  • R 3 denotes a radical of the formula selected from the group consisting of:
  • a further alternative embodiment of the present invention relates to a compound of the formula (I), wherein
  • x and y independently from each other denote zero or 1 and x+y is 1 or 2;
  • R and R independently from each other denote hydrogen, C ⁇ - -alkyl or CF or R 1 and R 2 together form a C ⁇ - 4 -alkylene bridge;
  • R 3 and R 4 independently from each other denote C ⁇ - -alkyl
  • R s denotes a monovalent radical of the formula
  • the compounds of the formula (I) according to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or are not like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
  • the racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform components.
  • Pharmaceutically acceptable salts according to the invention are non-toxic salts which in general are accessible by reaction of the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds (I) include the alkali metal salts, e.g.
  • the alkaline earth metal salts such as the magnesium and calcium salts
  • the quaternary ammonium salts such as, for example, the triethyl ammonium salt, acetates, benzene sulphonates, benzoates, dicarbonates, disulphates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexyl resorcinates, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylnitrates, methylsulphates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, polygalacturonates
  • hydrates are forms of the compounds of the formula (I) above which, in the solid or liquid state, form a molecular compound (solvate) by hydration with water.
  • examples of hydrates are sesquihydrates, monohydrates, dihydrates and trihydrates. Equally suitable are the hydrates of salts of the compounds according to the invention.
  • Halogen represents fluorine, chlorine, bromine and iodine. Preference is given to chlorine and fluorine.
  • alkylcarbonyl represents a straight-chain or branched alkyl radical preferrably having from 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, ⁇ o-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl and «-decyl.
  • alkyl groups having fewer carbon atoms such as, for example, C ⁇ -C -alkyl, are derived analogously from this definition.
  • C j -Cs-Cvcloalkyl represents a mono- or bicyclic alkyl radical having 3 to 8 carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • the corresponding cycloalkyl groups having fewer carbon atoms, such as, for example, C 3 -C 6 -cycloalkyl, are derived analogously from this definition.
  • Non-limiting examples of radicals include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl.
  • the corresponding alkoxycarbonyl groups having fewer carbon atoms such as, for example, C 3 -C 6 -alkoxycarbonyl, are derived analogously from this definition.
  • C j ⁇ -Cg-Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, «-propoxy, iso-pxopoxy, n-bvAoxy, iso-butoxy, tert-butoxy, w-pentoxy and n-hexoxy.
  • the corresponding alkoxy groups having fewer carbon atoms, such as, for example, C ⁇ -C 4 -alkoxy, are derived analogously from this definition.
  • Ci-C ⁇ -Dialkylamino represents an alkylamino radical having two (independently selected) alkyl substituents, illustratively and preferably representing NN-dimethylamino, N,N- diethylamino, N-ethyl-N-methylamino, N-meti yl-N-n-propylamino, N-isopropyl-N-n- propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N- methylamino.
  • Cfi-C ⁇ -Aryl represents an aromatic radical preferably having 6 to 14, more preferably 6 to 10 carbon atoms.
  • Cg-Cui-aryl radicals include phenyl, and naphthyl.
  • Heteroaryl in the context of the invention represents a preferably 5- to 13-membered heteroaryl or a 5- to 13-membered aromatic heterocycle having from 1, up to 4, heteroatoms from the group consisting of ⁇ , O and S, which ring or ring system can be linked via a carbon atom or a nitrogen atom, if such an atom is present.
  • pyridyl examples which may be mentioned are: pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolicenyl, indolyl, benzo[b]thienyl, benzo[b] furyl, benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl.
  • Preferred examples include pyrazolyl, pyrazinyl, pyrrolyl, imidazoyl, triazolyl, indolyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl, imidazolyl and thienyl.
  • Heterocycle in the context of the invention represents a preferably 3- to 13-membered saturated or partially unsaturated heterocycle having from 1, up to 4, heteroatoms from the group consisting of N, O and S, which ring or ring system can be linked via a carbon atom or a nitrogen atom, if such an atom is present.
  • Examples which may be mentioned are: tetrahydropyranyl, aziridyl, azepanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, and 1,4-diazepinyl. Preference is given to azepanyl, piperazinyl, piperidinyl, morpholinyl and pyrrolidinyl.
  • C ⁇ -Alkylene or C ⁇ -alkylene bridge represents a linear or branched, bivalent alkylene radical preferably having 1 to 4 carbon atoms, also known as alkandiyl.
  • Non-limiting examples include methylene, ethylene, propylene, ⁇ -methylethylene, ⁇ -methylethylene, ⁇ - ethylethylene, ⁇ -ethylethylene, butylene, ⁇ -methylpropylene, ⁇ -methylpropylene, and ⁇ - methylpropylene.
  • CyCin-Bridged bicycloalkyl represents a bicyclic alkyl radical having 5 to 10 carbon atoms also containing an alkylene bridge.
  • Non-limiting examples include [2.2.1]bicycloheptane, [2.2.2]bicyclooctanetane, [2.1.1]bicyclohexane,
  • a ring system represents a mono-, bi- or tricyclic system of fused rings. These rings share two ring members. These ring members are preferably adjacent ([0]-bridge).
  • Non limiting examples include naphthalene, benzo[2,3]dioxolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and indole.
  • a * symbol next to a bond denotes the point of attachment in the molecule.
  • the compounds according to the invention exhibit an unforeseeable, useful pharmacological and pharmacokinetic activity spectrum. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of disorders in humans and animals.
  • the compounds of this invention may be formulated as a solution of lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or in buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium acetate.
  • the compounds of the present invention may be encapsulated, tableted, or incorporated into an emulsion (oil-in-water or water-in-oil) syrup for oral administration.
  • Pharmaceutically acceptable solids or liquid carriers which are generally known in the pharmaceutical formulary arts, may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch (corn or potato), lactose, calcium sulfate dihydrate, terra alba, croscarmellose sodium, magnesium stearate or stearic acid, talc, pectin, acacia, agar, gelatin, maltodextrins and microcrystalline cellulose, or colloidal silicon dioxide.
  • Liquid carriers include syrup, peanut oil, olive oil, corn oil, sesame oil, saline, and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 10 mg to about 1 g per dosage unit.
  • the dosage ranges for administration of the heterocyclics disclosed in this invention are those to produce the desired affect.
  • the dosage will generally vary with age, body weight, extent of the disease, and contraindications, if any.
  • the dosage will also be dete ⁇ nined by the existence of any adverse side effects that may accompany the compounds. It is always desirable, whenever possible, to keep adverse side effects to a minimum.
  • One skilled in the art can easily determine the appropriate dosage, scheduling, and method of administration for the exact formulation of the composition being used in order to achieve the desired effective concentration in the individual patient.
  • the dosage can vary from between about 1 mg/kg/day to about 500 mg/kg/day, and preferable from between about 1 mg/kg/day to about 50 mg/kg/day.
  • the present invention also relates to a process for making the compounds.
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures.
  • the compounds (I) can be synthesized according to the reaction sequence shown in Method Al above.
  • the compounds (VIII) can be synthesized by reacting amino compounds (VI) with compounds (VII), wherein L is a leaving group, for example a halogen radical such as Cl, or a radical of the formula -OC(O)R 5 , wherein R 5 is defined as optionally substituted C ⁇ -alkyl or -CH 2 C(O)OR 4 .
  • Compounds (IN) are obtained by reacting compounds (NIII) with a dehydrating agent such as, e.g., phosphorous pentoxide.
  • the compounds (LV) can also be directly converted to the compounds (f) according to the General Method Bl.
  • treatment of compounds (LV) with compounds (X) and (III) gives compounds (I).
  • the compounds (VI) are commercially available or can be synthesized according to methods commonly known to those skilled in the art (H. Mayer et al., Heterocycles 31, 1035 (1990); E. M ⁇ ller (ed.), "Methoden der Organischen Chemie” (Houben-Weyl), 4 th ed., Vol. 11/1 Stickstoff-Neritatien II, Georg Thieme Nerlag, Stuttgart 1957; Shepard et al. in J. Org. Chem. 17, 568 (1952) and in J. Am. Chem. Soc. 72, 4364 (1950)).
  • the compounds (Nil) are commercially available or can be synthesized according to methods commonly known those skilled in the art [e.g. via acylation of acetic acid with an alkyl chloroformate or dialkyl carbonate (March, Advanced Organic Chemistry, 3 rd ed., p. 440-441, Wiley 1985) and converting the resulting monoester of malonic acid into e.g. the corresponding acid chloride or anhydride by methods commonly known to those skilled in the art (see e.g. March, Advanced Organic Chemistry, 3 rd ed., p. 355, 388, Wiley 1985)].
  • Suitable solvents comprise the customary organic solvents which are inert under the reaction conditions.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane
  • hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene, chlorobenzene
  • ketones such as acetone
  • esters such as ethyl acetate
  • nitriles such as acetonitrile
  • heteroaromatics such as pyridine
  • polar solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide
  • mixtures such as dimethyl formamide and hexamethyl phosphoric acid tris-amide
  • the compounds (Nil) are generally employed in an amount of from 1 to 4 mol per mol of compounds (NI); an equimolar amount or slight excess of compounds (VII) is preferred.
  • the reaction between the compounds (VI) and (VH) is preferably carried out in the presence of a base.
  • Non-limiting examples include alkali metal hydrides and alkali metal alkoxides such as, for example, sodium hydride and potassium tert-butoxide; C ⁇ -C -alkyl amines such as, for example, triethyl amine; cyclic amines such as, for example, piperidine, pyridine, dimethylamino pyridine and -preferably - l,8-diazabicyclo[4.3.0]undec-7-ene (DBU).
  • the base is generally employed in an amount of from 1 to 4 mol per mol of compounds (VI); an equimolar amount or slight excess of the base is preferred.
  • the reaction of the compounds (VI) and (Nil) can generally be carried out within a relatively wide temperature range. In general, the reaction is carried out within a range of from -20 to
  • 200°C preferably from 0 to 70°C, and more preferably at room temperature.
  • dehydrating agents such as, for example, P 2 O 5 or POCl 3 are generally employed in an amount of from 1 to 10 mol, preferably from 3 to 8 mol, per mol of compounds (VHf).
  • the cyclization reaction of the compounds (NIL-) to yield the compounds (IN) is also preferably carried out in a solvent.
  • a solvent ⁇ on-limiting examples comprise the customary organic solvents which are inert under the reaction conditions. They preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy.
  • ethane hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene, chlorobenzene; esters such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; heteroaromatics such as pyridine; polar solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide; and mixtures thereof.
  • hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane,
  • Toluene is preferred, if the reaction is carried out with P 2 O 5 , and acetonitrile is preferred, if the reaction is carried out with POCl 3 (Benovsky, Stille, Tetrahedron Lett. 38, 8475-8478 (1997)).
  • the temperature for the cyclization reaction of compounds (NLII) is preferably within a range of from 60 to 200°C and more preferably within a range of from 80 to 120°C.
  • the above process steps are generally carried out under atmospheric pressure. However, it is also possible to carry them out under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).
  • the reaction time can generally be varied within a relatively wide range, i general, the reaction is finished after a period of from 2 to
  • the compounds (II) are commercially available or can be synthesized according to methods commonly known to those skilled in the art (LT. Harrison and S. Harrison, Compendium of Organic Synthetic Methods, pp. 132-176, Wiley-Interscience; E. M ⁇ ller
  • the compounds (III) are commercially available.
  • reaction of the compounds (LV) with compounds (II) and (HI), or with compounds (X) and (in), or with compounds (IX), or with compounds (XI), can be carried out as a one-pot synthesis, preferably in a solvent.
  • Suitable solvents comprise the customary organic solvents which are inert under the reaction conditions.
  • Non-limiting examples include ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachlori.de, dichloroethane, trichloroethylene, chlorobenzene; alcohols such as methanol, ethanol, n- propanol, isopropanol; esters such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; heteroaromatics such as pyridine; polar solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide; and mixtures of the above-mentioned solvents.
  • the compounds (LU) are generally employed in an amount of from 1 to 3 mol per mol of compounds (LI); an equimolar amount or slight excess of compounds (LU) is preferred.
  • the compounds (LV) are generally employed in an amount of from 0.1 to 1 mol, preferably from 0.3 to 1 mol, per mol of compounds (II).
  • the compounds (LX) or (XI) are generally employed in an amount from 1 to 3 mol per mol of compounds (IV); an equimolar amount or slight excess of compounds (III) is preferred.
  • the reactions of the compounds (IV) with compounds (II) and (IE), or with compounds (X) and (III), or with compounds (DC), or with compounds (XL), are preferably carried out in the presence of a base.
  • a base include alkali metal hydrides and alkali metal alkoxides such as, for example, sodium hydride and potassium tert-butoxide; Cwalkyl amines such as, for example, triethyl amine; cyclic amines such as, for example, pyridine, dimethylamino pyridine, l,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and - preferably - piperidine.
  • the base is generally employed in an amount of from 0,1 to 1 mol, preferably from 0,3 to 1 mol, per mol of compounds (II) or compounds (V), respectively.
  • the reactions of the compounds (LV) with compounds (II) and (III), or with compounds (X) and (LQ), or with compounds (IX), or with compounds (XI), are generally carried out within a relatively wide temperature range, i general, they are carried out in a range of from -20 to 200°C, preferably from 0 to 100°C, and more preferably from 50 to 90°C.
  • the steps of this reaction are generally carried out under atmospheric pressure. However, it is also possible to carry them out under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).
  • the reaction time can generally be varied within a relatively wide range. In general, the reaction is finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
  • the reaction between the compounds (N) and H ⁇ XY is preferably carried out in a solvent.
  • Suitable solvents comprise the customary organic solvents which are inert under the reaction conditions.
  • Non-limiting examples include ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene, chlorobenzene; ketones such as acetone; esters such as ethyl acetate; nitriles such as acetonitrile; heteroaromatics such as pyridine; polar solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide; and mixtures of the above-mentioned solvents.
  • the compounds HNXY are generally employed in an amount of from 1 to 4 mol per mol of compounds (V); an equimolar amount or slight excess of compounds HNXY is preferred.
  • reaction between the compounds (V) and HNXY is preferably carried out in the presence of a coupling reagent by methods commonly known to those skilled in the art (see e.g. March, Advanced Organic Chemistry, 4 th ed., pp. 419-421 Wiley 1992).
  • Non-limiting examples include dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, N,N'-carbonyldiimidazole, pivaloyl chloride, bis(2-oxo-3- oxazolidinyl)phosphinic chloride and benzotriazol-l-yloxytris(pyrrolidino)- phosphonium hexafluorophosphate.
  • the coupling reagents may optionally be bound to a polymeric resin.
  • the coupling reagent is generally employed in an amount of from 1 to 4 mol per mol of compounds (V); an equimolar amount or slight excess of the reagent is preferred.
  • a promoter may be added to the coupling reaction.
  • Non-limiting examples include 1-hydroxybenzotriazole, N,N'-dimethylaminopyridine, and 3-hydroxy-3H-l,2,3- triazolo[4,5-b]-pyridine.
  • the promoter is generally employed in an amount from 0.1 to 1 mol per mol of compounds (V), preferably from 0.3 to 1 mol, per mol of compounds (V).
  • the reaction of the compounds (V) and HNXY can generally be carried out within a relatively wide temperature range, hi general, the reaction is carried out within a range of from -20 to 200°C, preferably from 0 to 70°C, and generally at room temperature.
  • Compounds (LX) and (XI) are commercially available or can be synthesized according to methods commonly known to those skilled in the art (H. Feuer (ed.) "The Chemistry of the Nitro and Nitroso Groups” Interscience Publishers, New York, 1969, pp. 76-117).
  • Compounds (I) wherein R 3 is hydrogen can be synthesized by General Method A or B using compounds (III) or (V) respectively wherein R 3 is hydrogen.
  • the compounds obtained through General Method A or B can be converted into an isomer, a pharmaceutically acceptable salt, a hydrate or a hydrate of a pharmaceutically acceptable salt thereof
  • the compounds of the present invention are inhibitors of phosphodiesterase 10a (PDE 10a).
  • PDE 10a phosphodiesterase 10a
  • the biological tests described below show that the compounds (I) exhibit a pronounced anti-proliferation activity against tumor cells; they are therefore useful for the treatment of cancer.
  • our investigations showed that they are also useful for treatment of conditions of pain and/or for the lowering of the temperature of the body in fever conditions.
  • the compounds according to the invention can be used as active ingredients for the production of medicaments against carcinomatous disorders.
  • they can be converted into the customary formulations such as tablets, coated tablets, aerosols, pills, granules, syrups, emulsions, suspensions and solutions using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the compounds according to the invention are used in an amount such that their concentration is approximately 0.5 to approximately 90% by weight, based on the ready-to-use formulations, the concentration being dependent, inter alia, on the indication of the medicament.
  • the formulations can be produced, for example, by extending the active compounds with solvents and/or excipients having the above properties, where, if appropriate, additionally emulsifiers or dispersants and, in the case of water as the solvent, an organic solvent can additionally be added.
  • Administration can be carried out in a customary manner, preferably orally, transdermally or parenterally, for example perlingually, buccally, interperitoneally, intravenously, nasally, rectally or ihhalationally.
  • the compounds according to the invention are also suitable for use in veterinary medicine.
  • the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practice. Depending on the kind of animal to be treated, the veterinary surgeon can determine the nature of use and the dosage.
  • the present invention provides compounds for the use in a medical application, in particular for combating cancer.
  • the invention further provides a method of manufacturing a pharmaceutical composition by combining at least one of the compounds of the invention with at least one pharmacologically acceptable formulating agent.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient an effective amount of at least one of the compounds of the invention and at least one pharmacologically acceptable formulating agent.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient an effective amount of at least one of the compounds of the invention and at least one pharmaceutical active ingredient which is different from the compounds of the invention.
  • the invention further provides a medicament in dosage unit form comprising an effective amount of a compound according to the invention together with an inert pharmaceutical carrier.
  • the invention further provides a method of combating cancer in mammals comprising administering to a mammal in need thereof an antiproliferative effective amount of at least one compound according to the invention either alone or in admixture with a diluent or in the form of a medicament.
  • TMCremophor® non-ionic emulsifier from BASF, Germany DBU l,8-diazabicyclo[5.4.0]undec-7-ene DMEM Dulbecco's Modified Eagle Medium, Life Technologies,
  • HPLC equipment Thermo Separation Products P4000, AS3000, UN3000HR
  • Racemic l-(4-fluorophenyl)-ethylamine (commercially available) was resolved by (+)- tartaric acid following the procedures of A. Ault (Org. Synth., 1973, Coll. Vol. 5, 932) and S. Takenaka et al. (J.C.S. Perkin II, 1978, 95).
  • the organic material was extracted from the dark biphasic mixture using ethyl acetate (3000 mL). The combined organic extracts were washed with brine (3 x 2000 mL) and concentrated to 1/3 volume. The resultant dark oil was placed on a pad of silica gel 60 (400 cc) and eluted using ethyl acetate/hexane (1:1). The desired fractions were concentrated to a yellow oil which was seeded with a small amount of crystals of the title compound and placed in a refrigerator overnight.
  • LTMP lithium tetramethylpiperidine
  • butyllithium 37.14 mmol, 14.86 mL
  • 2,2,6,6-tetramethylpiperidine 42.86 mmol, 7.23 mL
  • tetrahydrofuran 15 mL
  • the mixture was stirred at 0 °C for 1 h.
  • This solution was added slowly to a solution of 1,2-bromofluorobenzene (5.0 g, 28.57 mmol, 3.12 mL) in tetrahydrofuran (90 mL) at - 75 °C.
  • the amines used in this experiment were prepared as 0.5 M solution in dichloromethane by using Bohdan weight station.
  • the amine solutions (270 ⁇ l, 135.0 ⁇ mol) were dispensed into 96-well format FlexChem ® Multiple Synthesis Reactor Block by using Tecan station.
  • Ethyl 2-(3-carboxyphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,l- a]isoquinoline-l-carboxylate 60mg/lml DCM, 137.8 ⁇ mol, Intermediate 1.3.
  • PS-DCC resin (n-cyclohexylcarbodiimide, n'- methyl polystyrene HL, 1.9 mmol/g, 140 mg, 266 ⁇ mol) was then loaded to each well of the 96-well format FlexChem ® Multiple Synthesis Reactor Block. The block was then sealed and stirred by rotation motion in a FlexChem ® Rotating Oven at ambient temperature for 12 h. The solution in each well was released to 96 deep well plate. The resin was washed with dichloromethane (3 X 2 ml) and the dichloromethane was released to the other deep well plates.
  • 4-(4-Formyl-3-methoxyphenoxy)-butyryl aminomethyl resin (NovaBiochem; 10.0 g, 0.78 mmol/g) is suspended in dichloromethane (80 ml)/trimethyl orthoformiate (40 ml). Propylamine (2.31 g, 5 equiv.) is added and the reaction mixture is shaken at room temperature overnight. The mixture is filtered and the resin is washed twice with dimethyl- formamide. The resin is re-suspended in dimethylformamide (100 ml), and tetrabutylammonium borohydride (4.01 g, 2 equiv.) is added to the mixture.
  • the propylamine resin from above (3.00 g, 2.34 mmol) is suspended in dichloromethane (30 ml). N,N-diisopropyl ethylamine (1.81 g, 6 equiv.) is added with stirring, followed by 3-formylbenzoic acid chloride (1.18 g, 3 equiv.). The mixture is shaken for 1 h at room temperature. The resin is filtered and repeatedly washed with methanol, dimethylformamide, methanol, dichloromethane and diethyl ether, and dried in vacuo.
  • the fo ⁇ nylbenzoic acid amide resin from above (1.00 g, 0.78 mmol) is suspended in dioxane (6 ml)/isopropanol (3 ml).
  • the respective nitroalkane (5 equiv.) and ammonium acetate 300 mg, 5 equiv.) are added, and the mixture is shaken at 100 °C overnight.
  • the resin is filtered, repeatedly washed (methanol, water, dimethylformamide, methanol, dichloromethane and diethyl ether), and dried in vacuo.
  • test compounds were serially diluted in DMSO using two-fold dilutions to stock concentrations ranging typically from 200 ⁇ M to 1.6 ⁇ M (final concentrations in the assay range from 4 ⁇ M to 0.032 ⁇ M).
  • 96-well assay isoplates (Wallac Inc., Atlanta, GA, U.S.A.) were loaded with 2 ⁇ L of the serially diluted individual test compounds followed by 50 ⁇ L of a dilution of crude recombinant PDE lOa-containing Sf9 cell lysate.
  • the dilution of the lysate was selected such that less than 70%> of the substrate is converted during the later incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/hydrochloric acid pH
  • the substrate [5',8- 3 H] adenosine 3',5'- cyclic phosphate (1 ⁇ Ci/ ⁇ L; Amersham Pharmacia Biotech., Piscataway, NJ, U.S.A.), was diluted 1:2000 in assay buffer (assay buffer: 50 mM Tris/hydrochloric acid pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA) to give a final working concentration of 0.0005 ⁇ Ci/ ⁇ L.
  • assay buffer 50 mM Tris/hydrochloric acid pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA
  • MDA-MB-231 human breast carcinoma cells (ATCC # HTB26) were cultured in standard growth medium (DMEM), supplemented with 10%. heat-inactivated FBS, 10 mM HEPES, 2 mM glutamine, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin) at 37°C in 5% CO 2 (vol/vol) in a humidified incubator. Cells were plated at a density of 3000 cells per well in 100 ⁇ L growth medium in a 96 well culture dish. 24 hours after plating, lactate dehydrogenase (LDH) activity was determined using the Cytotox 96 Non-radioactive
  • Cytotoxicity Kit (Promega, Madison WI, U.S.A.) to yield T 0 LDH values. Briefly, cells were lysed with the addition of 200 ⁇ L of Lysis Buffer (included in the Promega Kit) and lysates were further diluted 1:50 in Lysis Buffer. 50 ⁇ L of diluted cell lysate were transferred to a fresh 96 well culture plate. The assay was initiated with the addition of 50 ⁇ L of substrate per well. Color development was allowed to proceed for 10-15 minutes.
  • the assay was terminated with the addition of 50 ⁇ L of Stop Solution (included in the Promega Kit). Optical densities were determined spectrophotometrically at 490 nm in a 96 well plate reader (SpectraMax 250, Molecular Devices, Sunnyvale, CA, U.S.A.).
  • Test compounds were dissolved in 100%) DMSO to prepare 10 mM stocks. Stocks were further diluted 1 :250 in growth medium to yield working stocks of 40 ⁇ M test compound in 0.4%) DMSO. Test compounds were serially diluted in growth medium containing 0.4%> DMSO to maintain constant DMSO concentrations for all wells. 50 ⁇ L of fresh growth medium and 50 ⁇ L of diluted test compound were added to each culture well to give a final volume of 200 ⁇ L. The cells with and without individual test compounds were incubated for 72 hours at which time LDH activity was measured to yield T 2h values. Optionally, the IC 50 values can be detennined with a least squares analysis program using compound concentration versus percent inhibition.
  • T 72 ctr i LDH activity at 72 hours in the absence of test compound
  • MDA-MB-231 cells are cultured as described above. The cells are harvested by trypsinization, washed, counted, adjusted to 2.5x10 7 cells/mL with ice cold phosphate-buffered saline (PBS), and subsequently stored on ice until transplantation.
  • Test compounds are formulated for oral administration in a vehicle for oral administration composed of polyethylene glycol-400, Cremophor®, ethanol and 0.9% saline (40:5:5:50).
  • Tumor measurements are performed twice per week. Tumor weights are calculated using the formula (a x vX)!2, where a and w refer to the larger and smaller dimensions collected at each measurement.. Animals are sacrificed on day 15 after transplantation and plasma was harvested for pharmacokinetic analyses.
  • An MX-1 breast tumor xenograft model is maintained by serial passage in NCr nu/nu female mice (Taconic Farms, Germantown, NY, USA). Tumors are aseptically harvested from mice when they weigh approximately lg. The envelope and any non- viable areas are dissected and the viable tissue is cut into 3 x 3 x 3 mm cubes. These fragments are implanted in the axilary region of the flank of recipient mice using a trochar.
  • mice Treatment in anti-tumor efficacy studies is intiated when all mice have tumors ranging in size from 75-125 mg. There are typically 10 mice in each experimental group. Each experiment contains an untreated control group to monitor tumor growth kinetics, a vehicle-treated control group, and a positive agent control group to assess the response of the model in each experiment to an agent with an expected degree of anti-tumor efficacy. Lack of confonnance of any of the controls to the historical ranges for the model constitutes a reason to nullify the study. The test compounds were administered starting at different dosages (e.g. 75 and 150 mg/kg) and different schedules (e.g. qld x 10, bid x 10).
  • Test compounds are formulated for oral administration once per day in a vehicle composed of 51%) PEG400/ 12% ethanol/ 12% Cremophor® EL/ 0.1 N hydrochloric acid .
  • Tumor size is recorded in whole mm as measured in two perpendicular dimensions.
  • Animal body weights are recorded in tenths of grams. Both measurements are collected two to three times per week. Animals are sacrificed on day 10 after the last dose and last measurements.
  • Tumor weights are calculated using the equation (/ x w 2 )/2, where / and w refer to the larger and smaller dimensions collected at each measurement. Efficacy is measured as the percent suppression of tumor growth expressed as % ⁇ T/ ⁇ C, where ⁇ T and ⁇ C represent the change in the size of the average tumor in the treated and control groups, respectively, over the treatment period. Significance is evaluated using a Student's t-test with a p ⁇ 0.05.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • a single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
  • the Rliodigel is suspended in ethanol and the active component is added to the suspension.
  • the water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés 2-substitués pyrrolo[2.1-a]dihydroisoquinoline qui inhibent phosphodiesterase 10a et sont utiles contre le cancer.
PCT/US2002/040328 2001-12-18 2002-12-18 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer Ceased WO2003051877A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002366362A AU2002366362A1 (en) 2001-12-18 2002-12-18 2-substituted pyrrolo(2.1-a)isoquinolines against cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US34136701P 2001-12-18 2001-12-18
US60/341,367 2001-12-18
US34231001P 2001-12-19 2001-12-19
US60/342,310 2001-12-19

Publications (1)

Publication Number Publication Date
WO2003051877A1 true WO2003051877A1 (fr) 2003-06-26

Family

ID=26992477

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/040328 Ceased WO2003051877A1 (fr) 2001-12-18 2002-12-18 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer

Country Status (2)

Country Link
AU (1) AU2002366362A1 (fr)
WO (1) WO2003051877A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003130A1 (fr) * 2003-06-30 2005-01-13 Altana Pharma Ag Nouveaux pyrrolodihydroisoquinolines utiles dans le traitement du cancer
WO2005002579A1 (fr) * 2003-06-30 2005-01-13 Altana Pharma Ag Derives de pyrrolo-dihydroisoquinoline comme inhibiteurs de pde10
WO2005028426A1 (fr) * 2003-09-19 2005-03-31 Chugai Seiyaku Kabushiki Kaisha Nouveau derive de 4-phenylamino-benzaldoxime et son utilisation en tant qu'inhibiteur de mek
WO2005035514A3 (fr) * 2003-10-08 2005-07-14 Vertex Pharma Modulateurs des transporteurs des cassettes de fixation de l'atp
EP1645556A1 (fr) * 2004-10-07 2006-04-12 Boehringer Ingelheim International GmbH Derives d'arylpiperazine-benzoylamide utiles comme agents pharmaceutiques
WO2006089815A1 (fr) * 2005-01-12 2006-08-31 Nycomed Gmbh Nouvelles pyrrolodihydroisoquinolines utilisees en tant qu'inhibiteurs de pde10
JP2007537163A (ja) * 2004-05-06 2007-12-20 サイトキネティクス・インコーポレーテッド 化合物、組成物、および方法
WO2008044054A3 (fr) * 2006-10-12 2008-08-14 Astex Therapeutics Ltd Composés pharmaceutiques
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US7745663B2 (en) 2004-07-26 2010-06-29 Chugai Seiyaku Kabushiki Kaisha 5-Substituted-2-phenylamino benzamides as MEK inhibitors
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
WO2011008597A1 (fr) * 2009-07-14 2011-01-20 Schering Corporation Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10
WO2012080220A1 (fr) * 2010-12-13 2012-06-21 Katholieke Universiteit Leuven, K.U. Leuven R&D Nouveaux composés pour le traitement de maladies neurodégénératives
US8277807B2 (en) 2006-10-12 2012-10-02 Astex Therapeutics Limited Pharmaceutical combinations
US8383619B2 (en) 2008-04-11 2013-02-26 Astex Therapeutics Limited Pharmaceutical compounds
US8394789B2 (en) 2008-02-08 2013-03-12 Msd Oss B.V. (Dihydro)pyrrolo[2,1-α]isoquinolines
US8653084B2 (en) 2006-10-12 2014-02-18 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
RU2575174C1 (ru) * 2015-03-12 2016-02-20 федеральное государственное автономное образовательное учреждение высшего образования "Российский университет дружбы народов" (РУДН) СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ 5,6-ДИГИДРОПИРРОЛО[2,1-a]ИЗОХИНОЛИНОВ, СОДЕРЖАЩИХ В ПОЛОЖЕНИИ 2 ФУНКЦИОНАЛЬНУЮ ГРУППУ
WO2016023028A3 (fr) * 2014-08-08 2016-05-26 The Regents Of The University Of Michigan Inhibiteurs de la kinase du récepteur couplé aux protéines g 2 et procédés d'utilisation de ceux-ci
US10155259B2 (en) 2011-09-11 2018-12-18 Merck Sharp & Dohme B.V. FSH receptor antagonists
WO2023060811A1 (fr) * 2021-10-11 2023-04-20 丽珠集团新北江制药股份有限公司 Intermédiaire de fluralaner et procédé de préparation de fluralaner associé
US11952378B1 (en) 2023-12-14 2024-04-09 King Faisal University Pyrrolo[2,3-c]isoquinoline-1,2-dione compounds as CK2 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048144A1 (fr) * 2000-12-13 2002-06-20 Bayer Aktiengesellschaft Pyrrolo (2.1-a) dihydroisoquinolines et utilisation en tant qu'inhibiteurs de phosphodiesterase 10a

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048144A1 (fr) * 2000-12-13 2002-06-20 Bayer Aktiengesellschaft Pyrrolo (2.1-a) dihydroisoquinolines et utilisation en tant qu'inhibiteurs de phosphodiesterase 10a

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDERSON W K ET AL: "SYNTHESIS AND ANTILEUKEMIC ACTIVITY OF BIS(CARBAMOYL)OXYMETHYL-SUBSTI TUTED PYRROLO2,1-AISOQUINOLINES, PYRROLO1,2-AQUINOLINES, PYRROLO2,1-AISOBENZAZEPINES, AND PYRROLO1,2-ABENZAZEPINES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 31, no. 11, 1988, pages 2097 - 2102, XP001068970, ISSN: 0022-2623 *

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004253690B2 (en) * 2003-06-30 2010-03-25 Nycomed Gmbh Pyrrolodihydroisoquinolines as PDE10 inhibitors
WO2005002579A1 (fr) * 2003-06-30 2005-01-13 Altana Pharma Ag Derives de pyrrolo-dihydroisoquinoline comme inhibiteurs de pde10
JP2009513494A (ja) * 2003-06-30 2009-04-02 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ１０阻害剤としてのピロロジヒドロイソキノリン
EA012110B1 (ru) * 2003-06-30 2009-08-28 Алтана Фарма Аг Пирролодигидроизохинолины как ингибиторы pde10
JP2009513495A (ja) * 2003-06-30 2009-04-02 フォーエスシー アクチエンゲゼルシャフト 癌の治療において有効な新規のピロロジヒドロイソキノリン
WO2005003130A1 (fr) * 2003-06-30 2005-01-13 Altana Pharma Ag Nouveaux pyrrolodihydroisoquinolines utiles dans le traitement du cancer
WO2005003129A1 (fr) * 2003-06-30 2005-01-13 Altana Pharma Ag Pyrrolodihydroisoquinolines comme inhibiteurs de pde10
JPWO2005028426A1 (ja) * 2003-09-19 2007-11-15 中外製薬株式会社 新規４−フェニルアミノ−ベンズアルドオキシム誘導体並びにそのｍｅｋ阻害剤としての使用
WO2005028426A1 (fr) * 2003-09-19 2005-03-31 Chugai Seiyaku Kabushiki Kaisha Nouveau derive de 4-phenylamino-benzaldoxime et son utilisation en tant qu'inhibiteur de mek
JP4931419B2 (ja) * 2003-09-19 2012-05-16 中外製薬株式会社 新規４−フェニルアミノ−ベンズアルドオキシム誘導体並びにそのｍｅｋ阻害剤としての使用
US8084645B2 (en) 2003-09-19 2011-12-27 Chugai Seiyaku Kabushiki Kaisha 4-phenylamino-benzaldoxime derivatives and uses thereof as mitogen-activated protein kinase kinase (MEK) inhibitors
US7598412B2 (en) 2003-10-08 2009-10-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2005035514A3 (fr) * 2003-10-08 2005-07-14 Vertex Pharma Modulateurs des transporteurs des cassettes de fixation de l'atp
JP2007537163A (ja) * 2004-05-06 2007-12-20 サイトキネティクス・インコーポレーテッド 化合物、組成物、および方法
US7745663B2 (en) 2004-07-26 2010-06-29 Chugai Seiyaku Kabushiki Kaisha 5-Substituted-2-phenylamino benzamides as MEK inhibitors
US8575391B2 (en) 2004-07-26 2013-11-05 Chugai Seiyaku Kabushiki Kaisha 5-substituted-2-phenylamino benzamides as MEK inhibitors
EP1645556A1 (fr) * 2004-10-07 2006-04-12 Boehringer Ingelheim International GmbH Derives d'arylpiperazine-benzoylamide utiles comme agents pharmaceutiques
WO2006089815A1 (fr) * 2005-01-12 2006-08-31 Nycomed Gmbh Nouvelles pyrrolodihydroisoquinolines utilisees en tant qu'inhibiteurs de pde10
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US8530469B2 (en) 2005-04-13 2013-09-10 Astex Therapeutics Ltd. Therapeutic combinations of hydroxybenzamide derivatives as inhibitors of HSP90
US8816087B2 (en) 2005-04-13 2014-08-26 Astex Therapeutics Limited Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US8101648B2 (en) 2005-04-13 2012-01-24 Astex Therapeutics, Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US9914719B2 (en) 2005-04-13 2018-03-13 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US8106057B2 (en) 2006-03-01 2012-01-31 Astex Therapeutics, Ltd. Dihydroxyphenyl isoindolylmethanones
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
JP2010505933A (ja) * 2006-10-12 2010-02-25 アステックス、セラピューティックス、リミテッド 医薬化合物
US8277807B2 (en) 2006-10-12 2012-10-02 Astex Therapeutics Limited Pharmaceutical combinations
WO2008044054A3 (fr) * 2006-10-12 2008-08-14 Astex Therapeutics Ltd Composés pharmaceutiques
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds
US9428439B2 (en) 2006-10-12 2016-08-30 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
US8653084B2 (en) 2006-10-12 2014-02-18 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
RU2495037C2 (ru) * 2008-02-08 2013-10-10 Мерк Шарп и Доум Б.В. (дигидро)пирроло[2,1-а]изохинолины
US8394789B2 (en) 2008-02-08 2013-03-12 Msd Oss B.V. (Dihydro)pyrrolo[2,1-α]isoquinolines
US8664218B2 (en) 2008-04-11 2014-03-04 Astex Therapeutics Ltd. Pharmaceutical compounds
US8383619B2 (en) 2008-04-11 2013-02-26 Astex Therapeutics Limited Pharmaceutical compounds
WO2011008597A1 (fr) * 2009-07-14 2011-01-20 Schering Corporation Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10
WO2012080220A1 (fr) * 2010-12-13 2012-06-21 Katholieke Universiteit Leuven, K.U. Leuven R&D Nouveaux composés pour le traitement de maladies neurodégénératives
US9284271B2 (en) 2010-12-13 2016-03-15 Katholieke Universiteit Leuven, K.U. Leuven R&D Compounds for the treatment of neurodegenerative diseases
US10155259B2 (en) 2011-09-11 2018-12-18 Merck Sharp & Dohme B.V. FSH receptor antagonists
WO2016023028A3 (fr) * 2014-08-08 2016-05-26 The Regents Of The University Of Michigan Inhibiteurs de la kinase du récepteur couplé aux protéines g 2 et procédés d'utilisation de ceux-ci
US10023564B2 (en) 2014-08-08 2018-07-17 The Regents Of The University Of Michigan G protein-coupled receptor kinase 2 inhibitors and methods for use of the same
RU2575174C1 (ru) * 2015-03-12 2016-02-20 федеральное государственное автономное образовательное учреждение высшего образования "Российский университет дружбы народов" (РУДН) СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ 5,6-ДИГИДРОПИРРОЛО[2,1-a]ИЗОХИНОЛИНОВ, СОДЕРЖАЩИХ В ПОЛОЖЕНИИ 2 ФУНКЦИОНАЛЬНУЮ ГРУППУ
WO2023060811A1 (fr) * 2021-10-11 2023-04-20 丽珠集团新北江制药股份有限公司 Intermédiaire de fluralaner et procédé de préparation de fluralaner associé
US11952378B1 (en) 2023-12-14 2024-04-09 King Faisal University Pyrrolo[2,3-c]isoquinoline-1,2-dione compounds as CK2 inhibitors

Also Published As

Publication number Publication date
AU2002366362A1 (en) 2003-06-30

Similar Documents

Publication Publication Date Title
WO2003051877A1 (fr) 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer
US7723347B2 (en) Substituted phenylamino-pyrimidines
US8329716B2 (en) Hetaryloxy-substituted phenylamino pyrimidines as Rho kinase inhibitors
US7737153B2 (en) Heteroaryloxy-substituted phenylaminopyrimidines as rho-kinase inhibitors
US9085575B2 (en) Tri- and tetracyclic pyrazolo[3,4-B]pyridine compounds as antineoplastic agent
US20040138249A1 (en) Pyrrolo (2.1a)dihydroisoquinolines and their use as phosphodiesterase 10a inhibitors
US20080249105A1 (en) Pyrrolopyridine-Substituted Benzol Derivatives for Treating Cardiovascular Diseases
US20030236271A1 (en) Fused heteroaryl derivatives
JPH11513398A (ja) タンパク質チロシンキナーゼ阻害剤としての二環式複素芳香族化合物
BR122018075851B1 (pt) Compostos relacionados ao tratamento de doença hiperproliferativa e processos para preparar compostos
MX2008014618A (es) Composiciones y metodos para inhibidores de cinasas del receptor fgf.
BR112013004750B1 (pt) Derivados de quinolina e quinoxalina como inibidores da cinase
US20080318946A1 (en) Di-amino-substituted heterocyclic compounds and methods of use
JPWO2004043936A1 (ja) Ｐｌｋ阻害剤
EP3966208A2 (fr) Composés et méthodes de traitement du cancer
TWI860797B (zh) 新穎acc抑制劑
WO2003014117A1 (fr) Derives de 3-pyrrolo[2.1-a]isoquinoleine substitues
WO2003014116A1 (fr) Derives de pyrrolo[2.1-a]isoquinoline
WO2023185073A1 (fr) Inhibiteur de parp7 et son utilisation
WO2012121168A1 (fr) Inhibiteur de kinase
AU2007272830B2 (en) Alkyne-substituted pyridone compounds and methods of use
US20170015664A1 (en) Fused Acridine Derivative and Pharmaceutical Composition, Preparation Method and Use Thereof
KR20160010522A (ko) 피리미딘-4-일)옥시)-1h-인돌-1-카르복스아미드 유도체 및 그의 용도
WO2006110447A2 (fr) Derives de pyrimidine
HK40042713A (en) Oxazino-quinazoline and oxazino-quinazoline type compound, preparation method therefor, and uses thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP