WO2003014117A1 - Derives de 3-pyrrolo[2.1-a]isoquinoleine substitues - Google Patents

Derives de 3-pyrrolo[2.1-a]isoquinoleine substitues Download PDF

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WO2003014117A1
WO2003014117A1 PCT/US2002/024877 US0224877W WO03014117A1 WO 2003014117 A1 WO2003014117 A1 WO 2003014117A1 US 0224877 W US0224877 W US 0224877W WO 03014117 A1 WO03014117 A1 WO 03014117A1
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alkyl
group
alkoxy
aryl
heterocyclyl
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PCT/US2002/024877
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English (en)
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Marcus Bauser
Jens-Kerim ERGÜDEN
Dietmar Flubacher
Paul Naab
Thorsten-Oliver Repp
Jürgen Stoltefuss
Nils Burkhardt
Andrea Sewing
Michael Schauer
Karl-Heinz Schlemmer
Olaf Weber
Stephen J. Boyer
Mark Miglarese
Shihong Ying
Ulrich Niewöhner
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Bayer Corporation
Bayer Aktiengesellschaft
NIEWÖHNER, Maria
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Publication of WO2003014117A1 publication Critical patent/WO2003014117A1/fr

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    • 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 3 -substituted pyrrolo[2.1-a]isoquinoline derivatives which are inhibitors of phosphodiesterase 10a, a process for preparing those com- pounds and a method of treating cancer in humans and animals by administering those 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 phos- phodiesterases (PDEs), which hydrolyze cAMP to 5 '-AMP.
  • PDEs 3 ',5' cyclic nucleotide phos- phodiesterases
  • Signal transduction via cAMP is associated with transcriptional events that can result in the inhibition of cellular proliferation (TJ. Shaw et al, Exp. Cell Res. 273, 95 (2002); T.W. Moody et al, Ann. N.Y. Acad. Sci. 921, 26 (2000); W.L. Lowe et al, Endocrinology. 138, 2219 (1997)); D.A. Albert, J. Clin. Invest. 95, 1490
  • 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 PDElOa (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" Me, Et, i -Pr, C g H ⁇
  • the compounds B are described as having anti-tumor activity due to their ability to intercalate into DNA. It is not mentioned that these compounds have any PDE 10a inhibitory activity.
  • R H, OCH 3
  • R" CH 3
  • R"' C 6 H 5
  • R H, CH 3 , OCH 3
  • R H, CH 3
  • the present invention relates to a compound ofthe formula
  • x and y independently from each other denote zero or 1 and x+y is 1 or 2;
  • R 1 and R 2 independently from each other denote hydrogen, C 1-4 -alkyl or CF 3) or R 1 and R 2 together form a C 1- -alkylene bridge;
  • R 3 denotes hydrogen, formyl, (C 1- -alkyl)-carbonyl, (C 1-4 -alkoxy)-carbonyl, NO 2 , NR 6 R 7 , C 1-4 -alkyl-NR 6 R 7 , C 1-4 -alkyl-OR 8 , C ⁇ -alkyl-COOR 8 , C 6-10 -aryl-C 1-4 -alkyl wherein the aryl moiety is optionally substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl, and C 1-4 -alkoxy;
  • R 6 and R 7 independently from each other denote hydrogen, C 1- -alkyl, C 3-8 - cycloalkyl, or C 6-10 -aryl-C 1-4 -alkyl wherein the aryl moiety is optionally substituted with 1 to 3 radicals selected from the group consisting of OH, Cj.
  • R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl which may contain up to 2 further hetero atoms selected from the group consisting of N, O and S, which heterocyclyl can further be substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl, C 1- -alkoxy, C 6-10 -aryl and aromatic 4- to 9- membered heterocyclyl with 1 to 4 hetero atoms selected from the group consisting of N, O and S;
  • R denotes hydrogen or C 1-4 -alkyl
  • R 4 denotes C 1-4 -alkyl
  • C 1-6 -alkyl which can be further substituted with one or more radicals selected from the group consisting of C ⁇ -6 -alkoxy, OH, and NH 2 ;
  • C 1-6 -alkoxy which can be further substituted with one or more radicals selected from the group consisting of C 1-6 -alkoxy, OH, and NH 2 ;
  • phenyloxy or benzyloxy wherein the phenyl moieties can contain one further substituent selected from the group consisting of C 1- -alkyl, C 1-6 -alkoxy, halogen and NO 2 ;
  • saturated 5- to 7-membered nitrogen-containing heterocyclyl which is linked to the C 6-10 -aryl moiety via the nitrogen atom and may contain up to 2 further heteroatoms selected from the group consisting of N, O and S and which saturated heterocyclyl can be further substituted with one or more radicals selected from the group consisting of C 1-6 -alkoxy, OH and NH 2 ;
  • R and R 10 independently from each other denote hydrogen, C 1-6 -alkyl, (C 1-6 -alkyl)-carbonyl, (C 1-6 -alkoxy)-carbonyl, C 1-6 - alkylsulfonyl, (C 1-6 -alkylamino)-carbonylamino, (C 6-1 o-aryl- amino)-carbonylamino,
  • R 9 and R 10 together with the nitrogen atom to wliich they are attached, form a 5- to 7-membered saturated, partially unsaturated or aromatic heterocyclyl which can contain up to 3 further hetero atoms selected from the group consisting of N, O and S, and which heterocyclyl can contain 1 to 3 substituents selected from the group consisting of C 1-6 -alkyl, C- 1-6 -alkoxy, C 6-10 -aryl and aromatic 4- to 9-membered heterocyclyl with 1 to 4 hetero atoms selected from the group consisting of N, O and S;
  • R 11 is hydrogen, C 1-6 -alkyl or C 6-1 o-aryl
  • C 1-12 -alkyl wliich can contain 1 to 3 substituents selected from the group consisting of C 1-6 -alkyl, C- 1-6 -alkoxy, C 6-1 o-aryl and aromatic 4- to 9-membered heterocyclyl with 1 to 4 hetero atoms selected from the group consisting of N, O and S;
  • C 3-8 -cycloalkyl which can contain 1 to 3 substituents selected from the group consisting of C 1-6 -alkyl, C- 1-6 -alkoxy, COOR 11 wherein R 11 is as defined above, C 6-10 -aryl and aromatic 4- to 9-membered heterocyclyl with 1 to 4 hetero atoms selected from the group consisting of N, O and S;
  • An 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 1 and R 2 independently from each other denote C 1-4 -alkyl or CF ;
  • R 3 denotes hydrogen, formyl, (C 1-4 -alkyl)-carbonyl, (C 1- -alkoxy)-carbonyl, NO 2 , NR 6 R 7 , C 1-4 -alkyl-NR 6 R 7 , C 1-4 -alkyl-OR 8 , C 1-4 -alkyl-COOR 8 , or C 6-10 -aryl-C 1-4 -alkyl wherein the aryl moiety can be substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl and C 1-4 -alkoxy;
  • R 6 and R 7 independently from each other denote hydrogen, C 1- -alkyl, C 3-8 - cycloalkyl, or C 6-10 -aryl-C 1-4 -alkyl wherein the aryl moiety can be substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl, and C 1-4 -alkoxy;
  • R 6 and R 7 together with the nitrogen atom to wliich they are attached form a 5- to 7-membered heterocyclyl which may contain up to 2 further hetero atoms selected from the group consisting of N, O, and S and which heterocyclyl can be further substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl, C 1- -alkoxy, C 6-10 -aryl and aromatic 4- to 9-membered heterocyclyl with 1 to 3 hetero atoms selected from the group consisting of N, O, and S;
  • R 8 denotes hydrogen or C 1- -alkyl;
  • R 4 denotes C 1-4 -alkyl
  • phenyl optionally having 1 to 3 further substituents selected from the group consisting of F, CI, Br; C 1-6 -alkyl; C 1-6 -alkoxy; OH; NR 9 R 10 and COOR 11 ;
  • indolyl optionally having 1 to 3 further substituents selected from the group consisting of F, CI, Br; C 1-6 -alkyl; C 1-6 -alkoxy; OH; NR 9 R 10 and COOR 11 ;
  • R 9 to R 11 independently from each other denote C 1-6 -alkyl
  • 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 1 and R 2 independently from each other denote CH 3 or C 2 H 5 ;
  • R 3 denotes hydrogen, formyl, (C 1-4 -alkyl)-carbonyl, (C 1-4 -alkoxy)-carbonyl, NO 2 , NR 6 R 7 , C 1-4 -alkyl-NR 6 R 7 , C 1-4 -alkyl-OR 8 , C 1-4 -alkyl-COOR 8 , or C 6-10 -aryl-C 1-4 -alkyl wherein the aryl moiety can be substituted with 1 to 3 radicals selected from the group consisting of OH, C 1- -alkyl and C 1-4 -alkoxy;
  • 5- to 7-membered heterocyclyl which may contain up to 2 further hetero atoms selected from the group consisting of N, O, and S and which heterocyclyl can be further substituted with 1 to 3 radicals selected from the group consisting of OH, C 1-4 -alkyl, C 1-4 -alkoxy, C 6-10 -aryl and aromatic 4- to 9-membered heterocyclyl with 1 to 3 hetero atoms selected from the group consisting of N, O, and S;
  • R denotes hydrogen or C 1- -alkyl
  • R 4 denotes CH 3 or C 2 H 5 ;
  • R 5 is
  • phenyl optionally having 1 to 3 further substituents selected from the group consisting of CI; C 1-4 -alkyl; C 1-4 -alkoxy; OH; NR 9 R 10 , and
  • indolyl optionally having 1 to 3 further substituents selected from the group consisting of F, CI, Br; C 1-6 -alkyl; C 1-6 -alkoxy; OH; NR 9 R 10 , and COOR 11 ;
  • R 9 to R 11 independently from each other denote C 1-4 -alkyl
  • 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 CH 3 or C H 5 ;
  • R denotes hydrogen, formyl, (C 1-4 -alkyl)-carbonyl, (C 1-4 -alkoxy)-carbonyl, NO 2 , NH 2 , C 1-4 -alkyl-NR 6 R 7 , C 1-4 -alkyl-OR 8 , C 1-4 -alkyl-COOR 8 , or phenyl-C 1-4 -alkyl wherein the phenyl moiety can be substituted with 1 to 3 C 1-4 -alkyl or C 1- -alkoxy moieties;
  • R 6 and R 7 independently from each other denote hydrogen, C 1-4 -alkyl, C 3-6 - cycloalkyl, or phenyl-C 1-4 -alkyl wherein the phenyl moiety can be substituted with 1 to 3 C 1-4 -alkyl or C 1-4 -alkoxy radicals;
  • R and R together with the nitrogen atom to which they are attached, form a saturated 5- to 7-membered heterocyclyl which may contain up to 2 further hetero atoms selected from the group consisting of N, O, and S and which saturated heterocyclyl can be further substituted with 1 to 3 radicals selected from the group consisting of C 1-4 -alkyl, C 1-4 -alkoxy, phenyl and pyridyl;
  • R 8 denotes hydrogen or C 1-4 -alkyl
  • R 4 denotes CH 3 or C 2 H 5 ;
  • phenyl optionally having 1 to 3 further substituents selected from the group consisting of CI; C 1-4 -alkyl; C 1- -alkoxy; OH; NR 9 R 10 ; and COOR 11 ; wherein R >9 + to. R .11 independently from each other denote C 1-4 -alkyl;
  • a bond with a dotted line thereunder, _ ⁇ denotes a bond which alternatively is a single bond or a double bond.
  • Pharmaceutically acceptable salts according to the invention are non-toxic salts which in general are accessible by reaction ofthe 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, dihydro- chlorides, 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, poly- galactur
  • the present invention includes both the individual enantiomers or diastereomers and the corresponding racemates, diastereomer mixtures and salts of the compounds ac- cording to the invention.
  • all possible tautomeric forms ofthe compounds described above are included according to the present invention.
  • the diastereomer mixtures can be separated into the individual isomers by chromatographic processes.
  • the racemates can be resolved into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
  • the substituents if not stated otherwise, in general have the following meaning:
  • Alkyl per se as well as the prefixes "alkyl” and “alk” in the terms “alkylcarbonyl”, “alkylsulphonyl”, “alkylaminocarbonylamino”, “alkoxy”, and “alkoxycarbonyl” represent a linear or branched alkyl radical preferably having 1 to 12, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl.
  • alkylcarbonyl include acetyl, ethylcarbonyl, propyl- carbonyl, isopropylcarbonyl, butylcarbonyl, and isobutylcarbonyl.
  • alkylcarbonyl and acyl are used synonymously.
  • alkylsulphonyl include methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, and isobutylsulphonyl.
  • alkylaminocarbonylamino include methylaminocarbo- nylamino, ethylaminocarbonylamino, propylaminocarbonylamino, isopropylamino- carbonylamino, butylaminocarbonylamino, and isobutylaminocarbonylamino.
  • alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, and isohexoxy.
  • alkoxycarbonyl include methoxycarbonyl, ethoxy- carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and isobutoxy- carbonyl.
  • Alkylene represents a linear or branched (bivalent) alkylene radical preferably having 1 to 4 carbon atoms.
  • Non-limiting examples include methylene, ethylene, propylene, ⁇ -methylethylene, ⁇ -methylethylene, ⁇ -ethylethylene, ⁇ -ethylethylene, butylene, ⁇ - methylpropylene, ⁇ -methylpropylene, and ⁇ -methylpropylene.
  • Cycloalkyl represents a saturated cycloalkyl radical preferably having 3 to 8 carbon atoms.
  • Non-limiting examples include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • Aryl per se and in the terms “aryloxy”, “aryl-alkyl”, and “arylaminocarbonylamino” represents an aromatic radical preferably having from 6 to 14, more preferably 6 to 10 carbon atoms.
  • aryl radicals include phenyl, benzyl, naphthyl, and phenanthrenyl.
  • Non-limiting examples of aryloxy radicals include phenyloxy and benzyloxy.
  • Non-limiting examples of aryl-alkyl radicals include benzyl.
  • Non-limiting examples of arylaminocarbonylamino radicals include phenyl- aminocarbonylamino, benzylaminocarbonylamino, naphthylaminocarbonylamino, and phenanthrenylaminocarbonylamino.
  • Heterocyclyl in the context ofthe invention represents a saturated, partially saturated or aromatic 4- to 9-membered, for example 5- to 6-membered ring which can contain from 1 to 3 hetero atoms selected from the group consisting of S, N and O and wliich ring can be bound via a carbon atom or a nitrogen atom, if such an atom is present.
  • Non-limiting heterocyclyl examples include: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, thienyl, furyl, pyrrolyl, N-methylpyrrolyl, indazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl, thiomorpholinyl or piperidyl.
  • Preferred examples include thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl.
  • heteroaryl and “hetaryl” denotes an aromatic heterocyclic radical.
  • Halogen in the context of the invention represents fluorine, chlorine, bromine, and iodine.
  • the present invention also relates to a process for manufacturing the compounds according to the invention comprising the reaction of a compound ofthe formula
  • R 3 and R 5 are as defined above, and optionally
  • [C] the conversion of the compound obtained through either process [A] or [B] into an isomer, a pharmaceutically acceptable salt, a hydrate or a hydrate of a pharmaceutically acceptable salt thereof.
  • 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; T.D. Harris and G.P. Roth, J. Org. Chem. 44, 146 (1979); E. M ⁇ ller (ed.), "Methoden der Organischen Chemie” (Houben-Weyl), Vol. VII/1 Sauerstoff-Veritatien IL, Georg Thieme Verlag, Stuttgart 1954).
  • the compounds (III) are commercially available.
  • the compounds (FV) can be synthesized by reacting compounds ofthe formula
  • R 4 is as defined above and
  • L is a leaving group, for example a halogen radical such as CI, or a radical of the formula
  • 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-Veritatien II, Georg Thieme Verlag, Stuttgart 1957; Shepard et al. in J. Org. Chem. 17, 568 (1952) and in J. Am. Chem. Soc. 72, 4364 (1950)).
  • the compounds (VII) 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, tri- chloroethylene, chlorobenzene
  • ketones such as acetone
  • esters such as ethyl acetate
  • nitriles such as acetonitrile
  • heteroaromatics such as pyridine
  • optionally N-alkylated carboxylic acid amides such as dimethyl formamide and dimethyl acetamide
  • optionally N-alkylated carboxylic acid amides such as dimethyl
  • the compound (NH) is generally employed in an amount of from 1 to 4 mol per mol of compound (NL); an equimolar amount or slight excess of compound (VH) is preferred.
  • the reaction between the compounds (VI) and (VH) is preferably carried out in the presence of a base.
  • a base ⁇ on-limiting examples include alkali metal hydrides and alkali metal alkoxides such as, for example, sodium hydride and potassium tert-butoxide; C 1 -C 4 -alkyl amines such as, for example, triethyl amine; cyclic amines such as, for example, piperidine, pyridine, dimethylamino pyridine and - preferably - 1,8-diaza- bicyclo[4.3.0]undec-7-ene (DBU).
  • the base is generally employed in an amount of from 1 to 4 mol per mol of compound (VI); an equimolar amount or slight excess ofthe 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; POCl 3 , or methane sulfonic anhydride are generally employed in an amount of from 1 to 10 mol, preferably from 1 to 2 mol of methane sulfonic anhydride or 4 to 8 mols of P 2 O 5 and POCl 3 , respectively, per mol of compound (NIH) in each case.
  • the cyclization reaction of the compounds (VLJI) to yield the compounds (LV) is also preferably carried out in 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 tetra- chloride, dichloroethane, trichloroethylene, chlorobenzene; esters such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; heteroaromatics such as pyridine; optionally N-alkylated carboxylic acid amides such as
  • Toluene is preferred if the reaction is carried out with P 2 O 5 or methane sulfonic anhydride; 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 (VLIL) 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. In general, the reaction is finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
  • reaction ofthe compounds (IN) with either compounds (II) and (HI) or with compound (N) can be carried out as a one-pot synthesis, preferably in a solvent.
  • Suitable solvents comprise the customary organic solvents wliich are inert under the reaction conditions.
  • Non-limiting examples include ethers such as diethyl ether, dioxane, tetra- hydrofuran, 1,2-dirnethoxy ethane; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloro- ethylene, 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; optionally N-alkylated carboxylic acid amides such as dimethyl formamide and dimethyl acetamide; alkyl sulphoxides such as dimethyl sulph
  • the compounds (Hi) are generally employed in an amount of from 1 to 3 mol per mol of compound (H); an equimolar amount or slight excess of compound (HI) is particu- larly preferred.
  • the compounds (IN) are generally employed in an amount of from 0.1 to 1 mol, preferably from 0.3 to 1 mol, per mol of compounds (H).
  • the reactions ofthe compounds (IN) with either compounds (H) and (HI) or with compound (V) are preferably carried out in the presence of a base.
  • a base ⁇ on-limiting examples include alkali metal hydrides and alkali metal alkoxides such as, for example, sodium hydride and potassium tert-butoxide; C 1-4 -alkyl amines such as, for example, triethyl amine; cyclic amines such as, for example, pyridine, dimemylamino pyridine, 1,8-di- azabicyclo[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 compound (H) or compound (V), respectively.
  • the reactions of the compounds (LV) with either compounds (H) and (HI) or with compound (V) are generally carried out within a relatively wide temperature range. In 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.
  • compounds (I) wherein R 3 is C 1-4 -alkyl- ⁇ R 6 R 7 , C 1-4 -alkyl-OR 8 , C 1-4 - alkyl-COOR 8 or C 6-1 o-aryl-C 1-4 -alkyl can be synthesized from compounds wherein R 3 is C 1-4 -alkyl (which themselves can be obtained according to one of the above processes A or B) by reaction with a halogenating agent such as sulfuryl chloride
  • halogenated intermediate obtained after the first ofthe above reaction steps can either be isolated and then reacted with the desired nucleophile or directly be converted into the desired product by reaction with a respective nucleophile.
  • R 3 is formyl
  • compounds wherein R 3 is methyl which themselves can be obtained according to one of the above processes A or B) by reaction with manganese dioxide in an organic solvent commonly used for such reactions such as, for example, an ether such as dioxane under conditions known to the skilled man.
  • the formyl compounds thus obtained can also be converted into compounds (I) wherein R 3 is CH 2 NR 6 R 7 by a reductive animation reaction commonly known to the skilled man.
  • R 3 is C 1-4 -alkylcarbonyl
  • compounds (IN) with compounds (N), wherein R 3 is C 1-4 -alkylcarbonyl
  • compounds (N) wherein R 3 is C 1-4 -alkylcarbonyl
  • these derivatives can be prepared from nitromethyl-alkylketones (compare D.C. Baker et al., Synthesis 1978; 478-479) and activated aldehydes, e.g. benzylidene- butyl-amines (see Dornow et al., Liebigs Ann. Chem. 602: 14, 19 (1957)).
  • R 3 is ⁇ O 2
  • R 3 is methyl (which themselves can be obtained according to one of the above processes A or B) by reaction with HNO 3 in acetic acid under conditions commonly used for such reactions and known to the skilled man.
  • These nitro compounds can further be converted into compounds wherein R 3 is NR 6 R 7 by a hydrogenation of the nitro group to the respective amino group under conditions commonly used for such reactions and known to the skilled man, and optionally alkylating the amino group under conditions commonly used for such reactions and known to the skilled man.
  • the compounds ofthe 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 ofthe 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 accord- ing to the invention are used in an amount such that their concentration is approxi- mately 0.5 to approximately 90% by weight, based on the ready-to-use formulations, the concentration being dependent, inter alia, on the indication ofthe 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, trans- dermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or inhalationally.
  • the compounds according to the invention are also suitable for use in veterinary medicine.
  • the compounds or their non-toxic salts can be ad- ministered in a suitable formulation in accordance with general veterinary practice.
  • the veterinary surgeon can determine the nature of use and the dosage.
  • the present invention provides compounds and salts thereof for the use in a medicinal 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 ofthe 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 ofthe compounds ofthe 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 ofthe compounds ofthe invention and at least one pharmaceutically active ingredient wliich is different from the compounds ofthe 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 humans and animals comprising the administration of an 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.
  • Solvent ratios, dilution ratios and concentrations in solutions of liquids in liquids are ratios and concentrations by volume.
  • Full-length recombinant PDE 10a was expressed in Sf9 insect cells (Invitrogen, Carlsbad, CA, U.S.A.) using the Bac-to-BacTM Baculovirus Expression System (Life Technologies, Gaithersburg, MD, U.S.A.). 48 hours post infection, cells were harvested and resuspended in 20 mL (per IL culture) of Lysis Buffer (50 mM Tris- HCl, pH 7.4, 50 mM NaCl, 1 mM MgCl 2 , 1.5 mM EDTA, 10% glycerol plus 20 ⁇ L
  • Lysis Buffer 50 mM Tris- HCl, pH 7.4, 50 mM NaCl, 1 mM MgCl 2 , 1.5 mM EDTA, 10% glycerol plus 20 ⁇ L
  • Protease Inhibitor Cocktail Set III [CalBiochem, La Jolla, CA, U.S.A.]). Cells were sonicated at 4°C for 1 minute and centrifuged at 10,000 RPM for 30 minutes at 4°C. Supernatant was removed and stored at -20°C for activity assays.
  • 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 ofthe serially diluted individual test compounds followed by 50 ⁇ L of a dilution of crude recombinant PDE lOa-containing Sf9 cell lysate.
  • the dilution ofthe lysate was selected such that less than 70% ofthe substrate is converted during the later incubation (typical dilution: 1:10 000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA, 0.2% BSA).
  • the substrate [5',8- 3 H] adenosine 3',5'-cyclic phosphate (1 ⁇ Ci/ ⁇ L; Amersham Pharmacia Biotech., Piscataway, NJ, U.S.A.
  • assay buffer 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA
  • the enzymatic assay was initiated by addition of 50 ⁇ L (0.025 ⁇ Ci) of diluted substrate.
  • MDA-MB-231 human breast carcinoma cells (ATCC # HTB26) were cultured in standard growth medium (DMEM), supplemented with 10% heat-inactivated FBS, lO 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, LDH activity was determined using the Cytotox 96 Non-radioactive Cytotoxicity Kit (Promega, Madison, Wl, U.S.A.) to yield T 0h LDH values.
  • cells were lysed with the addition of 200 ⁇ L of Lysis Buffer (included in the Promega Kit) and lysates were further diluted in Lysis Buffer so that LDH values fell within the standard curve.
  • 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 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 1l values. Optionally, the ICso values can be determined with a least squares analysis program using compound concentration versus percent inhibition.
  • T 72h ctr i LDH activity at 72 hours in the absence of test compound
  • Test compounds are formulated for oral administration in a vehicle for oral administration composed of polyethylene glycol-400, TMCremophor, 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 w 2 )/!. 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, U.S.A.). 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 conformance 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 HCl. 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. Abbreviations used in this specification
  • the substituted 2-phenethyl amines are commercially available or can be prepared in analogy to any one of the following procedures, e.g. starting from the corresponding benzaldehydes (see also Shepard et al. in J. Org. Chem. 17, 568 (1952) and in J. Am. Chem. Soc. 72, 4364 (1950)).
  • 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
  • Example 17 a A mixture of 100 mg (0,234 mmol) of ethyl 2-(3-chlorophenyl)-8,9- dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2, 1 -a]isoquinoline- 1 -carboxylate (Inter- mediate 3a) and 500 mg of manganese dioxide in 3 mL of dioxane was stirred for 2 hours at 100°C. The mixture was cooled, filtrated, and the solvent was evaporated.
  • Example 17b As a second compound the respective dehydro compound ethyl 3- formyl-8,9-dimethoxy-2-(3-chlorophenyl)-pyrrolo[2, 1 -a]isoquinoline- 1 -carboxylate having a melting point of 155-157°C could be obtained:

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Abstract

L'invention concerne des 3-pyrrolo[2.1-a]dihydroisoquinoléines qui sont des inhibiteurs de phosphodiestérase 10a et qui peuvent servir pour lutter contre les cancers.
PCT/US2002/024877 2001-08-06 2002-08-05 Derives de 3-pyrrolo[2.1-a]isoquinoleine substitues WO2003014117A1 (fr)

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Cited By (7)

* 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
WO2008001182A1 (fr) * 2006-06-26 2008-01-03 Pfizer Products Inc. Composés hétéroaryliques tricycliques comme inhibiteurs de pde10
WO2010030027A1 (fr) 2008-09-10 2010-03-18 Mitsubishi Tanabe Pharma Corporation Composés cycliques aromatiques azotés à 6 chaînons et leur utilisation
US8338420B1 (en) 2002-12-04 2012-12-25 Mitsubishi Tanabe Pharma Corporation Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor
US8394789B2 (en) 2008-02-08 2013-03-12 Msd Oss B.V. (Dihydro)pyrrolo[2,1-α]isoquinolines
US8969376B2 (en) 2010-02-26 2015-03-03 Mitsubishi Tanabe Pharma Corporation Pyrazolopyrimidine compounds and their use as PDE10 inhibitors
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

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP2362A (en) * 2005-01-07 2012-02-08 Pfizer Prod Inc Heteroaromatic quinoline compounds and their use as PDE10 inhibitors.
AU2006205797A1 (en) * 2005-01-12 2006-07-20 4Sc Ag Pyrrolodihydroisoquinolines as antiproliferative agents
US20080161338A1 (en) * 2005-01-12 2008-07-03 Altana Pharma Ag Novel Pyrrolodihydroisoquinolines as Pde 10 Inhibitors
WO2012044562A2 (fr) * 2010-09-30 2012-04-05 Merck Sharp & Dohme Corp. Inhibiteurs de pyrazolopyrimidine pde10

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1153670A (en) * 1966-12-07 1969-05-29 Siphar Sa Isoquinoline Derivatives and preparation thereof
WO1998055118A2 (fr) * 1997-06-05 1998-12-10 Geange Ltd. Utilisation de derives aromatiques heterocycliques d'azote dans le traitement topique de maladies des tissus epitheliaux
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1153670A (en) * 1966-12-07 1969-05-29 Siphar Sa Isoquinoline Derivatives and preparation thereof
WO1998055118A2 (fr) * 1997-06-05 1998-12-10 Geange Ltd. Utilisation de derives aromatiques heterocycliques d'azote dans le traitement topique de maladies des tissus epitheliaux
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 MURINE ANTINEOPLASTIC ACTIVITY OF BIS (CARBAMOYLOXY(METHYL DERIVATIVES OF PYRROLO 2,1-AISOQUINOLINE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 10, no. 27, October 1984 (1984-10-01), pages 1321 - 1325, XP001070339, ISSN: 0022-2623 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8338420B1 (en) 2002-12-04 2012-12-25 Mitsubishi Tanabe Pharma Corporation Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor
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
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
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
EA012110B1 (ru) * 2003-06-30 2009-08-28 Алтана Фарма Аг Пирролодигидроизохинолины как ингибиторы pde10
AU2004253690B2 (en) * 2003-06-30 2010-03-25 Nycomed Gmbh Pyrrolodihydroisoquinolines as PDE10 inhibitors
WO2008001182A1 (fr) * 2006-06-26 2008-01-03 Pfizer Products Inc. Composés hétéroaryliques tricycliques comme inhibiteurs de pde10
US8394789B2 (en) 2008-02-08 2013-03-12 Msd Oss B.V. (Dihydro)pyrrolo[2,1-α]isoquinolines
WO2010030027A1 (fr) 2008-09-10 2010-03-18 Mitsubishi Tanabe Pharma Corporation Composés cycliques aromatiques azotés à 6 chaînons et leur utilisation
US8969376B2 (en) 2010-02-26 2015-03-03 Mitsubishi Tanabe Pharma Corporation Pyrazolopyrimidine compounds and their use as PDE10 inhibitors
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

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