Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—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 chemical compounds that selectively inhibit glucose transporter 1 (GLUT1 ), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
• GLUT1 glucose transporter 1
• Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal and kidney epithelial cells depends on the presence of secondary active NaVglucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by co-transport of Na + ions down their electrochemical gradient.
• glucose carriers protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2
• transport facilitators major facilitator superfamily
• organic anion and cation transporters yeast hexose transporter
• plant hexose/ proton symporters plant hexose/ proton symporters
• bacterial sugar/ proton symporters a superfamily of transport facilitators (major facilitator superfamily) including organic anion and cation transporters, yeast hexose transporter, plant hexose/ proton symporters, and bacterial sugar/ proton symporters.
• Basal glucose transporters function as glucose channels and are required for maintaining the basic glucose needs of cells. These GLUTs are constitutively expressed and functional in cells and are not regulated by (or sensitive to) insulin. All cells use both glycolysis and oxidative phosphorylation in mitochondria but rely overwhelmingly on oxidative phosphorylation when oxygen is abundant, switching to glycolysis at times of oxygen deprivation (hypoxia), as it occurs in cancer. In glycolysis, glucose is converted to pyruvate and two ATP molecules are generated in the process. Cancer cells, because of their faster proliferation rates, are predominantly in a hypoxic (low oxygen) state. Therefore, cancer cells use glycolysis (lactate formation) as their predominant glucose metabolism pathway.
• Such a glycolytic switch not only gives cancer higher potentials for metastasis and invasiveness, but also increases cancer's vulnerability to external interference in glycolysis.
• the reduction of basal glucose transport is likely to restrict glucose supply to cancer cells, leading to glucose deprivation that forces cancer cells to slow down growth or to starve.
• GLUT proteins contain 12 transmembrane domains and transport glucose by facilitating diffusion, an energy-independent process.
• GLUT1 transports glucose into cells probably by alternating its conformation.
• GLUT1 exposes a single substrate-binding site toward either the outside or the inside of the cell. Binding of glucose to one site triggers a conformational change, releasing glucose to the other side of the membrane.
• Results of transgenic and knockout animal studies support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing.
• the GLUT proteins differ in their kinetics and are tailored to the needs of the cell types they serve.
• GLUT1 is a high affinity glucose transporter
• GLUT1 expression was also found to be significantly higher than that of any other glucose transporters.
• GLUT1 is the most highly expressed hexose transporter in ErbB2- and PyVMT-induced mouse mammary carcinoma models, and that reducing the level of GLUT1 using shRNA or Cre/lox results in reduced glucose usage, reduced growth on plastic and in soft agar, and impaired tumor growth in nude mice (Christian D. Young et al., PLoS ONE, August 201 1 , Volume 6, Issue 8, e23205, 1 -12).
• inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.
• WO201 1 /1 19866(A1 ) discloses composition and methods for glucose transport inhibition
• WO2012/051 1 17(A2) discloses substituted benzamides as GLUT1 inhibitors.
• pyrazolopyrimidine compounds have not been reported in the context of GLUT1 inhibition.
• WO2005/1 17909(A2) discloses, inter alia, substituted pyrazolopyrimidine compounds which inhibit p70S6 and/or Akt kinases.
• US2004/0204400A1 discloses substituted pyrazolopyrimidine compounds for the treatment of infections by enteroviruses.
• the present invention covers compounds of general formula (I) :
• R B represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
• halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
• each * represents the point of attachment to said phenyl- group; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a Ci -C&-alkyl-, C 2 -C&-alkenyl-,
• said group is optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 9 groups ; represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• C 3 -C 7 -cycloalkyl- group represents a hydrogen atom or a CrC 3 -alkyl-, CrC 3 -alkoxy-,
• R 5 represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• R 6 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R 7 represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
• n is an integer of 2 or 3 ;
• p is an integer of 1 or 2 ;
• t is an integer of 3, 4 or 5 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same ; for use in the treatment or prophylaxis of a disease.
• the present invention further relates to a pharmaceutical composition comprising a compound of formula (I), supra.
• the present invention further relates to the use of a compound of formula (I), supra, for the prophylaxis or treatment of a disease.
• the present invention further relates to the use of a compound of formula (I), supra, for the preparation of a medicament for the prophylaxis or treatment of a disease.
• the present invention further relates to the compounds of formula (I), supra, per se, wherein the following compounds are excluded:
• the present invention further relates to methods of preparing compounds of general formula (I), supra.
• halogen atom or "halo-” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
• Ci-C&-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g.
• said group has 1 , 2, 3 or 4 carbon atoms (“CrC4-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“CrC3-alkyl”), e.g. a methyl, ethyl, n-propyl- or /so-propyl group.
• CrC4-alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms
• CrC3-alkyl e.g. a methyl, ethyl, n-propyl- or /so-propyl group.
• halo-CrCe-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term " ⁇ - Ce-alkyl” is defined supra, and in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
• Said halo-Ci-C&-alkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , or -CH 2 CF 3 .
• d-Ce-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent group of formula -0-(Ci-C&-alkyl), in which the term “d-Ce-alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso- propoxy, n- butoxy, iso- butoxy, tert- butoxy, sec- butoxy, pentoxy, iso- pentoxy, or n-hexoxy group, or an isomer thereof.
• halo-CrCe-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C&-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
• said halogen atom is F.
• Said halo-CrCe-alkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or - OCH 2 CF 3 .
• Ci-C&-alkoxy-CrCe-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C&-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C&-alkoxy group, as defined supra, e.g.
• halo-Ci-Ce-alkoxy-CrCe-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent CrCe-alkoxy-CrCe-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
• said halogen atom is F.
• Said halo-CrCe-alkoxy-CrCe-alkyl group is, for example, CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or
• C 2 -C&-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C 3 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
• Said alkenyl group is, for example, a vinyl, allyl, (f)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (f)-but-2-enyl, (Z)-but-2-enyl, (f)-but- l -enyl, (Z)-but- l -enyl, pent-4-enyl, (f)-pent-3-enyl, (Z)-pent-3-enyl, (f)-pent-2-enyl, (Z)-pent-2-enyl, (f)-pent- l -enyl, (Z)-pent- l -enyl, hex-5-enyl, (f)-hex-4-enyl, (Z)-hex-4-enyl, (f)-hex-3-enyl, (Z)-hex-3-enyl, (f)-hex-2-enyl, (Z)-he
• C 2 -C&-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C3-alkynyl").
• Said C 2 -C&-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, l -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1
• alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl.
• C3-C7-cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms.
• Said C 3 -C 7 -cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring.
• said ring contains 3, 4, 5 or 6 carbon atoms (“C3-C6-cycloalkyl").
• C 4 -C8-cycloalkenyl is to be understood as preferably meaning a monovalent, monocyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one or two double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C 4 -C6-cycloalkenyl”).
• Said C 4 -Cs-cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl, or cyclohexenyl group.
• said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 7-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "4- to 6-membered heterocycloalkyl").
• said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
• 4-membered ring such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolid
• heterocycloalkenyl may contain one or more double bonds, e.g.
• aryl is to be understood as preferably meaning a monovalent, aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C 6 -Ci4-aryl” group), particularly a ring having 6 carbon atoms (a "C 6 -aryl” group), e.g. a phenyl group; or a ring having 9 carbon atoms (a "Cg-aryl” group), e.g.
• an indanyl or indenyl group or a ring having 10 carbon atoms
• a "Cio-aryl” group e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a biphenyl group (a "Ci 2 -aryl” group), or a ring having 13 carbon atoms, (a "Ci3-aryl” group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci 4 -aryl” group), e.g. an anthracenyl group.
• the aryl group is a phenyl group.
• heteroaryl is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
• heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.;
• the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
• the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
• the heteroaryl group is a pyridinyl group.
• d-d as used throughout this text, e.g. in the context of the definition of "C C 6 -alkyl”, “C C 6 -haloalkyl”, “C C 6 -alkoxy”, or “d-d- haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “d-d” is to be interpreted as any subrange comprised therein, e.g.
• d-d as used throughout this text, e.g. in the context of the definitions of "C 2 -d-alkenyl” and “C 2 -d-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -d” is to be interpreted as any sub-range comprised therein, e.g.
• d-d as used throughout this text, e.g. in the context of the definition of "d-d-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term "C3-C7" is to be interpreted as any sub-range comprised therein, e.g.
• the term "leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
• the leaving group as used herein is suitable for nucleophilic aliphatic and/or aromatic substitution, e.g.
• halogen atom in particular chloro, bromo or iodo, or a group selected from methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro- benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl- benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy
• protecting group is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M.
• said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl, acetyl or tetrahydropyranoyl-, or carbamate based groups, such as tert. -butoxycarbonyl (Boc), or can include silicon, as in e.g. 2-(trimethylsilyl)ethoxymethyl (SEM).
• substituted sulfonyl groups such as mesyl-, tosyl- or phenylsulfonyl-
• acyl groups such as benzoyl, acetyl or tetrahydropyranoyl-
• carbamate based groups such as tert. -butoxycarbonyl (Boc)
• Boc tert. -butoxycarbonyl
• Si 2-(trimethylsilyl)ethoxymethyl
• the term "one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
• the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
• the compounds of this invention contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired.
• Asymmetric carbon atoms may be present in the (R) or (S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
• Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations are included within the scope of the present invention. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
• the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
• appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
• the optically active bases or acids are then liberated from the separated diastereomeric salts.
• a different process for separation of optical isomers involves the use of chiral chromatography (e.g. , chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
• Suitable chiral HPLC columns are manufactured by Diacel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable.
• Enzymatic separations, with or without derivatisation are also useful.
• the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
• the invention also includes all suitable isotopic variations of a compound of the invention.
• An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
• isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 1 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 3 S, 36 S, 18 F, 36 Cl, 82 Br, 123 l, 124 l, 129 l and 131 1, respectively.
• Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution studies.
• Tritiated and carbon-14, i.e. , 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
• isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
• the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio.
• Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
• the compounds of the present invention may exist as tautomers.
• any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, viz. :
• the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
• the compounds of the present invention can exist as N -oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
• the present invention includes all such possible N-oxides.
• the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
• the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
• polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
• the amount of polar solvents, in particular water may exist in a stoichiometric or non- stoichiometric ratio.
• stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
• the present invention includes all such hydrates or solvates.
• the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
• Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
• pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
• pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
• S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
• a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2- (4- hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium or magnesium salt
• an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N- methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 - amino-2,3,4-butantriol.
• basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
• diamyl sulfates long chain halides such as decyl, lau
• acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
• the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
• the present invention relates to compounds of general formula (I) :
• * indicates the point of attachment of said groups with the rest of the molecule; represents a hydrogen atom or a -OH, -SH, -NH 2 ,CrC3-alkoxy-,
• halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-C 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-d-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
• each * represents the point of attachment to said phenyl- group; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a Ci -C&-alkyl-, C 2 -C&-alkenyl-,
• said group is optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 9 groups ; represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• C 3 -C 7 -cycloalkyl- group represents a hydrogen atom or a CrC 3 -alkyl-, CrC 3 -alkoxy-,
• R 5 represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• R 6 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R 7 represents a hydrogen atom or a Ci -C&-alkyl-, trifluoromethyl- or
• Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
• n is an integer of 2 or 3 ;
• p is an integer of 1 or 2 ;
• t is an integer of 3, 4 or 5 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same ;
• the present invention relates to compounds of general formula (I), supra, wherein the following compounds are excluded: 4-[4-(2-methoxyphenyl)piperazin-1 -yl] - 1 -phenyl-1 H-pyrazolo[3,4-d]pyrimidine, 1 -(4-fluorophenyl)-4-[4-(2-methoxyphenyl)piperazin-1 -yl]-
• R A is selected from the group consisting of: wherein * indicates the point of attachment of said groups with the rest of the molecule.
• R A represents:
• R A represents:
• R A represents:
• R A represents:
• R B represents a hydrogen atom or a -OH, -NH 2 , CrC3-alkoxy-, HO-Ci -C3-alkyl-, HO-C 2 -C 3 -alkoxy-, fluoro-CrC 3 -alkyl-,
• R B represents a hydrogen atom or a -OH, -NH 2 , CrC 3 -alkoxy-, HO-Ci -C 3 -alkyl-, HO-C 2 -C 3 -alkoxy-, or a -S- (Ci -C 3 -alkyl)- group.
• R B represents a hydroxymethyl- group.
• R B represents represents a
• R B represents represents a -OH group. In another particularly preferred embodiment, R B represents represents a -NH 2 group.
• R B represents represents a methoxy- group.
• R B represents represents an ethoxy- group.
• R B represents represents a -SCH3 group.
• each R c independently represents a halogen atom, or a -CN, -OH, Ci-C&-alkoxy-, Ci-C&-alkyl-, fluoro-CrC3-alkyl-,
• two R c groups in ortho- position to each other on the phenyl- group together form a bridge :
• each R c independently represents a chloro atom or a -CN group group.
• each R c independently represents a chloro atom.
• each R c independently represents a fluoro atom.
• R D represents a hydrogen atom or a methyl- group.
• R D represents a methyl- group. In a more preferred embodiment, R D represents a hydrogen.
• R 1 represents a hydrogen atom or a
• R 1 represents a
• R 1 represents a
• R 1 represents a cyclopentyl-, cyclohexyl-, cyclopentylmethyl-, cyclohexylmethyl-, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl-, phenyl-, thien-2-yl- or benzyl- group, wherein said phenyl- or benzyl- group is optionally substituted, identically or differently, with 1 or 2 R 9 groups ;
• R 1 represents a phenyl- group, wherein said group is optionally substituted, identically or differently, with 1 or 2 R 9 groups .
• R 1 represents a phenyl- group, wherein said group is optionally substituted, once with fluoro, chloro, bromo, methoxy- or methyl-.
• R 1 represents a phenyl- group, wherein said group is optionally substituted, once with fluoro or methyl-. In another particularly preferred embodiment, R 1 represents a phenyl- group.
• R 1 represents a cyclopentyl-, cyclohexyl-, cyclopentylmethyl-, cyclohexylmethyl-, tetrahydropyran-4-yl or tetrahydropyran-4-ylmethyl- group. In another particularly preferred embodiment, R 1 represents a cyclopentyl- group.
• R 1 represents a
• R 1 represents a cyclohexyl- group. In another particularly preferred embodiment, R 1 represents a
• R 1 represents a
• R 1 represents a
• R 2 represents a hydrogen atom or a
• R 2 represents a hydrogen atom or a
• R 2 represents a hydrogen atom or a methyl- group.
• R 2 represents a hydrogen atom. In another particularly preferred embodiment, R 2 represents a methyl- group. In another preferred embodiment, R 3 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-, fluoro-CrC3-alkyl-, fluoro-CrC3-alkoxy- or
• R 3 represents a hydrogen atom or a CrC3-alkyl-, trifluoromethyl- or HO-Ci -C 2 -alkyl- group.
• R 3 represents a hydrogen atom or a methyl- group.
• R 3 represents a hydrogen atom.
• R 5 represents a hydrogen atom or a
• R 5 represents a hydrogen atom or a methyl- group. In a particularly preferred embodiment, R 5 represents a hydrogen atom.
• R 6 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-, fluoro-CrC3-alkyl-, fluoro-CrC3-alkoxy- or
• R 6 represents a hydrogen atom or a CrC3-alkyl-, trifluoromethyl- or HO-Ci -C 2 -alkyl- group.
• R 6 represents a hydrogen atom or a methyl- group. In another particularly preferred embodiment, R 6 represents a hydrogen atom.
• R 8 and R 8a represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, C 3 -C 7 -cycloalkyl-,
• R 8b and R 8c represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, Ci -C 3 -alkoxy-CrC 3 -alkyl-, C 3 -C 7 -cycloalkyl- or aryl-Ci -C&-alkyl- group.
• R 8a and R 8b together with the nitrogen atom they are attached to, form a 4- to 7-membered heterocycloalkyl- group, which is optionally substituted once with a CrC 3 -alkyl-, C 3 -C 7 -cycloalkyl- or a phenyl- group, the phenyl- group being optionally substituted 1 , 2 or 3 times, identically or differently, with halogen, CrC 3 -alkyl- or CrC 3 -alkoxy-.
• R 8 and R 8a represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)- (Ci -C&-alkyl)-, 4- to 7-membered heterocycloalkyl-,
• R 8b and R 8c represent, independently from each other, a hydrogen atom, or a Ci-C4-alkyl-, Ci-C3-alkoxy-CrC3-alkyl-, C3-C&-cycloalkyl- or a benzyl- group.
• R 8a and R 8b together with the nitrogen atom they are attached to, form a 4- to 7-membered heterocycloalkyl- group, which is optionally substituted once with a
• R 8 and R 8a represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl-, C3-C 7 -cycloalkyl-, (C3-C 7 -cycloalkyl)-(Ci-C&-alkyl)-, 4- to 7-membered heterocycloalkyl-,
• R 8b and R 8c represent, independently from each other, a hydrogen atom or a CrC3-alkyl- or a methoxy-Ci-C3-alkyl- group.
• R 8a and R 8b together with the nitrogen atom they are attached to, form a 4- to 7-membered heterocycloalkyl- group, which is optionally substituted once with a C1-C3- alkyl- or a phenyl- group, the phenyl- group being optionally substituted once with fluoro, chloro, methyl or methoxy-.
• R 8 and R 8a represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C 7 -cycloalkyl-, (C3-C 7 -cycloalkyl)-(Ci-C&-alkyl)-, 5- or 6-membered heterocycloalkyl-, (5- or 6-membered heterocycloalkyl)-(Ci-C4-alkyl)-, phenyl-, naphthyl-, 5- or 6-membered heteroaryl-, phenyl-Ci-C4-alkyl-, (phenyl)-O- (CrC4-alkyl)- or (5- or 6-membered heteroaryl)-Ci-C4-alkyl- group;
• R 8a and R 8b together with the nitrogen atom they are attached to, form a 4- to 6-membered
• heterocycloalkyl- group which is optionally substituted once with a
• R 8a represents a hydrogen atom.
• R 8a represents a
• R 8a represents a
• R 8a represents a
• R 8b represents a hydrogen atom or a CrC3-alkyl- or a 2-methoxyethyl- group.
• R 8b represents a hydrogen atom. In another particularly preferred embodiment, R 8b represents a methyl- group.
• R 8c represents a hydrogen atom or a CrC3-alkyl- or a 2-methoxyethyl- group. In another particularly preferred embodiment, R 8c represents a hydrogen atom.
• R 8c represents a methyl- group.
• R 8a and R 8b together with the nitrogen atom they are attached to, form an azetidino, morpholino or N-phenylpiperazine ring, wherein said phenyl- group attached to the piperazine ring is optionally substituted once by methoxy-.
• R 9 represents a halogen atom, or a -CN, CrC 6 -alkoxy-, d-C 6 -alkyl-, fluoro-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-,
• aryl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c .
• R 9 represents a halogen atom, or a -CN, CrC 6 -alkoxy-, d-d-alkyl-, fluoro-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-,
• aryl- and heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c .
• aryl- and the 5- or 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c .
• aryl- an 5- or 6-membered heteroaryl- group is substituted, one or more times, identically or differently, with R c .
• R 9 represents a fluoro, chloro, or bromo atom, or a -CN, Ci-C 3 -alkoxy-, methyl-, ethyl-, phenyl-,
• R 9 represents a fluoro atom. In another particularly preferred embodiment, R 9 represents a chloro atom.
• R 9 represents a bromo atom.
• R 9 represents a -CN group. In another particularly preferred embodiment, R 9 represents a methyl- group.
• R 9 represents a methoxy- group.
• R 10 represents a halogen atom, or a
• R 10 represents a halogen atom, or a
• R 11 , R 11a , R 11b , R 11c represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group.
• R 11 , R 11a , R 11b , R 11c represent, independently from each other, a hydrogen atom or a CrC3-alkyl- group.
• R 11 , R 11a , R 11b , R 11c represent, independently from each other, a hydrogen atom or a CrC 2 -alkyl- group. In another particularly preferred embodiment, R 11 , R 11a , R 11b , R 11c represent, independently from each other, a hydrogen atom or a methyl- group.
• n is an integer of 0, 1 , 2 or 3. In a particularly preferred embodiment, m is an integer of 0, 1 or 2.
• m is an integer of 0 or 1.
• m is an integer of 0.
• m is an integer of 1.
• n is an integer of 2 or 3.
• n is an integer of 2.
• n is an integer of 3.
• p is an integer of 1 or 2.
• p is an integer of 1 .
• p is an integer of 2. In another preferred embodiment, t is an integer of 3, 4 or 5.
• t is an integer of 3 or 4.
• R A is selected from the group consisting of:
• R B represents a hydrogen atom or a -OH, -NH 2 , CrC3-alkoxy-,
• each * represents the point of attachment to said phenyl- group; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a CrC&-alkyl-, Ci-C&-alkoxy-,
• said group is optionally substituted, identically or differently, with 1 , 2, 3, or 4 R 9 groups ; represents a hydrogen atom or a CrC3-alkyl- group; represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R ! represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci -C6-alkyl)-,
• Ci -C&-alkyl- Ci -C 3 -alkoxy-Ci -C 3 -alkyl-, C 3 -C 7 -cycloalkyl- or aryl-Ci -C&-alkyl- group ;
• R 8a and R 8b together with the nitrogen atom they are attached to, form a
• aryl-, heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c ;
• Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
• n is an integer of 2 or 3 ;
• p is an integer of 1 or 2 ;
• t is an integer of 3, 4 or 5 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A is selected from the group consisting of:
• R B represents a hydrogen atom or a -OH, -NH 2 , CrC3-alkoxy-,
• R D represents a hydrogen atom or a methyl- group
• R D represents a hydrogen atom or a Ci -C&-alkyl-, Ci -C&-alkoxy-
• said group is optionally substituted, identically or differently, with 1 , 2, or 3 R 9 groups ; represents a hydrogen atom or a CrC3-alkyl- group ; represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• fluoro-CrC3-alkyl-, fluoro-CrC3-alkoxy- or HO-Ci -C3-alkyl- group represents a hydrogen atom ; represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• Ci -C&-alkyl- represent, independently from each other, a hydrogen atom or a Ci -C&-alkyl-, C3-C 7 -cycloalkyl-, (C3-C 7 -cycloalkyl)- (Ci -C&-alkyl)-,
• R 8a and R 8b together with the nitrogen atom they are attached to, form a
• aryl- and 5- or 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c ;
• Ci-C 3 -alkyl- group m is an integer of 0, 1 or 2;
• n is an integer of 2 or 3;
• p is an integer of 1 or 2;
• t is an integer of 3 or 4; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A is selected from the group consisting of:
• R B represents a hydrogen atom or a -OH, -NH 2 , CrC 3 -alkoxy-,
• each * represents the point of attachment to said phenyl- group ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a d-d-alkyl-, d-d-alkoxy-,
• Ci-C 3 -alkoxy-CrC 3 -alkyl- C 3 -C 7 -cycloalkyl-, -(CH 2 ) p -C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocycloalkyl-,
• said group is optionally substituted, identically or differently, with 1 , 2, or 3 R 9 groups ; represents a hydrogen atom or a CrC 3 -alkyl- group ; represents a hydrogen atom or a CrC 3 -alkyl-, CrC 3 -alkoxy-,
• R 5 represents a hydrogen atom
• R 6 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R 8a and R 8b together with the nitrogen atom they are attached to, form a
• CrC 3 -alkyl- group is an integer of 0, 1 or 2;
• R A is selected from the group consisting of:
• R B represents a -OH, -NH 2 , CrC 2 -alkoxy- or a -S-(Ci-C 2 -alkyl)- group;
• each * represents the point of attachment to said phenyl- group ; represents a hydrogen atom or a methyl- group; represents a Ci -C&-alkyl-, C3-C7-cycloalkyl-, - (CH 2 ) p -C3-C7-cycloalkyl,
• said group is optionally substituted, identically or differently, with 1 or 2 R 9 groups ; represents a hydrogen atom or a methyl- group ; represents a hydrogen atom or a CrC3-alkyl-, trifluoromethyl- or
• HO-CrC 2 -alkyl- group represents a hydrogen atom; represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• Ci -C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, C3-C 7 -cycloalkyl-, (C3-C 7 -cycloalkyl)- (Ci -C&-alkyl)-,
• R 8a and R 8b together with the nitrogen atom they are attached to, form a
• aryl- and 5- or 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R c ;
• p is an integer of 1 or 2
• t is an integer of 3 or 4 or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R D represents a hydrogen atom or a methyl- group; represents a Cs-Ce-cycloalkyl-, -(CH 2 )p-C5-C&-cycloalkyl, 5- or 6-membered heterocycloalkyl-, - (CH 2 ) p -(5- or 6-membered heterocycloalkyl), phenyl-, thien-2-yl or - (CH 2 ) p -phenyl group,
• R 3 represents a hydrogen atom
• R 6 represents a hydrogen atom
• Ci -C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci -C&-alkyl-, C3-C 7 -cycloalkyl-, (C3-C 7 -cycloalkyl)- (Ci -C&-alkyl)-,
• R 8a and R 8b together with the nitrogen atom they are attached to, form a
• m is an integer of 0 or 1 ;
• n is an integer of 2 or 3;
• p is an integer of 1 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A represents
• R 8a and R 8b together with the nitrogen atom they are attached to, form an azetidino, morpholino or N-phenylpiperazine ring, wherein said phenyl- group attached to the piperazine ring is optionally substituted once by methoxy-;
• n is an integer of 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A represents
• R 6 represents a hydrogen atom
• n is an integer of 2 or 3; or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A re resents
• * indicates the point of attachment of said groups with the rest of the molecule; represents a -OH or a methoxy- group; represents a -CN group; represents a hydrogen atom; represents a cyclohexyl- or phenyl- group,
• R A re resents
• R B represents a methoxy- group
• R D represents a hydrogen atom
• R 1 represents a phenyl- group which is optionally substituted once by
• R 3 represents a hydrogen atom
• R 5 represents a hydrogen atom
• R 6 represents a hydrogen atom
• m is an integer of 0 or 1 ;
• n is an integer of 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A re resents
• R 5 represents a hydrogen atom
• R 6 represents a hydrogen atom
• m is an integer of 0 or 1 ;
• n is an integer of 2 or 3; or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A represents
• R B represents a methoxy- group
• R D represents a hydrogen atom
• R 1 represents a phenyl- group
• R 2 represents a hydrogen atom or a methyl- group
• R 6 represents a hydrogen atom; m is an integer of 0 or 1 ;
• n is an integer of 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A re resents
• R B represents a methoxy- group
• R D represents a hydrogen atom
• R 1 represents a phenyl- group
• R 2 represents a hydrogen atom or a methyl- group
• R 6 represents a hydrogen atom; m is an integer of 0;
• n is an integer of 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• R A is selected from the roup consisting of:
• * indicates the point of attachment of said groups with the rest of the molecule. represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
• R 2 represents a hydrogen atom ;
• R 3 represents a hydrogen atom ;
• R 5 represents a hydrogen atom ;
• R 6 represents a hydrogen atom ;
• R 7 represents a hydrogen atom ; 8
• R 9 represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
• n is an integer of 2 or 3 ;
• P is an integer of 1 or 2 ;
• q is an integer of 0 or 1 ;
• t is an integer of 3, 4 or 5 ;
• x is an integer of 0, 1 or 2.
• R A is selected from the group consisting of:
• * indicates the point of attachment of said groups with the rest of the molecule. represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
• halogen atom independently represents a halogen atom, or a -CN, -OH, Ci-C&-alkoxy-, Ci-C&-alkyl- or halo-Ci-C&-alkyl- group; represents a hydrogen atom; represents a C3-C7-cycloalkyl-, -(CH 2 ) p -C3-C7-cycloalkyl,
• said group is optionally substituted, identically or differently, with 1 , 2 or 3 R 9 groups ; represents a hydrogen atom or a Ci-C&-alkyl- or C3-C 7 -cycloalkyl- group ; represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R 6 represents a hydrogen atom or a CrC3-alkyl-, CrC3-alkoxy-,
• R 9 represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
• m is an integer of 0, 1 , 2 or 3 ;
• n is an integer of 2 or 3 ;
• p is an integer of 1 or 2 ;
• q is an integer of 0 or 1.
• * indicates the point of attachment of said groups with the rest of the molecule. represents a hydrogen atom or a -OH, -NH 2 , CrC3-alkoxy-,
• R c independently represents a halogen atom, or a -OH or a Ci-C&-alkyl- group
• R D represents a hydrogen atom; represents a C3-C 7 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, -(CH 2 ) p -aryl or heteroaryl- group,
• R 2 represents a hydrogen atom
• R 3 represents a hydrogen atom
• R 5 represents a hydrogen atom
• R 6 represents a hydrogen atom ;
• aryl- or heteroaryl- group is optinally substituted, one or more times, identically or differently, with R c ;
• m is an integer of 0 or 1
• n is an integer of 2 or 3
• p is an integer of 1 or 2
• q is an integer of 0 or 1 .
• the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
• the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula
• R A , R B , R c , R D , m, and n are as defined supra.
• the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula (VI) :
• R A , R B , R c , R D , m, and n are as defined supra.
• the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
• the present invention covers compounds of general formula (III): )
• the present invention covers the use of the intermediate compounds :
• R A is as defined for the compounds of general formula (I), supra, and LG is a leaving group
• R B , R c and m are as defined for the compounds of general formula (I), supra, and LG is a leaving group;
• R A , R B , R c , R D , m, and n are as defined supra.
• compositions of the compounds of the invention may comprise further steps like e.g. the introduction of a protective group and the cleavage of the protective group.
• compositions containing one or more compounds of the present invention can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
• a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
• a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
• a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
• the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
• the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
• the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
• the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
• binders such as acacia, corn starch or gelatin
• disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
• Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
• Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
• Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
• the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
• Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
• the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more coloring agents ; one or more flavoring agents ; and one or more sweetening agents such as sucrose or saccharin.
• Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
• sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
• the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 , 1 -dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable sur
• Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
• Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
• Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene- oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
• suitable detergents include cationic detergents
• compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
• the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
• surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
• compositions may be in the form of sterile injectable aqueous suspensions.
• suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
• Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
• sterile fixed oils are conventionally employed as solvents or suspending media.
• any bland, fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid can be used in the preparation of injectables.
• a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
• compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritation excipient are, for example, cocoa butter and polyethylene glycol.
• transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
• the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference).
• patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
• Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
• a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
• the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
• Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
• One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .
• compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
• Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et al. , "Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .
• Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellants (examples include but are not limited to carbon dioxide, CCl 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3 ) air displacement agents (examples include but are not limited to nitrogen and argon) ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, e
• FD&C Red No. 20 FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
• clarifying agents include but are not limited to bentonite
• emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
• encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
• flavorants examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
• humectants include but are not limited to glycerol, propylene glycol and sorbitol
• levigating agents include but are not limited to bentonite
• emulsifying agents include but are not limited to
• compositions according to the present invention can be illustrated as follows:
• Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
• Lyophilised powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
• the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
• Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention
• Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
• Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
• Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
• Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
• the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
• the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
• the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
• the present invention relates also to such combinations.
• the compounds of this invention can be combined with known anti-hyper- proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
• Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
• Preferred additional pharmaceutical agents are: 131 1-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 1 19), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmole
• Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
• anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et a/. , publ.
• anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
• the compounds of the invention may also be administered in combination with protein therapeutics.
• protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-
• Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
• cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
• the compounds of formula (I), supra, as described and defined herein have surprisingly been found to effectively and selectively inhibit GLUT1 and may therefore be used for the treatment and/or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
• leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
• the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
• Another particular aspect of the present invention is the use of a compound of general formula (I), described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
• a compound of general formula (I) described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
• Another particular aspect of the present invention is the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
• the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
• the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders.
• Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
• This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
• Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
• BPH benign prostate hyperplasia
• solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
• Those disorders also include lymphomas, sarcomas, and leukemias.
• breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
• cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
• brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
• Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
• Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
• Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers.
• Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
• Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
• liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
• Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
• Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
• Lymphomas include, but are not limited to AIDS- related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
• Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
• Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
• treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
• the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
• the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
• the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
• Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
• "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
• a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
• the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
• the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
• the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
• the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
• the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
• the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
• a general strategy to assemble the molecules of the invention consists in a coupling reaction to form the carbon-nitrogen bond linking the heteroaromatic moiety R A and the heteroalicyclic head group of an intermediate of general formula (III) as outlined in Scheme 1 :
• This step employs a heterocyclic precursor (II), in which R A is as defined for the compounds of general formula (I), supra, and in which LG is a leaving group suitable for nucleophilic aromatic substitution, such as fluoro, chloro, bromo, or a triflate group, or a moiety suitable for metal catalysed amination reactions, e.g. bromo or iodo, which is coupled with an intermediate (III), in which R B , R c , R D , m and n are as defined for the compounds of general formula (I).
• intermediates (III ) if not commercially available, can be prepared e.g.
• the coupling reaction may be carried out as an aromatic nucleophilic substitution reaction using a dipolar solvent, e.g. DMF, DMSO, HMPA, or acetonitrile at elevated temperatures with or without applying microwave irradiation.
• a dipolar solvent e.g. DMF, DMSO, HMPA, or acetonitrile
• Addition of a base for example triethylamine, DIPEA, DBU, sodium carbonate, potassium carbonate, cesium carbonate or the like, may be advantageous.
• the coupling can be carried out using a metal catalysed coupling reaction known to the person skilled in the art (for a general overview see: D. S. Surry, S. L. Buchwald, Chem. Sci. 201 1 , 2, 27-50. ).
• reaction can be accomplished inter alia by a Buchwald amination reaction well known to the person skilled in the art. Subsequent removal of the protective group yields intermediates of the formula (V), being subjected subsequently to another coupling or substitution reaction with intermediates of formula (VI), in which R B , R c and m are as defined for the compounds of general formula (I), and in which LG stands for a leaving group, giving rise to compounds of the general formula (I).
• Intermediate arenes of the formula (VI) and monoprotected cyclic diamines of formula (IV) both are well known to the person skilled in the art and are commercially available in many cases.
• heterocyclic precursors of the general formula (II), including those discussed below based on a pyrazolopyrimidine core (I la), triazolopyrimidine core (Mb), purine core (lie), triazolopyridine core (lid) or pyrazolopyridine core (lie), llf), llg), and (llh) can be prepared by methods known from the literature.
• a pyrazolopyrimidine core (I la), triazolopyrimidine core (Mb), purine core (lie), triazolopyridine core (lid) or pyrazolopyridine core (lie), llf), llg), and (llh) can be prepared by methods known from the literature.
• the synthesis of several heterocyclic systems preferred within this invention is shown here in detail.
• a more general overview on fused bicyclic hetarenes can be found in the chemical literature, for instance in "Y. Yamamoto (editor), Science of Synthesis - Hetarenes and related Ring Systems Volume 16, Thieme, Stuttgart,
• Scheme 3 Synthesis of pyrazolopyrimidine derivatives (la) via precursors of formula (lla) Pyrazolopyrimidine precursors of the formula (lla), in which R 1 , R 3 and R 6 are as defined for the compounds of general formula (I), supra, can be prepared as shown in Scheme 3 according to the method published in the literature (C. C. Cheng, R. K. Robins, J. Org. Chem. 1956, 21, 1240-1256).
• Diaminopyrimidines of formula (VII) are available by initial introduction of the R 1 -containing moiety by aromatic nucleophilic substitution followed by reduction of the nitro group, starting from commercial 2,4-dichloro-5-nitropyrimidine, as outlined in Scheme 4. Alternatively 2,4-dichloro-5-aminopyrimidine may be used. Diaminopyrimidines of the formula (VII) are then reacted with sodium nitrite (method described in WO 2008/137436 and by Semple et al, Bioorganic Med. Chem. Lett.
• the bicyclic heterocycle is built from 2,4- dichloronicotinaldehyde (method described in WO 2010/ 106333) and hydrazines R 1 -NH-NH 2 , in which Ri is as defined for the compounds of general formula (I ), via intermediate hydrazone formation and subsequent cyclisation and addition of N-nucleophile of the formula (III), in which R B , R c , R D , m and n are as defined for the compounds of general formula (I ), in one step using 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, to give compounds of the formulae (le) and (If), respectively.
• DBU 1 ,8- diazabicyclo[5.4.0]undec-7-ene
• Scheme 7 Preparation of pyrazolopyridines of the formulae (le) and (If)
• 4-bromo-2-fluoronicotinaldehyde can be used instead of 2,4-dichloronicontinaldehyde as shown in Scheme 8.
• This alternative method allows for the isolation of the intermediate bromo- pyrazolopyridines of the formula (lie), in which R 1 is as defined for the compounds of general formula (I).
• R 3 substituents A method for the introduction of various R 3 substituents is exemplarily shown in Scheme 9 for the pyrazolopyridine derivatives of the formula (llh), in which R 1 and R 3 are as defined for the compounds of general formula (I), R 3 however being different from hydrogen, and can be accomplished for instance via a iodination reaction as described in WO 2012/38743 employing readily available intermediates (llf) and giving rise to iodo compounds of the formula (llg). Iodine can then be used for metal catalysed carbon-carbon bond forming reactions such as the Suzuki or the Sonogashira coupling, optionally followed by further modification, in order to introduce various R 3 groups.
• Scheme 10 Route to pyrazolopyridine derivatives of formula (Ih) suitable for late-stage R 1 diversification Using the strategy described above, pyrazolopyrimidines of the formula (Ih), in which R B , R c , R D , R 1 , R 3 , R 6 , m and n are as defined for the compounds of general formula (I ), R 1 however being different from hydrogen, can be synthesized starting from 2-aminopyrazole-carboxamide derivatives which are elaborated to the pyrazolopyrimidine core and then coupled to an intermediate of general formula (III ) as described in Scheme 3, to give pyrazolopyrimidine derivatives of the formula (Ig), featuring a hydrogen attached to N-1 .
• R 1 different from hydrogen is then carried out by a metal catalyzed coupling with a compound of the formula R 1 -LG, in which R 1 is as defined for the compounds of general formula (I ) but different from hydrogen, and in which LG stands for a leaving group suitable for nucleophilic substitution, such as fluoro, chloro, bromo, or a triflate group, or a moiety suitable for metal catalysed amination reactions, e.g. bromo or iodo.
• the coupling reagent may involve palladium (for a general overview see: D. S. Surry, S. L. Buchwald, Chem. Sci. 201 1 , 2, 27-50. ), or copper (for a general overview see:J.X. Qiao, P.Y.S. Lam, Synthesis 201 1 , 829-856).
• Chemical compound names were generated using the software ACD Name batch, Version 12.01 , by Advanced Chemical Development, Inc. ; in doubt, the chemical identity of intermediates and example compounds is primarily to be defined by their chemical structure as shown in the experimental section.
• NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
• Step 1
• Step 1
• step 1 350 mg (1.43 mmol) of 4- chloro-1 -(2-methylphenyl)-1 H-pyrazolo[3,4-d]pyrimidine (preparation known: Bioorganic & Medicinal Chemistry Letters, 2004, vol.14, p.2121 - 2126 or WO2005/47288) and 266 mg (1.43 mmol) Mono-Boc-piperazine gave tert-butyl 4-[1 - (2-methylphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1 -carboxylate: 531 mg (91% yield).
• step 2 In analogy to the synthesis of intermediate 8A) step 2) 531 mg (1.35 mmol) of tert- butyl 4-[1 -(2-methylphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1 - carboxylate gave 1 -(2-methylphenyl)-4-(piperazin-1 -yl)-1 H-pyrazolo[3,4-d]pyrimidine hydrochloride which was used without any further purification. Step 3:
• Step 1
• step 1 288 mg (1.25 mmol) of intermediate 1A) and 300 mg (1.50 mmol) (+/-)-1 -Boc-2-methyl-piperazine gave tert- butyl (+/-)-tert-butyl 2-methyl-4-(1 -phenyl-1 H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1 -carboxylate: 338 mg (65% yield).
• step 2) 338 mg (0.86 mmol) (+/-)- tert-butyl 2-methyl-4-(1 -phenyl-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1 - carboxylate gave (+/-)-4-(3-methylpiperazin-1 -yl)-1 -phenyl-1 H-pyrazolo[3, 4- d]pyrimidine hydrochloride which was used without any further purification.
• Step 3 In analogy to the synthesis of intermediate 8A) step 3) 283 mg (0.86 mmol) (+/-)-4- (3-methylpiperazin-1 -yl)-1 -phenyl-1 H-pyrazolo[3,4-d]pyrimidine hydrochloride gave the desired material: 224 mg (84% yield).
• Step 1
• Step 1
• step2 1.69 g (7.20 mmol) 6-chloro-N 4 -(2- methylphenyl)pyrimidine-4,5-diamine of stepi ) gave the desired material: 1.54 g (84% yield).
• Step 1
• step 1 4.5 g (23.2 mmol) 4,6-dichloro-5- nitropyrimidine and 2.07 g (18.6 mmol) 2-fluoroaniline gave the desired 6-chloro-N 4 - (2-fluorophenyl)pyrimidine-4,5-diamine: 587 mg (24% yield).
• step2 1.65 g (6.91 mmol) 6-chloro-N 4 -(2- fluorophenyl)pyrimidine-4,5-diamine of stepi ) gave the desired material: 1.50 g (78% yield).
• Step 1
• step 1 2.91 g (17.7 mmol) 4,6-dichloropyrimidine-5- amine and 3.00 g (17.7 mmol) methyl 4-amino-3-fluorobenzoate gave the desired methyl 4-[(5-amino-6-chloropyrimidin-4-yl)amino]-3-fluorobenzoate: 1.46 g (28% yield).
• step2 1.78 g (6.0 mmol) methyl 4-[(5-amino-6- chloropyrimidin-4-yl)amino]-3-fluorobenzoate and in change additional 6.05 mL 37% aq. hydrochloric acid gave the desired material: 1.67 g (86% yield).
• Step 1
• step 1 5.56 g (28.6 mmol) 4,6-dichloropyrimidine-5- amine and 4.50 g (23.2 mmol) methyl trans-4-aminocyclohexanecarboxylate hydrochloride gave the desired methyl trans-4-[(5-amino-6-chloropyrimidin-4- yl)amino]cyclohexanecarboxylate: 3.35 g (39% yield).
• step2 3.35 g (11.8 mmol) methyl trans-4-[(5-amino- 6-chloropyrimidin-4-yl)amino]cyclohexanecarboxylate and in change additional 5.0 mL 37% aq. hydrochloric acid gave the desired material: 2.92 g (81 % yield).

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