Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the invention relates to new pyridylalkane, alkene and alkine carboxa ides substituted with a cyclic imide and with a saturated or one or several-fold unsaturated hydrocarbon residue in the carboxylic acid group, methods for the synthesis of these compounds, medicaments containing these and their production as well as their therapeutic use especially as cytostatic agents and immunosuppresive agents, for example, in the treatment or prevention of various types of tumors inhibition of abnormal cell growth and control of immune reactions, for example of autoimmune diseases.
• radiation for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.
• ⁇ -pyridyl alkane and/or alkene amides with antiallergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti- histamine action, wherein the amide components of these compounds contain a piperizine or homopiperizine ring and the pyridine ring can be linked together in the 2-, 3- or 4- position.
• JP 63,179,869 describes further pyridyl amides, ⁇ -pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component.
• structured compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) as well as in J. Med. Chem. 1989, 583-593.
• heterocyclic carboxamides which can be substituted at an end of the molecule by completely different heterocycles such as thiophene, guinoline, indole, benzimidazole or indazole as well as pyridine are described in J. Med. Chem., 1996, pages 4692-4706. However, these compounds possess an activity directed against psychoses .
• Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl-substituted alkyl chain with a piperidine ring or piperidine ring or piperazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P.
• pyridyl (alkyl) carbonamides pyridyl (alkyl) sulfonamides and analogous ureas, wherein the pyridine ring is bound directly or over a methylene bridge with the amide group are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties .
• WO 91/15 485 the production of pyridine-3 , 5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below with the pharmaphoric cyclic imide group in very important structural features, for example by their dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping.
• the compounds disclosed in WO 89/07 443 in the form of optically pure R (-) -niguldipin and further analogous dihydropyridines with cytotoxic activity have larger structural differences. However, as compared to these known compounds, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural differences.
• tricyclic amide compounds which possess an anti-proliferative activity. All of these compounds described therein are distinguished in that they must imperatively possess a tricyclic anellated ring system with at least one nitrogen atom, for example 6, ll-dihydro-5H- benzo [5, 6] cyclohepta [1, 2-b]pyridinyl ring system as a pharmaphoric group, whereby the molecule portion opposite this tricyclic anellated system is uncommonly variable and represents one of numerous variation possibilities among numerous substitution possibilities of the given pyridyl substitution.
• a further meaningful difference in the substitution of these molecules in comparison to the compounds according to the invention is to be seen in the lack of the present structural element D as well as the absence of the cyclic imide group which must be present.
• a further essential difference of the compounds according to the invention in comparison to these tricyclic compounds is to be recognized in the presence of the terminal 3-pyridyl- substitution which must be present.
• the presence of this particular type of imide required according to the invention as well as the particular bond in the 3 -position of the pyridine ring according to the substitution of the invention in comparison to the above mentioned anti-proliferative compounds of the state of the art indicates that this 3- pyridyl substitution as well as the cyclic imide group can be a factor for the anti-tumor action.
• the compounds according to the invention cover a different tumor spectrum from those named in the PCT/WO publications with this necessarily present tricyclic anellated ring system.
• a treatment possibility in tumors is merely mentioned which is made in connection with a potential inhibition of the farnesyl protein transferase, whereby this mechanism relates to the expression of the activated ras- oncogene.
• the compounds according to the invention with the 3 -pyridyl-substitution required according to the invention are not limited to the therapy of tumor cells of this type with abnormal production of the ras- oncogene; rather, the therapy possibilities with the new compounds according to the invention extend to the combat of numerous other types of tumors with different causal mechanisms as well as immunosuppressive treatment possibilities such as autoimmune diseases.
• saturated unsaturated or aromatic anellated bi-, tri- or tetracyclic imides with 8 to 18 ring atoms of which, aside from the essential imide nitrogen atom, one to three further hetero-atoms can be present selected from N and/or S and/or O;
• saturated or unsaturated spirocyclic imides optionally anellated once or twice, and with a total of 9 to 23 ring atoms among which, aside from the essential imide nitrogen atom, one to three further hetero-atoms can be present selected from N and/or S and/or O; whereby these cyclic imides can be substituted independently of each other by one to five of the same or different groups as described in detail below:
• Subject matter of the invention are further pharmacologically acceptable acid addition salts of the compounds of Formula (I) with inorganic or organic acids.
• Preferable examples for addition salts with suitable inorganic acids are hydrochlorides , hydrobromides, hydroiodides, sulfates and phosphates.
• Addition salts of organic acids are preferably acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and tosylates.
• Compounds of Formula (I) as well as their acid addition salts can also be optionally present as hydrates or other solvates.
• the invention includes such hydrates and solvates.
• Halogen means fluorine, chlorine, bromine or iodine
• Alkyl can be straight chained or branched and preferably signifies a C ⁇ Cg-alkyl residue, especially a methyl-, ethyl- , propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert- butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl- , neopentyl-, cyclopropylethyl- , cyclobutylmethyl- or hexyl group.
• a C ⁇ Cg-alkyl residue especially a methyl-, ethyl- , propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert- butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-
• Alkylene signifies for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene .
• Alkenyl preferably signifies ( ⁇ -Cg-alkenyl and can be straight chained or branched and preferably signifies an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2- pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl- , 3-methyl-2- butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2, 2-dimethyl-3-butenyl-group.
• Alkenylene signifies for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or decenylene.
• Alkinyl preferably signifies C2 ⁇ Cg-alkinyl which can be straight chained or branched and can preferably signify an ethinyl-, propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5- hexinyl- or 4-methyl-2-pentinyl group.
• Alkinylene signifies for example propinylene, butinylene, pentinylene, hexinylene, hexeninylene, heptinylene, octinylene, noninylene or decinylene.
• Cycloalkyl is preferably a C -Cg-cycloalkyl residue, especially a cyclopropyl-, cyclobutyl-, cyclopentyl- , cyclohexyl-, cycloheptyl- or cyclooctyl group.
• Hydroxyalkyl contains a hydroxyl group in one of the above mentioned alkyl residues, especially in a C ⁇ -Cg-alkyl residue, whereby among the C ] _-Cg-hydroxyalkyl residues, the hydroxymethyl- and the hydroxyethyl residue are preferred.
• alkoxy residues preferably C ⁇ -
• Cg-alkoxy or C 3 -C 8 -cycloalkyloxyl contain one of the above mentioned preferred C ⁇ _-Cg-alkyl- , or C 3 ⁇ Cg-cycloalkyl residues .
• Particularly preferred groups for this are the methoxy-, ethoxy-, isopropoxy-, tert-butoxy-, cyclopentyloxy- and cyclohexyloxy groups .
• Alkoxy, especially Ci-Cg-alkoxy, entirely or partially replaced by fluorine is for example difluoromethoxy, trifluoromethoxy or 2, 2, 2-trifluoroethoxy.
• Aralkyl such as phenylal yl, especially phenyl-C ] _-C3-alkyl and/or diarylalkyl such as diphenyl-C ⁇ C3-alkyl contain one and/or two phenyl groups on a methyl-, ethyl-, propyl- or isopropyl group at any position.
• Alkylidene residues especially C]_-Cg-alkylidene, C ⁇ -Cg- cycloalkylidene, phenyl-C ⁇ -C3 ⁇ alkylidene and diphenyl-C ⁇ C3- alkylidene correspond to the above named preferred C ⁇ -Cg- alkyl-, C3-Cg-cycloalkyl-, phenyl-C]_-C3-alkyl- and diphenyl- C]_-C3-alkyl groups, but are respectively bound over a double bond.
• alkylthio residues contain one of the above mentioned preferred C ⁇ -Cg-alkyl groups.
• Particularly preferred groups are the methylthio-, ethylthio- , isopropylthio- and tert-butylthio groups.
• Cyclopentyloxy- and cyclopentylthio- and/or cyclohexyloxy- and cyclohexylthio residues represent preferred C3-Cg-cyclo- alkyloxy and C3-Cg-cycloalkylthio.
• alkanoyloxy residues preferably contain an aliphatic acyl group with 1 to 7 carbon atoms.
• alkanoyloxy groups are the acetoxy- , propionyloxy- and pivaloyloxy groups.
• Alkoxycarbonyl groups preferably C2-C7-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the above mentioned alkoxy groups, especially C ⁇ -Cg-alkoxy groups.
• Preferred alkoxycarbonyl groups are the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl- , isobutox carbonyl- and tert-butoxycarbonyl groups.
• alkylaminocarbonyl especially C2-C 7 -alkylaminocarbonyl and dialkylaminocarbonyl groups, preferably C 3 -C 2 . 3 -dialkylaminocarbonyl groups, contain an alkylamino- and/or dialkylamino residue whose alkyl groups correspond especially to the C ⁇ Cg-alkyl groups of the above description.
• Preferred groups are the dimethylaminocarbonyl- , diethylaminocarbonyl- and diisopropylaminocarbonyl groups.
• C2-C7-carboxyalkyl and C3-C7-carboxyalkenyl contain a carbonyl group on one of the above named C ⁇ -Cg-alkylene and/or C2-Cg-alkenylene residues.
• Preferred are the carboxymethyl-, carboxyethyl-, carboxyethenyl-, carboxybutyl- and carboxybutadienyl groups.
• Ci-Cg-aminoalkyl contains an amino group in one of the above named C_-Cg-alkyl residues. Preferred are the aminomethyl- and the aminoethyl residues.
• Formula NR 4 R ⁇ are one of the below mentioned alkylamino groups, especially C ⁇ -C -alkylamino groups and/or dialkylamino groups, especially di- (C ⁇ -Cg-alkyl) amino groups.
• Alkylamino especially contains one of the above mentioned C ] _-
• Cg-alkyl groups are the methylamino- , ethylamino-, propylamino-, isopropylamino-, butylamino-, and the tert-butylamino groups.
• Phenyl- C 1 -C 3 -alkylamino contains a phenyl group on a methylamino-, ethylamino-, propylamino- or isopropylamino residue on any carbon atom.
• the preferred di- (C ⁇ -Cg-alkyl) amino residue carries two of the same or different of the above mentioned C ⁇ Cg-alkyl groups on the nitrogen atom.
• Preferred groups are the dimethylamino- , diethylamino-, dipropylamino- , diisopropylamino-, isopropyl-, methylamino-, dibutylamino- or tert-butylmethylamino groups.
• Acyl especially C;j_-Cg-acyl, signifies the residue of an aliphatic saturated or unsaturated, straight chained, branched or cyclic carboxylic acid.
• Preferred acyl residues are formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl- , cyclopropylcarbonyl- , pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and dimethylacryloyl groups.
• Alkanesulfonyl, especially C ⁇ -Cg-alkanesulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl- , pentanesulfonyl- or hexanesulfonyl groups.
• Saturated or unsaturated monocyclic imides with 5 to 7 ring atoms among which, aside from the essential imide nitrogen atom, one or two further hetero-atoms can be present are for example pyrrol-2, 5-dione, pyrrolidin-2, 5-dione, imidazolidin- 2,4-dione, oxazolidin-2, -dione, thiazolidin-2, -dione, imidazolidin-2, 4, 5-trione, 1,2, 4-oxadiazolidin-3, 5-dione, piperidin-2, 6-dione, 3H-pyridin-2, 6-dione, piperazin-2, 6- dione, morpholin-3, 5-dione, thiomorpholin-3, 5-dione, azepin- 2,7-dione, 3, 6-dihydroazepin-2, 7-dione, hexahydroazepin-2, 7- dione, hexahydro-1, 3-diazepin-2, 4-
• Saturated or unsaturated or aromatic anellated, bi-, tri- or tetracyclic imides with 8 to 18 ring atoms among which, aside from the essential imide nitrogen, one to three further hetero-atoms can be present, are for example dihydro- cyclopentapyrrol-1, 3-dione, tetrahydrocyclopentapyrrol-1, 3- dione, pyrrolo [3, 4-c]pyrrol-l, 3-dione, dihydropyrrolo [3, 4- c]pyrrol-l, 3-dione, tetrahydropyrrolo [3, 4-c]pyrrol-l, 3-dione, pyrrolo [3, 4-b]pyrrol-4, 6-dione, dihydropyrrolo [3, 4-b]pyrrol- 4, 6-dione, tetrahydropyrrolo [3, 4-b]pyrrol-4, 6-dione, pyrrolo [1, 2-c] imidazol-1, 3-dione, tetrahydropyrrolo [
• Saturated or unsaturated spirocyclic imides optionally anellated once or twice, and with a total of 9 to 23 ring atoms among which, aside from the essential imide nitrogen atom, one to three further hetero-atoms can be present are for example 2-azaspiro [4.4]nonan-l, 3-dione, 2,7- diazaspiro [4. ]nonan-l, 3-dione, 1, 3-diazaspiro [4.4] nonan-2, 4- dione, l-thia-3-azaspiro [4. ]nonan-2, 4-dione, l-oxa-3- azaspiro [4.4] nonan-2, 4-dione, 1,3, 7-triazaspiro [4.
• nonan-2 4-dione, 2- azaspiro [4.5] decan-1, 3-dione, 2, 8-di-azaspiro [4.5] decan-1, 3- dione, 1, 3, 7-triazaspiro [4.5] decan-2, 4-dione, 1,3,8- triazaspiro [4.5] decan-2, 4-dione, l-oxa-3, 8-diaza- spiro [ .5] decan-2, 4-dione, 8-azaspiro [4.5] decan-7, 9-dione, 7- azaspiro [4.5] decan-6, 8-dione, 3-azaspiro [5.5] undecan-2, 4- dione, 2-azaspiro [5.5] undecan-1, 3-dione, as well as spiro [dioxoimidazolidin-indanes] ,
• Saturated or unstaturated four- to seven-membered heterocycles with one or two hetero-atoms are for example azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydropyridine, piperidine, tetrahydroazepine, hexahydroazepine, pyrazolidine, piperazine, morpholine, thiomorpholine, thiomorpholin-1, 1- dioxide, hexahydrodiazepine or hexahydrooxazepine.
• Monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are for example furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl.
• Anellated bicyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 12 ring atoms are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptenyl, tetrahydrobenzocycloheptenyl, benzocyclooctenyl or hexahydrobenzocyclooctenyl .
• their mono- or dioxo-derivates also included, i.e. for example, the indanone, tetralone, benzocycloheptenone or tetrahydrobenzocycloheptenone groups.
• Anellated bicyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 12 ring atoms are for example imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, isoindolinyl, benzoimidazolyl, indazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzotriazolyl, chromanyl, benzopyranyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, tetrahydrobenzooxepinyl, tetrahydrobenzothiepinyl, benzoaze
• heterocyclic ring systems their mono- or dioxo derivates and/or optionally their possible tautomers are additionally included, i.e. for example, ring systems such as indolinone, isatin, benzooxazolone and/or its tautomer hydroxybenzooxazole, as well as benzoisoxazolone, benzothiazolone, benzoisothiazolone and benzoimidazolone and/or their tautomers hydroxybenzoisoxazole, as well as hydroxybenzothiazole, hydroxybenzoisothiazole and hydroxybenzoimidazole, indazolinone, and chromanone, chromone, quinolinone, dihydroquinolinone and tetrahydrobenzoazepinones .
• ring systems such as indolinone, isatin, benzooxazolone and/or its tautomer hydroxybenzooxazole, as well as benzoiso
• the invention concretely relates to new i ide- substituted pyridylalkane, pyridylalkene and pyridylalkine acid amides of the general Formula (I)
• R 1 is selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkinyl, tri- fluoromethyl, cycloalkyl, hydroxyalkyl, hydroxy, alkoxy, cycloalkyloxy, aralkyloxy such as benzyloxy, alkanoyloxy, alkylthio, alkoxycarbonyl, alkanoyloxy, alkylthio, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkyla inocarbonyl, carboxy, aryl such as phenyl, aryloxy such as phenoxy, arylthio such as phenylthio, heteroaryloxy such as pyridyloxy, heteroarylthio such as pyridylthio, and NR 4 R 5 , whereby
• R 4 and R 5 are selected independently from each other from hydrogen, alkyl, alkenyl, alkinyl, aralkyl such as benzyl and aryl such as phenyl;
• R 2 is selected from hydrogen, halogen, cyano, alkyl, trifluoromethyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
• alkyl is selected from hydrogen, alkyl, alkenyl, alkinyl, hydroxy, alkoxy and aryloxy such as benzyloxy;
• k 0 or 1
• A is selected from alkylene, optionally substituted one to three-fold by alkyl, hydroxy, alkoxy, fluorine, or aryl such as phenyl,
• alkylene wherein a methylene unit is isosterically replaced by O, S, NR 6 , CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amine group and R 6 is selected from hydrogen, alkyl, alkenyl, acyl or alkanesulfonyl;
• alkenylene optionally substituted once or twice by alkyl, hydroxy, alkoxy, fluorine, cyano or aryl such as phenyl;
• alkadienylene optionally substituted once or twice by alkyl, fluorine, cyano or aryl such as phenyl;
• D is selected from alkylene, optionally substituted once or twice by alkyl, hydroxy, or alkoxy;
• alkenylene optionally substituted once or twice by alkyl, hydroxy, or alkoxy
• alkinylene optionally substituted once or twice by alkyl, hydroxy, or alkoxy
• alkylene alkenylene or alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR', CO, SO or SO2, whereby B is synonymous with
• R 6 but is selected independently thereof
• monocyclic aromatic five- or six-membered heterocycles which can contain one to three hetero-atoms selected from N and/or S and/or O and are either bound directly or bound over a methylene group or a methine group,
• anellated bicyclic, aromatic or partial hydrated carbocyclic ring systems with 8 to 12 ring atoms which are either bound directly or bound over a methylene or a methine group anellated bicyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 12 ring atoms, whereby one to three ring atoms can be selected from N and/or S and/or 0 and are either bound directly or bound over a methylene or a methine group,
• aryl and heteroaryl residues as substituents of the cyclic imides can be substituted themselves by one to three of the same or different groups selected from
• E contains a heterocyclic aromatic ring with simultaneous substitution by free hydroxy, mercapto or amino groups as well as the acid addition salts of the above defined compounds including their hydrates and solvates.
• R 1 is selected from hydrogen, halogen, cyano, C ⁇ -Cg-alkyl, C3 ⁇ Cg-alkenyl,
• C2-Cg-alkinyl trifluoromethyl, C3-Cg-cycloalkyl, C j -Cg- hydroxyalkyl, hydroxy, C ] _-Cg-alkoxy, C3-C8- cycloalkyloxy, benzyloxy, C ⁇ -C7-alkanoyloxy, C ] _-Cg- alkylthio, C2 ⁇ C7-alkoxycarbonyl, aminocarbonyl, C2-C7- alkylaminocarbonyl, C ⁇ -C ⁇ -dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR 4 R 5 , whereby
• R 4 and R 5 are selected independently from each other from hydrogen, C ⁇ -Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkinyl, benzyl and phenyl;
• R 2 is selected from hydrogen, halogen, cyano, C ] _-Cg-alkyl, trifluoromethyl, hydroxy, Cj-Cg-alkoxy and benzyloxy;
• R3 is selected from hydrogen, C]_-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkinyl, hydroxy, C ⁇ -Cg-alkoxy and benzyloxy;
• k 0 or 1
• A is selected from
• C ⁇ -Cg-alkylene optionally substituted one to three-fold by C-L ⁇ C3-alkyl, hydroxy, C ⁇ -C3-alkoxy, fluorine, or phenyl ;
• C2 _ Cg-alkylene in which a methylene unit is isosterically replaced by 0, S, NR 6 , CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R 6 is selected from hydrogen, C ⁇ -Cg-alkyl, C3 ⁇ Cg- alkenyl, C_-Cg-acyl or C ⁇ -Cg-alkanesulfonyl;
• C2-Cg-alkenylene optionally substituted once or twice by C ⁇ C3-alkyl, hydroxy, C ⁇ -C3-alkoxy, fluorine, cyano or phenyl;
• saturated or unsaturated monocyclic imides with 5 to 7 ring atoms of which, aside from the essential imide nitrogen atom, one or two further hetero-atoms can be present selected from N and/or S and/or 0;
• saturated or unsaturated spirocyclic imides optionally anellated once or twice, and with a total of 9 to 23 ring atoms of which, aside from the essential imide nitrogen atom, one to three further hetero-atoms can be present selected from N and/or S and/or 0;
• cyclic imides can be substituted by one to five of the same or different groups selected independently from each other from halogen, cyano, C ⁇ -Cg-alkyl, C]_-Cg-alkylidene, trifluoromethyl, C3-Cg-cycloalkyl, C3-Cg-cycloalkylidene, phenyl-C]_-C3-alkyl, phenyl-C ⁇ -C3-alkylidene, diphenyl-C ] _-C3- alkyl, diphenyl-C ⁇ -C3-alkylidene, triphenylmethyl, phenyl, hydroxy, C]_-Cg-hydroxyalkyl, C ⁇ -Cg-alkoxy, C -Cg-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, naphthyloxy, mercapto, Ci-Cg-alkylthio, phenylthio, nap
• monocyclic aromatic five- or six-membered heterocycles which can contain one to three hetero-atoms selected from N and/or S and/or 0 and are either bound directly or bound over a methylene group or a methine group,
• anellated bicyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 12 ring atoms whereby one to three ring atoms can be selected from N and/or S and/or 0 and are either bound directly or bound over a methylene or a methine group. and whereby aryl and heteroaryl residues as substituents of the cyclic imides can be substituted themselves by one to three of the same or different groups selected from
• the invention relates to compounds of the general formula (I)
• R 1 is selected from hydrogen, halogen, cyano, Ci-Cg-alkyl, trifluoromethyl, ethinyl, hydroxy, C ⁇ C4-alkoxy, benzyloxy, C ] _-C4-alkyl- thio, C2-C5 ⁇ alkoxycarbonyl, aminocarbonyl, C3-C9- dialkylaminocarbonyl, carboxy, phenoxy, phenylthio and pyridyloxy;
• R 2 is selected from hydrogen, fluorine, chlorine, bromine, C- ⁇ -C4-alkyl, trifluoromethyl, hydroxy, C ⁇ C4-alkoxy;
• R-3 is selected from hydrogen, C_-C3 ⁇ alkyl, allyl, hydroxy, C ] _-C3-alkoxy and benzyloxy;
• k 0 or 1
• A is selected from
• C2 _ Cg-alkylene wherein a methylene unit is isosterically replaced by 0, S, NH, N(CH3> or CO, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group;
• ethinylene D is selected from
• E is selected from saturated or unsaturated monocyclic imides with 5 to 7 ring atoms, for example, pyrrol-2, 5-dione, pyrrolidin- 2, 5-dione, imidazolidin-2, 4-dione, oxazolidin-2, 4-dione, thiazolidin-2, 4-dione, imidazolidin-2, 4, 5-trione, piperidin-2, 6-dione, 3H-pyridin-2, 6-dione, piperazin- 2, 6-dione, morpholin-3, 5-dione, azepin-2, 7-dione, 3,6- dihydroazepin-2, 7-dione, hexahydroazepin-2, 7-dione, hexahydro-1, 3-diazepin-2, 4-dione, hexahydro-1, 4- diazepin-2, 7-dione, 3, 7-dihydro-l, 2, 5-triazepin-4, 6- dione, hex
• unsaturated or aromatic anellated tricyclic imides such as, for example, benzo [4, 5] thieno [2, 3-c]pyrrol-l, 3- dione, thienoisoindol-1, 3-dione, benzoisoindol-1, 3- dione, dihydrobenzoisoindol-1, 3-dione, tetrahydrobenzoisoindol-1, 3-dione, pyrrolo [3, 4- g] quinolin-6, 8-dione, tetrahydropyrrolo [3, 4- g] quinazolin-6, 8-dione, 1,2, 4-triazolo [1, 2-a] cinnolin- 7,9-dione, dihydrocarbolin-1, 3-dione, 4H-benzo [h] isoquinolin-1, 3-dione, benzo [de] isoquinolin-1, 3-dione, dibenzo [c, e] azepin-5, 7-
• unsaturated or aromatic anellated tetracyclic imides such as, for example, dihydro-4H-acenaphtho- [1, 8- a, c]pyrrol-l, 3, 10-trione, 6H-pyrrolo [3, 4-c] carbazol-1, 3- dione, dibenzoisoindol-1, 3-dione, naphthoisoindol-1, 3- dione, tetrahydronaphthoisoindol-1, 3-dione, dibenzo [de, h] -isoquinolin-1, 3-dione, dihydro-12H-2-aza- pleiaden-1, 3-dione, lH-anthra[l, 9-c, d] azepin-2, 4-dione,
• anellated bicyclic aromatic or partially hydrated heterocyclic rings systems with 8 to 11 rings atoms, whereby one to three ring atoms can be selected from N and/or S and/or 0 and are either bound directly or bound over a methylene group or a methine group,
• aryl and heteroaryl residues as substituents of the cyclic imides can be substituted themselves by one to three of the same or different groups selected from
• the invention relates to compounds of the general formula (I)
• R 1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, C ⁇ -C4-al oxy, phenoxy, methylthio, ethylthio, methoxycarbonyl, aminocarbonyl and carboxy;
• R 2 is selected from hydrogen, chlorine, methyl, hydroxy and methoxy
• R 3 is hydrogen
• A is selected from
• C4-Cg-alkenylene optionally substituted by methyl or hydroxy
• C4 ⁇ Cg-alkinylene optionally substituted by hydroxy
• C2 ⁇ Cg-alkylene, C4-Cg-alkenylene or C4-Cg-alkinylene in which a methylene unit is isosterically replaced by 0, NH, N(CH 3 ), or CO, or an ethylene group is isosterically replaced by a group NH-CO and/or CO-NH, or a propylene group is isosterically replaced by a group NH-CO-NH or NH-CO-O and/or O-CO-NH;
• anellated bicyclic imides such as phthalimide, tetra- hydrophthalimide, homophthalimide, pyrrol-3,4- dicarboximide, 2, 5-dihydropyrrol-3, 4-dicarboximide, thiophen-2, 3-dicarboximide, thiophen-3, 4-dicarboximide, pyridin-2, 3-dicarboximide, pyridin-3, 4-dicarboximide, pyridazin-3, -dicarboximide, 1, 1-dioxo-benzo [d] - isothiazol-3-one, isatoic acid imide, 4H-2, 6- naphthyridin-1, 3-dione, lH-pyrido[2, 3-d] pyrimidin-2, 4- dione,
• anellated tricyclic imides such as naphthalin-1, 2- dicarboximide, 1,2,3, -tetrahydronaphthalin-l, 2- dicarboximide, naphthalin-2, 3-dicarboximide, 1,8- naphthalimide, diphenic acid imide, benzothiophen-2, 3- dicarboximide, benzothiophen-4, 5- dicarboximide, quinolin-6, 7-dicarboximide, quinazolin-6, 7- dicarboximide,
• anellated tetracyclic imides such as 7, 8- dihydroacenaphthen-2 (6H) -on-1, 8a-dicarboximide, anthracen-2, 3-dicarboximide, anthracen-1, 9- dicarboximide, phenanthren-9, 10-dicarboximide, 12a, 12b- dihydro-12H-2-azapleiaden-l, 3-dione, lH-anthraceno [1, 9- c, d] azepin-2, 4-dione, carbazol-5, 6-dicarboximide,
• bridged polycyclic imides such as cyclopentan-1, 3- dicarboximide, cyclohex-2-en-l, 4-dicarboximide, bicyclo [2.2.1] -hept-5-en-2, 3-dicarboximide, 7-oxa- bicyclo [2.2.1] -hept-5-en-2, 3-dicarboximide, bicyclo [2.2.2] -oct-5-en-2, 3-dicarboximide, benzobicyclo [2.2.2] -octan-2, 3-dicarboximide, dibenzobicyclo [2.2.2] -octan-2, 3-dicarboximide, dibenzobicyclo [2.2.2] -octan-2, 3-dicarboximide, dibenzobicyclo [2.2.2] -octan-2, 3-diacetic acid imide and
• spirocyclic imides such as 1, 3-diazaspiro [4.4] nonan-2, 4- dione, l-thia-3-azaspiro [4.4] nonan-2, 4-dione, l-oxa-3, 7- diazaspiro [4.4] nonan-2, 4-dione, l-oxa-3, 8- diazaspiro [4.5] decan-2, 4-dione, spiro [dioxoimidazolidin- indane] , spiro [dioxoimidazolidin-piperidine] , spiro [di- oxoimidazolidin-oxoindoline] spiro [dioxoimidazolidin- tetrahydronaphthaline] , and spiro [2, 6-dioxopiperidin- tetrahydronaphthaline] ,
• furyl furylmethyl, thienyl, thienylmethyl, oxazolyl, isox- azolyl, thiazolyl, thiazolyl ethyl, imidazolyl, oxadiazolyl, pyridyl, pyridylmethyl, pyrazinyl, pyrimidinyl;
• aryl and heteroaryl residues as substituents of the cyclic imides can be substituted themselves by one to three of the same or different groups selected from
• R 1 is selected from hydrogen, fluorine, methyl, trifluoromethyl, ethylthio; .
• R 2 is hydrogen
• R 3 is hydrogen
• A is selected from ethylene or butylene, optionally substituted by hydroxy or one or two fluorine atoms, or
• C4 ⁇ Cg-alkinylene or C4 ⁇ Cg-alkylene, C4 ⁇ Cg-alkenylene or C4-Cg-alkinylene, wherein one or two methylene units is isosterically replaced by 0, NH or CO;
• E is selected from monocyclic imides such as succinimide, maleinimide, glutarimide, imidazolidindione, imidazolidintrione, thiazolidindione, oxazolidindione, piperazin-2, 6-dione, hexahydrodiazepin-2, 7-dione,
• anellated bicyclic imides such as phthalimide, ho o- phthalimide, pyridin-2, 3-dicarboximide, pyridin-3, - dicarboximide, isatoic acid imide,
• anellated tricyclic imides such as naphthalin-1, 2- dicarboximide, naphthalin-2, 3-dicarboximide, 1,8- naphthalimide, diphenic acid imide,
• anellated tetracyclic imides such as 7, 8-dihydroace- naphthen-2 (6H) -on-1, 8a-dicarboximide, anthracen-2, 3- dicarboximide, anthracen-1, 9-dicarboximide, phenanthren- 9, 10-dicarboximide,
• bridged polycyclic imides such as bicyclo [2.2.1] -hept-5- en-2, 3-dicarboximide, 7-oxa-bicyclo [2.2.1] -hept-5-en- 2, 3-dicarboximide, benzobicyclo [2.2.2] -octan-2, 3- dicarboximide, dibenzobicyclo [2.2.2] -octan-2, 3- dicarboximide, and
• spirocyclic imides such as spiro [dioxoimidazolidin- indane] , spiro [dioxoimidazolidin-piperidine] , spiro [dioxoimidazolidin-oxoindoline] and spiro [dioxoimidazolidin-tetrahydronaphthaline] ,
• cyclic imides can be substituted by one to four of the same or different groups selected independently from each other from halogen, C]_-C4-Alkyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy, benzyloxy, phenoxy, phenylthio, pyridylthio, phenylsulfonyl, sulfo, carboxy, C2-C7- carboxyalkyl, C2 ⁇ C7-carboxyalkenyl, C2 ⁇ C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, aminomethyl, dimethylamino, diethylamino, phenylamino, pyridylamino; benzyl, benzylidene, phenylethyl, naphthylmethyl, diphenylmethyl, diphenylmethylene, triphenylmethyl
• aryl and heteroaryl residues as substituents of the cyclic imides can be substituted themselves by one to three of the same or different groups selected from
• Reactive derivatives of compound (II) can be, for example, its activated esters, anhydrides, acid halides (especially acid chlorides) or simple low alkyl esters.
• Suitable activated esters are, for example, p-nitrophenyl ester, 2,4, 6-trichlorophenyl ester, pentachlorophenyl ester, cyano- methyl ester, esters of N-hydroxysuccinimide, N-hydroxy- phthalimides, 1-hydroxybenzotriazole, N-hydroxypiperidine, 2- hydroxypyridine, 2-mercaptopyridine, etc.
• Anhydrides can be symmetric anhydrides or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates .
• Aromatic for example chloroformic phenyl ester
• araliphatic for example chloroformic benzyl ester
• aliphatic chloroformates for example chloroformic methyl ester, ethyl ester or isobutyl ester
• Reaction of compounds (II) with compounds (III) can also be carried out in the presence of condensation agents such as dicyclohexylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl) - carbodiimide hydrochloride, N,N' -carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, etc. If carbodiimides are used as the condensation agent, reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1- hydroxybenzotriazole, N-hydroxypiperidine, etc. can be advantageously added.
• condensation agents such as dicyclohexylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl) - carbodiimide hydrochloride, N,N' -carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy-1
• Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts.
• the salts of inorganic acids are to be preferred, i.e. hydrochlorides, hydrobromides or sulfates for example.
• Reaction of compounds (II) or their reactive derivatives with compounds (III) is normally carried out in a suitable, preferably inert solvent.
• aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1, 2-dichloroethane, trichloroethylene) , ethers (for example diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether) , ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methyl- pyrrolidone are to be named. Pure solvents, as well as mixtures of two or more, can be used.
• the reaction is optionally carried out in the presence of an auxiliary base.
• auxiliary base Suitable examples for this are alkali metal carbonates (sodium carbonate, potassium carbonate) , alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate) , or organic bases such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-me hylmorpholine or pyridine.
• a suitable excess of compound (III) can also be used as a base. If compounds (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent.
• reaction temperatures can - depending on reactivity of the educts - vary in a wide range. Generally, the reaction is carried out at temperatures between -40°C and 180°C, preferably between -10°C and 130°C, especially at the boiling point of the solvent used.
• the starting compounds (II) and (III) are known and/or can be produced according to known methods in an analogous manner. Moreover, the production of representative examples is described below.
• Suitable organophosphorous 111 compounds are triarylphosphines particularly such as triphenylphosphine or trialkylphosphines particularly such as tributylphosphine .
• triarylphosphines particularly such as triphenylphosphine or trialkylphosphines particularly such as tributylphosphine .
• mixed aryl- alkylphosphines can also be used such as for example methyldiphenylphosphine, or trialkyl phosphites such as tri ethyl phosphite, triethyl phosphite or tributyl phosphite .
• Suitable aliphatic azo compounds are, for example, azodicarboxylic esters such as azodicarboxylic dimethyl ester, but especially azodicarboxylic diethyl ester and azodicarboxylic acid diisopropyl ester.
• Azodicarboxamides can be used as further aliphatic azo compounds such as, for example, N,N,N' ,N' -tetramethylazodicarboxadiamide, N,N,N',N'- tetraisopropylazodicarboxadiamide or 1, 1 ' - (azodicarbonyl) -di- piperidine.
• newer reagents are named in Org. Prep. Proced. Int. 28, 129-164 (1996) .
• Reaction of compounds (IV) with compounds (V) is normally carried out in a suitable, preferably aprotic solvent.
• aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example, dichloromethane, chloroform, 1, 2-dichlorethane, trichlorethylene) , ethylacetate, acetonitrile and especially ethers such as diethyl ether, diisopropyl ether, methyl-tert- butyl ether, glycoldimethyl ether, dioxane and, particularly preferred, tetrahydrofuran are to be named. Pure solvents as well as mixtures of two or more can be used.
• the reaction is generally carried out in the manner such that the compounds of formula (IV) and (V) and the organophosphorous 111 compound are dissolved together in the suitable solvent and the solution of the aliphatic azo compound is stirred into this.
• a solution of compounds of formulas (IV) and (V) and the aliphatic azo compound can be added to the solution of the organophosphorous 111 compound.
• the reaction is suitably carried out under inert gas.
• the reaction temperature can vary, depending on the reactivity of the components, in the range of -20°C to 120°C, preferably between -10°C and 80°C, particularly preferred between 0°C and 30°C.
• the starting compounds of formula (IV) can be obtained themselves in that carboxylic acids of the formula (II) are reacted with amino alcohols of formula (VI) ,
• CDI carbonyldiimidazole
• H-NMR-Spectrum proton resonance spectrum, taken at 100 MHz .
• ⁇ singlet
• d doublet
• t triplet
• dt doublet-triplet
• m multiplet
• ar aromatic
• py pyridine .
• Batch size 4.4 g (20.0 mmol) N- (4-hydroxybutyl) -3-pyridin-3- yl-acrylamide, 5.2 g (19.8 mmol) triphenylphosphine, 4.1 g (20.1 mmol) 3-benzyl-2, 4, 5-trioxo-imidazolidine (production according to Ishii et al., J.Med. Chem. 3_9, 1924 (1996) ) and 3.5 g (20.0 mmol) azodicarboxylic acid diethyl ester in 60 ml THF.
• pre-purification chromatography first occurs with CHC1 3 /CH 3 0H (95/5 to 90/10) and this is further purified by flash chromatography with CHC1 3 /CH 3 0H (95/5) : Amorphous solid with MP. 83 - 85°C; Yield 0.9 g (7%).
• the resinous residue is chromatography pre-purified over silica gel with CHC1 3 /CH 3 0H (95/5) and further purified by flash chromatography with CHC1 3 /CH 3 0H (95/5) . After withdraw of the solvent, this is crystallized from acetic acid ethyl ester: Colorless crystals with MP. 141 - 143°C; Yield 0.6 g (9%) •
• V(C 0) 1750, 1690, 1650,
• the reaction mixture is heated under reflux for 5 hours.
• Batch size 42.1 g (0.193 mol) di-tert-butyldicarbonate and 100 g (1.35 mol) 1, 3-diaminopropane in 1000 ml dioxane.
• Batch size 7.0 g (28.0 mmol) 2, 3-diphenylmaleinic acid anhydride and 4.9 g (28.0 mmol) N- (tert-butoxycarbonyl) -1, 3- diaminopropane in 140 ml toluene.
• the reaction mixture is heated under reflux for 10 hours.
• the filtrate is first extracted with 50 ml toluene and thereafter with 200 ml dichloromethane.
• the combined organic phases are washed three times each with 20 ml water, dried over sodium sulfate and, subsequently, the solvent is removed under vacuum.
• the accumulated crude product is further processed without further purification: Yield 24.6 g (79%) of a colorless oil.
• Batch size 5.0 g (20.0 mmol) 2, 3-diphenylmaleinic acid anhydride and 4.3 g (20.0 mmol) N- (tert-butoxycarbonyl) -1, 6- diaminohexane in 100 ml toluene.
• the accumulated crude product is further processed without further purification: Yield 5.6 g (90%) of a yellow amorphous solid.
• the active ingredients according to the invention can be processed to the desired medicaments in the form of their acid addition salts, hydrates or solvates individually or in combination with each other, optionally under addition of other active ingredients.
• these can also optionally be separately present next to each other in the medicine packaging, for example as tablets next to vials, depending on the requirements.
• Further subject-matter of the invention is a method for the treatment of the human or animal body in which a compound, or compound mixture according to formula (I) , wherein the substituents have the above described meanings, is administered for treatment of tumors and/or as a cytostatic agent, cancerostatic agent for inhibition of abnormal cell growth, for anti-proliferative therapy or prevention or as an immunosuppressing agent, optionally in combination with further cytostatic or immunosuppressive active ingredients or other active ingredients suitable for the named indications.
• the invention relates to a compound or compound mixture according to formula (I) for use in a therapeutic method in which the therapeutic use is carried out in connection with one or more medical indications with tumors or for immunosuppression, optimally in combination with further pharmaceuticals suitable for the named indications.
• a method for the production of medicaments with an amount of one or more compounds according to formula (I) which are suitable for the processing of these active ingredients together with respective suitable pharmaceutically acceptable carriers and adjuvants for finished medicinal forms equally belongs to the scope of protection according to the invention.
• the respective suitable medicinal form is selected for the suitable therapeutic application.
• 0.001 to 1000, 2000, 3000, 4000 or 5000 mg, preferably 0.01 to 100 mg, in a preferred manner 1 to 10 mg, especially also 1, 2, 5, 10, 20, 25, 30, 50, 100, 200, 300, 400, 500, 600 or 800 mg single doses are considered as applicable dose units.
• the invention also relates to the use of the compounds according to formula (I) for treatment in the above indications, as well as a diagnostic agent.
• medicaments with an amount of one or more compounds according to the invention and/or their use in the application according to the invention occurs in the customary manner by means of common pharmaceutical technology methods.
• the active ingredients as such or in the form of their salts are processed together with suitable, pharmaceutically acceptable adjuvants and carriers to medicinal forms suitable for the various indications and types of application.
• the medicaments can be produced in such a manner that the respective desired release rate is obtained, for example a quick flooding and/or a sustained or depot effect.
• Preparations for parenteral use, to which injections and infusions belong, are among the most important systemically employed medicaments for tumor treatment as well as for other indications .
• injections are administered for the treatment of tumors.
• These are prepared either in the form of vials or also as so-called ready-to-use injection preparations, for example as ready-to-use syringes or single use syringes in addition to perforation bottles for multiple withdrawals.
• Administration of the injection preparations can occur in the form of subcutaneous (s.c), intramuscular (i.m.), intravenous (i.v.) or intracutaneous (i.e.) application.
• the respective suitable injection forms can especially be produced as solutions, crystal suspensions, nanoparticular or colloid-disperse systems, such as for example, hydrosols.
• the injectable formulations can also be produced as concentrates which can be adjusted with aqueous isotonic dilution agents to the desired active ingredient dosage. Furthermore, they can also be produced as powders, such as for example lyophilisates, which are then preferably dissolved or dispersed immediately before application with suitable diluents .
• the infusions can also be formulated in the form of isotonic solutions, fat emulsions, liposome formulations, microemulsions and liquids based on mixed micells, for example, based on phospholipids .
• infusion formulations can also be prepared in the form of concentrates to dilute.
• the injectable formulations can also be applied in the form of continuous infusions as in stationary as well as in outpatient therapy, for example in the form of mini-pumps.
• Albumin, plasma expanders, surface active compounds, organic solvents, pH influencing compounds, complex forming compounds or polymeric compounds can be added to the parenteral medicinal forms, especially as substances for influencing the adsorption of the active ingredients to protein or polymers or also with the aim of decreasing the adsorption of the active ingredient to materials such as injection instruments or packaging materials, for example plastic or glass.
• the active ingredients can be bound to nanoparticles in the preparations for parenteral use, for example on finely dispersed particles based on poly (meth) acrylates, polyacetates, polyglycolates, polyamino acids or polyether urethanes .
• the parenteral formulations can also be constructively modified as depot preparations, for example on the multiple unit principle, where the active ingredients are incorporated in a most finely distributed and/or dispersed, suspended form or as crystal suspensions, or on the single unit principle, where the active ingredient is enclosed in a medicinal form, for example, a tablet or a seed which is subsequently implanted.
• these implantations or depot medicaments in single unit and multiple unit medicinal forms consist of so-called biodegradable polymers, such as for example, polyether urethanes of lactic and glycolic acid, polyether urethanes, polyamino acids, poly (meth) acrylates or polysaccharides .
• Sterilized water pH value influencing substances, such as for example organic and inorganic acids or bases as well as their salts, buffer substances for setting the pH value, agents for isotonicity, such as for example sodium chloride, monosodium carbonate, glucose and fructose, tensides and/or surface active substances and emulsifiers, such as for example, partial fatty acid esters of polyoxyethylene sorbitan (Tween®) or for example fatty acid esters of polyoxethylene (Cremophor®) , fatty oils such as for example peanut oil, soybean oil and castor oil, synthetic fatty acid esters, such as for example ethyl oleate, isopropyl myristate and neutral oil (Miglyol®) as well as polymer adjuvants such as for example gelatine, dextran, polyvinylpyrrolidone, organic solvent additives which increase solubility, such as for example propylene glycol, ethanol, N,N-dimethyl
• thickening agents to prevent the settling of the active ingredients from tensides and peptizers, to secure the ability of the sediment to be shaken, or complex formers, such as EDTA, ensues.
• complex formers such as EDTA
• This can also be achieved with the various polymeric agent complexes, for example with polyethylene glycols, polystyrol, carboxymethylcellulose, Pluronics® or polyethylene glycol sorbitan fatty acid esters.
• the active ingredient can also be incorporated in liquid formulations in the form of inclusion compounds, for example with cyclodextrins .
• dispersion agents are also suitable.
• builders are also used, such as for example mannite, dextran, saccharose, human albumin, lactose, PVP or gelatine varieties.
• active ingredients are not incorporated in the liquid medicinal formulations in the form of a base, they are used in the form of their acid addition salts, hydrates or solvates in the preparations for parenteral use.
• a further systemic application form of importance is peroral administration as tablets, hard or soft gelatine capsules, coated tablets, powders, pellets, microcapsules, oblong compressives, granules, chewable tablets, lozenges, gums or sachets.
• These solid peroral administration forms can also be prepared as sustained action and/or depot systems.
• film or matrix forming substances such as for example ethylcellulose, hydroxypropylmethylcellulose, poly (meth) acrylate derivatives (for example Eudragit®) , hydroxypropylmethylcellulose phthalate are suitable in organic solutions as well as in the form of aqueous dispersions.
• bio-adhesive preparations are also to be named in which the increased retention time in the body is achieved by intensive contact with the mucus membranes of the body.
• An example of a bio- adhesive polymer is the group of Carbomers®.
• compressives such as for example non-disintegrating tablets in oblong form of a suitable size with a slow release of active ingredient
• compressives are especially suitable.
• mixtures of pellets which release at the various places are employable, for example mixtures of gastric fluid soluble and small intestine soluble and/or gastric fluid resistant and large intestine soluble pellets.
• the same goal of releasing at various sections of the gastrointestinal tract can also be conceived by suitably produced laminated tablets with a core, whereby the coating of the agent is quickly released in gastric fluid and the core of the agent is slowly released in the small intestine milieu.
• the goal of controlled release at various sections of the gastrointestinal tract can also be attained by multilayer tablets .
• the pellet mixtures with differentially released agent can be filled into hard gelatine capsules.
• Anti-stick and lubricant and separating agents such as flame dispersed silicone dioxide, disintegrates, such as various starch types, PVC, cellulose esters as granulating or retarding agents, such as for example wax-like and/or polymeric compounds on the basis of
• Eudragit®, cellulose or Cremophor® are used as a further adjuvants for the production of compressives, such as for example tablets or hard and soft gelatine capsules as well as coated tablets and granulates.
• Anti-oxidants such as for example saccharose, xylite or mannite, masking flavors, aromatics, preservatives, colorants, buffer substances, direct tableting agents, such as for example microcrystalline cellulose, starch and starch hydrolysates (for example Celutab®) , lactose, polyethylene glycols, polyvinylpyrrolidone and dicalcium phosphate, lubricants, fillers, such as lactose or starch, binding agents in the form of lactose, starch varieties, such as for example wheat or corn and/or rice starch, cellulose derivatives, for example methylcellulose, hydroxypropylcellulose or silica, talcum powder, stearates, such as for example magnesium stearate, aluminium stearate, calcium stearate, talc, siliconized talc, stearic acid, acetyl alcohol or hydrated fats, etc. are also used.
• direct tableting agents such as for example microcrystalline cellulose, starch and
• oral therapeutic systems constructed especially on osmotic principles, such as for example GIT (gastrointestinal therapeutic system) or OROS (oral osmotic system) , are also to be mentioned.
• GIT gastrointestinal therapeutic system
• OROS oral osmotic system
• Effervescent tablets or tabsolute both of which represent immediately drinkable instant medicinal forms which are quickly dissolved or suspended in water are among the perorally administrable compressives.
• perorally administrable forms are also solutions, for example drops, juices and suspensions, which can be produced according to the above given method, and can still contain preservatives for increasing stability and optionally aromatics for reasons of easier intake, and colorants for better differentiation as well as antioxidants and/or vitamins and sweeteners such as sugar or artificial sweetening agents.
• preservatives for increasing stability and optionally aromatics for reasons of easier intake, and colorants for better differentiation as well as antioxidants and/or vitamins and sweeteners such as sugar or artificial sweetening agents.
• Ion exchange resins in combination with one or more active ingredients are also to be mentioned for the production of liquid injestable forms.
• a special release form consists in the preparation of so-called floating medicinal forms, for example based on tablets or pellets which develop gas after contact with body fluids and therefore float on the surface of the gastric fluid.
• so-called electronically controlled release systems can also be formulated by which active ingredient release can be selectively adjusted to individual needs.
• a further group of systemic administration and also optionally topically effective medicinal forms are represented by rectally applicable medicaments.
• suppositories and enema formulations.
• the enema formulations can be prepared based on tablets with aqueous solvents for producing this administration form.
• Rectal capsules can also be made available based on gelatine or other carriers.
• Hardened fat such as for example Witepsol®, Massa
• Estarinum®, Novata®, coconut fat, glycerol-gelatine masses, glycerol-soap-gels and polyethylene glycols are suitable as suppository bases .
• pressed implants are suitable which are preferably formulated on the basis of so-called biodegradable polymers .
• transdermal systems are also to be emphasized which distinguish themselves, as with the above-mentioned rectal forms, by circumventing the liver circulation system and/or liver metabolism.
• These plasters can be especially prepared as transdermal systems which are capable of releasing the active ingredient in a controlled manner over longer or shorter time periods based on different layers and/or mixtures of suitable adjuvants and carriers.
• membrane infiltration increasing substances and/or permeation promoters such as for example oleic acid, Azone®, adipinic acid derivatives, ethanol, urea, propylglycol are suitable in the production of transdermal systems of this type for the purpose of improved and/or accelerated penetration.
• vaginally or genitally applicable emulsions creams, foam tablets, depot implants, ovular or transurethral administration instillation solutions.
• highly sterile eye ointments, solutions and/or drops or creams and emulsions are suitable.
• otological drops, ointments or creams can be designated for application to the ear.
• semi-solid formulations such as for example gels based on
• Carbopols® or other polymer compounds such as for example poly inylpyrolidone and cellulose derivatives is also possible.
• emulsions For customary application to the skin or also to the mucus membrane, normal emulsions, gels, ointments, creams or mixed phase and/or amphiphilic emulsion systems (oil/water- water/oil mixed phase) as well as liposomes and transfersomes can be named.
• Sodium algenate as a gel builder for production of a suitable foundation or cellulose derivatives such as for example guar or xanthene gum
• inorganic gel builders such as for example aluminium hydroxides or bentonites (so- called thixotropic gel builder)
• polyacrylic acid derivatives such as for example Carbopol®, polyvinylpyrolidone, microcrystalline cellulose or carboxymethylcellulose are suitable as adjuvants and/or carriers.
• amphiphilic low and high molecular weight compounds as well as phospholipids are suitable.
• the gels can be present either as hydrogels based on water or as hydrophobic organogels, for example based on mixtures of low and high molecular paraffin hydrocarbons and Vaseline.
• Anionic, cationic or neutral tensides can be employed as emulsifiers, for example alkalized soaps, methyl soaps, amine soaps, sulfonated compounds, cationic soaps, high fatty alcohols, partial fatty acid esters of sorbitan and polyoxyethylene sorbitan, for example lanette types, wool wax, lanolin, or other synthetic products for the production of oil/water and/or water/oil emulsions.
• Hydrophilic organogels can be formulated, for example, on the basis of high molecular polyethylene glycols. These gel-like forms are washable.
• Osmotically effective acids and bases such as for example hydrochloric acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, monosodium carbonate, further buffer systems, such as for example citrate, phosphate, tries-buffer or triethanolamine are used for adjusting the pH value .
• Preservatives for example such as methyl- or propyl benzoate (parabenes) or sorbic acid can be added for increasing stability.
• Pastes powders or solutions are to be mentioned as further topically applicable forms.
• Pastes often contain lipophilic and hydrophilic auxiliary agents with very high amounts of fatty matter as a consistency-giving base.
• Powders or topically applicable powders can contain for example starch varieties such as wheat or rice starch, flame dispersed silicon dioxide or silica, which also serve as diluents, for increasing flowability as well as lubricity as well as for preventing agglomerates.
• starch varieties such as wheat or rice starch
• flame dispersed silicon dioxide or silica which also serve as diluents, for increasing flowability as well as lubricity as well as for preventing agglomerates.
• Nose drops or nose sprays serve as nasal applicaticn forms .
• nebulizers or nose creams or ointments can come to use.
• nose spray or dry powder formulations as well as controlled dosage aerosols are also suitable for systemic administration of the active ingredients .
• These pressure and/or controlled dosage aerosols and dry powder formulations can be inhaled and/or insufflated. Administration forms of this type also certainly have importance for direct, regional application in the lung or bronchi and larynx.
• the dry powder compositions can be formulated for example as active ingredient-soft pellets, as an active ingredient-pellet mixture with suitable carriers, such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• suitable carriers such as for example lactose and/or glucose.
• propellant gas for aerosol spray formulations and/or controlled dosage aerosols tetrafluoroethane or HFC 134a and /or heptafluoropropane or HFC 227 are suitable, wherein non- fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as for example propane, butane or dimethyl ether can be preferred.
• propellant-free, manual pump systems can also be used.
• the propellant gas aerosols can also suitably contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins or soya lecithin.
• surface active adjuvants such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins or soya lecithin.
• solutions for instillation for example for transurethral administration in bladder tumors or genital tumors, or for profusion in liver tumors or other organ carcinomas are suitable.
• the respective suitable medicinal forms can be produced in accordance with the prescription and procedures based on pharmaceutical-physical fundamentals as they are described for example in the following handbooks and are included in the present inventive subject-matter with respect to the production of the respective suitable medicaments: Physical Pharmacy (A.N. Martin, J. Swarbrick, A. Cammarata) , 2nd Ed., Philadelphia Pennsylvania, (1970), German version: Physikalische Pharmazie, (1987) , 3rd edition, Stuttgart;
• active ingredient used according to the invention 5.000 g acid sodium phosphate 5.000 g sodium tartrate 12.000 g benzyl alcohol 7.500 g water for injection purposes to 1000.000 ml
• the solution is produced according to the customary method, sterilized and filled into 10 ml vials.
• One vial contains 50 mg of the compound according to the invention.
• Parenteral Solution active ingredient used according to the invention 1.000 g hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g water for injection purposes to 1000.000 ml
• the solution is produced according to a customary method by stirring; the medicinal form is adjusted to a suitable pH value by acid addition and subsequently filled into 100 ml vials and sterilized.
• a vial contains 100 mg of the compound according to the invention.
• active ingredient used according to the invention 10.000 g soya lecithin 20.000 g saturated triglycerides 100.000 g sodium hydroxide 7.650 g water for injection purposes to 1000.000 ml
• the active ingredient (s) used according to the invention is dispersed in the saturated triglycerides . Then the soya lecithin is added under stirring, and subsequent to this, the aqueous solution of sodium hydroxide is added with subsequent homogenization. The dispersion is sterilized and filled into 10 ml vials. A vial contains 50 mg of the compound according to the invention.
• active ingredient used according to the invention 10.000 g polylactic acid /polygylcolic acid polymer 70.000 g polyvinylpyrrolidone 0.200 g gelatine 2.000 g soya lecithin 2.000 g isotonic sodium chloride solution to 1000.000 ml
• the active ingredient is incorporated into the biodegradable polymer comprising polylactic acid and polyglycolic acid by a suitable method (spray drying, solvent-evaporation or phase separation) and subsequently subjected to a sterilization process.
• the particles are introduced into a 2 -chamber ready-made syringe in which the adjuvant solution, which is also produced in a sterile manner, is filled.
• the biodegradable microparticles are mixed with the dispersion agent shortly before application and dispersed.
• a ready-made syringe contains 200 mg of the active compound according to the invention.
• active ingredient used according to the invention 25,000 g soya lecithin 25,000 g arachis oil 400,000 g benzyl alcohol 50,000 g Miglyole ® to 1000,000 g
• the active ingredient is dispersed together with soya lecithin and arachis oil.
• the benzyl alcohol is dissolved in
• Miglyole ® and added to the dispersion.
• the entire dispersion is sterilized and subsequently filled into vials with 2 ml content.
• a vial contains 50 mg active ingredient.
• the solution named under example b) can also be used for perfusion of liver for example.
• so-called perforation bottles vials
• infusion solutions with an amount of one or more active ingredients according to the invention can also be made available in the customary manner under addition of buffer substances for adjustment of physiological pH value and/or the isotonicity and/or a best possible suitable pH value for the medicinal form (euhydria) and optional further required nutrients, vitamins, amino acids, ⁇ tablizers and other necessary adjuvants, possibly in combination with further medicinal agents suitable for the mentioned indications.
• active ingredient used according to the invention 10.000 g lactose 5.200 g starch, soluble 1.800 g hydroxypropylmethylcellulose 900 g magnesium stearate 100 g
• the above components are mixed with each other and compacted in a conventional manner, wherein a tablet weight of 180 mg is set. Each tablet contains 100 mg active ingredient. If desired, the tablets obtained in this manner are coated, provided with a film coat and/or enterically coated.
• active ingredient used according to the invention 10.000 g flame dispersed silicon dioxide 500 g corn starch 2.250 g stearic acid 350 g ethanol 3.0 1 gelatine 900 g purified water 10.0 1 talcum 300 g magnesium stearate 180 g
• a granulate is produced which is pressed to the desired coated tablet cores .
• Each core contains 50 mg of active ingredient.
• the core can be further processed in a customary manner to coated tablets .
• a gastric fluid resistant or retarding film coat can be applied in a known manner.
• active ingredient used according to the invention 0.050 g glycerine 0.500 g sorbite, 70% solution 0.500 g sodium saccharinate 0.010 g methyl-p-hydroxybenzoate 0.040 g aromatic agent q.s. sterile water q.s. to 5 ml
• the above-mentioned components are mixed in a customary manner to a suspension and filled in a suitable drink vial having 5 ml conten .
• active ingredient used according to the invention 0.030 g lactose 0.100 g stearic acid 0.004 g talcum purum 0.015 g sweetener q.s. aromatic agent q.s. rice starch q.s. to 0.500 g
• the active ingredient is compacted together with the adjuvants under high pressure to sublingual tablets, favourably in oblong form.
• active ingredient used according to the invention 0.050 g fatty acid glyceride mixture (Miglyole ® ) q.s. to 0.500 g
• the active ingredient is impasted together with the fluid carrier mixture and mixed together with further adjuvants suitable for the encapsulation and filled into elastic soft gelatine capsules which are sealed.
• active ingredient used according to the invention 0.150 g microcrystalline cellulose 0.100 g hydroxypropylmethylcellulose 0.030 g mannite 0.100 g ethylcellulose 0.050 g triethyl citrate 0.010 g
• the active ingredient is mixed together with the adjuvants, microcrystalline cellulose, hydroxypropylmethylcellulose and mannite, wet with granulation liquid and formed into pellets. These are subsequently coated with a solution of ethylcellulose and triethyl citrate in organic solvents in a fluidized-bed apparatus.
• a hard gelatine capsule contains 150 mg of active ingredient .
• active ingredient used according to the invention 0.500 g
• Vaseline oil q.s. to 100.000 g
• active ingredient used according to the invention 10.000 g propylene glycol 50.000 g paraffin, liquid 100.000 g paraffin wax 100.000 g
• the active ingredient (s) used according to the invention is dissolved in propylene glycol at ca. 60°C.
• the lipophilic components are melted at 60-70°C and subsequently combined with the active ingredient solution.
• the ointment is emulsified at first at 60-70°C and subsequently cooled to 35-40°C under constant emulsification and then filled in 10 g tubes.
• a tube contains 100 mg of the compound according to the invention.
• composition which is characterized in that it contains an active ingredient (s) used according to the invention as a base or a physiologically acceptable salt thereof together with carriers and/or diluents customary for this and suitable for administration by means of inhalation.
• active ingredient (s) used according to the invention as a base or a physiologically acceptable salt thereof together with carriers and/or diluents customary for this and suitable for administration by means of inhalation.
• physiologically acceptable salts of the active ingredients are, as already illustrated in the synthesis section, acid addition salts derived from inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4- hydroxybenzoate, 4-chlorobenzoate, p-tosylate, methane sulfonate, ascorbate, salicylate, acetate, formate, succinate, lactate, glutarate, gluconate or tricarballylate.
• inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4- hydroxybenzoate, 4-chlorobenzoate, p-tosylate, methane sulfonate, ascorbate, salicylate, acetate, format
• the administration of the active ingredient (s) used of the invention by means of inhalation occurs according to the invention in conventional ways customary for administrations of this form, for example in the form of a commercial controlled dosage aerosol or in combination with a spacer.
• a metering valve is delivered with whose help, a dosed amount of the composition is administered.
• the present compositions can be formulated for example as aqueous solutions or suspensions and be administered by means of an atomizer.
• Aerosol spray formulations in which the active ingredient is either suspended with one or two stabilizers in a propellant as a carrier and/or diluent, for example tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 can equally be used, whereby however, non-fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as propane, butane or dimethyl ether, can be preferred. Thereby, propellant-free manual pump systems or dry powder systems as described below can also be used.
• the propellant aerosols can also contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.
• surface active adjuvants such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.
• the medicaments with an amount of compounds according to the invention can also be formulated in the form of dry powder compositions, for example as active ingredient- soft pellets or as an active ingredient-powder mixture with a suitable carrier, such as for example lactose and/or glucose.
• a suitable carrier such as for example lactose and/or glucose.
• the powder compositions can be formulated and administered as single doses or as multiple doses.
• the compounds according to the invention are preferably administered by means of a controlled dosage aerosol or in the form of a dry powder dosage formulation, wherein the latter preferably contains glucose and/or lactose as a carrier substance.
• all applicators are generally suitable which are suitable for controlled dosage aerosols and/or a dry powder dosage formulation, such as for example usual applicators for the nose, mouth and or pharynx, or also devices standing under propellant gas for the delivery of a spray (as controlled dosage aerosol or dry powder dosage formulation) as they are also used for inhalations in the nose, mouth and/or pharynx.
• a further embodiment can also consist of an aqueous solution of the active ingredient (s) used according to the invention, which also optionally contains further active ingredients and/or additives, which are applied by means of an ultrasound atomizer.
• active ingredient used according to the invention 0.500 mg 0.66 stabilizer 0.075 mg 0.10
• active ingredient used according to the invention 0.250 mg 0.32
• the micronized active ingredient is, after previous dispersion in a small amount of the stabilizer, placed in a suspension vessel in which the bulk amount of propellant gas solution is found.
• the corresponding suspension is dispersed by means of a suitable stirring system (for example high performance mixer or ultrasound mixer) until an ultra-fine dispersion results.
• the suspension is then continuously held in flux in a filling apparatus suitable for cold propellants or pressure fillings.
• the suspension can also be produced in a suitable cooled stabilizer solution in HFC 134a/227.
• the examples c) to d) describe the composition and production of dosage dry powder formulations .
• active ingredient used according to the invention 0.500 mg
• active ingredient used according to the invention 0.500 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
• active ingredient used according to the invention 0.250 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
• the active ingredient is formulated after micronization under addition of steam as pellets with an MMAD between 0,1 and 0,3 mm diameter and brought to use in a multi-dose powder applicator.
• the active ingredient is micronized, thereafter, bulk material is mixed with the lactose in the given amounts, and subsequently, filled in a multi-dose powder inhalator.
• the active ingredient or the medicinal agent in the form of the respective suitable pharmaceutical acceptable salt and/or acid addition salts can be present, insofar as the base is not preferred in each case.
• the tumor growth inhibiting activity of the substances was determined on human tumor cells in standardized in vitro test systems. In the screening tests, the substances gave IC 5 o- values in a concentration range of 0.1 nM to 10 ⁇ M.
• FCS foetal calf serum
• the test was ended and the protein amount in the individual wells was determined with the sulforhodamin-B- method (according to P. Skehan et al . : New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. J. Natl. Cancer Inst. 82: 1107-1112, 1990).
• the IC 50 ⁇ values (defined as that concentration in which the cell growth was inhibited by 50%) was taken from the dose-response curves and given as a comparative measurement for the activity of the test compounds .
• FCS foetal calf serum
• the test was ended and the protein amount in the individual wells was determined with the sulforhodamin-B-method (according to P. Skehan et al . : New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. J. Natl. Cancer Inst. 82: 1107-1112, 1990).
• the IC 50 -values (defined as that concentration in which the cell growth was inhibited by 50%) was taken from the dose-response curves and given as a comparative measurement for the activity of the test compounds.
• HT-29 cells derived from a human colon carcinoma plated at a density of 20,000 cells/ml in 12-well plastic dishes. Cultivation occurred in Richters IMEM-ZO nutrient medium with 5% foetal calf serum (FCS) in a tissue culture incubator with a gas mixture of 5% C0 2 and 95% air at a temperature of 37°C.
• FCS foetal calf serum
• FCS foetal calf serum
• the light extinction was measured in an ELISA reader at 450 nm wave length. The backgrounds were each subtracted from the typical measured valves. (The ICso-values (defined as that concentration in which the cell growth was inhibited by 50%) was taken from the dose-response curves and given as a comparative measurement for the activity of the test compounds .
• the compounds of formula (I) and their salts permit a therapeutic use in malignant illnesses of humans and animals through their excellent inhibition of the growth of tumor cells.
• the anti-neoplastic activity of the described substances can be used for prophylactic, adjunct, palliative, and curative treatment of solid tumors, leukemic illnesses and lymphomas as well as for decreasing or preventing metastasis formation in humans and animals.
• the therapeutic use is possible in the following illnesses for example: gynaecological tumors, ovarian carcinomas, testicle tumors, prostate carcinomas, skin cancer, kidney cancer, bladder tumors, oesophagus carcinomas, stomach cancer, rectal carcinomas, pancreas carcinomas, thyroid cancer, adrenal tumors, leukemia and lymphomas, Hodgkin's disease, tumor illnesses of the CNS, soft-tissue sarcomas, bone sarcomas, benign and malignant mesotheliomas, but especially intestine cancer, liver cancer, breast cancer, bronchial and lung carcinomas, melanomas, acute and chronic leukemias .
• Benign papillomatosis tumors can also be limited in their growth with the named substances .
• the broad effectiveness of the new compounds were tested for example in very different human tumor cells in vitro according to the methods described in point 1. Thereby, the following IC50 valves were obtained for the compound Nr. 195 for example: Cell line Source IC50-values [mM]
• the novelty of the compounds can be expected to have an independent activity profile in the effectiveness against the various tumor types.
• tumors which are resistant to customary cytostatic agents, for example can respond entirely to these substances.
• combinations of the new compounds with known pharmaceuticals used in chemotherapy are promising as long as their properties are complimented in a suitable manner.
• anti- metabolites for example cytarabine, 5-fluorouracil, 6- mercaptopurine, methotrexate
• alkylating agents for example busulfane, carmustine, cisplatin, carboplatin, cyclophospha ide, dacarbazine, melphalane, thiotepa
• DNA- intercalating substances and topoisomerase inhibitors for example actinomycin D, daunorubicin, doxorubicin, mitomycin C, mitoxantrone, etoposide, teniposide, topotecane, irinotecane
• spindle poisons for example vincristine, navelbine, taxol, taxoter
• hormonally active agents for example tamoxifene, flutamide, formestane, gosereline
• Resistant tumor cells can be made sensitive again for example by interaction of the new compounds with a mechanism of resistance for common cytostatic agents (for example P- glycoprotein, MRP, glutathione-S-transferase, metallothionein) .
• common cytostatic agents for example P- glycoprotein, MRP, glutathione-S-transferase, metallothionein
• the spleen of a Swiss mouse served as a lymphocyte source.
• the lymphocyte population was isolated from the spleen cell suspension over a ficoll gradient and taken up in IMEM-ZO culture medium with 0,1% dextran 70,000 and 2% foetal calf serum.
• the cells were plated at a density of ca.
• the independent structural class of the compounds can also be expected to be successful for an efficient combination with known immunosuppressive agents such as for example cyclosporin A, tacrolimus, rapamycin, azathioprine and glucocorticoids .
• immunosuppressive agents such as for example cyclosporin A, tacrolimus, rapamycin, azathioprine and glucocorticoids .

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