WO1999031064A1 - Aryl-substituted pyridylalkane, alkene, and alkine carboxamides useful as cytostatic and immunosuppressive agents - Google Patents

Aryl-substituted pyridylalkane, alkene, and alkine carboxamides useful as cytostatic and immunosuppressive agents Download PDF

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Publication number
WO1999031064A1
WO1999031064A1 PCT/EP1998/008272 EP9808272W WO9931064A1 WO 1999031064 A1 WO1999031064 A1 WO 1999031064A1 EP 9808272 W EP9808272 W EP 9808272W WO 9931064 A1 WO9931064 A1 WO 9931064A1
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phenyl
alkyl
hydroxy
aromatic
ring
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PCT/EP1998/008272
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French (fr)
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Elfi Biedermann
Max Hasmann
Roland Löser
Benno Rattel
Friedemann Reiter
Barbara Schein
Klaus Seibel
Klaus Vogt
Katja Wosikowski
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Klinge Pharma Gmbh
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Priority to DE69830855T priority Critical patent/DE69830855T2/en
Priority to AU22740/99A priority patent/AU2274099A/en
Priority to AT98966352T priority patent/ATE299495T1/en
Priority to JP2000538991A priority patent/JP4838934B2/en
Priority to EP98966352A priority patent/EP1042291B1/en
Priority to DK98966352T priority patent/DK1042291T3/en
Publication of WO1999031064A1 publication Critical patent/WO1999031064A1/en
Priority to US09/596,086 priority patent/US7320993B1/en

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    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D417/02—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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to new pyridylal ane, alkene and alkine carboxamides substituted with a saturated, one or several- fold unsaturated hydrocarbon residue in the carboxylic acid grouping, 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 and control of immune reactions, for example of autoimmune diseases.
  • radiation for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.
  • ⁇ -pyridylalkane and/or alkene amides with anti-allergic 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, co-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 (alkyl) carbonamides pyridyl (alkyl) sulfonamides and analogous ureas, wherein the amide portion is bound to piperidine ring over an alkyl chain, are disclosed in published EP-A-0 479 601 as active ingredients with anti- arrhythmic properties.
  • alkane and alkene amides of ⁇ - imidazolyl alkane/alkene amines with a chain of up to 6 C- atoms are also comprised by the general formula published in WO 93/14070 as antagonists of the histamine-H3 receptor with an i-convulsive, anti-depressive, anti-allergic and anti- secretory action.
  • a compound is concretely described or even mentioned for a pyridyalkane or alkene amide .
  • 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 in very important structural features, for example by the 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.
  • the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural difference, whereby the therapy possibilities according to the invention with the new compounds extend to the combat of numerous other types of tumors with different causal mechanisms as well as for immunosuppressive treatment possibilities such as autoimmune diseases .
  • the new aryl-substituted pyridyl carboxamides are comprised by the following general formula:
  • G is selected from Gl, G2, G3, G4, G5 or G6 under the proviso that G must contain at least one aromatic ring whereby Gl, G2, G3, G4, G5 and G6 correspond to the following formulas :
  • each L represents a suitable nucleofuge
  • compounds of formula (I), wherein G has the meaning G4 to G6 according to the above definition can also be produced in that starting products of formula (IV) are reacted with a carboxylic acid, thiocarbamic acid carbamic acid, sulfonic acid and/or phosphinic acid of formula (VIb) to (Vie),
  • m, Y, Z, R 8 , R 9 , R 10 , R 12 , Ar 1 , Ar 2 and optionally the group NR R 9 have the above meanings or with their derivatives capable of reaction, preferably in the presence of auxiliary bases in solvents and under conditions as they are described in method (A) , or
  • R 8 has the meanings defined above, preferably in absolute, inert solvents as they are considered in the above method (B3), especially at a -.action temperature which can vary in the range of -20°C to 150°C, preferably at 20°C to 100°C.
  • 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, lactate ⁇ , 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 Ci-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 Ci-Cg-alkyl residue especially a methyl-, ethyl - , propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert- butyl-, cyclopropylmethyl- , pentyl-, isopentyl-, tert-
  • Alkylene signifies for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene or dodecamethy1ene .
  • Alkenyl preferably signifies C3-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, heptadienylene, octenylene, octadienylene, nonenylene, nonadienylene or decenylene, decadienylene, undecenylene, undecadienylene, dodecenylene or dodecadienylene .
  • 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, noneninylene, decinylene, deceninylene, undecinylene or dodecinylene .
  • Cycloalkyl is preferably a C3-C8-c cloalkyl residue, especially a cyclopropyl- , cyclobutyl-, cyclopentyl-, cyclohexyl-, cycloheptyl- or cyclooctyl group.
  • Cycloalkylene preferably signifies cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene .
  • Hydroxyalkyl contains a hydroxyl group in one of the above mentioned alkyl residues, especially in a Ci-C -alkyl residue, whereby among the C ⁇ Cg-hydroxyalkyl residues, the hydroxymethyl- and the hydroxyethyl residue are preferred.
  • alkoxy residues preferably C j _ -
  • Cg-alkoxy or C3-C8-cycloalkoxy especially contain one of the above mentioned preferred alkyl and/or cycloalkyl groups with up to 6 or 8 carbon atoms .
  • Particularly preferred groups for this are the methoxy-, ethoxy-, isopropoxy-, tert-butoxy- , cyclopentyloxy- and cyclohexyloxy groups .
  • Alkoxy, especially C ⁇ Cg-alkoxy, entirely or partially replaced by fluorine is for example difluoromethoxy, trifluoromethoxy or 2 , 2 , 2-trifluoroethoxy .
  • Aralkyl such as phenylalkyl, especially phenyl-C ⁇ -C3 ⁇ alkyl and/or diarylalkyl such as diphenyl-C -C3-alkyl or triaralkyl such as triphenylmethyl contain 1 and/or 2 and/or 3 phenyl groups on a methyl-, ethyl-, propyl- or isopropyl group at any position.
  • benzyl- and diphenylmethyl residues are particularly preferred.
  • alkylthio residues contain one of the above mentioned preferred C ⁇ -Cg-alkyl groups, especially the methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups.
  • alkanoyloxy residues preferably contain an aliphatic acyl group with 1 to 7 carbon atoms.
  • alkanoyloxy groups are the acetoxy- , propionyloxy- and pivaloyloxy groups .
  • Carboxyalkyl, especially C2 ⁇ C7-carboxyalkyl, and carboxyalkenyl, especially C3-C7 ⁇ carboxyalkenyl, contain a carboxyl group on one of the above named alkylene and alkenyl residues especially C ⁇ -Cg-alkylene and/or C2-Cg-alkenylene residues.
  • alkylene and alkenyl residues especially C ⁇ -Cg-alkylene and/or C2-Cg-alkenylene residues.
  • the carboxymethyl-, carboxyethyl-, carboxyethenyl-, carboxybutyl- and carboxybutadienyl residues are preferred.
  • 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- , isobutoxycarbonyl- and tert-butoxycarbonyl groups.
  • alkylaminocarbonyl especially C2-C7-alkylaminocarbonyl and dialkylaminocarbonyl groups, preferably C3-C13 -dialkylaminocarbonyl groups, contain an alkylamino- and/or dialkylamino residue whose alkyl groups especially correspond to the C ] _-Cg-alkyl groups of the above description.
  • Preferred groups are the dimethylaminocarbonyl- , diethylaminocarbonyl- and diisopropylaminocarbonyl groups.
  • aminoalkyl residues especially C -Cg-aminoalkyl residues, each contain an amino group in one of the above named C ⁇ -Cg- alkyl residues, whereby the aminomethyl- and aminoethyl groups are particularly preferred.
  • the amino group of the Formula NR 4 R 5 is one of the below mentioned alkylamino groups, especially C ⁇ -Cg-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 Preferred groups are the methylamino- , ethylamino-, propylamino- , isopropylamino- , butylamino-, and the tert-butylamino groups.
  • the preferred di- (C 1 -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 Ci-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 is preferably the methanesulfonyl- , ethanesulfonyl- , propanesulfonyl- , butanesulfonyl- , pentanesulfonyl- or hexanesulfonyl groups.
  • Saturated four- to seven-membered heterocycles with one or two hetero-atoms are for example azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydropyridine, piperidine, hexahydroazepine, piperazine, morpholine, thiomorpholine, 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 bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl , tetrahydronaphthyl , dihydrobenzocycloheptenyl , tetrahydrobenzocycloheptenyl , biphenylenyl, fluoroenyl, anthryl, dihydroanthryl , phenanthryl, dihydrophenanthryl , dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl .
  • Anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to preferably 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl , benzofuryl, dihydrobenzofuryl , benzothienyl, dihydrobenzothienyl, indolyl , indolinyl, isoindolinyl , benzimidazolyl , indazolyl, benzooxazolyl , benzoisoxazolyl , benzothiazolyl , benzoisothiazolyl , benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl , isothiazolopyridyl , imidazopyridyl, pyrazolopyridyl , thienopyrimidinyl , chromanyl , benzopyranyl
  • Saturated and unsaturated, four- to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or 0, are for example azetidine, pyrrolidine, piperidine, (IH) -tetrahydropyridine, hexahydroazepine, (IH) -tetrahydroazepine, pyrazolidine, piperazine, morpholine, thiomorpholine thiomorpholin-1, 1- dioxide, hexahydrodiazepine or hexahydrooxazepine .
  • Anellated bi- or tricyclic, aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring (as the group —NR 8 R 9 ) which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, are for example indoline, isoindoline, (1H)- dihydroquinoline, (IH) -tetrahydroquinoline, (2H)- tetrahydroisoquinoline, (IH) -tetrahydroquinoxaline, (4H)- dihydrobenzooxazine, (4H) -dihydrobenzothiazine, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo [c] azepine, (IH) -tetrahydrobenzo [d] azepine, (5H)
  • the invention relates to new pyridylalkane, pyridylalkene and pyridylalkine acid amides of the general formula (I)
  • aryl such as phenyl, aryloxy such as phenoxy, arylthio such as phenylthio, heteroaryloxy such as pyridyloxy, heteroarylthio such as pyridylthio, and NR ⁇ R 5 , whereby
  • R ⁇ and R ⁇ are selected independently of each other from hydrogen, alkyl, alkenyl, alkinyl, aralkyl such as benzyl and aryl such as phenyl;
  • R2 is selected from hydrogen, halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
  • R-3 is selected from hydrogen, alkyl, alkenyl, alkinyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
  • k is the number 0 or 1
  • 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 S0 2 , whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R 6 is 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
  • alkylene with at least 3 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl;
  • alkinylene with at least 3 carbon atoms or alkeninylene, with at least 5 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl; as well as
  • G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
  • G 1 has the meaning
  • R 8 is selected from aralkyl such as benzyl or diphenylmethyl, aryl such as phenyl ; 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or
  • R ⁇ is selected from hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl; aralkyl such as benzyl, aryl such as phenyl; saturated or unsaturated, four- to six-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or 0;
  • monocyclic aromatic five- or seven-membered heterocycles which can contain one to three heteroatoms selected from N and/or S and/or 0 and are either bound directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
  • R 10 is synonymous with R 9 , but can be selected independently thereof, and also hydroxy;
  • ⁇ y is the grouping
  • G 3 is selected from
  • n is the number 0, 1 or 2
  • X has the meaning NR 11 , 0 or S, whereby R 11 has the same meaning as R ⁇ , but is selected independently thereof, or the grouping NR 8 R 9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
  • G 4 is selected from
  • Z has the meaning 0 or S;
  • R 11 has the above meaning
  • R 12 is selected from alkyl, aryl such as phenyl; monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or 0; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or
  • G 6 is selected from
  • Ar 1 and Ar 2 are selected independently from each other from aryl such as phenyl or naphthyl as well as heteroaryl such as pyridyl;
  • R 8 R 9 and NR 8 R 9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, cycloalkyl, aralkyl such as benzyl, aryl such as phenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxy entirely or partially substituted by fluorine, aralkyloxy such as benzyloxy, aryloxy such as phenoxy, mercapto, alkylthio, arylthio such as phenylthio, sulfo, carboxy, carboxyalkyl, carboxyalkenyl, alkoxy
  • alkyl- and cycloalkyl residues in the group G can be substituted by one or two of the same or different residues selected from hydroxy, carboxy, alkoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl, amino, mono-alkylamino and di- ( alkyl ) amino;
  • G represents a heterocyclic aromatic ring or one which simultaneously contains substitutions by free hydroxy-, mercapto- or amino groups; as well as the corresponding
  • the invention relates to new pyridylalkane, pyridylalkene and pyridylalkine acid amides of the formula (I)
  • R- is selected from hydrogen, halogen, cyano, C ⁇ -Cg-alkyl, C3-Cg-alkenyl,
  • C2-Cg-alkinyl trifluoromethyl, C3-Cg-cycloalkyl, C ⁇ -Cg- hydroxyalkyl, hydroxy, C ⁇ -Cg-alkoxy, C3-C8- cycloalkyloxy, benzyloxy, C ⁇ -C7-alkanoyloxy, C_-Cg- alkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7- alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR 4 R 5 , whereby
  • R 4 and R 5 are selected independently of 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, C ] _-Cg-alkoxy and benzyloxy;
  • R 3 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 -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 ⁇ C - 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;
  • C4-Cg-alkadienylene optionally substituted once or twice by C ⁇ -C3 ⁇ alkyl, fluorine, cyano or phenyl;
  • C3-C 2 _a l k y lene ' optionally substituted once or twice by C -Cg-alkyl, hydroxy, C -Cg-alkoxy or phenyl;
  • G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
  • G 1 has the meaning
  • n 0 or 1
  • C ⁇ -Cg-alkyl is selected from hydrogen, C ⁇ -Cg-alkyl, C 3 -Cg-alkenyl, C2-Cg-alkinyl, C3- Cg-cycloalkyl; benzyl, phenyl; saturated or unsaturated, four- to seven-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or O;
  • 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
  • R 10 is synonymous with R 9 , but is selected independently thereof, or can be hydroxy;
  • G 2 is the grouping
  • G 3 is selected from
  • n is the number 0, 1 or 2
  • X has the meanings NR 11 , 0 or S, whereby
  • R 11 has the same meanings as R 4 , but is selected independently thereof, or the grouping NR 8 R 9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
  • anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least an aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
  • G 4 is selected from
  • R 11 has the above meaning
  • G 6 is selected from
  • Ar 1 and Ar 2 are selected independently of each other from phenyl, pyridyl or naphthyl;
  • alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different groups, selected from hydroxy, carboxy, C2 _ C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C ⁇ -Cg-alkyl) amino;
  • the invention relates to new compounds according to the general formula (I)
  • R 1 is selected from hydrogen, halogen, cyano, C ⁇ -Cg-alkyl, trifluoromethyl, ethinyl, hydroxy, C -C4-alkoxy, benzyloxy, C -C4-alkyl- thio, C2 _ C5-alkoxycarbonyl, aminocarbonyl, C3 ⁇ Cg- dialkylaminocarbonyl, carboxy, phenoxy, phenylthio and pyridyloxy;
  • 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-alkenylene optionally substituted once or twice by C -C3 ⁇ alkyl, phenyl, hydroxy and/or fluorine;
  • C3-C ⁇ 2 _a l k yl ene ' optionally substituted once or twice by C ⁇ -C3 ⁇ alkyl, hydroxy or phenyl;
  • G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
  • n is the number 0 or 1
  • R 8 is selected from benzyl, diphenylmethyl, phenyl
  • C ⁇ -Cg-alkyl is selected from hydrogen, C ⁇ -Cg-alkyl, C3-Cg-alkenyl, C2 ⁇ Cg-alkinyl, C3- CQ-cycloalkyl; benzyl, phenyl; azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, hexahydroazepinyl, piperazinyl, morpholinyl or hexahydrodiazepinyl ;
  • benzofuryl benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoiso- thiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, quinolinyl, isoquinolinyl, ox
  • R 10 is synonymous with R 9 , but is selected independently thereof, or is hydroxy;
  • G 2 is the grouping — C R 8 R 9 ( G2 )
  • R 8 and R 9 can also be a ring system bound over the carbon atom, selected from indanyl, indenyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl; indolinyl, isoindolinyl, oxoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroacridinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, be
  • G 3 is selected from
  • n is the number 0 or 1
  • X has the meaning NR 11 , 0 or S, whereby
  • R 11 is selected from hydrogen, C -C3-alkyl, allyl, propinyl, benzyl and phenyl, or the grouping
  • NR 8 R 9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (4H)- dihydrobenzooxazine, (4H) -dihydrobenzothiazine, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo-
  • Z has the meaning 0 or S
  • R 11 has the above meaning
  • R 12 is selected from phenyl, indenyl, naphthyl, anthryl; furyl, thienyl, thiazolyl, pyridyl, indolyl, benzothienyl or quinolinyl;
  • G 6 is selected from
  • Ar 1 and Ar 2 are selected independently of each other from phenyl, pyridyl or naphthyl;
  • aromatic ring systems in the substituents R 1 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , Ar 1 and Ax 2 and/or in ring systems CR 8 R 9 and NR 8 R 9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C ⁇ -Cg-alkyl, trifluoromethyl, C3 ⁇ Cg- cycloalkyl, benzyl, phenyl, hydroxy, C ⁇ -Cg-hydroxyalkyl, C ⁇
  • alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C -Cg-alkyl) amino .
  • the invention relates to compounds according to the general formula (I)
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, C -C4-alkoxy, phenoxy, methylthio, ethylthio, methoxycarbonyl, aminocarbonyl and carboxy;
  • R 2 is selected from hydrogen, chlorine, methyl, hydroxy and ethoxy;
  • R 3 is hydrogen
  • A is selected from
  • c 3 -c 10 ⁇ alk y lene ' C3-C ⁇ o _a lke n yl en e or C3-C o ⁇ lkinylene, wherein, respectively, 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 isosterically replaced by a group NH-CO-NH or NH-CO-O and/or O-CO-NH;
  • G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
  • G 1 has the meaning
  • R 8 is selected from benzyl, diphenylmethyl, phenyl
  • R 9 is selected from hydrogen, C -C3 ⁇ alkyl, C3-Cg-cycloalkyl, benzyl, phenyl, indanyl, indenyl, naphthyl, anthryl; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, i idazolyl, thiadiazolyl, triazolyl, pyridyl,
  • benzofuryl benzothienyl, indolyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoimidazolyl and benzotriazolyl;
  • R 10 is synonymous with R 9 , but is selected independently thereof, or can be hydroxy;
  • G 2 is the grouping
  • n is the number 0 or 1
  • X has the meaning NR 11 , 0 or S, whereby
  • R 11 is selected from hydrogen, C -C3-alkyl, benzyl and phenyl, or the grouping NR 8 R 9 can also be a nitrogen heterocycle bound over the nitrogen atom selected from indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo- [c] azepine, (IH) -tetrahydrobenzo [d] azepine, (5H)- tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo- [b] thiazepine, carbazole, 1, l-dioxo-l-thia-2-aza- acenaphthene, ( 10H)
  • Y is selected from methylene, ethenylene, or represents a bond
  • Z has the meaning 0 or S
  • R 11 has the above meaning
  • R 12 is selected from phenyl, naphthyl, anthryl; thienyl, pyridyl, benzothienyl or quinolinyl;
  • Ar 1 and Ar 2 are selected independently of each other from phenyl, pyridyl or naphthyl;
  • alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C ⁇ -Cg-alkyl) amino .
  • the invention relates to compounds according to the general formula (I)
  • R 1 is selected from hydrogen, fluorine, methyl, trifluoromethyl, ethylthio;
  • R 2 is hydrogen
  • R 3 is hydrogen
  • C3 ⁇ Cg-alkylene, C3-Cg-alkenylene or C3 ⁇ Cg-alkinylene, in which one or two methylene units are isosterically replaced by 0, NH or CO; is selected from cyclopentylphenylmethylene, cyclohexylphenylmethyl, cyclohexylhydroxyphenylmethyl , diphenylmethyl , diphenylhydroxymethyl, diphenylmethylene, diphenylethyl, diphenylhydroxy ethyl, diphenylethylene, triphenylmethyl, triphenylethyl, triphenylhydroxyethyl, triphenylethylene, naphthylmethylene, naphthyl, tetrahydronaphthyl, hydroxytetrahydronaphthyl, tetrahydronaphthylidene, fluoroenyl, hydroxyfluoroenyl, fluoroenylidene, t
  • phenyl-thienylmethyl phenyl-thienylhydroxymethyl, phenyl-thienylmethylene, dithienylmethyl, dithienylhydroxymethyl, dithienylmethylene, phenyl- furylmethyl, phenyl-furyl-hydroxymethyl, phenyl- furylmethylene, phenyl-pyridylmethyl, phenyl- pyridylhydroxymethyl, phenyl-pyridyImethylene;
  • phenylpyrrolyl diphenylpyrrolyl, phenylthienyl, diphenyl-thienyl, phenylpyrazolyl, diphenylpyrazolyl, phenylimidazolyl, diphenylimidazolyl, phenylpyridyl, diphenylpyridyl, indolyl, oxoindolinyl, benzoimidazolyl, oxobenzoimidazolyl, benzothiazolyl, oxobenzothiazolyl, benzoisothiazolyl, benzooxazolyl, oxobenzooxazolyl, benzotriazolyl;
  • diphenylacetylamino diphenylacetyl-phenylamino, diphenylpropionylamino, diphenylacryloylamino, naphthylacetylamino, furoylacrylamino, benzoylamino, naphthoylamino, oxofluoroenylcarbonylamino, furoylamino;
  • diphenylmethylaminocarbonylamino dibenzylaminocarbonylamino, naphthylmethylaminocarbonylamino, dibenzylaminocarbonylamino, biphenylylaminocarbonylamino, naphthylaminocarbonylamino, be zylphenylaminocarbonylamino, diphenylaminocarbonyl- amino ; diphenyla inocarbonyl-phenylamino; diphenylfurylaminocarbonylamino, indolinyl-N-carbonyl- a ino, isoindolinyl-N-carbonylamino, IH, 3H- benzo [de] isoquinolinyl-N-carbonylamino, tetrahydrobenzoazepinyl-N-carbonylamino, phenyl- tetrahydrobenzoazepinyl-N-carbo-nylamino, dihydrod
  • aromatic ring systems in G can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C ⁇ -Cg-alkyl, trifluoromethyl, C3 ⁇ Cg- cycloalkyl, benzyl, phenyl, hydroxy, C -Cg-hydroxyalkyl, C ⁇
  • alkyl and cycloalkyl residues in the group G can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C ⁇ -Cg-alkyl) amino .
  • Reactive derivatives of compound (II) can be, for example, 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, cyanomethyl ester, esters of N-hydroxysuccinimide, N-hydroxyphthalimides, 1-hydroxybenzotriazole, N-hydroxypiperidine, of 2- hydroxypyridine , of 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 1 -carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy-l, 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 1 -carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy
  • 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) are 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 a ⁇ 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-methylmorpholine 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 a ⁇ 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 in the following.
  • each L is a suitable nucleofuge.
  • the type of nucleofuge L and the conditions of the reaction depend on he nature of the residue to be transmitted.
  • a suitable alkylation agent and/or arylation agent of formula (Va) wherein , n, R 8 , R 9 and R 10 are as defined above and the leaving group L can be the reactive derivatives of an alcohol for example, a halogen atom such as chlorine, bromine or iodine, or a sulfonic acid ester, i.e.
  • a methanesulfonyloxy residue for example, a methanesulfonyloxy residue, trifluoromethansulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy-, p-brom- benzenesulfonyloxy-, m-nitrobenzenesulfonyloxy residue.
  • the reaction of compounds (IV) and (Va) are usually conducted in a suitably inert solvent .
  • solvents can be for example, aromatic hydrocarbons (benzene, toluene, xylene) , ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether) , ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone) , polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic ⁇ olvent ⁇ such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone .
  • aromatic hydrocarbons benzene, toluene, xylene
  • ethers for example tetrahydrofuran, dioxane, glycol dimethyl ether
  • ethyl acetate
  • compounds of formula (I), wherein G has the meanings G4 to G6 according to the above definition can also be produced according to method (B2) by reacting compounds of formula (IV) with a carboxylic acid, thiocarbamic acid, Carbamic acid, sulfonic acid and/or phosphinic acid of the formulas (VIb) to (Vie) , wherein , Y,
  • Preferred derivatives of carboxylic acids (VIb) and/or ⁇ ulfonic acid ⁇ (VId) which are capable of reaction are ⁇ ymmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides, especially acyl- and/or sulfonyl chloride ⁇ .
  • Preferred derivative ⁇ of carbamic acid ⁇ and/or thiocarbamic acid ⁇ (VIc) and/or pho ⁇ phinic acid ⁇ (Vie) which are capable of reaction are the carbamoyl , thiocarbamoyl and/or pho ⁇ phinyl halide ⁇ , especially carbamyl, thiocarbamoyl and/or phosphinyl chlorides.
  • the reaction of the acids (VI) and/or their reactive derivatives with compounds (IV) preferably occurs in the presence of auxiliary base ⁇ in ⁇ olvent ⁇ and under condition ⁇ as they are described in method (A) .
  • R 8 and R 9 or, optionally, the residues NR 8 R 9 , have the meanings according to the above definitions .
  • Bis-trichloromethyl carbonate (tripho ⁇ gene) and carbonyldiimidazole have been proven as particularly reactive carbonyl group transmitters.
  • the reaction of compounds of formula (IV) with tripho ⁇ gene and/or carbonyldiimidazole are typically conducted in an ab ⁇ olute, inert ⁇ olvent in the pre ⁇ ence of a tertiary organic amine a ⁇ an auxiliary ba ⁇ e in ⁇ uch a manner that the solution of compound ⁇ (IV) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter.
  • reaction requires molar ratios of 1 : 1 for the reaction of compound (IV) and carbonyldiimidazol, and, in contra ⁇ t, a ratio of 1 : 0.35 for the u ⁇ e of triphosgene.
  • compound (VII) i ⁇ added in ⁇ tochiometric amounts or in exces ⁇ as a solution or a solid, whereby the reaction is typically completed at elevated temperature.
  • Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons (for example dichloromethane, chloroform, 1, 2-dichloroethane, trichloroethylene) , ethers (for example diethyl ether, tetrahydrofuran, dioxane) , esters such as ethyl acetate, butyl acetate, acetonitrile or polar aprodic ⁇ olvents ⁇ uch a ⁇ formamide or dimethylformamide . Pure solvents as well as mixtures of variou ⁇ ⁇ olvent ⁇ can be u ⁇ ed.
  • hydrocarbons such as hexane, heptane, benzene, toluene, xylene
  • chlorinated hydrocarbons for example dichloromethane, chloroform, 1, 2-dichloroethan
  • reaction temperature ⁇ can lie between -40°C and 50°C for the first partial reaction, preferably 0°C to 30°C, and between 0°C and 150°C for the second partial reaction, preferably 20°C to 120°C.
  • reaction of the compounds of formula (IV) with the i ⁇ ocyanate ⁇ and/or i ⁇ othio cyanate ⁇ of formula (VIII) are conducted thereby in an ab ⁇ olute, inert solvents as they are named in method (B3) .
  • Mixtures of various ⁇ olvents can also be u ⁇ ed.
  • the reaction temperatures can vary in the region from -20°C to 150°C, but preferably lie at 20°C to 100°C.
  • the compounds (I) are first normally obtained in form of their free ba ⁇ e ⁇ or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acid ⁇ are obtained in a typical manner by converting the ba ⁇ e with the desired acid in a ⁇ uitable ⁇ olvent. Depending on the number of basic center ⁇ of compound ⁇ (I) , one or more equivalent acid ⁇ per mole of base can be bound.
  • Suitable solvent ⁇ are, for example, chlorinated hydrocarbon ⁇ ⁇ uch a ⁇ dichloromethane or chloroform; ether ⁇ ⁇ uch as diethyl ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methyl ketone; e ⁇ ter ⁇ ⁇ uch as methyl acetate or ethyl acetate or low molecular alcohol ⁇ ⁇ uch as methanol, ethanol or i ⁇ opropanol ,- and water.
  • Pure solvents as well as mixtures of two or three ⁇ olvent ⁇ can al ⁇ o be u ⁇ ed.
  • the ⁇ alts can be i ⁇ olated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates .
  • the bases can be recovered from the ⁇ alt ⁇ by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.
  • CDI carbonyldiimidazole
  • EDC N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • TEA triethylamine
  • the acid chloride obtained in this manner is suspended in 20 ml abs. dichloromethane and cooled in an ice bath at ca. 0°C under moisture exclusion.
  • 2.4 g (7.5 mmol) 8 8-bis- (4-fluorophenyl) -octylamine in 40 ml abs. dichloromethane together with 0.9 g (9.0 mmol) TEA are added dropwise to the suspension.
  • the ice bath is removed and the reaction is stirred for a further two hours at RT .
  • the mixture is subsequently concentrated, taken up in 10% sodium hydroxide solution and extracted three time with acetic acid ethyl ester.
  • the combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum.
  • the residue is chromatographicaliy purified over silica gel with CHCI 3 /CH3OH (95/5) and. After withdraw of the solvent, the residue is dissolved in methanol and added to a methanolic HCI solution.
  • the drawn off HCI salt is crystallized twice from 70 ml acetone. Colorless crystals with MP . 126 - 129°C. Yield 2.4 g (42%) .
  • Batch size 3.5 g (23.5 mmol) 3- (3-pyridyl) -acrylic acid, 4.0 g (31,5 mmol) oxalyl chloride and 6.0 g (21.1 mmol) 4-(3,3- diphenyl-ureido) -butylamine .
  • pre-purification first occurs by chromatography over silica gel with CHCl 3 /CH 3 OH/NHOH (85/15/2) and, subsequently, flash-chromatography is carried out with CHCI 3 /CH 3 OH (95/5) . Subsequently, a crystallization from acetonitrile occurs. Colorless crystals with MP . 183°C. Yield 4.6 g (70%) .
  • pre-purification first occurs by chromatography on silica gel with CHC1 3 /CH 3 0H (95/5) and, subsequently, flash-chromatography is carried out with CHCI3/CH 3 OH (95/5) . .Amorphous solid material with MP . 61 - 63°C. Yield 2.3 g (23%) .
  • the formed precipitate is filtered off chromatographicaliy purified over silica gel with CHCl 3 /CH 3 OH
  • the amine is added dropwise at -15°C, and the reaction mixture is stirred for three hours at this temperature.
  • chloroform is used for extraction. Purification occurs by chromatography over silica gel with CHCl 3 /CH 3 OH (95/5) . Subsequently, this is crystallized three times from 20 ml and 13 ml 1-chlorobutane and 10 ml acetonitrile. Beige colored crystals with MP . 101 - 102°C. Yield 1.0 g (20%) .
  • the production of the phthalimide occurs analogously to Example i) d) .
  • Batch size 66.0 g (183 mmol) 8-hydroxy-8, 8-d ⁇ phenyl-octyl bromide and 33.3 g (180 mmol) phthalimide potassium salt.
  • the reaction time is increased to five hours .
  • the reaction mixture is concentrated under vacuum.
  • the residue is taken up in chloroform and washed twice each with 50 ml 10% NaOH solution.
  • the organic phase is dried over sodium sulfate and subsequently, the solvent is removed under vacuum.
  • the accumulated crude product is further purified without further processing: Yield 6.7 g (97%) .
  • dichloromethane is used for extraction.
  • the purification occurs by chromatography on silica gel with dichloromethane: Yield 23.8 g (78%).
  • the reaction mixture is filtered and the filtrate is concentrated under vacuum.
  • the residue is taken up in 180 ml dichloromethane and washed twice each with 20 ml 10% NaOH solution.
  • the organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum .
  • the accumulated crude product is crystallized from 12 ml acetic acid ethyl ester: Yield 4.4 g (81%).
  • the reaction mixture is filtered and the filtrate is concentrated under vacuum .
  • the residue is taken up in 120 ml acetic acid ethyl ester and washed twice each with 10 ml 10% NaOH solution.
  • the organic phase is dried over sodium sulfate and subsequently the solvent is removed under vacuum .
  • the accumulated crude product is further processed without further purification: Yield 4.0 g (78%).
  • reaction of the amine occurs analogously to reaction viii) a) .
  • the organic phase is first washed with 30 ml 10% NaOH solution and then twice each with 50 ml water.
  • the purification occurs by chromatography on silica gel CHCI 3 /CH 3 OH (99/1). Yield 8.25 g (93%).
  • dichloromethane is used for extraction.
  • the purification occurs by chromatography on silica gel with chloroform: Yield 26.2 g (64%) .
  • reaction of the amine occurs analogously to reaction viii) a) .
  • the reaction mixture is stirred at RT for 12 hours, subsequently concentrated under vacuum and the residue is distributed between 80 ml chloroform and 80 ml water.
  • the aqueous phase is made alkaline with 30% sodium hydroxide solution and extracted twice each with 50 ml chloroform by shaking.
  • the combined organic phases are dried over sodium sulfate and subsequently, the solvent is removed under vacuum.
  • the accumulated crude product is further processed without further purification: Yield 1.7 g (58%).
  • 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- o-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 micelles, 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®) a ⁇ 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-d
  • 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.
  • 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.
  • the pellet mixtures with differentially released agent can be filled into hard gelatine capsules.
  • Anti- stick and lubricant and separating agents such as x-ray amorphic 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 a ⁇ 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 a ⁇ 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 injectable forms.
  • a ⁇ pecial release form con ⁇ ists 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 polyvinylpyrolidone 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.
  • the gel ⁇ can be pre ⁇ ent either a ⁇ hydrogel ⁇ ba ⁇ ed on water or a ⁇ hydrophobic organogel ⁇ , for example ba ⁇ ed on mixtures of low and high molecular paraffin hydrocarbons and Vaseline.
  • Anionic, cationic or neutral tensides can be employed as emulsifier ⁇ , for example alkalized ⁇ oap ⁇ , methyl soap ⁇ , amine ⁇ oap ⁇ , sulfonated compounds, cationic soap ⁇ , 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.
  • emulsifier ⁇ for example alkalized ⁇ oap ⁇ , methyl soap ⁇ , amine ⁇ oap ⁇ , sulfonated compounds, cationic soap ⁇ , 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 ba ⁇ es such as for example hydrochloric acid, citric acid, ⁇ odiu hydroxide ⁇ olution, pota ⁇ sium hydroxide solution, monosodium carbonate, further buffer system ⁇ , ⁇ uch a ⁇ for example citrate, phosphate, tries-buffer or triethanolamine are used for adjusting the pH value .
  • Preservative ⁇ for example ⁇ uch as methyl- or propyl benzoate (parabenes) or sorbic acid can be added for increasing stability.
  • Pastes powders or ⁇ olutions 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 con ⁇ istency-giving base.
  • Powders or topically applicable powders can contain for example starch varieties such as wheat or rice starch, flame dispersed silicon dioxide or ⁇ ilica, which also serve as diluents, for increasing flowability as well a ⁇ lubricity as well as for preventing agglomerate .
  • starch varieties such as wheat or rice starch
  • flame dispersed silicon dioxide or ⁇ ilica which also serve as diluents, for increasing flowability as well a ⁇ lubricity as well as for preventing agglomerate .
  • Nose drops or nose spray ⁇ serve as na ⁇ al application forms .
  • nebulizer ⁇ 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.
  • 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 i ⁇ adju ⁇ ted to a ⁇ uitable pH value by acid addition and ⁇ ub ⁇ equently 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 thi ⁇ , the aqueou ⁇ solution of sodium hydroxide is added with sub ⁇ equent 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 ⁇ uitable method (spray drying, solvent-evaporation or pha ⁇ e ⁇ eparation) 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 disper ⁇ ed together with ⁇ oya lecithin and arachis oil.
  • the benzyl alcohol is dissolved in
  • Miglyole ® and added to the dispersion.
  • the entire disper ⁇ ion i ⁇ sterilized and ⁇ ubsequently 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.
  • ⁇ o-called perforation bottles which can al ⁇ o be optionally preserved, and infusion solution ⁇ 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 pos ⁇ ible ⁇ uitable pH value for the medicinal form (euhydria) and optional further required nutrient ⁇ , vitamin ⁇ , amino acid ⁇ , stablizers and other necessary adjuvants, pos ⁇ ibly in combination with further medicinal agent ⁇ ⁇ uitable for the mentioned indication ⁇ .
  • buffer substances for adjustment of physiological pH value and/or the isotonicity and/or a best pos ⁇ ible ⁇ uitable pH value for the medicinal form (euhydria) and optional further required nutrient ⁇ , vitamin ⁇ , amino acid ⁇ , stablizers and other necessary adjuvants, pos ⁇ ibly in combination with further medicinal agent ⁇ ⁇ uitable for the mentioned indication ⁇ .
  • active ingredient used according to the invention 10.000 g lactose 5.200 g starch, soluble 1.800 g hydroxypropylmethylcellulose 900 g magne ⁇ ium 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 u ⁇ ed 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 magne ⁇ ium 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. If de ⁇ ired, a gastric fluid resi ⁇ tant 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 sorbitol, 70% ⁇ olution 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 content .
  • 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. ⁇ . aromatic agent q. ⁇ . rice ⁇ tarch q. ⁇ . to 0.500 g
  • the active ingredient i ⁇ 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 adjuvant ⁇ , 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
  • the above-mentioned adjuvant ⁇ are melted and further processed together with the active ingredient to an ointment in a customary manner.
  • 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 ingredien ( ⁇ ) u ⁇ ed according to the invention is dissolved in propylene glycol at ca . 60 °C. At the same time, the lipophilic components are melted at 60-70°C and rti

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Abstract

The invention relates to new pyridylalkane, alkene and alkine acid amides substituted with an aryl and/or heteroaryl residue according to general formula (I), 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 immunosuppressive agents, for example in the treatment or prevention of various types of tumors and control of immune reactions such as autoimmune diseases.

Description

ARYI^SUBSΗTUTED PYRIDYLALKANE, ALKENE, AND ALKINE CARBOXAMIDES USEFUL AS CYTOSTAΗC AND IMMUNOSUPPRESSIVE AGENTS
The invention relates to new pyridylal ane, alkene and alkine carboxamides substituted with a saturated, one or several- fold unsaturated hydrocarbon residue in the carboxylic acid grouping, 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 and control of immune reactions, for example of autoimmune diseases.
A pressing need exists for new pharmaceuticals and/or medicaments for cytostatic therapy which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents, whereby treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.), with operative procedures, heat treatment, etc.
Additionally, from another point of view, there exists a strong need in the field of tumor therapy for new compounds, for example for overcoming or avoiding resistances, which enrich the pallet of cancerostatics based on new modes of action in the ideal case.
This object was successfully solved by the creation of the pyridylalkane, alkene and alkine carboxamide derivatives as defined in detail in the claims and medicaments containing these as well as the use of these compounds, optionally in combination with other suitable active ingredients and adjuvants, especially for cytostatic and immunosuppressive therapy or prevention.
It is known from the art that various pyridine compounds substituted in a specific manner have pharmacologically useful properties; however, in contrast to the actions of the compounds according to the invention, these lie in completely different fields of indication.
Thus, ω-pyridylalkane and/or alkene amides with anti-allergic 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, co-pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. Similarly 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.
The synthesis and phaiπnacological evaluation of 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 the publication EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P. Furthermore, pyridyl (alkyl) carbonamides, pyridyl (alkyl) sulfonamides and analogous ureas, wherein the amide portion is bound to piperidine ring over an alkyl chain, are disclosed in published EP-A-0 479 601 as active ingredients with anti- arrhythmic properties.
Further structurally closely related compounds are represented by the piperidine compounds described in EP-A-0 330 026. These known compounds are distinguished by an anti- cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesia, senile dementia, mania and Alzheimer's disease.
Compounds in the form of α, ω-diaryl-substituted 2- aminopentan-3-oles or 4-aminopent-l-en-3-oles whose nitrogen atom can be substituted, among others, by 3- or 4- pyridylcarbonyl , pyridylalkylcarbonyl or pyridylalkenecarbonyl are known from WO 94/01402 on the basis of a few exemplified substitutions. However, these known compounds represent tachykinin antagonists which are used for the treatment of pain, inflammation, migraines and arthritis.
Further amides with a piperidine residue and specific several-fold substituted 2-aryl-4-piperidyl-butylamine and their use as neurokinin antagonists are named in GB 2 304 714 A, however no concrete examples of a compound are disclosed for a 3 -pyridyl substitution as an aryl residue.
Aside from esters, ethers, thioethers or thioamides and many other functional derivatives, alkane and alkene amides of ω- imidazolyl alkane/alkene amines with a chain of up to 6 C- atoms are also comprised by the general formula published in WO 93/14070 as antagonists of the histamine-H3 receptor with an i-convulsive, anti-depressive, anti-allergic and anti- secretory action. However, not a single example of a compound is concretely described or even mentioned for a pyridyalkane or alkene amide .
In 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 in very important structural features, for example by the 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 pyridyl compounds, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural difference, whereby the therapy possibilities according to the invention with the new compounds extend to the combat of numerous other types of tumors with different causal mechanisms as well as for immunosuppressive treatment possibilities such as autoimmune diseases .
In view of this art, the finding that the compounds according to the general formula (I) with the particular substitutions defined below have superior pharmacological activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses over a broad anti- proliferative spectrum, was completely unexpected.
The pharmacological finding that, aside from the cytostatic effectiveness, especially with different tumor spectra, the compounds according to the invention also possess immunosuppressive properties and additionally favorable abortive properties without harmful mutagenic effects is to be considered as equally surprising. As a result of the particular molecular structure now found, a further class of compounds with, among others, pronounced cancerosta ic, cytostatic, anti-proliferative and abnormal cell growth- inhibiting activity with a novel mode of action is offered.
The new aryl-substituted pyridyl carboxamides are comprised by the following general formula:
Figure imgf000007_0001
wherein G is selected from Gl, G2, G3, G4, G5 or G6 under the proviso that G must contain at least one aromatic ring whereby Gl, G2, G3, G4, G5 and G6 correspond to the following formulas :
(CRo9R_ι 1n0., _ RR£ (Gl)
= C R8R9 (G2)
Figure imgf000007_0002
NR8R9
(G3b)
-NR 11 (CR9R10)m R£ (G4a)
Figure imgf000007_0003
Figure imgf000007_0004
-NR11 SO, R12 (G5)
Figure imgf000007_0005
whose substituent meanings are more closely specified below. The synthesis of these new compounds occurs by means of known analogous methods, whose suitable provisions, reactants such as respective suitable starting and intermediate products as well as solvents are illustrated below in detail. Summarizing, the various suitable method variants are based on the following steps:
according to method (A) , compounds of the formula (I) are prepared in the manner that carboxylic acids of formula (II),
Figure imgf000008_0001
wherein R^, Y , A and k have the meanings given above or their reactive derivatives are reacted with compounds of formula (III)
H N-
RJ (III) wherein D, G and R3 are defined above, for example in the form of their activated esters, anhydrides, acid halides, especially acid chlorides, or simple lower alkyl esters as free bases or acid addition salts, optionally in the presence of condensation agents, for example carbodiimides, in a suitable, preferably inert solvent or polar aprotic solvent or solvent mixture, as well as, optionally, in the presence of an auxiliary base in the form of a carbonate or organic amine, at a reaction temperature especially between -40°C and 180°C, preferably between -10°C and 130°C; or
according to method (B) , compounds of formula (I), wherein G corresponds to the meanings of G3a, G4, G5 or G6, and, optionally X is equal to NR-'--'-, can be produced that compounds of formula (IV)
Figure imgf000009_0001
are reacted with suitable alkylation or arylation agents and/or carboxylic acid, carbamic acid, thiocarbamic acid, sulfonic acid or phosphinic acid derivatives of formula (Va) to (Ve),
L (CH2)n (CR9R1°)m R{ (Va)
C Y (CR9R10)m Rc
II (Vb) o
Figure imgf000009_0002
SO, 12
(Vd)
Figure imgf000009_0003
wherein each L represents a suitable nucleofuge, or
according to method (Bl), compounds of formula (I), wherein G has the meanings of G3a with X = NR1! according to the above definition, can also be produced in the manner that compounds of formula (IV) are reacted in a suitable inert solvent and/or solvent mixture with a suitable alkylation and/or arylation agent of formula (Va) , wherein m, n, R8, R9 and R10 are defined as above and the leaving group L can be a reactive derivative of an alcohol, for example a halogen atom, or sulfonic acid ester, whereby the reaction preferably takes place in the presence of bases as named above in method (A) and, in the case of the use of compounds of formula (Va) in the form of their chlorides or bromides as starting products, the reaction can be accelerated by addition of alkali metal iodides such as sodium iodide or potassium iodide and whereby the reaction temperature can vary, especially between 0°C and 180°C, preferably between 20°C and 130°C; or
according to method (B2), compounds of formula (I), wherein G has the meaning G4 to G6 according to the above definition, can also be produced in that starting products of formula (IV) are reacted with a carboxylic acid, thiocarbamic acid carbamic acid, sulfonic acid and/or phosphinic acid of formula (VIb) to (Vie),
HO C Y (CR9R10)m R8 (vib )
O
HO C NR8R9 (vie )
Z
HO S02 R12 (VId)
HO. Λ
\ Ar1 P (Vie )
O \Ar2
wherein m, Y, Z, R8, R9, R10, R12, Ar1, Ar2 and optionally the group NR R9 have the above meanings or with their derivatives capable of reaction, preferably in the presence of auxiliary bases in solvents and under conditions as they are described in method (A) , or
according to method (B3), compounds of formula (I), wherein G represents a carbamoyl residue according to the definition G4b with Z = 0, i.e. is a group
NR11 C NR8R9
II o can also be produced in the manner that compounds of formula (IV), wherein X = NR11 are reacted to an intermediate product with a carbonyl group transmitter, preferably with a bis- trichloromethy carbonate (triphosgene) or carbonyldiimidazole, especially in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base and, subsequently, without purification or isolation of the intermediate product, this is reacted with a primary or secondary amine of formula (VII),
H NR8R9 (VII)
wherein R8 and R9 or optionally the residue NR8R9 have the meanings according to the above definitions, whereby the temperature for the first partial reaction can lie especially between -40°C and 50°C, preferably at 0°C to 30°C, and, for the second partial reaction, between 0°C and 150°C, preferably in the range of 20°C to 120°C, and whereby compounds of formula (I) wherein G represents a thiocarbamoyl residue according to the definition G4b with Z = S, i.e. is a group
NR11 C NR8R9
II S
can be produced in an identical manner from the starting compounds of the formulas (IV) and (VII) in that thiocarbonyldiimidazole or thiophosgene is used as a thiocarbonyl group transmitter, or
according to method (B4), compounds of formula (I), wherein G represents a carbamoyl residue or thiocarbamoyl residue according to the definition G4b with R9 = hydrogen, i.e. is a group
NR11 C NHR8
II z can be produced in the manner, that the starting compounds of formula (IV) , wherein X = NR11 are reacted with an isocyanate or isothiocyanate of formula (VIII),
Z = C=N — R8 (VIII)
wherein R8 has the meanings defined above, preferably in absolute, inert solvents as they are considered in the above method (B3), especially at a -.action temperature which can vary in the range of -20°C to 150°C, preferably at 20°C to 100°C.
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, lactateε, 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.
In the compounds of Formula (I) which are defined below and in the claims in detail, the definitions for their atoms or atomic groups preferably have the following meanings :
Halogen means fluorine, chlorine, bromine or iodine;
Alkyl can be straight chained or branched and preferably signifies a Ci-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 . Alkylene signifies for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene or dodecamethy1ene .
Alkenyl preferably signifies C3-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, heptadienylene, octenylene, octadienylene, nonenylene, nonadienylene or decenylene, decadienylene, undecenylene, undecadienylene, dodecenylene or dodecadienylene .
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, noneninylene, decinylene, deceninylene, undecinylene or dodecinylene .
Cycloalkyl is preferably a C3-C8-c cloalkyl residue, especially a cyclopropyl- , cyclobutyl-, cyclopentyl-, cyclohexyl-, cycloheptyl- or cyclooctyl group.
Cycloalkylene preferably signifies cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene . Hydroxyalkyl contains a hydroxyl group in one of the above mentioned alkyl residues, especially in a Ci-C -alkyl residue, whereby among the C^Cg-hydroxyalkyl residues, the hydroxymethyl- and the hydroxyethyl residue are preferred.
Aside from the oxygen atom, alkoxy residues, preferably Cj_ -
Cg-alkoxy or C3-C8-cycloalkoxy, especially contain one of the above mentioned preferred alkyl and/or cycloalkyl groups with up to 6 or 8 carbon atoms . Particularly preferred groups for this are the methoxy-, ethoxy-, isopropoxy-, tert-butoxy- , cyclopentyloxy- and cyclohexyloxy groups .
Alkoxy, especially C^Cg-alkoxy, entirely or partially replaced by fluorine is for example difluoromethoxy, trifluoromethoxy or 2 , 2 , 2-trifluoroethoxy .
Aralkyl such as phenylalkyl, especially phenyl-Cχ-C3~alkyl and/or diarylalkyl such as diphenyl-C -C3-alkyl or triaralkyl such as triphenylmethyl contain 1 and/or 2 and/or 3 phenyl groups on a methyl-, ethyl-, propyl- or isopropyl group at any position. Among these, benzyl- and diphenylmethyl residues are particularly preferred.
Aside from the sulphur atom, alkylthio residues contain one of the above mentioned preferred C^-Cg-alkyl groups, especially the methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups.
Aside from the oxygen atom, alkanoyloxy residues preferably contain an aliphatic acyl group with 1 to 7 carbon atoms. Among preferred alkanoyloxy groups are the acetoxy- , propionyloxy- and pivaloyloxy groups .
Carboxyalkyl, especially C2~C7-carboxyalkyl, and carboxyalkenyl, especially C3-C7~carboxyalkenyl, contain a carboxyl group on one of the above named alkylene and alkenyl residues especially Cχ-Cg-alkylene and/or C2-Cg-alkenylene residues. Among these, the carboxymethyl-, carboxyethyl-, carboxyethenyl-, carboxybutyl- and carboxybutadienyl residues are preferred.
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- , isobutoxycarbonyl- and tert-butoxycarbonyl groups.
Aside from the carbonyl group, alkylaminocarbonyl, especially C2-C7-alkylaminocarbonyl and dialkylaminocarbonyl groups, preferably C3-C13 -dialkylaminocarbonyl groups, contain an alkylamino- and/or dialkylamino residue whose alkyl groups especially correspond to the C]_-Cg-alkyl groups of the above description. Preferred groups are the dimethylaminocarbonyl- , diethylaminocarbonyl- and diisopropylaminocarbonyl groups.
.Aminoalkyl residues, especially C -Cg-aminoalkyl residues, each contain an amino group in one of the above named Cχ-Cg- alkyl residues, whereby the aminomethyl- and aminoethyl groups are particularly preferred.
Aside from the unsubstituted amino group, the amino group of the Formula NR4R5 is one of the below mentioned alkylamino groups, especially C^-Cg-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. Preferred groups are the methylamino- , ethylamino-, propylamino- , isopropylamino- , butylamino-, and the tert-butylamino groups. The preferred di- (C1-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 Ci-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 four- to seven-membered heterocycles with one or two hetero-atoms, are for example azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydropyridine, piperidine, hexahydroazepine, piperazine, morpholine, thiomorpholine, 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 bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl , tetrahydronaphthyl , dihydrobenzocycloheptenyl , tetrahydrobenzocycloheptenyl , biphenylenyl, fluoroenyl, anthryl, dihydroanthryl , phenanthryl, dihydrophenanthryl , dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl . Their mono- or dioxo- derivates, i.e. for example the residues of indanone, tetralone, anthrone, anthraquinone, fluoroenone, phenanthrone, dibenzocycloheptenone, dihydrodibenzo- cycloheptenone or tetrahydrodibenzocyclooctenύne are also to be understood as partially hydrated carbocyclic ring systems.
Anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to preferably 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl , benzofuryl, dihydrobenzofuryl , benzothienyl, dihydrobenzothienyl, indolyl , indolinyl, isoindolinyl , benzimidazolyl , indazolyl, benzooxazolyl , benzoisoxazolyl , benzothiazolyl , benzoisothiazolyl , benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl , isothiazolopyridyl , imidazopyridyl, pyrazolopyridyl , thienopyrimidinyl , chromanyl , benzopyranyl , quinolinyl, isoquinolinyl , dihydroquinolinyl, tetrahydroquinolinyl, benzodioxanyl , quinoxalinyl, quinazolinyl, naphthyridinyl , carbazolyl, tetrahydrocarbazolyl, pyridoindolyl , 1, l-dioxo-l-thia-2-aza- acenaphtene, acridinyl, phenanthridinyl , dihydrophenanthridinyl , dihydrobenzoisoquinolinyl , phenothiazinyl , dihydrodibenzooxepinyl , benzocycloheptathienyl , dihydrothienobenzothiepinyl , dihydrodibenzothiepinyl , octahydrodibenzothiepinyl , dibenzoazepinyl , dihydrodibenzoazepinyl , octahydrodibenzoazepinyl , benzocycloheptapyridyl , dihydrobenzocycloheptapyridyl , pyridobenzoazepinyl , dihydropyridobenzoazepinyl , dihydropyridobenzodiazepinyl , dihydrodibenzooxazepinyl , dihydropyridobenzooxepinyl , dihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl . Furthermore, their mono- or dioxo-derivates and/or optionally their possible tautomers are also to be understood as partially hydrated heterocyclic ring systems, i.e. for example the residues of indolinone, isatin, of benzoxazolone and/or its tautomer hydroxybenzoxazole, of benzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazolone and/or their tautomers hydroxybenzoisoxazole, hydroxybenzothiazole, hydroxybenzoisothiazole and hydrox - benzimidazole, of indazolinone, of oxazolopyridinones , thiazolopyridinones, pyrazolopyridinones and imidazo- pyridinones and/or their tautomers hydroxyoxazolopyridines , hydroxythiazolopyridines, hydroxypyrazolopyridines and hydroxyimidazopyridine, the residues of chromanone, chromone, quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone, phenanthridone, benzoisoquinolinone of dihydrodibenzooxepinones , benzocycloheptathiophenones , dihydrothienobenzothiepinones , dihydrodibenzothiepinones , dihydrodibenzoazepinones , benzocycloheptapyridinones , dihydropyridobenzoxazepinones , dihydropyridobenzo- diazepinones , dihydropyridobenzooxazepinones , dihydrodibenzothiazepinones and of dihydropyridobenzo- thiazepinones .
Saturated and unsaturated, four- to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or 0, are for example azetidine, pyrrolidine, piperidine, (IH) -tetrahydropyridine, hexahydroazepine, (IH) -tetrahydroazepine, pyrazolidine, piperazine, morpholine, thiomorpholine thiomorpholin-1, 1- dioxide, hexahydrodiazepine or hexahydrooxazepine .
Anellated bi- or tricyclic, aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring (as the group —NR8R9) which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, are for example indoline, isoindoline, (1H)- dihydroquinoline, (IH) -tetrahydroquinoline, (2H)- tetrahydroisoquinoline, (IH) -tetrahydroquinoxaline, (4H)- dihydrobenzooxazine, (4H) -dihydrobenzothiazine, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo [c] azepine, (IH) -tetrahydrobenzo [d] azepine, (5H) - tetrahydrobenzo [b] oxazepine, (5H) - tetrahydrobenzo [b] thiazepine, 1,2,3, 4-tetrahydro-9H- pyrido [3, 4-b] indole, ( 10H) -dihydroacridine, (10H)- dihydrophenanthridine, 1, 2, 3, 4-tetrahydroacridanone, (10H)- phenoxazine, ( 10H) -phenothiazine, (5H) -dibenzoazepine, (5H)- dihydrodibenzoazepine, (5H) -octahydrodibenzoazepine, dihydrobenzo [d, e] isoquinoline, (5H) -dihydrodibenzodiazepine, (5H) -benzo [b] -pyrido [f] azepine, (5H) - dihydrobenzo [b] pyrido [f] azepine, (11H) -di- hydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] - thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H)- dihydrodibenzo [b, f] -thiazepine, (5H) - tetrahydrodibenzoazocine, (11H) -dihydrobenzo [e] -pyrido [b] - 1, 4-diazepin-6-one or (11H) -dihydrobenzo [b] pyri-do [e] -1, 4- diazepin-5-one .
Concretely, the invention relates to new pyridylalkane, pyridylalkene and pyridylalkine acid amides of the general formula (I)
Figure imgf000019_0001
wherein the substituents have the following meanings
is selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkinyl, fluoroalkyl such as trifluoromethyl, cycloalkyl, hydroxyalkyl, hydroxy, alkoxy, cycloalkyloxy, aralkyloxy such as benzyloxy, alkanoyloxy, alkylthio, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, aryl such as phenyl, aryloxy such as phenoxy, arylthio such as phenylthio, heteroaryloxy such as pyridyloxy, heteroarylthio such as pyridylthio, and NR^R5, whereby
R^ and R^ are selected independently of each other from hydrogen, alkyl, alkenyl, alkinyl, aralkyl such as benzyl and aryl such as phenyl;
R2 is selected from hydrogen, halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
R-3 is selected from hydrogen, alkyl, alkenyl, alkinyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
k is the number 0 or 1,
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, NR6, CO, SO or S02, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R6 is hydrogen, alkyl, alkenyl, acyl or alkanesulfonyl;
1, 2-cyclopropylene;
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;
1, 3, 5-hexatrienylene, optionally substituted by alkyl, fluorine, cyano or aryl such as phenyl; and
ethinylene
D is selected from
alkylene with at least 3 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl;
alkenylene with at least 3 carbon atoms or alkadienylene with at least 5 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl ;
alkinylene with at least 3 carbon atoms or alkeninylene, with at least 5 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl; as well as
alkylene, alkenylene or alkinylene each with at least 3 carbon atoms, wherein one to three methylene units, with the exception of the (G) -terminal methylene group, are isosterically replaced by 0, S, NR7, CO, SO or SO2, whereby R7 is synonymous with R6, but is selected independently thereof;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
— (CRR°>m— R8 (G1) whereby m is the number 0 or 1, and R8 is selected from aralkyl such as benzyl or diphenylmethyl, aryl such as phenyl ; 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
R^ is selected from hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl; aralkyl such as benzyl, aryl such as phenyl; saturated or unsaturated, four- to six-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or 0;
monocyclic aromatic five- or seven-membered heterocycles, which can contain one to three heteroatoms selected from N and/or S and/or 0 and are either bound directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
R10 is synonymous with R9, but can be selected independently thereof, and also hydroxy;
<y is the grouping
= CRδR9 (G2)
which is bound to D by means of a double bond,
wherein R8 and R9 have the above meaning, or whereby this grouping =CR8R9 can also be a ring system bound over the carbon atom, selected from anellated bi- and tricyclic partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring; anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0;
G3 is selected from
— X— (CH2)n— (CR9R1°)m— R8 (G3a) or NR8R9 (G3b)
whereby m and the substituents R8, R9 and R10 can have above meanings, and
n is the number 0, 1 or 2,
X has the meaning NR11, 0 or S, whereby R11 has the same meaning as R^, but is selected independently thereof, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
G4 is selected from
-NR >1 I1 I C (CR ?93oR1I0U)i m Rc
II ! G4 a ) O or
-NR 11 C NR8R9
II ; G4b ) , z
with the proviso, that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C<- or - C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above defined meanings with the proviso that the residues
Figure imgf000024_0001
cannot be identical, and
is selected from methylene, ethylene, ethenylene, cycloalkylene or represent a bond, and Z has the meaning 0 or S;
G5 has the meaning
NR11 S02 R2 (G5)
wherein R11 has the above meaning, and
R12 is selected from alkyl, aryl such as phenyl; monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or 0; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or
0 and the linkage can occur either over an aromatic or a hydrated ring;
G6 is selected from
Figure imgf000025_0001
wherein X can have the above meanings and
Ar1 and Ar2 are selected independently from each other from aryl such as phenyl or naphthyl as well as heteroaryl such as pyridyl;
and whereby aromatic ring systems in the substituents R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, .Ar1 and Ar2 and/or in ring systems ==C R8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, cycloalkyl, aralkyl such as benzyl, aryl such as phenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxy entirely or partially substituted by fluorine, aralkyloxy such as benzyloxy, aryloxy such as phenoxy, mercapto, alkylthio, arylthio such as phenylthio, sulfo, carboxy, carboxyalkyl, carboxyalkenyl, alkoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl, nitro, amino, a inoalkyl, ono-alkylamino, di- (alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl- and cycloalkyl residues in the group G can be substituted by one or two of the same or different residues selected from hydroxy, carboxy, alkoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl, amino, mono-alkylamino and di- ( alkyl ) amino;
the cis- and trans-isomers as well as E- and Z-isomers of the above defined compounds, especially in the case that A is a cyclopropane ring or D contains one or more double bonds, including the enantiomers, diastereomers and other isomers of the above defined compounds, optionally in pure form or as their racemic and/or non-racemic mixtures;
the tautomers of the above defined compounds, in the optinal case that G represents a heterocyclic aromatic ring or one which simultaneously contains substitutions by free hydroxy-, mercapto- or amino groups; as well as the corresponding
acid addition salts of the compounds defined above including their hydrates and solvates.
According to a preferred embodiment, the invention relates to new pyridylalkane, pyridylalkene and pyridylalkine acid amides of the formula (I)
Figure imgf000027_0001
wherein the substituents have the following meanings:
R- is selected from hydrogen, halogen, cyano, Cχ-Cg-alkyl, C3-Cg-alkenyl,
C2-Cg-alkinyl, trifluoromethyl, C3-Cg-cycloalkyl, Cχ-Cg- hydroxyalkyl, hydroxy, Cχ-Cg-alkoxy, C3-C8- cycloalkyloxy, benzyloxy, Cχ-C7-alkanoyloxy, C_-Cg- alkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7- alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR4R5, whereby
R4 and R5 are selected independently of each other from hydrogen, Cχ-Cg-alkyl, C3-Cg-alkenyl, C3~Cg-alkinyl, benzyl and phenyl;
R2 is selected from hydrogen, halogen, cyano, C -Cg-Alkyl, trifluoromethyl, hydroxy, C]_-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 is 0 or 1,
A is selected from
C]_-Cg-alkylene, optionally substituted one to three-fold by C -C3-alkyl, hydroxy, Cι~C3-alkoxy, fluorine, or phenyl; C2-Cg-alkylene, in which a methylene unit is isosterically replaced by 0, S, NR6, CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R6 is selected from hydrogen, C -Cg-alkyl, C3~C - alkenyl, C;-Cg-Acyl or C]_-Cg-alkanesulfonyl;
1, 2-cyclopropylene;
C2-Cg-alkenylene, optionally substituted once or twice by Cχ-C3-alkyl, hydroxy, Cχ-C3-alkoxy, fluorine, cyano or phenyl;
C4-Cg-alkadienylene, optionally substituted once or twice by Cχ-C3~alkyl, fluorine, cyano or phenyl;
1, 3, 5-hexatrienylene, optionally substituted by C1-C3- alkyl, fluorine, cyano or phenyl; as well as
ethinylene
is selected from
C3-C 2_alkylene' optionally substituted once or twice by C -Cg-alkyl, hydroxy, C -Cg-alkoxy or phenyl;
c3~c12-alkenylene or C5-Cχ2~aιkadienylene, optionally substituted one or twice by C -Cg-alkyl, hydroxy, Cχ-Cg- alkoxy or phenyl;
C3-Cχ2-alk:Lrj-Ylene or C5-C 2-alkeninylene, optionally substituted one or twice by C -Cg-alkyl, hydroxy, Cχ-Cg- alkoxy or phenyl; and
C3-C]_2-alkylene/ C3-C 2~alkenylene or C3~C 2_ alkinylene, wherein, with the exception of the (G)- terminal methylene group, one to three methylene units are isosterically replaced by O, S, NR7, CO, SO or SO2, whereby R7 is synonymous with R6, but is selected independently thereof;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
Figure imgf000029_0001
and
m is 0 or 1,
is selected from benzyl, diphenylmethyl, phenyl; 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
is selected from hydrogen, Cχ-Cg-alkyl, C3-Cg-alkenyl, C2-Cg-alkinyl, C3- Cg-cycloalkyl; benzyl, phenyl; saturated or unsaturated, four- to seven-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or O;
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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
R10 is synonymous with R9, but is selected independently thereof, or can be hydroxy;
G2 is the grouping
= CR8R9 (G2)
which is bound to D by means of a double bond, wherein R8 and R9 have the above meaning or whereby the grouping = CR8R9 can also be a ring system bound over the carbon atom, selected from anellated bi- and tricyclic partial hydrated carbocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least an aromatic ring; anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0;
G3 is selected from
X (CH2)n (CR9R10)m R8 (G3a) or
NR8R9
(G3b)
whereby m and the substituents R8, R9 and R10 can have the above meanings, and
n is the number 0, 1 or 2
X has the meanings NR11, 0 or S, whereby
R11 has the same meanings as R4, but is selected independently thereof, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least an aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
G4 is selected from
NR11 C Y (CR9R1°) >m_ (G4a)
or -NR11 C NR8R9
II :c4b), z
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C^- or -^C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above meaning with the proviso that the residues
Figure imgf000032_0001
cannot be identical, and
is selected from methylene, ethylene, ethenylene, C3~C7-cycloalkylene or represents a bond, and
is 0 or S;
has the meaning
-NR 11 SO >12 ( G5 )
wherein R11 has the above meaning, and
is selected from
C -Cg-alkyl, phenyl; monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or 0; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least an aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms, especially up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring;
G6 is selected from
(G6l
wherein X can have the above meanings and
Ar1 and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl;
and whereby aromatic ring systems in the substituents R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, .Ar1 and Ar2 and/or in ring systems =C R8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, C3~Cg- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl, C ~ Cg-alkoxy, Cχ-Cg-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C^-Cg-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2~C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C -Cg-aminoalkyl, mono-C^-Cg-alkylamino, di- (C -Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different groups, selected from hydroxy, carboxy, C2_C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (Cχ-Cg-alkyl) amino;
the cis- and trans-isomers, E- and Z-isomers of the above defined compounds, especially in the case that A is a cyclopropane ring or D contains one or more double bonds, including the corresponding enantiomers, diastereomers and other isomers of the above defined compounds, optionally in pure form or as their racemic and/or non-race ic mixtures;
the tautomers of the above defined compounds, in the optional case that G represents or contains a heterocyclic aromatic ring with simultaneous substitution by free hydroxy-, mercapto- or amino groups; as well as the corresponding
acid addition salts of the compounds defined above including their hydrates and solvates .
According to a further, particularly preferred embodiment, the invention relates to new compounds according to the general formula (I)
Figure imgf000034_0001
wherein the substituents have the following meaning:
R1 is selected from hydrogen, halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, ethinyl, hydroxy, C -C4-alkoxy, benzyloxy, C -C4-alkyl- thio, C2_C5-alkoxycarbonyl, aminocarbonyl, C3~Cg- dialkylaminocarbonyl, carboxy, phenoxy, phenylthio and pyridyloxy;
is selected from hydrogen, fluorine, chorine, bromine, C -C4-alkyl, trifluoromethyl, hydroxy, Cχ-C4-alkoxy;
R3 is selected from hydrogen, Cχ-C3~alkyl, allyl, hydroxy, C]_-C3~alkoxy and benzyloxy;
k is 0 or 1,
A is selected from
C -Cg-alkylene, optionally substituted once or twice by
C -C3~alkyl, hydroxy, fluorine or phenyl;
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, and
1, 2-cyclopropylene;
C2-Cg-alkenylene, optionally substituted once or twice by C -C3~alkyl, phenyl, hydroxy and/or fluorine;
C4-Cg-Alkadienylene, optionally substituted once or twice by methyl or fluorine;
1, 3, 5-hexatrienylene, optionally substituted by methyl or fluorine, and
ethinylene
D is selected from
C3-Cχ2_alkylene' optionally substituted once or twice by Cχ-C3~alkyl, hydroxy or phenyl;
C3-C 2-alkenylene, optionally substituted once or twice by C -C3-alkyl, hydroxy or phenyl; c3- cJ2~"alkinylene , optionally substituted once or twice by Cχ-C3-alkyl, hydroxy or phenyl, and
C3-Cχ2~al^ylene, C3-C 2~ lkenylene or C3-Cχ2-alkinylene, wherein one to three methylene units are isosterically replaced by 0, S, NH, N(CH3), N(C0CH3), N(S02CH3), CO or so2;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
has the meaning
Figure imgf000036_0001
whereby m is the number 0 or 1,
R8 is selected from benzyl, diphenylmethyl, phenyl;
benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluoroenyl, oxofluoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, bound directly or over a methylene group;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chro anonyl, benzopyranyl, chromonyl, quinolyl, isoquinolinyl, dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, 1, l-dioxo-l-thia-2-aza-acenaphthenyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, oxodihydrophenanthridinyl, dihydrobenzoisochinolinyl, oxodihydrobenzosoquinolinyl, phenothiazinyl, dihydrodibenzooxepinyl , oxodihydrodibenzooxepinyl , benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzo- thiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl, octahydrodibenzoazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, oxodihydropyridobenzoazepinyl, dihydropyridobenzo- diazepinyl, oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl, dihydropyridobenzooxepinyl, dihydropyridobenzooxazepinyl, oxodihydropyridobenzo- oxazepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzo- thiazepinyl or oxodihydropyridobenzothiazepinyl, bound directly or over a methylene group;
is selected from hydrogen, Cχ-Cg-alkyl, C3-Cg-alkenyl, C2~Cg-alkinyl, C3- CQ-cycloalkyl; benzyl, phenyl; azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, hexahydroazepinyl, piperazinyl, morpholinyl or hexahydrodiazepinyl ;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iso-thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, triazinyl, bound directly or over a methylene group
indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluoroenyl, oxofluoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzo- cycloheptenyl, bound directly or over a methylene group;
benzofuryl, benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoiso- thiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, quinolinyl, isoquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, carbazolyl, pyridoindolyl, dihydrobenzoisoquinolinyl, phenothiazinyl, bound directly or over a methylene group;
R10 is synonymous with R9, but is selected independently thereof, or is hydroxy;
G2 is the grouping — C R8R9 ( G2 )
which is bound to D over a double bond, wherein R8 and R9 have the above meaning, or whereby the grouping = c R8R9 can also be a ring system bound over the carbon atom, selected from indanyl, indenyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl; indolinyl, isoindolinyl, oxoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroacridinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzo- cycloheptapyridinyl, pyridobenzoazepinyl, dihydropyrido- benzoazepinyl, oxodihydropyridobenzooxepinyl, dihydropyridobenzothiepinyl ;
G3 is selected from
— X — (CH2)n— (CR9R1°)m R8 (G3a) or NR8R9 (G3b)
whereby and the substituents R8, R9 and R10 can have the above defined meanings and
n is the number 0 or 1,
X has the meaning NR11, 0 or S, whereby
R11 is selected from hydrogen, C -C3-alkyl, allyl, propinyl, benzyl and phenyl, or the grouping
NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (4H)- dihydrobenzooxazine, (4H) -dihydrobenzothiazine, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo-
[c] azepine, ( IH) -tetrahydrobenzo [d] azepine, (5H)- tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo-
[b] thiazepine, 1,2,3, 4-tetrahydro-9H-pyrido [3, 4- bjindole, carbazole, tetrahydrocarbazole, 1, 1-di-oxo-l- thia-2-aza-acenaphthene, ( 10H) -dihydroacridine, (10H)- dihydrophenanthridine, 1, 2, 3, 4-tetrahydroacridanone,
(10H) -phenoxazine, (10H) -phenothiazine, dihydrobenzo [d, e] iso-quinoline, (5H) -dibenzoazepine,
(5H) -dihydrodibenzoazepine, (5H) -octahydrodi- benzoazepine, (5H) -dihydrodibenzodiazepine, (5H)- benzo [b] pyrido [ f] azepine, (5H) -dihydrobenzo [b] pyrido-
[f] azepine, ( 11H) -dihydrodibenzo [b, e] oxazepine, (11H)- dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo-
[b, f] oxazepine, (10H) -dihydrodibenzo [b, f] thiazepine,
(5H) -tetrahydrodibenzoazocine, (11H) - dihydrobenzo [ejpyrido [b] -1, 4-diazepin-6-one or (11H)- dihydrobenzo [b] pyrido [e] -1, 4-diazepin-5-one;
is selected from
—NR11— C — Y — (CR9R1°)m — R8 (G4a)
O or
—NR11—C — RR9 (G4b) /
Z
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or - C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above meanings with the proviso that the residues
Figure imgf000041_0001
cannot be identical, and
is selected from methylene, ethylene, ethenylene, cyclopropylene or represents a bond, and
Z has the meaning 0 or S;
has the meaning
-NR11 SO' >12
(G5)
wherein R11 has the above meaning, and
R12 is selected from phenyl, indenyl, naphthyl, anthryl; furyl, thienyl, thiazolyl, pyridyl, indolyl, benzothienyl or quinolinyl;
G6 is selected from
Figure imgf000041_0002
wherein X can have the above meanings and
.Ar1 and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl;
and whereby aromatic ring systems in the substituents R1, R3, R8, R9, R10, R11, R12, Ar1 and Ax2 and/or in ring systems =CR8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C^-Cg-alkyl, trifluoromethyl, C3~Cg- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl, C ~
Cg-alkoxy, C -Cg-Alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C^-Cg-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2_C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C -Cg-aminoalkyl, mono-C]_-Cg-alkylamino, di-
(C -Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C -Cg-alkyl) amino .
According to a very particular embodiment the invention relates to compounds according to the general formula (I)
Figure imgf000042_0001
wherein the substituents have the following meanings:
R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, C -C4-alkoxy, phenoxy, methylthio, ethylthio, methoxycarbonyl, aminocarbonyl and carboxy; R2 is selected from hydrogen, chlorine, methyl, hydroxy and ethoxy;
R3 is hydrogen;
k is 0,
A is selected from
C2_Cg-alkylene, optionally substituted once or twice by hydroxy or fluorine;
C2~Cg-alkylene, wherein a methylene unit is isosterically replaced by 0, S, or CO, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group;
C2_Cg-alkenylene, optionally substituted by methyl and/or fluorine;
C4-Cg-alkadienylene, optionally substituted by methyl;
ethinylene;
D is selected from
C3-C]_Q-alkylene, optionally substituted by methyl, hydroxy or phenyl;
C3-Cχo-al':enylene' optionally substituted by methyl, hydroxy or phenyl;
C3-C]_o-alkinylene, optionally substituted by hydroxy or phenyl;
c3-c10~alkylene' C3-Cχo_alkenylene or C3-C o~ lkinylene, wherein, respectively, a methylene unit is isosterically replaced by 0, NH, N(CH3), or CO, or an ethylene group is isosterically replaced by a group NH-CO and/or CO-NH, or a propylene group isosterically replaced by a group NH-CO-NH or NH-CO-O and/or O-CO-NH;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
(CR9R10)m R8 (Gi) whereby m is the number 0 or 1,
R8 is selected from benzyl, diphenylmethyl, phenyl;
indanyl, indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluoroenyl, oxofluoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, bound directly or over a methylene group;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, thienopyrimidinyl, chromanonyl, quinolyl, isoquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazoleyl, pyridoindolyl, 1,1-dioxo-l- thia-2-aza-acenaphthenyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, dihydrobenzoisoquinolinyl, oxodihydrobenzoisoquinolinyl, dihydrodibenzooxepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl, benzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl, oxodihydropyridobenzodiazepinyl, dihydropyridobenzooxepinyl or dihydrodibenzothiazepinyl, bound directly or over a methylene group;
R9 is selected from hydrogen, C -C3~alkyl, C3-Cg-cycloalkyl, benzyl, phenyl, indanyl, indenyl, naphthyl, anthryl; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, i idazolyl, thiadiazolyl, triazolyl, pyridyl,
benzofuryl, benzothienyl, indolyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoimidazolyl and benzotriazolyl;
R10 is synonymous with R9, but is selected independently thereof, or can be hydroxy;
G2 is the grouping
= CR8R9 (G2)
which is bound to D over a double bond, wherein R8 and R9 have the above meaning, or whereby the grouping =CR8R9 can also be a ring system bound over the carbon atom, selected from indanyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl ; indolinyl, isoindolinyl, oxoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroacridinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzocyclohepta- pyridinyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl , oxodihydropyridobenzo- oxepinyl , dihydropyridobenzothiepinyl ;
;3 is selected from
X (CH2)n (CR9R10) (G3a) or m R£
NR8R9 (G3b)
whereby m and the substituents R8, R9 and R10 can have the above defined meanings and
n is the number 0 or 1,
X has the meaning NR11, 0 or S, whereby
R11 is selected from hydrogen, C -C3-alkyl, benzyl and phenyl, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom selected from indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo- [c] azepine, (IH) -tetrahydrobenzo [d] azepine, (5H)- tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo- [b] thiazepine, carbazole, 1, l-dioxo-l-thia-2-aza- acenaphthene, ( 10H) -dihydroacridine, (10H)- dihydrophenanthridine, dihydrobenzo [d, e] isoquinoline, (5H) -dihydrodibenzoazepine, (5H) -dihydrodibenzodiazepine, (5H) -dihydrobenzo [b]pyrido [f] azepine, (11H)- dihydrodiben-zo [b, e] oxazepine, (11H) -dihydrodibenzo- [b, e] thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H) -dihydrodibenzo [b, f] thiazepine, (5H) - tetrahydrodibenzoazocine, ( 11H) -dihydrobenzo [ejpyrido [b] -1, 4-diazepin-6-one or (11H)- dihydrobenzo [b]pyrido [e] -1, -diazepin-5-one;
is selected from
-NR 11 C (CR9R10) <
II m R !G4a: o or
Figure imgf000047_0001
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or ->C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above meanings with the proviso that the residues
Figure imgf000047_0002
cannot be identical, and
Y is selected from methylene, ethenylene, or represents a bond, and
Z has the meaning 0 or S;
G5 has the meaning
-NR11 SO R12 (G5)
wherein R11 has the above meaning, and
R12 is selected from phenyl, naphthyl, anthryl; thienyl, pyridyl, benzothienyl or quinolinyl;
is selected from
Figure imgf000048_0001
wherein X can have the above meanings and
Ar1 and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl;
and whereby aromatic ring systems in the substituents R1, R3, R8, R9, R10, R11, R12, Ar1 and Ar2 and/or in ring systems =CR8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, C3-Cg- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl, Cχ~
Cg-alkoxy, C -Cg-Alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, Cχ-Cg-alkylthio, phenylthio, sulfo, carboxy, C2~C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2_C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, Cχ-Cg-aminoalkyl, mono-C -Cg-alkylamino, di-
(C -Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (Cχ-Cg-alkyl) amino . Furthermore, according to a very particularly preferred embodiment, the invention relates to compounds according to the general formula (I)
Figure imgf000049_0001
wherein the substituents have the following meanings:
R1 is selected from hydrogen, fluorine, methyl, trifluoromethyl, ethylthio;
R2 is hydrogen;
R3 is hydrogen;
is 0,
is selected from ethylene or butylene, optionally substituted by hydroxy or one or two fluorine atoms, or
OCH2, SCH2,
ethenylene or 1, 3-butadienylene;
is selected from
C3-Cg-alkylene, optionally substituted by hydroxy or phenyl;
C3-Cg-alkenylene, optionally substituted by phenyl,
C3-Cg-alkinylene; or
C3~Cg-alkylene, C3-Cg-alkenylene or C3~Cg-alkinylene, in which one or two methylene units are isosterically replaced by 0, NH or CO; is selected from cyclopentylphenylmethylene, cyclohexylphenylmethyl, cyclohexylhydroxyphenylmethyl , diphenylmethyl , diphenylhydroxymethyl, diphenylmethylene, diphenylethyl, diphenylhydroxy ethyl, diphenylethylene, triphenylmethyl, triphenylethyl, triphenylhydroxyethyl, triphenylethylene, naphthylmethylene, naphthyl, tetrahydronaphthyl, hydroxytetrahydronaphthyl, tetrahydronaphthylidene, fluoroenyl, hydroxyfluoroenyl, fluoroenylidene, tetrahydrobenzocycloheptenyl, hydroxytetrahydrobenzocycloheptenyl, tetrahydrobenzocycloheptenylidene, dihydrodibenzocycloheptenyl, hydroxydihydrodibenzo- cycloheptenyl, dihydrodibenzocycloheptenylidene;
phenyl-thienylmethyl, phenyl-thienylhydroxymethyl, phenyl-thienylmethylene, dithienylmethyl, dithienylhydroxymethyl, dithienylmethylene, phenyl- furylmethyl, phenyl-furyl-hydroxymethyl, phenyl- furylmethylene, phenyl-pyridylmethyl, phenyl- pyridylhydroxymethyl, phenyl-pyridyImethylene;
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzocycloheptapyridinyl, benzocycloheptapyridinylidene, dihydrobenzocycloheptapyridinyl, dihydrobenzocycloheptapyridinylidene, dihydrodibenzooxepinyl, dihydrodibenzooxepinylidene, dihydrodibenzothiepinyl, dihydrodibenzothiepinylidene;
phenylpyrrolyl, diphenylpyrrolyl, phenylthienyl, diphenyl-thienyl, phenylpyrazolyl, diphenylpyrazolyl, phenylimidazolyl, diphenylimidazolyl, phenylpyridyl, diphenylpyridyl, indolyl, oxoindolinyl, benzoimidazolyl, oxobenzoimidazolyl, benzothiazolyl, oxobenzothiazolyl, benzoisothiazolyl, benzooxazolyl, oxobenzooxazolyl, benzotriazolyl;
diphenylmethylamino, diphenylmethyl-methylamino, dibenzylamino, benzylphenylamino, cyclohexylphenylamino, triphenylmethylamino, biphenylylamino, diphenylamino; N- indolinyl, N-isoindolinyl, N-tetrahydroquinolinyl, N- tetrahydrobenzazepinyl, N-phenyl- tetrahydrobenzoazepinyl, N-l, l-dioxo-l-thia-2-aza- acenaphthenyl, N-1H, 3H-benzo [de] -isoquinolinyl, N- dihydrodibenzoazepinyl ;
diphenylmethyloxy, diphenylmethylthio;
diphenylacetylamino, diphenylacetyl-phenylamino, diphenylpropionylamino, diphenylacryloylamino, naphthylacetylamino, furoylacrylamino, benzoylamino, naphthoylamino, oxofluoroenylcarbonylamino, furoylamino;
diphenylmethylaminocarbonylamino, dibenzylaminocarbonylamino, naphthylmethylaminocarbonylamino, dibenzylaminocarbonylamino, biphenylylaminocarbonylamino, naphthylaminocarbonylamino, be zylphenylaminocarbonylamino, diphenylaminocarbonyl- amino ; diphenyla inocarbonyl-phenylamino; diphenylfurylaminocarbonylamino, indolinyl-N-carbonyl- a ino, isoindolinyl-N-carbonylamino, IH, 3H- benzo [de] isoquinolinyl-N-carbonylamino, tetrahydrobenzoazepinyl-N-carbonylamino, phenyl- tetrahydrobenzoazepinyl-N-carbo-nylamino, dihydrodibenzoazepin-N-carbonylamino, dihydrobenzopyridoazepinyl-N-carbonylamino;
tolylsulfonylamino, naphthylsulfonylamino, diphenylphosphinoylamino and diphenylphosphinoyloxy,
and whereby aromatic ring systems in G can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, C3~Cg- cycloalkyl, benzyl, phenyl, hydroxy, C -Cg-hydroxyalkyl, C ~
Cg-alkoxy, Cχ-Cg-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C -Cg-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2~C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, Cχ-Cg-aminoalkyl, mono-Cχ-Cg-alkylamino, di- (C -Cg-alkyl) amino and for two adjacent residues on the aromatic ring, methylenedioxy, and
whereby alkyl and cycloalkyl residues in the group G can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (Cχ-Cg-alkyl) amino .
Very particularly, preferred concrete embodiments of the invention are represented by the following end products :
(1) N- [8, 8-bis- (4-fluorophenyl) -octyl] -3-pyridin-3-yl-acryl- amide»hydrochloride (substance 23 as hydrochloride)
(2) N- [ 6- (3, 3-diphenyl-ureido) -hexyl] -3-pyridin-3-yl- acrylamide (substance 270)
(3) N- [4- (1-phenyl-l, 2,4, 5-tetrahydrobenzo [d] azepin-3-yl) - butyl] -3-pyridin-3-yl-acrylamide (substance 207)
(4) N- (8, 8-diphenyl-octyl) -3-pyridin-3-yl-acrylamide
(substance 17)
(5) N- (8-hydroxy-8, 8-diphenyl-octyl) -3-pyridin-3-yl- acrylamide (substance 41)
(6) N- [4- (3, 3-diphenyl-ureido) -butyl] -3-pyridin-3-yl- acrylamide (substance 268)
(7) N- [4- (IH, 3H-benzo [de] isoquinolin-2-yl) -butyl] -3-pyridin- 3-yl-acrylamide (substance 225)
(8) N- [6- (10, 11-dihydrodibenzo [b, f] azepin-5-yl- carbonylamino) -hexyl] -3-pyridin-3-yl-acrylamide (substance 295) (9) 3-pyrιdιn-3-yl-N- [6- (tosylammo) -hexyl] -acrylamide (substance 310)
(10) N- [4- (1, l-dιoxo-l-thιa-2-aza-acenaphthylen-2-yl) -butyl] - 3-pyrιdm-3-yl-acrylamιde (substance 214)
(11) N- ( 6-hydroxy-6, 6-dιphenyl-hexyl) -3-pyrιdm-3-yl- acrylamide (substance 31)
(12) N- (6, 6-d phenyl-hex-5-enyl) -3-pyrldin-3-yl-acrylamide
(substance 120)
(13) N- [4- (4, 5-d phenyl-ιmιdazol-l-yl) -butyl] -3-pyrιdm-3-yl- acrylamide (substance 63)
(14) N- [4- (trans-2-phenyl-cyclopropyl-carbonylammo) -butyl] - 3-pyrιdm-3-yl-acrylamιde (substance 250)
(15) N- (5-hydroxy-5, 5-dιphenyl-pentyl) -3-pyrιdm-3-yl- acrylamide (substance 27)
(16) N- (7-phenyl-heptyl) -3-pyrιdm-3-yl-acrylamιde (substance 3)
(17) N- (4-dιphenylacetylammo-butyl) -3-pyπdm-3-yl- acrylamide (substance 247)
(18) N- [4- (benzhydryl-ammo) -butyl] -3-pyrιdm-3-yl-acrylamιde
(substance 187) and
(19) N- (4- { [2- (benzhydrylmethylammo) -ethyl] -methylammo } - butyl) -3-pyrιdm-3-yl-acrylamιde (substance 193). Further subject-matter of the invention are known analogous methods already briefly mentioned above according to the different variants for the production of the compounds of formula (I) according to the invention.
According to the method (A) , compounds of formula (I) are obtained by reacting carboxylic acids of formula (II)
Figure imgf000054_0001
in which R1, R2 , A and k have the meanings given above or their reactive derivatives with compounds of formula (III)
H- —IM -
I III'
R'
wherein D, G and R^ are defined as above.
Reactive derivatives of compound (II) can be, for example, 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, cyanomethyl ester, esters of N-hydroxysuccinimide, N-hydroxyphthalimides, 1-hydroxybenzotriazole, N-hydroxypiperidine, of 2- hydroxypyridine , of 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) or aliphatic chloroformates (for example chloroformic methyl ester, ethyl ester or isobutyl ester) can be used for this.
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, N1 -carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy-l, 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.
Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts. For this, 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) are normally carried out in a suitable, preferably inert solvent. As examples, 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 aε mixtures of two or more, can be used.
The reaction is optionally carried out in the presence of an 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-methylmorpholine 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 aε equivalent.
The 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 in the following.
According to method (B) , compounds of formula (I), wherein G corresponds to the meanings G3a, G4, G5 or G6 and, optionally, X equals NR11, can also be produced by reacting compounds of formula (IV)
Figure imgf000056_0001
with suitable alkylation or Arylation agents and/or carboxylic acid, carbamic acid, thiocarbamic acid, sulfonic acid or phosphinic acid derivatives of formula (Va) to (Ve) ,
L (CH2)n (CR9R10)m R£ (Va]
-c (CR9R10) Rc
II m ( b) o L C NR8R9 (Vc)
SO, R 12 ( d)
L\ /Ar1 y (Ve)
°* Ar2
wherein each L is a suitable nucleofuge. The type of nucleofuge L and the conditions of the reaction depend on he nature of the residue to be transmitted.
Aside from method (A) , compounds of formula (I) in which G has the meaning of G3a with X = NR11 according to the above definition, can also be produced pursuant to a further method variant according to method (Bl) by reacting compounds of formula (IV) with a suitable alkylation agent and/or arylation agent of formula (Va) wherein , n, R8, R9 and R10 are as defined above and the leaving group L can be the reactive derivatives of an alcohol for example, a halogen atom such as chlorine, bromine or iodine, or a sulfonic acid ester, i.e. for example, a methanesulfonyloxy residue, trifluoromethansulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy-, p-brom- benzenesulfonyloxy-, m-nitrobenzenesulfonyloxy residue.
The reaction of compounds (IV) and (Va) are usually conducted in a suitably inert solvent . Such solvents can be for example, aromatic hydrocarbons (benzene, toluene, xylene) , ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether) , ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone) , polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic εolventε such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone . Pure εolventε aε well aε mixtureε of two or more can alεo be used. Preferably, the reactions are carried out in the presence of bases, whereby the same bases as named in method (A) above can be used. If chlorides or bromides are uεed aε compound (Va) , the reaction can be accelerated by the addition of alkali metal iodideε, for example εodium iodide, potassium iodide. The reaction temperatures can vary between 0°C and 180 °C depending on the reactivity of the educts, but preferably lie between 20°C and 130°C.
Aside from method (A), compounds of formula (I), wherein G has the meanings G4 to G6 according to the above definition, can also be produced according to method (B2) by reacting compounds of formula (IV) with a carboxylic acid, thiocarbamic acid, Carbamic acid, sulfonic acid and/or phosphinic acid of the formulas (VIb) to (Vie) , wherein , Y,
Z,R8, R9, R10 , R12, Ar1, Ar2 and, optionally, the group
NR8R9, have the above meanings,
HO - C (CR9R10)m R8 (VIb )
II O
HO " NR8R9 (Vi c)
HO S02 R >1'2^ (VI d)
Figure imgf000058_0001
or their derivatives capable of reacting.
Preferred derivatives of carboxylic acids (VIb) and/or εulfonic acidε (VId) which are capable of reaction are εymmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides, especially acyl- and/or sulfonyl chlorideε. Preferred derivativeε of carbamic acidε and/or thiocarbamic acidε (VIc) and/or phoεphinic acidε (Vie) which are capable of reaction are the carbamoyl , thiocarbamoyl and/or phoεphinyl halideε, especially carbamyl, thiocarbamoyl and/or phosphinyl chlorides. The reaction of the acids (VI) and/or their reactive derivatives with compounds (IV) preferably occurs in the presence of auxiliary baseε in εolventε and under conditionε as they are described in method (A) .
Aside from methods (A) and (B2), compounds of formula (I), wherein G represents a carbamoyl residue according to the definition NR11 C NR8R9
II O
can also be produced according to method (B3) by reacting compounds of formula (IV), wherein X = NR11, with a carbonyl group transmitter to an intermediate, and, subsequently, without purification or isolation of the intermediate, this is reacted with a primary or secondary amine of the formula (VII) ,
H NR8R9 (VII),
wherein R8 and R9 or, optionally, the residues NR8R9, have the meanings according to the above definitions .
Bis-trichloromethyl carbonate (triphoεgene) and carbonyldiimidazole have been proven as particularly reactive carbonyl group transmitters. The reaction of compounds of formula (IV) with triphoεgene and/or carbonyldiimidazole are typically conducted in an abεolute, inert εolvent in the preεence of a tertiary organic amine aε an auxiliary baεe in εuch a manner that the solution of compoundε (IV) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter. Thereby, the reaction requires molar ratios of 1 : 1 for the reaction of compound (IV) and carbonyldiimidazol, and, in contraεt, a ratio of 1 : 0.35 for the uεe of triphosgene. After complete reaction of the componentε to the intermediate product, compound (VII) iε added in εtochiometric amounts or in excesε as a solution or a solid, whereby the reaction is typically completed at elevated temperature. Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons (for example dichloromethane, chloroform, 1, 2-dichloroethane, trichloroethylene) , ethers (for example diethyl ether, tetrahydrofuran, dioxane) , esters such as ethyl acetate, butyl acetate, acetonitrile or polar aprodic εolvents εuch aε formamide or dimethylformamide . Pure solvents as well as mixtures of variouε εolventε can be uεed. Sometimes it is of advantage to carry out the firεt partial reaction at low temperature in a low-viεcosity, highly-volatile εolvent and to remove the εolvent after formation of the intermediate and replace it by a higher boiling εolvent. Amines such as for example triethylamine, ethyl diiεopropylamine, tributylamine, N-methylmorpholine or pyridine are εuitable as auxiliary bases. If compounds (IV) or (VII) are used as salts, the amount of the auxiliary base is increased accordingly. The reaction temperatureε can lie between -40°C and 50°C for the first partial reaction, preferably 0°C to 30°C, and between 0°C and 150°C for the second partial reaction, preferably 20°C to 120°C.
Compounds of formula (I), wherein G represents a thiocarbamoyl residue according to the definition G4b with Z = S, i.e., is a group
-NR 11 C NR8R9
II s can be produced in a completely corresponding manner from compounds (IV) and (VII), by using thiocarbonyldiimidazole or thiophosgene as a thiocarbonyl group transmitter.
Finally, aside from methods (A), (B2) and (B3), compounds of formula (I), wherein G represents a carbamoyl residue or thiocarbamoyl residue according to the definition G4b with R9 = hydrogen, i.e. is a group NR11 C NHR8
II Z can also be produced according to method (B4) by reacting starting compounds of the formula (IV) wherein X = NR11, with an isocyanate or isothiocyanate of the formula (VIII), in which R8 has the meaning according to definition,
Figure imgf000061_0001
Reaction of the compounds of formula (IV) with the iεocyanateε and/or iεothio cyanateε of formula (VIII) are conducted thereby in an abεolute, inert solvents as they are named in method (B3) . Mixtures of various εolvents can also be uεed. Thereby, the reaction temperatures can vary in the region from -20°C to 150°C, but preferably lie at 20°C to 100°C.
The compounds (I) are first normally obtained in form of their free baεeε or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acidε are obtained in a typical manner by converting the baεe with the desired acid in a εuitable εolvent. Depending on the number of basic centerε of compoundε (I) , one or more equivalent acidε per mole of base can be bound.
Suitable solventε are, for example, chlorinated hydrocarbonε εuch aε dichloromethane or chloroform; etherε εuch as diethyl ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methyl ketone; eεterε εuch as methyl acetate or ethyl acetate or low molecular alcoholε εuch as methanol, ethanol or iεopropanol ,- and water. Pure solvents as well as mixtures of two or three εolventε can alεo be uεed. The εalts can be iεolated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates .
The bases can be recovered from the εaltε by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.
Synthetic examples for end products according to the invention are given in the following for further illustrating the above method variants:
SYNTHETIC EXAMPLES for the end products of the invention according to formula (I)
In the production examples for the end products, the abbreviations stand for the following terms:
MP = melting point,
RT = room temperature,
MPLC = intermediate pressure liquid chromatography
THF = tetrahydrofuran,
DMF = dimethylformamide, abs . = abεolute,
CDI = carbonyldiimidazole,
EDC = N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide hydrochloride , HOBT = 1-hydroxybenzotriazole, TEA = triethylamine . H-NMR-Spectrum = proton resonance spectrum, taken at 100 MHz. The chemical shiftε are given in ppm againεt TMS aε a standard (δ = 0.0), whereby
8 = singlet, d = doublet, t = triplet, dt = doublet-triplet, m = multiplet, ar = aromatic, py = pyridine .
Example 1
N- [8 , 8-bis- (4-fluoro-phenyl) -octyl ] -3-pyridin-3-yl- acιrylamide»hydrochloride (Substance 23 as a hydrochloride)
1.34 g (9.0 mmol) 3- (3-pyridyl) -acrylic acid are suspended in 20 ml abs. dichloromethane and, after addition of two drops pyridine, are cooled in an ice bath to ca . 0°C under moisture exclusion. 2 ml (23.2 mmol) oxalyl chloride are slowly added, and the mixture is first stirred for 30 min under ice cooling and then overnight at RT . Subsequently, the solvent and oxalyl chloride are distilled off on a rotary evaporator. In order to completely remove the oxalyl chloride, the colourless residue is further dried for two hours under high vacuum. The acid chloride obtained in this manner is suspended in 20 ml abs. dichloromethane and cooled in an ice bath at ca. 0°C under moisture exclusion. 2.4 g (7.5 mmol) 8, 8-bis- (4-fluorophenyl) -octylamine in 40 ml abs. dichloromethane together with 0.9 g (9.0 mmol) TEA are added dropwise to the suspension. After complete addition, the ice bath is removed and the reaction is stirred for a further two hours at RT . The mixture is subsequently concentrated, taken up in 10% sodium hydroxide solution and extracted three time with acetic acid ethyl ester. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with CHCI3/CH3OH (95/5) and. After withdraw of the solvent, the residue is dissolved in methanol and added to a methanolic HCI solution. The drawn off HCI salt is crystallized twice from 70 ml acetone. Colorless crystals with MP . 126 - 129°C. Yield 2.4 g (42%) .
C28H3oF2N2θ3 • HCI (485.0;
IR-Spectrum (KBr) : v(NH) 3280 cm"1 v(C=0) 1670, 1635, 1550 cm" v(C=C) 1600 cm"1
^-NMR-Spectrum (CDC13) 1.00 - 2.15 (12H, , C-(CH2)6-C) 3.20 - 3.55 (2H, , CONHCH2) 3.84 (IH, t, Ar2CH, J=7.7 Hz) 6.80 - 8.00 (13H, m, Ar, Py,
CH=CH, NH, HCI) 8.30 - 8.45 (IH, m, Py) 8.60 - 8.75 (IH, , Py) 9.30 - 9.45 (IH, , Py)
Example 2
N- [6- (3 , 3-diphenyl-ureido) -he.xyl] -3-pyridin-3-γl-acrylamide (Substance 270)
Production analogous to Example 1. Batch size: 2.6 g (17.6 mmol) 3- (3-pyridyl) -acrylic acid, i ml (20.8 mmol) oxalyl chloride and 5.0 g (16.0 mmol) 6- (3, 3- diphenyl-ureido) -hexyla ine.
In the purification, chromatography first occurs over silica gel with CHC13/CH30H (100/0 bis 95/5), subsequently, this is crystallized from 25 ml acetic acid ethyl ester/petroleum ether (4/1) : Colorless crystals with MP . 105 - 107°C; Yield 1.1 g (15%) .
Figure imgf000065_0001
IR-Spectrum (KBrl v(NH) 3340, 3270 cm"1 v(C=0) 1655, 1540 cm"1 v(C=C) 1615 cm"1
^-NMR-Spectrum (CDCI3) : 1.25 - 1.80 (8H, , C-(CH2)4-C)
3.20 - 3.60 (4H, m, CONHCH2)
4.50 - 4.75 (IH, m, NH)
6.38 (IH, d, CH-CHCO, J=15.7 Hz)
6.40 - 6.65 (IH, , NH)
7.05 - 7.50 (11H, m, Ar, Py)
7.54 (IH, d, CH=CHCO, J=15.7 Hz)
7.60 - 7.75 (IH, m, Py)
8.50 - 8.60 (IH, m, Py)
8.60 - 8.70 (IH, , Py)
Example 3
N- [4- (1-phenyl-1 ,2, ,5-tetrahydrobenzo [d]azepin-3-yl) -butyl] 3-pyridin-3-yl-acrylamide (Substance 207)
Production analogous to Example 1 Batch size: 2.8 g (18.8 mmol) 3- (3-Pyridyl) -acrylic acid, 2.2 ml (25.5 mmol) oxalyl chloride and 5.0 g (17.0 mmol) 4-(l- phenyl-1, 2,4, 5-tetrahydrobenzo [d] azepin-3-yl) -butylamine .
In the purification, chromatography first occurs over silica gel with CHC13/CH30H (95/5) ; subsequently, the oily residue is rubbed with diisopropyl ether until crystillization occurs: Colorless crystals with MP . 92 - 94°C; Yield 0.7 g (9%) .
Figure imgf000066_0001
IR-Spectru (KBr) : v(NH) 3300 cm"1 v(C=0) 1655, 1530 cm"1 v(C=C) 1615 cm"1
^-NMR-Spectrum (CDC13) : 1.45 - 1.85 (4H, , C-CH2-CH2-C)
2.35 - 3.60 (10H, , N-CH2,
Tetrahydroazepine, CONHCH2)
4.30 - 4.55 (IH, m, ArCH)
6.10 - 6.35 (IH, m, NH)
6.37 (IH, d, CH=CHCO, J=15.7 Hz;
6.60 - 7.50 (10H, , Ar, Py)
7.59 (IH, d, CH=CHCO, J=15.7 Hz;
7.60 - 7.90 (IH, , Py) 8.50 - 8.65 (IH, , Py) 8.65 - 8.80 (IH, m, Py)
Example 4
N- (8, 8-diphenyl-octyl) -3-pyridin-3-yl-acrylamide (Substance 17) Production analogous to Example 1.
Batch size: 2.7 g (18.0 mmol) 3- (3-pyridyl) -acrylic acid, 5 ml (57.9 mmol) oxalyl chloride, 3.9 ml (28.0 mmol) TEA and 4.0 g (14,0 mmol) 8, 8-diphenyloctylamine .
In the purification, chromatography first occurs over silica gel with CHC13/CH30H (95/5); subsequently, this is crystallized twice from 100 ml acetic acid ethyl ester/diisopropyl ether: Colorless crystals with MP . 92 - 93°C in a yield of 3.1 g (54%) .
C28H32N3O 412.6)
IR-Spectrum (KBr) v(NH) 3240 cm"1 v(C=0) 1645, 1550 cm"1 v(C=C) 1610 cm-1
lH-NMR-Spectrum (CDC13) 1.10 - 2.20 (12H, , C-(CH2)6-C) 3.36 (2H, dt, CONHCH2, J=6.5 Hz,
J=12.7 Hz) 3.88 (IH, t, Ar2CH, J=7.7 Hz) 5.55 - 5.80 (IH, , NH) 6.43 (IH, d, CH=CHCO, J=15.6 Hz) 7.05 - 7.40 (11H, , Ar, Py) 7.61 (IH, d, CH=CHCO, J=15.6 Hz) 7.65 - 7.85 (IH, , Py) 8.50 - 8.65 (IH, m, Py) 8.65 - 8.80 (IH, m, Py) Example 5
N- (8-hydro.xy-8, 8-diphenyloctyl) -3-pyridin-3-yl-acryl.amide (Substance 41)
3.4 g (23.0 mmol) 3- (3-pyridyl) -acrylic acid and 3.7 g (23.0 mmol) CDI are heated under reflux in 50 ml THF under moisture exclusion. After one hour this is cooled to RT and 6.5 g (21.9 mmol) 8-hydroxy-8, 8-diphenyloctylamine, dissolved in 20 ml THF, is added dropwise. After complete addition, stirring is carried out for a further three hours at RT and this is left to stand overnight. 50 ml water is added to the mixture and extracted three times with acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate, and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with CHC13/CH30H (95/5) and subsequently, crystallized twice from 200 ml and 140 ml acetic acid ethyl ester: Colorless crystals with MP . 139 - 140°C in a yield of 3.7 g (39%).
Figure imgf000068_0001
IR-Spectru (KBr) v(NH) 3270 cm .-"1 v(C=0) 1660, 1540 cm"1
Figure imgf000068_0002
^-NMR-Spectrum (CDC13) : 1.05 - 1.70 (10H, m, C-(CH2)5-C) 2.05 - 2.40 (2H, m, C(OH)-CH2) 3.27 (2H, dt, CONHCH2, J=6.4 Hz,
J=12.3 Hz) 4.59 (IH, s, OH) 6.66 (IH, d, CH=CHCO, J=15.8 Hz) 7.05 - 7.65 (13H, m, Ar, Py,
CH=CHCO, NH) 7.75 - 7.90 (IH, m, Py) 8.45 - 8.60 (IH, m, Py) 8.65 - 8.75 (IH, m, Py)
Example 6
N- [4- (3 , 3-diphenyl-ureido) -butyl ] -3-pyridin-3-yl-acrylamide (Substance 268)
Production analogous to Example 1.
Batch size: 3.5 g (23.5 mmol) 3- (3-pyridyl) -acrylic acid, 4.0 g (31,5 mmol) oxalyl chloride and 6.0 g (21.1 mmol) 4-(3,3- diphenyl-ureido) -butylamine .
In the purification, chromatography first occurs with CHCI3/CH3OH (95/5) , subsequently; this is crystallized from 100 ml acetic acid ethyl ester. Beige colored crystals with MP. 123 - 125°C. Yield 4.1 g (46%).
Figure imgf000069_0001
IR-Spectrum (KBr) v(NH) 3400, 3280 cm-1 v(C=0) 1670, 1640, 1560 cm"1 v(C=C) 1600 cm"1
^-NMR-Spectru (CDC13) 1.45 - 1.70 (4H, m, C-CH2-CH2-C) 3.10 - 3.55 (4H, , CONHCH2) 4.60 - 4.80 (IH, m, NH) 6.50 (IH, d, CH=CHCO, J=15.7 Hz) 6.70 - 6.95 (IH, m, NH) 7.05 - 7.50 (11H, m, Ar, Py) 7.58 (IH, d, CH=CHCO, J=15.7 Hz) 7.60 - 7.80 (IH, m, Py) 8.45 - 8.60 (IH, , Py) 8.60 - 8.75 (IH, m, Py)
Example 7
N- [4- (lH,3H-benzo [de] isoquinolin-2-yl) -butyl] -3-pyridin-3-yl- acrylamide (Substance 225)
Production analogous to Example 1.
Batch size: 1.8 g (12.1 mmol) 3- (3-pyridyl) -acrylic acid, 4.0 g (31.5 mmol) oxalyl chloride and 2.6 g (10.8 mmol) 4-(lH,3H- benzo [de] isoquinolin-2-yl) -butylamine.
In the purification, chromatography first occurs over silica gel with CHCI3/CH3OH (90/10); subsequently, this is crystallized from 10 ml acetic acid ethyl ester: Colorless crystals with MP . 118 - 120°C in a yield of 0.37 g (9%) .
C24H25N30 .371.5]
IR-Spectrum (KBr) v(NH) 3260 cm"1 v(C=0) 1650, 1550 cm"1 v(C=C) 1615 cm"1
^- MR-Spectrum (CDCl3! 1.50 - 2.10 (4H, , C-CH2-CH2-C)
2.55 - 2.90 (2H, m, N-CH2)
3.25 - 3.55 (2H, , CONHCH2)
4.00 (4H, s, ArCH2) 5.60 (IH, d, CH=CHCO, J=15.6 Hz) 7.00 - 7.90 (10H, m, Ar, Py, NH,
CH=CHCO) 8.30 - 8.45 (IH, m, Py) 8.45 - 8.65 (IH, m, Py)
Example 8
N- [6- (10 , 11-dihydro-dibenzo [b, f]azepin-5-yl-carbonylamino) - hexyl] -3-pyridin-3-yl-acrylamide (Substance 295)
Production analogous to Example 1.
Batch size: 2.2 g (14.8 mmol) 3- (3-pyridyl) -acrylic acid, 2.5 g (19.7 mmol) oxalyl chloride, 4.5 g (44.5 mmol) TEA and 5.0 g (13.4 mmol) 6- ( 10, 11-dihydro-dibenzo [b, f] azepin-5-yl- carbonylamino) -hexylamine hydrochloride .
In the purification, chromatography first occurs over silica gel with CHCl3/CH3OH (95/5 to 93/7) subsequently, this is crystallized from 15 ml acetonitrile: Colorless crystals with MP. 97 - 99°C in a yield of 1.35 g (21%).
Figure imgf000071_0001
IR-Spectru (KBr) v(NH) 3280 cm"1 v(C=0) 1670, 1540 cm"1 v(C=C) 1620 cm"1
^-NMR-Spectrum (CDCl; 1.10 - 1.75 (8H, m, C-(CH2)4-C) 2.80 - 3.55 (8H, m, CONHCH2, ArCH2I 4.50 - 4.70 (IH, m, NH) 6.31 (IH, d, CH=CHCO, J=15.7 Hz) 6.65 - 6.85 (IH, m, NH) 7.00 - 7.40 (9H, m, Ar, Py) 7.50 (IH, d, CH=CHCO, J=15.7 Hz) 7.55 - 7.75 (IH, m, Py) 8.45 - 8.70 (2H, m, Py)
Example 9
3-Pyridin-3-yl-N- [6- (tosylamino) -hexyl ] -acrylamide (Substance 310)
Production analogous to Example 1.
Batch size: 4.1 g (27.5 mmol) 3- (3-pyridyl) -acrylic acid, 4.7 g (37.0 mmol) oxalyl chloride, 5.0 g (49.4 mmol) TEA and 8.6 g (25.0 mmol) 6- (tosylamino) -hexylamine»dihydrochloride .
In the purification, chromatography first occurs over silica gel with CHCl3/CH3OH (95/5) and subsequently crystallized from 60 ml acetonitrile: Colorless crystals with MP . 91 - 93°C in a yield of 4.0 g (40%).
Figure imgf000072_0001
IR-Spectrum (KBr): v(NH) 3320, 3280 cm"1 v(C=0) 1650, 1530 cm"1 v(C=C) 1620 cm"1
^-NMR-Spectrum (CDC13) : 1.15 - 1.70 (8H, m, C- (CH2) -C)
2.40 (3H, s, CH3)
2.75 - 3.05 (2H, m, S02NHCH2)
3.15 - 3.50 (2H, m, C0NHCH2)
5.55 - 5.80 (IH, , NH)
6.62 (IH, d, CH=CHCO, J=15.9 Hz) 6 . 60 - 6 . 85 ( IH, m, NH ) 7 . 15 - 7 . 95 ( 7H, m, Ar, Py,
CH=CHCO ) 8 . 45 - 8 . 60 ( IH, , Py) 8 . 60 - 8 . 80 ( IH, , Py)
Example 10
N- [4- (1 , l-dioxo-l-thia-2-aza-acenaphthylen-2-yl) -butyl ] -3- pyridin-3-yl-acrylamide (Substance 214)
8.0 g (36.3 mmol) N- (4-hydroxy-butyl) -3-pyridin-3-yl- acrylamide, 9.5 g (36.3 mmol) triphenylphosphine and 7.6 g (36.3 mmol) 1, 8-naphthalinsultam are suspended in 100 ml THF. .And 6.3 g (36.3 mmol) azodicarboxylic acid diethyl ester dissolved in 50 ml THF are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15°C) . The mixture is left standing overnight at RT without further cooling. Subsequently, the solvent is removed under vacuum and the residue is chromatography purified twice over silica gel with CHC13/CH30H (90/10) and CHCl3/CH3OH (99/1 to 95/5) and, after withdraw of the solvent, crystallized from 30 ml acetic acid ethyl ester. Colorless crystals with MP . 122 - 124°C. Yield 1.0 g (6%) .
C22H21N3O3S (407.5)
IR-Spectru (KBr): v (NH) 3280 cm"1 v(C=0) 1640, 1580 cm"1 v(C=C) 1610 cm"1
^-NMR-Spectrum (CDC13) : 1.60 - 2.35 (4H, m, C-CH2-CH2-C)
3.47 (2H, dt, CONHCH2, J=6.2 Hz, J=12.2 Hz) 3.87 (2H, t, S02NCH2, J=6.5 Hz)
6.25 - 6.60 (IH, m, NH)
6.49 (IH, d, CH=CHCO, J=15.7 Hz)
6.60 - 6.90 (IH, , Ar)
7.10 - 8.20 (8H, m, Ar, Py)
CH=CHCO) 8.40 - 8.85 (2H, m, Py)
Example 11
N- (6-hydroxy-6 , 6-diphenyl-he.xyl) -3-pyridin-3-yl-acrylamide (Substance 31)
Production analogous to Example 5.
Batch size: 3.2 g (21.6 mmol) 3- (3-pyridyl) -acrylic acid, 3.85 g (23.8 mmol) CDI and 4.2 g (25.9 mmol) 6-hydroxy-6, 6- diphenyl-hexylamine in 60 ml abs. THF.
In carrying out the reaction, the amine is added dropwise at 0°C. In the work-up, chloroform is used in the extraction. Purification occurs by chromatography on silica gel with CHCI3/CH3OH (92/8) . Subsequently, this is crystallized twice from 25 ml acetic acid ethyl ester and 45 ml acetonitrile. Colorless crystals with MP . 145 - 147°C. Yield 2.5 g (29%).
Figure imgf000074_0001
IR-Spectru (KBr): v (NH) 3240 cm"1 v(C=0) 1650, 1560 cm"1 v(C=C) 1610 cm"1
^-NMR-Spectru (CDC13) : 1.15 - 1.80 (6H, , C-(CH2)3-C)
2.15 - 2.65 (3H, m, C(OH)CH2) 3.20 - 3.50 (2H, m, CONHCH2) 5.65 - 6.00 (IH, m, NH) 6.42 (IH, d, CH=CHCO, J=15.7 Hz) 7.05 - 7.55 (11H, m, Ar, Py) 7.58 (IH, d, CH=CHCO, J=15.7 Hz) 7.60 - 7.85 (IH, m, Py) 8.40 - 8.60 (IH, m, Py) 8.60 - 8.80 (IH, m, Py)
Example 12
N- (6, 6-diphenyl-hex-5-enyl) -3-pyridin-3-yl-acrylamide (Substance 120)
Production analogous to Example 1.
Batch size: 2.6 g (17.4 mmol) 3- (3-pyridyl) -acrylic acid, 6.0 g (47.3 mmol) oxalyl chloride and 4.0 g (15.9 mmol) 6,6- diphenyl-hex-5-enylamine .
In the purification, chromatography first occurs with
CHCI3/CH3OH (90/10) and, subsequently, this is crystallized twice from acetic acid ethyl ester. Colorless crystals with
MP. 120 - 121°C. Yield 2.2 g (36%).
Figure imgf000075_0001
IR-Spectru (KBr) v(NH) 3250 cm"1 v(C=0) 1650, 1560 cm"1 v(C=C) 1610 cm"1
H-.NMR-Spectrum (CDC13! 1.30 - 1.85 (4H, m, C-CH2-CH2-C)
1.95 - 2.40 (2H, m, =CH-CH2)
3.20 - 3.60 (2H, m, CONHCH2)
5.70 - 5.90 (IH, m, NH) ^-NMR-Spectrum 6.06 (IH, t, =CH-CH2, J=7.3 Hz) (continuation) 6.43 (IH, d, CH=CHCO, J=15.6 Hz) 7.00 - 7.60 (11H, m, Ar, Py) 7.61 (IH, d, CH=CHCO, J=15.6 Hz) 7.65 - 7.95 (IH, m, Py) 8.50 - 8.65 (IH, m, Py) 8.65 - 8.90 (IH, m, Py)
Example 13
N- [4- (4 , 5-diphenyl-imidazol-l-yl) -butyl] -3-pyridin-3-yl- acryl-amide (Substance 63)
Production analogous to Example 1.
Batch size: 2.5 g (17.0 mmol) 3- (3-pyridyl) -acrylic acid, 5.9 g (46.3 mmol) oxalyl chloride and 4.5 g (15.4 mmol) 4-(4,5- diphenyl-imidazol-1-yl) -butylamine .
In the purification, pre-purification first occurs by chromatography over silica gel with CHCl3/CH3OH/NHOH (85/15/2) and, subsequently, flash-chromatography is carried out with CHCI3/CH3OH (95/5) . Subsequently, a crystallization from acetonitrile occurs. Colorless crystals with MP . 183°C. Yield 4.6 g (70%) .
Figure imgf000076_0001
IR-Spectrum (KBr) v(.NH) 3230 cm"1 v(C=0) 1665, 1550 cm"1 v(C=C) 1625 cm"1
^-NMR-Spectrum (CDC13) : 1.25 - 1.90 (4H, , C-CH2-CH2-C) 3.10 - 3.45 (2H, m, CONHCH2) 3.70 - 4.00 (2H, m, Imidazol-CH2) 6.49 (IH, d, CH=CHCO, J=15.7 Hz) 7.05 - 7.80 (15H, m, Ar, Py, NH, CH=CHCO, Imidazol) 8.45 - 8.60 (1H, m, Py) 8.60 - 8.75 (IH, m, Py)
Example 14
N- [4- (trans-2-phenyl-cyclopropyl-carbonylamino) -butyl] -3- pyridin-3-yl-acrylamide (Substance 250)
2.4 g (16.1 mmol) 3- (3-pyridyl) -acrylic acid and 5.3 ml (38.0 mmol) TEA are suspended in 80 ml abs. dichloromethane and cooled to ca. 0°C under moisture exclusion. 2.9 g (18.9 mmol) 88% HOBT and 3.6 g (18.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.3 g (17.0 mmol) 4- (trans-2-phenyl-cyclopropyl-carbonylamino) -butylamine are dissolved in 30 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. The formed precipitate is filtered off and crystallized from 120 ml isopropanol. Colorless crystals with MP. 194-196°C. Yield 4.2 g (71%).
Figure imgf000077_0001
IR-Spectrum (KBr) v(NH) 3280 cm"1 v(C=0) 1650, 1545 cm"1 v(C=C) 1620 cm"1
^-NMR-Spectrum ;CD3)2SO): 1.05 - 1.60 (6H, m, C-CH2-CH2-C, cyclopropane) 1.70 - 1.95 (IH, m, cyclopropane) 2.10 - 2.35 (IH, m, cyclopropane) 2.90 - 3.35 (4H, m, CONHCH2) 6.52 (IH, d, CH=CHC0, J=15.9 Hz) 7.00 - 7.55 (7H, m, Ar, Py,
CH=CHCO)
7.85 - 8.30 (3H, m, NH, Py)
8.45 - 8.60 (IH, , Py)
8.70 - 8.80 (IH, m, Py)
Example 15
N- (5-hydroxy-5 , 5-diphenyl-pentyl) -3-pyridin-3-yl-acrylamide (Substance 27)
Production analogous to Example 5.
Batch size: 1.7 g (11.3 mmol) 3- (3-pyridyl) -acrylic acid, 1.7 g (10. mmol) CDI and 2.4 g (9.4 mmol) 5-hydroxy-5, 5-diphenyl- pentylamine in 40 ml abs. THF.
In carrying out the reaction, the amine is added dropwise at 0°C. In the work-up chloroform is used for the extraction. Purification occurs by chromatography on silica gel with CHCI3/CH3OH (90/10) . Subsequently, crystallization occurs three times from acetic acid ethyl ester. Colorless crystals with MP. 157 - 159°C. Yield 1.1 g (30%).
Figure imgf000078_0001
IR-Spectrum (KBr): v(NH) 3250 cm"1 v(C=0) 1650, 1540 cm"1 v(C=C) 1610 cm"1
^-NMR-Spectrum (CDC13) : 1.20 - 1.85 (4H, , C-CH2-CH2-C)
2.15 - 2.50 (2H, , C(OH)CH2)
2.50 - 3.10 (IH, , OH)
3.20 - 3.50 (2H, , CONHCH2) 5.80 - 6.10 (IH, m, NH)
6.40 (IH, d, CH=CHCO, J=15.7 Hz)
7.00 - 7.90 (13H, , Ar, Py,
CH=CHCO) 8.45 - 8.60 (IH, m, Py) 8.60 - 8.80 (IH, m, Py)
Example 16
N- (7-phenyl-heptyl) -3-pyridin-3-yl-acrylamide (Substance 3)
Production analogous to Example 1.
Batch size: 5.1 g (33.9 mmol) 3- (3-pyridyl) -acrylic acid, 6.6 ml (76.4 mmol) oxalyl chloride and 5.9 g (30.8 mmol) 7- phenyl-heptylamine .
In the purification, pre-purification first occurs by chromatography on silica gel with CHC13/CH30H (95/5) and, subsequently, flash-chromatography is carried out with CHCI3/CH3OH (95/5) . .Amorphous solid material with MP . 61 - 63°C. Yield 2.3 g (23%) .
Figure imgf000079_0001
IR-Spectrum (KBr) : v(NH) 3280 cm"1 v(C=0) 1650, 1530 cm' v(C=C) 1610 cm"1
^-NMR-Spectrum (CDC13) : 1.10 - 1.80 (10H, , C-(CH2)5-C)
2.60 (2H, t, Ar-CH2, J=7.4 Hz) 3.38 (2H, dt, CONHCH2, J=6.5 Hz,
J=12.6 Hz) 5.80 - 6.10 (IH, m, NH) 6.47 (IH, d, CH=CHCO, J=15.6 Hz) 7.05 - 7.40 (6H, m, Ar, Py) 7.61 (IH, d, CH=CHCO, J=15.6 Hz) 7.65 - 7.85 (IH, , Py) 8.50 - 8.60 (IH, m, Py) 8.65 - 8.80 (IH, m, Py)
Example 17
N- (4-diphenylacetylamino-butyl) -3-pyridin-3-yl-acrylamide (Substance 247)
Production analogous to Example 14.
Batch size: 2.0 g (13.4 mmol) 3- (3-pyridyl) -acrylic acid, 3.0 g (29.6 mmol) TEA, 2.4 g (15.6 mmol) 88% HOBT, 3.0 g (15.6 mmol) EDC and 4.0 g (13.4 mmol) 4-diphenylacetylamino- butylamine hydrochloride .
In the purification, the formed precipitate is filtered off chromatographicaliy purified over silica gel with CHCl3/CH3OH
(95/5) and, subsequently, crystallized from 70 ml isopropanol. The formed crystals are once again purified by chromatography over silica gel with CHCl3/CH3OH (95/5) . .Amorphous solid material with MP. 171 - 172°C. Yield 2.85 g
(51%) .
Figure imgf000080_0001
IR-Spectrum (KBr) : v(NH) 3280 cm"1 v(C=0) 1660, 1640, 1545 cm"1 v(C=C) 1600 cm"1
^-NMR-Spectrum (CDC13) : 1.40 - 1.70 (4H, m, C-CH2-CH2-C)
3.20 - 3.50 (4H, , CONHCH2) 4.94 (IH, s, Ar2CH)
6.00 - 6.20 (IH, m, NH)
6.49 (IH, d, CH=CHCO, J=15.7 Hz) 6.60 - 6.80 (IH, m, NH)
7.05 - 7.50 (11H, , Ar, Py) 7.58 (IH, d, CH=CHCO, J=15.7 Hz) 7.60 - 7.80 (IH, , Py)
8.50 - 8.60 (IH, m, Py)
8.60 - 8.75 (IH, m, Py)
Example 18
N- [4- (benzhydryl-amino) -butyl] -3-pyridin-3-yl-acrylamide (Substance 187)
Production analogous to Example 5.
Batch size: 1.9 g (12.6 mmol) 3- (3-pyridyl) -acrylic acid, 2.5 g (15.1 mmol) CDI and 3.7 g (14.5 mmol) 4- (benzhydryl-amino) - butylamine in 60 ml abs. THF.
In carrying out the reaction, the amine is added dropwise at -15°C, and the reaction mixture is stirred for three hours at this temperature. In the work-up, chloroform is used for extraction. Purification occurs by chromatography over silica gel with CHCl3/CH3OH (95/5) . Subsequently, this is crystallized three times from 20 ml and 13 ml 1-chlorobutane and 10 ml acetonitrile. Beige colored crystals with MP . 101 - 102°C. Yield 1.0 g (20%) .
Figure imgf000081_0001
IR-Spectrum (KBr): v(NH) 3260 cm"1 v(C=0) 1660, 1560 cm"1
Figure imgf000081_0002
'H-aNMR-Spectrum (CDC13) : 1.45 - 1.90 (4H, m, C-CH2-CH2-C)
2.50 - 2.80 (2H, m, NCH2) 3.25 - 3.55 (2H, m, CONHCH2) 4.81 (IH, s, Ar2CH) 6.32 (IH, d, CH=CHCO, J=15.7 Hz) 6.30 - 6.55 (IH, m, NH) 7.10 - 7.80 (14H, m, Ar, Py, NH,
CH=CHCO) 8.45 - 8.75 (2H, m, Py)
Example 19
N- (4-{ [2- (benzhydryl-methyl-amino) -ethyl] -methyl-ammo } - butyl) -3-pyrιdm-3-yl-acrylamide (Substance 193)
Production analogous to Example 1.
Batch size: 5.5 g (36.8 mmol) 3- (3-pyrιdyl) -acrylic acid,
12.7 g (100.0 mmol) oxalyl chloride and 10.9 g (33.5 mmol) 4-
{ [2- (benzhydryl-methyl-ammo) -ethyl] -methyl-ammo }- butyla me .
In the purification, this s first chromatographed with
CHCI3/CH3OH (97/3 to 90/10) and, subsequently, the oily residue is rubbed with dusopropyl ether until crystallization occurs. Colorless crystals with MP . 89 -
91°C. Yield 3.0 g (19%) .
C29H36N4.O (456.6)
IR-Spectrum (KBr) : v(NH) 3300 cm"1 v(C=0) 1670, 1650, 1530 cm"1 v(C=C) 1620 cm"1
^-NMR-Spectrum (CDC13) : 1.40 - 1.75 (4H, m, C-CH2-CH2-C) 2.21 (6H, s, CH3)
2.25 - 2.75 (6H, m, NCH2)
3.20 - 3.55 (2H, m, C0NHCH2)
4.39 (IH, s, Ar2CH)
6.43 (IH, d, CH=CHCO, J=15.7 Hz)
7.00 - 7.55 (12H, m, Ar, Py, NH)
7.60 (IH, d, CH=CHCO, J=15.7 Hz)
7.65 - 7.85 (IH, m, Py)
8.50 - 8.60 (IH, m, Py)
8.65 - 8.80 (IH, m, Py)
Production of the Starting Substances
Example i)
8 , 8-bis- (4-fluorophenyl) -octylamine
a) 8-hydroxy-8, 8-bis- (4-fluorophenyl) -octyl bromide:
7.65 g (313.8 mmol) magnesium shavings are placed under protective gas atmosphere and 55.1 g (314.8 mmol) 4- bromofluorobenzene dissolved in 250 ml abs. THF are added dropwise so that the reaction mixture boils gently. After complete addition, the mixture is heated for 30 minutes under reflux, and, afterwards, the suspension is cooled. While cooling in an ice bath, a solution of 25.0 g (105.4 mmol) 8- bromoctanoic acid methyl ester in 100 ml abs. THF is added dropwise. Subsequently, the mixture is heated for a further 30 minutes under reflux. After cooling, NH4Cl-solution is added to the reaction and this is extracted by diisopropyl ether by shaking. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with petroleum ether/acetic acid ethyl ester (20/1 to 10/1) : Yield 36.4 g (87%) .
b) 8, 8-bis- (4-fluorophenyl) -oct-7-enyl bromide:
31.9 g (80 mmol) 8-hydroxy-8, 8-bis- (4-fluorophenyl) -octyl bromide dissolved in toluene are added to 0.3 g toluene sulfonic acid and the mixture is subsequently heated for an hour with water separator under reflux. A.fter withdraw of the solvent, the residue is chromatographicaliy purified over silica gel with petroleum ether/acetic acid ethyl ester (90/1) : Yield 28.6 g (94%) .
c) 8, 8-bis- (4-fluorophenyl) -octyl bromide:
9.7 g (25.5 mmol) 8, 8-bis- (4-fluorophenyl) -oct-7-enyl bromide are dissolved in 350 ml ethanol and added to 0.5 g palladium (5%) on activated carbon. The mixture is stirred under hydrogen atmosphere (ca. one hour) until the theoretical amount of hydrogen to be taken up is consumed. Subsequently, the mixture is filtered off from a catalyst and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with petroleum ether/acetic acid ethyl ester (80/1 to 40/1)): Yield 8.6 g (89%).
d) 2- [8, 8-bis- ( 4-fluorophenyl) -octyl] -isoindol-1, 3-dione :
9.0 g (23.6 mmol) 8, 8-bis- (4-fluorophenyl) -octyl bromide and 4.7 g (25.0 mmol) phthalimide potassium salt are stirred in 80 ml DMF for two hours at 70°C. After cooling, the mixture is concentrated and extracted with acetic acid ethyl ester and NaCl solution by shaking. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with petroleum ether/acetic acid ethyl ester (60/1 to 30/1) : Yield 8.1 g (77%) .
e) 8, 8-bis- (4-fluorophenyl) -octylamine :
8.1 g (18.1 mmol) 2- [8, 8-bis- (4-fluorophenyl) -octyl] - isoindol-1, 3-dione and 1.8 ml (37.0 mmol) hydrazine hydrate are heated under reflux in 50 ml ethanol for two hours. The cooled solution is concentrated under vacuum and the residue is purified by chromatography over silica gel with CHCI3/CH3OH/TEA (98/2/2): Yield 2.4 g (42%). Example ii )
6- (3 ,3-diphenyl-ureido) -hexylamine
8.0 g (69.0 mmol) hexamethylene diamine are dissolved in 20 ml dichloromethane and 10.0 g (42.3 mmol) N,N- diphenylcarbamide acid chloride dissolved in 20 ml dichloromethane are added dropwise under cooling. The mixture is stirred for 12 hours at RT and, subsequently 2M NaOH solution is added. The organic phase is washed with 30 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographicaliy purified over silica gel with CHC13/CH30H/TEA (95/5/0 bis 95/5/1) : Yield 5.7 g (43%) .
Example iii)
4- (1-phenyl-1 ,2, , 5-tetrahydro-benzo [d] azepin-3-yl) - butylamine
a) 2- [4- (1-phenyl-l, 2, 4, 5-tetrahydro-benzo [d] azepin-3-yl) - butyl] -isoindol-1, 3-dione :
20.0 g (89.5 mmol) 1-phenyl-l, 2, 4, 5- tetrahydrobenzo [d] azepine, 25.2 g (89.5 mmol) N-(4- bromobutyl) -phthalimide and 18.5 g (134.3 mmol) potassium carbonate are stirred in 200 ml DMF for 6 hours at 60°C. The mixture is concentrated under vacuum and the residue is distributed between 300 ml acetic acid ethyl ester and 100 ml water. The watery phase is extracted with 50 ml acetic acid ethyl ester and the combined organic phases are washed with water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dried: Yield 39.5 g. b) 4- (1-phenyl-l, 2,4, 5-tetrahydro-benzo [d] azepin-3-yl) - butylamine:
The reaction of the phthalimide to the amine follows analogously to Example i)e) .
Batch size: 38.0 g (< 89.5 mmol) 2- [4- (1-phenyl-l, 2, 4, 5- tetrahydro-benzo [d] azepin-3-yl) -butyl] -isoindol-1, 3-dione and 8.7 ml (179 mmol) hydrazine hydrate in 200 ml ethanol. The reaction mixture is filtered and the filtrate is concentrated under vacuum . The residue is taken up in 400 ml dichloromethane and washed twice each with 50 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The purification occurs chromatographicaliy over silica gel with CHCI3/CH3OH/TEA (95/5/0 to 90/9/1): Yield 15.6 g (59%).
Example iv)
8 , 8-diphenyloctylamine
a) 8-hydroxy-8, 8-diphenyloctyl bromide:
The Grignard reaction occurs analogously to Example i)a) . Batch size: 16 g (658 mmol) magnesium shavings, 103 g (656 mmol) bro obenzene and 52 g (219 mmol) 8-bromooctanoic acid ester: Yield 66.5 g (84%) .
b) 2- (8-hydroxy-8, 8-diphenyl-octyl) -isoindol-1, 3-dione :
The production of the phthalimide occurs analogously to Example i) d) . Batch size: 66.0 g (183 mmol) 8-hydroxy-8, 8-dιphenyl-octyl bromide and 33.3 g (180 mmol) phthalimide potassium salt. The reaction time is increased to five hours .
The purification occurs by crystalization from 1- chlorobutane: Yield 60.6 g (79%).
c) 2- (8, 8-dιphenyl-oct-7-enyl) -ιsomdol-1, 3-dιone :
The production of the double bond occurs analogously to Example l) b) .
Batch size: 39.6 g (92.7 mmol) 2- (8-hydroxy-8, 8-dιphenyl- octyl) -ιsomdol-1, 3-dιone and 0.3 g toluene sulfonic acid. The accumulated crude product is further processed without further purification: Yield 37.9 g (100%) .
d) 2- (8, 8-dιphenyl-octyl) -ιsomdol-1, 3-dιone :
The hydration of the double bond occurs analogously to Example l) c) .
Batch size: 20.0 g (48.9 mmol) 2- (8, 8-dιphenyl-oct-7-enyl) - ιsomdol-1, 3-dιone and 0,7 g palladium (5%) on activated carbon m ethanol/acetic acid ethyl ester (1/1) .
The accumulated crude product is further processed without further purification: Yield 18.9 g (94%) .
e) 8 , 8-dιphenyl-octylamme :
The reaction of the phthalimide to the amine occurs analogously to Example ι)e). Batch size: 18.5 g (45.0 mmol) 2- ( 8, 8-diphenyl-octyl) -iso- indol-1, 3-dione and 8.0 ml (160 mmol) hydrazine«hydrate in ethanol .
The reaction mixture is concentrated under vacuum. The residue is taken up in 400 ml chloroform and washed twice each with 50 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 12.6 g (100%) .
Example v)
8-hydroxy-8 , 8-diphenyl-octylamine
The reaction of the phthalimide to the amine occurs analogously to Example i)e).
Batch size: 10.0 g (23.4 mmol) 2- (8-hydroxy-8, 8-diphenyl- octyl ) -isoindol-1, 3-dione and 2.5 ml (51.4 mmol) hydrazine»hydrate in ethanol.
The reaction mixture is concentrated under vacuum. The residue is taken up in chloroform and washed twice each with 50 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and subsequently, the solvent is removed under vacuum. The accumulated crude product is further purified without further processing: Yield 6.7 g (97%) .
Example vi)
4 - (3 , 3-diphenyl-ureido) -butylamine
The reaction of the diamine occurs analogously to Example 21 Batch size: 10.5 g (45.3 mmol) N, N-diphenylcarbamic acid chloride and 12.0 g (136.3 mmol) 1, 4-diaminobutane in dichloromethane .
The purification occurs chromatographicaliy on silica gel with CHCl3/CH3OH/NH4OH (95/5/0 to 95/5/1): Yield 9.0 g (70%).
Example vii)
4- (IH, 3H-benzo [de] isoquinolin-2-yl) -butylamine
a) 4- (1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2-yl) -butylamine :
20 g (100.9 mmol) naphthalic acid anhydride and 9.9 g (111.0 mmol) 1, 4-diaminobutane are stirred for 6 hours in 250 ml toluene at 80°C. After cooling, the reaction mixture is concentrated under vacuum, taken up in 200 ml water and extracted three times each with 300 ml chloroform. The combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum . The residue is taken up in 150 ml acetic acid ethyl ester and the insoluble portion is filtered off. The solvent is removed under vacuum and the accumulated crude product is further processed without further purification: Yield 13.0 g (48%).
b) 4- (IH, 3H-benzo [de] isoquinolin-2-yl) -butylamine:
5.0 g (18.6 mmol) 4- ( 1, 3-dioxo-lH, 3H-benzo [de] isoquinolin-2- yl) -butylamine are dissolved in 200 ml THF and 6.1 g (160.7 mmol) LiAlH4 are added in portions under cooling. The suspension is stirred for 24 hours at RT and for 8 hours under reflux. After cooling, ethanol is carefully added dropwise until no more foam appears. The mixture is filtered and the filtrate is concentrated under vacuum . The residue is distributed between chloroform and water. The organic phase is dried over sodium sulfate and, after withdraw of the solvent, chromatographicaliy purified over silica gel with CHCI3/CH3OH/NH.4OH (90/10/0.5 to 90/10/1): Yield 2.2 g (49%).
Example viii)
6- (10 , 11-dihydro-dibenzo [b, f] zepin-5-yl-carbonylamino) - hexylamine»hydrochloride
a) N- [ 6- (10, 11-dihydro-dibenzo [b, f] azepin-5-yl- carbonylamino) -hexyl] -carbamic acid tert-butyl ester:
5.4 g (20.8 mmol) N, -diphenylcarbamic acid chloride, 4.5 g (20.8 mmol) N- ( tert-butoxycarbonyl) -1, 6-diaminohexane and 2.1 g (20.8 mmol) TEA are dissolved in 80 ml dichloromethane and stirred at RT for 12 hours. Subsequently, the mixture is washed twice each with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 8.75 g (85%).
b) 6- (10, 11-dihydro-dibenzo [b, f] azepin-5-yl-carbonylamino) - hexylamine»hydrochloride :
7.5 g (17.7 mmol) N- [ 6- ( 10, 11-dihydro-dibenzo [b, f] azepin-5- yl-carbonylamino) -hexyl] -carbamic acid tert-butyl ester are dissolved in 70 ml ethanol and, after addition of 3.8 ml (45 mmol) concentrated hydrochloric acid, heated for three hours under reflux. The cooled solution is concentrated under vacuum and the residue is crystallized from isopropanol: Yield 5.6 g (84%) .
Example ix)
6- (tosyl-amino) -hexylamine dihydrochloride a) N- [ 6- (tosyl-amino) -hexyl] -carbamic acid tert-butyl ester: The reaction of the amine occurs analogously to reaction viii) a) .
Batch size: 6.7 g (35.1 mmol) toluene-4-sulfonyl chloride, 7.5 g (35.0 mmol) N- (tert-butoxycarbonyl) -1, 6-diaminohexane and 3.6 g (35.6 mmol) TEA in 60 ml dichloromethane.
The accumulated crude product is further processed without further purification: Yield 13.5 g.
b) 6- (tosyl-amino) -hexylamine»dihydrochloride :
The release of the amine occurs analogously to Example viii) b) .
Batch size: 13.0 g (< 35 mmol) N- [ 6- (tosyl-amino) -hexyl] - carbamic acid tert-butyl ester and 7.7 ml (93 mmol) concentrated hydrochloric acid in 100 ml ethanol.
The reaction mixture is heated for three hours under reflux. The accumulated crude product is further processed without further purification: Yield 9.8 g (80%).
Example x)
N- (4-hydroxybutyl) -3-pyridin-3-yl-acrylamide
a) 3- (pyridin-3-yl) -acrylic acid- (N-hydroxysuccinimide ester) :
38,5 g (335 mmol) N-hydroxysuccinimide and 76.0 g (369 mmol) dicyclohexylcarbodiimide are dissolved in 700 ml dioxane and 50.0 g (335 mmol) 3- (3-pyridyl) -acrylic acid are added. The suspension is stirred at RT for 20 hours. The mixture is filtered and the filtrate is concentrated under vacuum . The residue is crystallized twice each from 400 ml isopropanol: Yield 36.2 g (44%) .
b) N- (4-hydroxybutyl) -3-pyridin-3-yl-acrylamide :
19 g (77,1 mmol) 3- (pyridin-3-yl) -acrylic acid- (N- hydroxysuccin-imide ester) are dissolved in 200 ml THF and 6.9 g (77.1 mmol) 4-amino-l-butanol are added. The mixture is stirred at RT for three days. After withdraw of the solvent the residue is chromatographicaliy purified over silica gel with CHCI3/CH3OH (90/10): Yield 10.7 g (63%).
Example xi)
6-hydroxy-6, 6-diphenyl-hexylamine
a) 6-hydroxy-6, 6-diphenyl-hexyl bromide:
The Grignard reaction occurs analogously to Example i)a) .
Batch size: 6.6 g (272.7 mmol) magnesium shavings, 42.8 g (272.7 mmol) bromobenzene and 19 g (90.9 mmol) 6- bromohexanoic acid methyl ester in 360 ml THF.
In the work-up, dichloromethane is used for extraction. The purification occurs by chromatography on silica gel with dichloromethane: Yield 23.8 g (78%).
b) 2- ( 6-hydroxy-6, 6-diphenyl-hexyl) -isoindol-1, 3-dione :
The production of the phthalimide occurs analogously to Example i) d) . Batch size: 23.8 g (71.4 mmol) 6-hydroxy-6, 6- diphenylhexylbromide and 13.2 g (71.4 mmol) phthalimide»potassium salt in 150 ml DMF.
The reaction time is increased to 6 hours at 70°C. In the work-up, the mixture is distributed between chloroform and water. The purification occurs by chromatography on silica gel with CHC13/CH30H (99/1): Yield 20.2 g (70%).
c) 6-hydroxy-6, 6-diphenyl-hexylamine :
The reaction of the phthalimide to the amine occurs analogously to Example i)e).
Batch size: 8.0 g (20.0 mmol) 2- ( 6-hydroxy-6, 6-diphenyl- hexyl) -isoindol-1, 3-dione and 2. g (40.0 mmol) hydrazine hydrate in 80 ml ethanol.
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 180 ml dichloromethane and washed twice each with 20 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum . The accumulated crude product is crystallized from 12 ml acetic acid ethyl ester: Yield 4.4 g (81%).
Example xii)
6, 6-diphenyl-hex-5-enylamine
a) 2- ( 6, 6-diphenyl-hex-5-enyl) -isoindol-1, 3-dione :
Die production of the double bond occurs analogously to Example i) b) . Batch size: 11.6 g (29.0 mmol) 2- ( 6-hydroxy-6, 6-diphenyl- hexyl) -isoindol-1, 3-dione and 0,3 g p-toluenesulfonic acid in 25 ml toluene.
The accumulated crude product is crystallized from 23 ml acetic acid ethyl ester: Yield 8.0 g (72%).
b) 6, 6-diphenyl-hex-5-enylamine :
The reaction of the phthalimide to the amine occurs analogously to Example i)e) .
Batch size: 7.8 g (20. mmol) 2- ( 6, 6-diphenyl—hex-5-enyl) - isoindol-1, 3-dione and 2.0 g (40.0 mmol) hydrazine»hydrate in 80 ml ethanol.
The reaction mixture is filtered and the filtrate is concentrated under vacuum . The residue is taken up in 120 ml acetic acid ethyl ester and washed twice each with 10 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and subsequently the solvent is removed under vacuum . The accumulated crude product is further processed without further purification: Yield 4.0 g (78%).
Example xiii)
4- ( ,5-diphenylimidazol-l-yl) -butylamine
a) 2- [4- (4, 5-diphenylimidazol-l-yl) -butyl] -isoindol-1, 3- dione :
1.7 g (70.8 mmol) sodium hydride are placed in 130 ml DMF and 1.0 g (54.5 mmol) , 5-diphenylimidazole are added under cooling. The suspension is stirred for four hours at RT and, subsequently, 15.4 g (54.5 mmol) N- (4-bromobutyl) -phthalimide dissolved in DMF is added dropwise under cooling. After complete addition, the reaction mixture is stirred for 12 hours at RT, 18 ml methanol are carefully added dropwise and the suspension is filtered. The filtrate is concentrated under vacuum and the residue is distributed between 500 ml chloroform and 170 ml water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dry dried. The residue is purified by chromatography on silica gel with CHCI3/CH3OH (95/5) and subsequently crystallized from methanol: Yield 16.5 g (72%).
b) 4- (4, 5-diphenyl-imidazol-l-yl) -butylamine :
The reaction of the phthalimide to the amine occurs analogously to Example i)e) .
Batch size: 14.0 g (33.2 mmol) 2- [4- (4, 5-diphenyl-imidazol-l- yl) -butyl] -isoindol-1, 3-dione and 3.3 ml (66.4 mmol) hydrazine hydrate in 130 ml ethanol.
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 250 ml chloroform and washed twice each with 25 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 9.0 g (93%).
Example xiv)
4 - (trans-2-phenyl-cyclopropyl-carbonylamino) -butylamine hydrochloride a) N- [4- (trans-2-phenyl-cyclopropyl-carbonylamino) -butyl] - carbamic acid tert-butyl ester:
The reaction of the amine occurs analogously to reaction viii) a) .
Batch size: 5.0 g (25.6 mmol) trans-2-phenylcyclopropane-l- carboxylic acid chloride, 4.8 g (25.6 mmol) N- (tert- butoxycarbonyl) -1, 4-diaminobutane and 2.6 g (25,6 mmol) TEA in 60 ml dichloromethane.
In the work-up, the organic phase is first washed with 30 ml 10% NaOH solution and then twice each with 50 ml water. The purification occurs by chromatography on silica gel CHCI3/CH3OH (99/1). Yield 8.25 g (93%).
b) 4- (trans-2-phenyl-cyclopropyl-carbonylamino) -butyl- amine»hydrochloride :
The release of the amine occurs analogously to Example viii) b) .
Batch size: 7.5 g (21.6 mmol) N- [4- ( trans-2-phenyl-cyclopro- pyl-carbonylamino) -butyl] -carbamic acid tert-butyl ester and 6.4 ml (77 mmol) concentrated hydrochloric acid in 150 ml ethanol .
The reaction mixture is heated for 6 hours under reflux. The accumulated crude product is further processed without further purification.: Yield 5.3 g (80%).
Example xv)
5-hydroxy-5 , 5-diphenyl-pentylamine
a ) 5-hydroxy-5 , 5-diphenyl-pentyl bromide : Die Grignard reaction occurs analogously to Example i)a).
Batch size: 9.3 g (382. mmol) magnesium shavings, 60.0 g (382.1 mmol) bromobenzene and 20.1 ml (127.4 mmol) ethyl 5- bromovalerate acid-ethylester in 510 ml THF.
In the work-up, dichloromethane is used for extraction. The purification occurs by chromatography on silica gel with chloroform: Yield 26.2 g (64%) .
b) 2- (5-hydroxy-5, 5-diphenyl-pentyl) -isoindol-1, 3-dione:
The production of the phthalimide occurs analogously to Example i) d) .
Batch size: 26.0 g (81.4 mmol) 5-hydroxy-5, 5-diphenyl-pentyl bromide and 15.1 g (81.4 mmol) phthalimide potassium salt in 170 ml DMF.
The reaction time is increased to 6 hours at 70°C. In the work-up, the mixture is distributed between chloroform and water. The purification occurs by chromatography on silica gel with chloroform: Yield 14.9 g (48%).
c) 5-hydroxy-5, 5-diphenyl-pentylamine :
The reaction of the phthalimide to the amine occurs analogously to Example i)e) .
Batch size: 5.0 g (13.0 mmol) 2- (5-hydroxy-5, 5-diphenyl- pentyl) -isoindol-1, 3-dione and 1.3 g (26.0 mmol) hydrazine hydrate in 50 ml ethanol.
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 120 ml chloroform and washed twice each with 10 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 2.4 g (72%).
Example xvi)
7-phenyl-heptylamine
a) 2- (7-phenylheptyl) -isoindol-1, 3-dione : b)
Production analogous to Example 10.
Batch size: 10.0 g (52.0 mmol) 7-phenyl-heptanol, 13.6 g (5.0 mmol) triphenylphosphine, 7.7 g (52.0 mmol) phthalimide and 8.2 ml (52.0 mmol) azodicarboxylic acid diethyl ester in 200 ml THF.
The purification occurs by chromatography on silica gel with dichloromethane: Yield 11.2 g (67%).
b) 7-phenylheptylamine:
The reaction of the phthalimide to the amine occurs analogously to Example i)e).
Batch size: 11.0 g (34.2 mmol) 2- (7-phenyl-heptyl) -isoindol- 1,3-dione and 3.4 g (68.4 mmol) hydrazine»hydrate in 100 ml ethanol .
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 300 ml chloroform and washed twice each with 20 ml 10% NaOH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 6.1 g (93%).
Example xvii)
4-diphenylacetylamino-butylamine»hydrochloride
a) N- (4-diphenylacetylamino-butyl) -carbamic acid tert-butyl ester:
The reaction of the amine occurs analogously to reaction viii) a) .
Batch size: 4.6 g (19.9 mmol) diphenylchloroacetyl chloride, 3.8 g (20.2 mmol) N- ( tert-butoxycarbonyl) -1, 4-diaminobutane and 2.1 g (20.7 mmol) TEA in 60 ml dichloromethane.
The purification occurs by crystallization from isopropanol: Yield 5.5 g (72%) .
b) 4-diphenylacetylamino-butylamine»hydrochloride :
The release of the amine occurs analogously to Example viii) b) .
Batch size: 5.5 g (14.4 mmol) N- (4-diphenylacetylamino- butyl) -carbamic acid tert-butyl ester and 4.1 ml (49 mmol) concentrated hydrochloric acid in 60 ml ethanol.
The reaction mixture is heated for three hours under reflux. The accumulated crude product is further processed without further purification: Yield 4.2 g (90%). Example xviii)
4- (benzhydryl-amino) -butylamine
a) N- [4- (benzhydryl-amino) -butyl] -carbamic acid tert-butyl ester:
5.0 g (26.6 mmol) N- (tert-butoxycarbonyl) -1, 4-diaminobutane 5.5 g (39.8 mmol) potassium carbonate and 0.9 g (5.3 mmol) potassium iodide are placed in 50 ml DMF and 6.6 g (26.6 mmol) benzhydryl bromide are added dropwise at RT . The mixture is stirred for 12 hours at 70°C and the suspension is filtered after cooling and the filtrate is concentrated under vacuum. The residue is taken up in 200 ml chloroform and washed with 100 ml water. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 10.8 g.
b) 4- (benzhydryl-amino) -butylamine :
The release of the amine occurs analogously to Example viii)b) .
Batch size: 4.6 g (< 11.3 mmol) N- [4- (benzhydryl-amino) - butyl] -carbamic acid tert-butyl ester and 5.2 ml (63 mmol) concentrated hydrochloric acid in 50 ml ethanol.
The reaction mixture is stirred at RT for 12 hours, subsequently concentrated under vacuum and the residue is distributed between 80 ml chloroform and 80 ml water. The aqueous phase is made alkaline with 30% sodium hydroxide solution and extracted twice each with 50 ml chloroform by shaking. The combined organic phases are dried over sodium sulfate and subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 1.7 g (58%).
Example xix)
4-{ [2- (benzhydryl-methylamino) -ethyl] -methyl-amino} - butylamine
a) Nl-benzhydryl-Nl ,N2-dimethyl-ethan-1, 2-diamine :
15.1 g (171 mmol) N, N' -dimethylethylenediamine, 35 g (255 mmol) potassium carbonate are placed in 250 ml DMF and 30.9 g (125 mmol) benzhydryl bromide are added dropwise at RT . The mixture is concentrated under vacuum. The residue is taken up in chloroform and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The purification occurs by chromatography on silica gel with chloroform: Yield 14.5 g (45%).
b) 2- (4-{ [2- (benzhydryl-methyl-amino) -ethyl] -methylamino} - butyl) -isoindol-1, 3-dione :
13.9 g (54,7 mmol) Nl-benzhydryl-Nl, N2-dimethyl-ethan-l, 2- diamine, 15.4 g (54.7 mmol) N- (4-bromobutyl) -phthalimide, 15.1 g (109.5 mmol) potassium carbonate and 1.6 g (10.6 mmol) sodium iodide are stirred for four hours in DMF at 70 °C. After cooling, the mixture is concentrated under vacuum and the residue is distributed between chloroform and water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dry. The purification occurs by chromatography on silica gel with CHCl3/CH3OH (100/0 to 99/1) : Yield 20.8 g (83%) . c) 4-{ [2- (benzhydryl-methylamino) -ethyl] -methyl-amino }- butylamine :
The reaction of the phthalimide to the amine occurs analogously to Example i)e) .
Batch size: 20.8 g (45.6 mmol) 2- (4- { [2- (benzhydryl-methylamino) -ethyl] -methyla ino } -butyl) -isoindol-1, 3-dione and 4.6 g (91.9 mmol) hydrazine-hydrate in 200 ml ethanol.
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in acetic acid ethyl ester and washed with 10% NaOH solution. The organic phase is dried over sodium sulfate and subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 10.9 g (73%) .
In the following Table a series of Examples for the end products according to the invention are listed:
Table 1 :
Exemplifying compounds of formula
(I) according to the invention
Figure imgf000104_0002
Table 1 (continuation)
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0002
Figure imgf000108_0003
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Table 1 (continuation) 110
Figure imgf000112_0001
Table 1 (continuation) 111
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Table 1 (continuation) 118
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Table 1 (continuation) 124
Figure imgf000126_0001
Figure imgf000127_0001
Table 1 (continuation)
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
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. In the case of the combination of active ingredients according to the invention with other medicinals, 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.
Furthermore, 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.
The use of one or more compounds according to formula (I) , for the production of medicaments for the treatment of the human or animal body, especially in connection with one or more medical indications in the treatment of tumors or for immunosuppression, optimally in combination with further pharmaceuticals suitable in these indications or the use of compounds according to formula (I) in a corresponding diagnosis method also represent an embodiment according to the invention. The respective suitable tumor indications are illustrated in the last section of the description in the discussion of the pharmacological test results.
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.
Depending on the medical indication being considered, the respective suitable medicinal form is selected for the suitable therapeutic application. In this connection, especially 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.
In the following, the production methods for the respective suitable medicaments as well as a series of examples for medicinal forms and pharmacological activities are described for more easy understanding of the invention. These examples provided in the following as well as the above synthesis examples serve for illustration of the claims without limiting the scope of protection.
The skilled person can correspondingly modify the invention within the frame of his normal capability without deviating from the protective scope. Therapeutic Administration Foinns
The production of 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. For this, 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. Thereby, 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 .
Preferably, 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- o-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 micelles, for example, based on phospholipids . As with injection preparations, 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. Often, 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®) aε 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-dimethylacetamide, propylene glycol or complex forming compounds such as for example citrates and urea, preservatives, such as for example hydroxypropyl benzoate and hydroxymethyl benzoate, benzyl alcohol, anti-oxidants, such as for example sodium sulphite and stabilizers, such as for example EDTA, are suitable as adjuvants and carriers in the production of preparations for parenteral use.
In suspensions, addition of 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. 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 . As further adjuvants, dispersion agents are also suitable. For production of lyophilisates, builders are also used, such as for example mannite, dextran, saccharose, human albumin, lactose, PVP or gelatine varieties.
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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, dispersion agents such as x-ray amorphic 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, sweetening agents, 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.
In this connection, 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.
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 .
Among the 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 aε antioxidants and/or vitamins and sweeteners such as sugar or artificial sweetening agents. This is also true for inspissated juices which are formulated with water before ingestion. Ion exchange resins in combination with one or more active ingredients are also to be mentioned for the production of liquid injectable forms.
A εpecial release form conεists 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. Furthermore, 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. Among these are 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.
For long-term application with a systematic active ingredient release up to several weeks, pressed implants are suitable which are preferably formulated on the basis of so-called biodegradable polymers .
As a further important group of systemically active medicaments, 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. Aside from suitable adjuvants and carriers such as solvents and polymeric components, for example based on Eudragit®, 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.
As topically, locally or regionally administration medicaments, the following are suitable as special formulations: vaginally or genitally applicable emulsions, creams, foam tablets, depot implants, ovular or transurethral administration Instillation solutions. For opthalmological application, highly sterile eye ointments, solutions and/or drops or creams and emulsions are suitable.
In the same manner, corresponding otological drops, ointments or creams can be designated for application to the ear. For both of the above-mentioned applications, the administration of semi-solid formulations, such as for example gels based on
Carbopols® or other polymer compounds such as for example polyvinylpyrolidone and cellulose derivatives is also possible .
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 aε 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. Furthermore, amphiphilic low and high molecular weight compounds aε well as phospholipids are suitable. The gelε can be preεent either aε hydrogelε baεed on water or aε hydrophobic organogelε, for example baεed on mixtures of low and high molecular paraffin hydrocarbons and Vaseline.
Anionic, cationic or neutral tensides can be employed as emulsifierε, for example alkalized εoapε, methyl soapε, amine εoapε, sulfonated compounds, cationic soapε, 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. Vaseline, natural or synthetic waxes, fatty acids, fatty alcoholε, fatty acid esters, for example as mono-, di-, or triglycerides, paraffin oil or vegetable oils, hardened castor oil or coconut oil, pig fat, synthetic fats, for example based on acrylic, caprinic, lauric and stearic acid, εuch as for example Softisan® or triglyceride mixtureε such as Miglyol® are employed as lipids in the form of fat and/or oil and/or wax-like components for the production of ointments, creams or emulsions.
Osmotically effective acids and baεes, such as for example hydrochloric acid, citric acid, εodiu hydroxide εolution, potaεsium hydroxide solution, monosodium carbonate, further buffer systemε, εuch aε for example citrate, phosphate, tries-buffer or triethanolamine are used for adjusting the pH value .
Preservativeε, for example εuch as methyl- or propyl benzoate (parabenes) or sorbic acid can be added for increasing stability.
Pastes, powders or εolutions 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 conεistency-giving base.
Powders or topically applicable powders can contain for example starch varieties such as wheat or rice starch, flame dispersed silicon dioxide or εilica, which also serve as diluents, for increasing flowability as well aε lubricity as well as for preventing agglomerate .
Nose drops or nose sprayε serve as naεal application forms . In this connection, nebulizerε or nose creams or ointments can come to use.
Furthermore, nose spray or dry powder formulations as well as controlled dosage aerosols are also suitable for systemic administration of the active ingredients. CQ
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Physical Pharmacy (A.N. Martin, J. Swarbrick, A. Cammarata) , 2nd Ed., Philadelphia Pennsylvania, (1970), German version: Physikalische Pharmazie, (1987), 3rd edition, Stuttgart;
R. Voigt, M. Bornschein, Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, Weinheim, (1984) , 5th edition;
P.H. List, Arzneimformenlehre, Wiεεenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1985) , 4th edition,-
H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart - New York, (1991) , 2nd edition;
A.T. Florence, D. Attwood, Physicochemical Principleε of Pharmacy, The Maximilian Press Ltd., Hong Kong, (1981);
L.A. Trisεel, Handbook on Injectable Drugs, American Society of Hospital Pharmacists, (1994) , 8th edition;
Y.W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York - Basel, (1987);
K.E. Avis, L. Lachmann, H.A. Liebermann, Pharmaceutical Dosage Forms: Parenteral Medications, volume 2, Marcel Dekker Inc., New York - Basel, (1986);
B.W. Mύller, Controlled Drug Delivery, Paperback APV, volume 17, issenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1987) ;
H. Asch, D. acetic , P.C. Schmidt, Technologie von Salben, Suspenεionen and Emulsionen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1984) ;
H.A. Liebermann, L. Lachman, J.B. Schwartz, Pharmaceutical Desage forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd Edition (1989) ; D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and Pharmaceutical Processes, in J.C. Williams, T. Allen, Handbook of Powder Technology, Elsevier Amsterdam - London - New York - Tokyo, (1994) ;
J.T. Carstenεen, Pharmaceutical Principles of Solid Dosage Forms, Technomic Publishing Co., Inc., Lancaster - Basel, (1993) .
PRODUCTION EXAMPLES
1. Injection therapeutics
a) Parenteral Solution
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.
b) 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 iε adjuεted to a εuitable pH value by acid addition and εubεequently filled into 100 ml vials and sterilized. A vial contains 100 mg of the compound according to the invention.
c) Parenteral Dispersion
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 thiε, the aqueouε solution of sodium hydroxide is added with subεequent homogenization. The dispersion is sterilized and filled into 10 ml vials. A vial contains 50 mg of the compound according to the invention.
d) Biodegradable Parenteral Depot Medicinal Form
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
First, the active ingredient is incorporated into the biodegradable polymer comprising polylactic acid and polyglycolic acid by a εuitable method (spray drying, solvent-evaporation or phaεe εeparation) 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.
e) Parenteral Dispersion for Subcutaneous Instillation
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 disperεed together with εoya lecithin and arachis oil. The benzyl alcohol is dissolved in
Miglyole® and added to the dispersion. The entire disperεion iε sterilized and εubsequently filled into vials with 2 ml content. A vial contains 50 mg active ingredient.
f) Parenteral Perfusions Solution
The solution named under example b) can also be used for perfusion of liver for example.
According to need, instead of ampules with injection εolution, εo-called perforation bottles (vials) , which can alεo be optionally preserved, and infusion solutionε 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 posεible εuitable pH value for the medicinal form (euhydria) and optional further required nutrientε, vitaminε, amino acidε, stablizers and other necessary adjuvants, posεibly in combination with further medicinal agentε εuitable for the mentioned indicationε.
2. Solid, Peroral Administrable Medicaments
a) Tablets
active ingredient used according to the invention 10.000 g lactose 5.200 g starch, soluble 1.800 g hydroxypropylmethylcellulose 900 g magneεium 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.
b) Coated Tablet Core
active ingredient uεed 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 magneεium stearate 180 g
From these components, 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. If deεired, a gastric fluid resiεtant or retarding film coat can be applied in a known manner.
c) Vials for Drinking
active ingredient used according to the invention 0.050 g glycerine 0.500 g sorbitol, 70% εolution 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 content .
d) Poorly Soluble Sublingual Tablets
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.ε. aromatic agent q.ε. rice εtarch q.ε. to 0.500 g
The active ingredient iε compacted together with the adjuvants under high pressure to sublingual tablets, favourably in oblong form.
e) Soft Gel Capsule
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.
f) Hard Gelatine Capsules
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 adjuvantε, 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.
3. Topically Administrable Medicinal Forms
a) Hydrophilic Ointment
active ingredient used according to the invention 0.500 g
Eucerinum anhydricum 60.000 g microcrystalline wax 15.000 g
Vaseline oil q.s. to 100.000 g
The above-mentioned adjuvantε are melted and further processed together with the active ingredient to an ointment in a customary manner.
b) Lipophilic Ointment
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
Vaseline to 1000.000 ml
The active ingredien (ε) uεed according to the invention is dissolved in propylene glycol at ca . 60 °C. At the same time, the lipophilic components are melted at 60-70°C and rti
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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 presεure and room temperature, εuch aε propane, butane or dimethyl ether, can be preferred. Thereby, propellant-free manual pump εysterns or dry powder systemε as described below can also be used.
Suitably, the propellant aerosols can also contain εurface active adjuvants, such aε for example isopropyl myristate, polyoxyethylene sorbitan fatty acid eεter, sorbitan trioleate, lecithins, oleic acid.
For administration by means of inhalation and/or inεufflation, the medicamentε with an amount of compoundε according to the invention can also be formulated in the form of dry powder compositions, for example as active ingredient- soft pellets or aε an active ingredient-powder mixture with a εuitable carrier, such as for example lactose and/or glucoεe . The powder compositions can be formulated and administered as single doses or aε 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 containε glucose and/or lactose as a carrier subεtance.
As applicatorε for inhalation of the pharmaceutical formulationε containing one or more of the active ingredient (ε) used according to the invention, all applicators are generally suitable which are suitable for controlled dosage aerosols and/or a dry powder dosage formulation, εuch aε for example usual applicators for the nose, mouth and or pharynx, or alεo deviceε standing under propellant gas for the delivery of a spray (as controlled dosage aerosol or dry powder doεage formulation) as they are also used for inhalationε in the noεe, mouth and/or pharynx. A further embodiment can also consiεt 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.
a) Controlled Dosage Aerosol
Intended dose per aerosol per εtroke % by weight
active ingredient uεed according to the invention 0.500 mg 0.66 stabilizer 0.075 mg 0.10
HFC 134a 75.500 mg 99.24
b) Controlled Dosage Aerosol
Intended dose per aerosol per εtroke % by weight
active ingredient uεed according to the invention 0.250 mg 0.32
Stabilizer 0.038 mg 0.05
HFC 227 79.180 mg 99.63
In the examples a) and b) the micronized active ingredient iε, 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 suspenεion iε 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 continuouεly held in flux in a filling apparatus suitable for cold propellantε or pressure fillings. Alternatively, 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 .
c) Dosage-Dry Powder Formulation
mg/dose
active ingredient used according to the invention 0.500 mg
d) Dosage-Dry Powder Formulation
mg/dose
active ingredient used according to the invention 0.500 mg lactose Ph. Eur. to 2.5 mg or to 5.0 mg
e) Dosage-Dry Powder Formulation mg/dose
active ingredient used according to the invention 0 . 250 mg lactose Ph. Eur. to 2 . 5 mg or to 5 . 0 mg
In example c) 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.
In the examples d) and e) 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.
In all of the examples set forth above, 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 .
PHARMACEUTICAL EXPERIMENTAL SECTION
1. Growth Inhibition of Human Tumor Cells
The tumor growth inhibiting activity of the substances waε determined on human tumor cellε in standardized in vitro test systems. In the screening tests, the substanceε gave IC50- values in a concentration range of 0.1 nM to 10 μM.
Example 1
HepG2 cells derived from a human liver 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 εerum (FCS) in a tiεεue culture incubator with a gaε mixture of 5% C02 and 95% air at a temperature of 37°C. One day after plating, the culture medium waε aεpirated from the cellε and replaced by fresh medium which contained the respective concentrations of the test subεtances . For the individual concentrations and the controls without test substances, three-fold batcheε were done for each. Three dayε after the beginning of treatment, the medium waε again renewed with the test compounds. After six days of substance incubation, 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 Aεεay for Anticancer-Drug Screening. J. Natl. Cancer Inst. 82: 1107-1112, 1990). The IC50-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 following results were obtained:
Figure imgf000156_0001
Example 2
A549 cells derived from a human lung carcinoma plated at a density of 20,000 cells/ml in 12-well plaεtic diεheε . Cultivation occurred in Richterε IMEM-ZO nutrient medium with 5% foetal calf εerum (FCS) in a tissue culture incubator with a gas mixture of 5% C02 and 95% air at a temperature of 37°C. One day after plating, the culture medium was aspirated from the cells and replaced by fresh medium which contained the respective concentrations of the test subεtanceε . For the individual concentrationε and the controlε without teεt εubεtances, three- fold batches were done for each. Three dayε after the beginning of treatment, the medium waε again renewed with the test compounds . After four days of subεtance incubation, the teεt waε 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 IC50-valueε (defined as that concentration in which the cell growth waε inhibited by 50%) waε taken from the dose-response curves and given as a comparative measurement for the activity of the test compounds .
The following resultε were obtained according to example 2 :
Figure imgf000157_0001
Example 3
HT-29 cells derived from a human colon carcinoma plated at a density of 20,000 cells/ml in 12-well plastic diεheε . Cultivation occurred in Richterε IMEM-ZO nutrient medium with 5% foetal calf serum (FCS) in a tiεεue culture incubator with a gaε mixture of 5% C02 and 95% air at a temperature of 37 °C. One day after plating, the culture medium waε aspirated from the cells and replaced by fresh medium which contained the respective concentrations of the teεt εubεtanceε. For the individual concentrationε and the controlε without teεt substances, three-fold batches were done for each. Three days after the beginning of treatment, the medium was again renewed with the test compounds. After four days of substance incubation, the test was ended and the protein amount in the individual wellε waε 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 IC50-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 as follows.
The following reεultε were obtained according to example 3 :
Figure imgf000158_0001
Example 4
THP-1 cellε derived from a human monocytic leukemia plated at a denεity of 200,000 cells/ml in 96-well plastic dishes. Cultivation occurred in RPMI 1640 nutrient medium with 10% foetal calf serum (FCS) in a tiεεue culture incubator with a gas mixture of 5% C02 and 95% air at a temperature of 37°C. For the individual concentrations and the controls without test εubstances as well aε for the background with nutrient medium but without cells, three-fold batches were done for each. After four dayε of εubstance incubation 20 μl WST-1 reagent (Boehringer Mannheim) was respectfully pipetted in each individual well. After 30 to 60 minute incubation in the tissue culture incubator at 37 °C and 5% CO2 , 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 IC50-values (defined aε that concentration in which the cell growth waε inhibited by 50%) was taken from the doεe-reεponse curves and given as a comparative measurement for the activity of the test compounds .
The following results were obtained:
Figure imgf000159_0001
2. Indications
The compounds of formula (I) and their salts permit a therapeutic use in malignant illnesεeε of humans and animals through their excellent inhibition of the growth of tumor cells. The anti-neoplaεtic activity of the described substances can be used for prophylactic, adjunct, palliative, and curative treatment of solid tumors, leukemic illnesses and lymphomas aε well aε for decreaεing or preventing metastaεis 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 diseaεe, tumor illneεseε 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 leukemiaε. Benign papillomatosis tumorε can alεo be limited in their growth with the named εubstances. The broad effectiveness of the new compounds were tested for example in very different human tumor cellε in vitro according to the methods described in point 1. Thereby, the following IC50 valves were obtained for the compound Nr. 120 for example:
Figure imgf000160_0001
The novelty of the compoundε can be expected to have an independent activity profile in the effectiveneεε againεt the variouε tumor typeε . Thuε, tumorε which are reεiεtant to cuεtomary cytostatic agents, for example, can reεpond entirely to these substances. In addition, based on the independent characteristicε , combinations of the new compoundε with known pharmaceuticalε used in chemotherapy are promising as long as their properties are complimented in a suitable manner. The integration of the new structures in a therapy scheme could be successful with one or more substances from the following classes for example: anti- metabolites (for example cytarabine, 5-fluorouracil, 6- mercaptopurine, methotrexate) , alkylating agents (for example busulfane, carmuεtine, ciεplatin, carboplatin, cyclophosphamide, dacarbazine, melphalane, thiotepa) , DNA- intercalating substances and topoisomerase inhibitors (for example actinomycin D, daunorubicin, doxorubicin, mitomycin C, mitoxantrone, etoposide, teniposide, topotecane, irinotecane) , spindle poisonε (for example vincriεtine, navelbine, taxol, taxoter) , hormonally active agents (for example tamoxifene, flutamide, formeεtane, goεereline) or other cytoεtatic agentε with complex modes of action (for example L-asparaginase, bleomycin, hydroxyurea) . Resistant tumor cells can be made senεitive again for example by interaction of the new compoundε with a mechanism of resistance for common cytostatic agents (for example P- glycoprotein, MRP, glutathione-S-transferase, metallothionein) .
3. Immunosuppressing Activity
Many anti-tumor agents have not only a cytotoxic effect on tumor cells, but also on the blood cell system. This leadε to a weakening of the immune defence, which can, in turn, be specifically employed to suppresε the rejection reaction after an organ tranεplantation for example. Alεo use of the main compounds, optionally in combination with other immunological diseaseε (for example, psoriasis or autoimmune diseases) seems likely. In order to teεt the possibility for a therapeutic use in illnesεes of this type, the substance activity was tested on freshly isolated lymphocytes as follows :
The spleen of a Swiss mouse served as a lymphocyte source. The lymphocyte population was isolated from the spleen cell 148 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. 500,000 cells/well/ml in a 12-well plate, 1 ml doubly concentrated test substance solution was pipetted per well and this was subsequently incubated in a tissue culture incubator at 37°C and 5% C0 . After 2 days, a 1 ml-aliquot with 5 μl of the fluorescent dye solutions propidium iodide (8 mg/ml) and 3 , 3 ' -dihexyloxacarbocyanin iodide (40 μg/ml) each was added per well, and incubated for 3 minuteε at room temperature. Subsequently, 10,000 cells per each sample were measured on a flow-through cytometer and the percentage amount of vital cells in the population waε determined. By meanε of the dose- response curves, IC50-values were calculated which were also employed in the following Tables for the characterization of the individual substances :
Figure imgf000162_0001
The independent structural class of the compounds can also be expected to be successful for an efficient combination with known immunosuppreεεive agents such aε for example cycloεporin A, tacrolimuε, rapamycin, azathioprine and glucocorticoidε .

Claims

1. Pyridylalkane, pyridylalkene and pyridylalkine acid amides of the general formula (I)
Figure imgf000163_0001
wherein the substituents have the following meanings:
Rl is selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkinyl, fluoroalkyl such as trifluoromethyl, cycloalkyl, hydroxyalkyl, hydroxy, alkoxy, cycloalkyloxy, aralkyloxy such as benzyloxy, 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^R^, whereby
R4 and R5 are selected independently of each other from hydrogen, alkyl, alkenyl, alkinyl, aralkyl such as benzyl and aryl such as phenyl;
R^ is selected from hydrogen, halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy;
R-3 is selected from hydrogen, alkyl, alkenyl, alkinyl, hydroxy, alkoxy and aralkyloxy such as benzyloxy; is the nui╬▒ber 0 or 1 ,
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, NR6, CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R6 is hydrogen, alkyl, alkenyl, acyl or alkanesulfonyl;
1, 2-cyclopropylene;
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;
1, 3, 5-hexatrienylene, optionally substituted by alkyl, fluorine, cyano or aryl such as phenyl; and
ethinylene
is selected from
alkylene with at least 3 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl;
alkenylene with at least 3 carbon atoms or alkadienylene with at least 5 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl ; WO 99/31064 ,._ PCT/EP98/08272
163
alkinylene with at least 3 carbon atoms or alkeninylene, with at least 5 carbon atoms, optionally substituted once or twice by alkyl, hydroxy, alkoxy or aryl such as phenyl; as well as
alkylene, alkenylene or alkinylene each with at least 3 carbon atoms, wherein one to three methylene units, with the exception of the (G) -terminal methylene group, are isosterically replaced by 0, S, NR7, CO, SO or SO2, whereby R' is synonymous with R6, but is selected independently thereof;
G is selected from Gl, G2, G3, G4, G5 or G╬▓ with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
Figure imgf000165_0001
whereby m is the number 0 or 1, and
R^ is selected from aralkyl such as benzyl or diphenylmethyl, aryl such as phenyl; 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a WO 99/31064 .16,4. PCT/EP98/08272
hydrated ring and either directly or over a methylene group;
R^ is selected from hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl; aralkyl such as benzyl, aryl such as phenyl; saturated or unsaturated, four- to six-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or 0;
monocyclic aromatic five- or seven-membered heterocycles, which can contain one to three heteroatoms selected from N and/or S and/or 0 and are either bound directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
R10 is synonymous with R9, but can be selected independently thereof, and also hydroxy;
G2 is the grouping
= CR8R9 (G2)
which is bound to D by means of a double bond,
wherein R^ and R9 have the above meaning, or whereby this grouping -= C R8R9 can also be a ring system bound over the carbon atom, selected from anellated bi- and tricyclic partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring; anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0;
G3 is selected from
ΓÇö XΓÇö (CH2)nΓÇö (CR 0)m ΓÇö R 8 (G3a) or
Figure imgf000167_0001
whereby m and the substituents R8, R9 and R10 can have above meanings, and
n is the number 0, 1 or 2,
X has the meaning NR11, 0 or S, whereby
R11 has the same meaning as R4, but is selected independently thereof, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
G4 is selected from
NR11 C Y (CR9R10)mm RR8 (G4a) O or ΓÇö R"ΓÇöC ΓÇö NR R9 (G4b) /
Z
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or - C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above defined meanings with the proviso that the residues
Figure imgf000168_0001
cannot be identical, and
Y is selected from methylene, ethylene, ethenylene, cycloalkylene or represent a bond, and
Z has the meaning 0 or S;
G^ has the meaning
NR11 S02 R12 (G5)
wherein R11 has the above meaning, and
R--2 is selected from alkyl, aryl such as phenyl; monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or 0; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring;
is selected from
Figure imgf000169_0001
wherein X can have the above meanings and
Ar^- and Ar2 are selected independently from each other from aryl such as phenyl or naphthyl as well as heteroaryl such as pyridyl;
and whereby aromatic ring systems in the substituents R^, R2, R3, R4, R5, R8, R9, R10, R11, R12, Ar1 and Ar2 and/or in ring systems =C R8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, alkyl, fluoroalkyl such as trifluoromethyl, cycloalkyl, aralkyl such as benzyl, aryl such as phenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxy entirely or partially substituted by fluorine, aralkyloxy such as benzyloxy, aryloxy such as phenoxy, mercapto, alkylthio, arylthio such as phenylthio, sulfo, carboxy, carboxyalkyl, carboxyalkenyl, alkoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl, nitro, amino, aminoalkyl, mono-alkylamino, di- (alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the group G can be substituted by one or two of the same or different residues selected from hydroxy, carboxy, alkoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl, amino, mono-alkylamino and di- ( lkyl) amino;
the cis- and trans-isomers as well as E- and Z-isomers of the above defined compounds, especially in the case that A is a cyclopropane ring or D contains one or more double bonds, including the enantiomers, diastereomers and other isomers of the above defined compounds, optionally in pure form or as their racemic and/or non-racemic mixtures;
the tautomers of the above defined compounds, in the optional case that G represents a heterocyclic aromatic ring or one which simultaneously contains substitutions by free hydroxy, mercapto or amino groups; as well as the corresponding
acid addition salts of the above defined compounds including their hydrates and solvates.
2. Pyridylalkane, pyridylalkene and pyridylalkine acid amides of the formula (I)
Figure imgf000170_0001
wherein the substituents have the following meanings
R1 is selected from hydrogen, halogen, cyano, Cχ-Cg-alkyl, C3~Cg-alkenyl,
C2-Cg-alkinyl, trifluoromethyl, C3-Cg-cycloalkyl, Cχ-Cg- hydroxyalkyl, hydroxy, C -Cg-alkoxy, C3-C8- cycloalkyloxy, benzyloxy, C -C7-alkanoyloxy, Cχ-Cg- alkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7- alkylaminocarbonyl, C3-C23-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR4R5, whereby R4 and R5 are selected independently of each other from hydrogen, Cχ-Cg-alkyl, C3-Cg-alkenyl, C3~Cg-alkinyl, benzyl and phenyl;
R2 is selected from hydrogen, halogen, cyano, Cχ-Cg-Alkyl, trifluoromethyl, hydroxy, C -Cg-alkoxy and benzyloxy;
R3 is selected from hydrogen, C -Cg-alkyl, C3-Cg-alkenyl, C3~Cg-alkinyl, hydroxy, Cχ-Cg-alkoxy and benzyloxy;
k is 0 or 1,
A is selected from
C -Cg-alkylene, optionally substituted one to three-fold by Cχ-C3~alkyl, hydroxy, Cχ-C3-alkoxy, fluorine, or phenyl;
C2~Cg-alkylene, in which a methylene unit is isosterically replaced by 0, S, NR6, CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R6 is selected from hydrogen, C -Cg-alkyl, C3~C - alkenyl, Cχ-Cg-Acyl or Cχ-Cg-alkanesulfonyl;
1, 2-cyclopropylene;
C2~Cg-alkenylene, optionally substituted once or twice by C -C3-alkyl, hydroxy, Cχ-C3~alkoxy, fluorine, cyano or phenyl;
C^-Cg-alkadienylene, optionally substituted once or twice by C -C3~alkyl, fluorine, cyano or phenyl; 1, 3, 5-hexatrienylene, optionally substituted by C1-C3- alkyl, fluorine, cyano or phenyl; as well as
ethinylene
D is selected from
c3-c12-alkylene' optionally substituted once or twice by Cχ-Cg-alkyl, hydroxy, Cχ-Cg-alkoxy or phenyl;
c3~c12-alkenVlene or C5-Cχ2_alkadienylene, optionally substituted one or twice by C -Cg-alkyl, hydroxy, C -Cg- alkoxy or phenyl;
C3-Cχ2~alkinylene or C5-C 2~alke inylene, optionally substituted one or twice by Cχ-Cg-alkyl, hydroxy, C -Cg- alkoxy or phenyl; and
c3~c12-alkylene' C3-Cχ2~alkenylene or C3~Cχ2~ alkinylene, wherein, with the exception of the (G) - terminal methylene group, one to three methylene units are isosterically replaced by 0, S, NR7, CO, SO or SO2, whereby R7 is synonymous with R6, but is selected independently thereof;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
Figure imgf000172_0001
and
m is 0 or 1,
R8 is selected from benzyl, diphenylmethyl, phenyl; 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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
is selected from hydrogen, Cχ-Cg-alkyl, C3~Cg-alkenyl, C2-Cg-alkinyl, C3-
Cg-cycloalkyl ; benzyl, phenyl; saturated or unsaturated, four- to seven-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or 0;
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 over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, and at least one aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, especially with up to 16 ring atoms, ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
RIO is synonymous with R9, but is selected independently thereof, or can be hydroxy;
G2 is the grouping
= CR8R9 (G2)
which is bound to D by means of a double bond, wherein R8 and R9 have the above meaning or whereby the grouping =CR8RS can also be a ring system bound over the carbon atom, selected from anellated bi- and tricyclic partial hydrated carbocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least an aromatic ring; anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0;
G3 is selected from
X (CH2)n (CR9Rl┬░)m R8 (G3a) or
NR8R9
(G3b)
whereby m and the substituents R8, R9 and R10 can have the above meanings, and
n is the number 0, 1 or 2
X has the meaning NR11, 0 or S, whereby R11 has the same meanings as R4, but is selected independently thereof, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least an aromatic ring, which, aside from the essential nitrogen atom, can contain 1 or 2 further hetero-atoms selected from N and/or S and/or 0; and
G4 is selected from
-NR 11 c (CR9R10)
II m Rc (G4a) o or
-NR11 C NR8R9
II (G4b), z
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or - C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the groupi .ing NR8┬░DR9:' can have the above meaning with the proviso that the residues
Figure imgf000175_0001
cannot be identical, and
is selected from methylene, ethylene, ethenylene, C3-C7-cycloalkylene or represents a bond, and
Z is 0 or S;
G^ has the meaning
-NR 11 SO' ,12 : G5 )
wherein RU has the above meaning, and
.12 is selected from
C -Cg-alkyl, phenyl; monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or 0; anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, especially up to 16 ring atoms, and at least an aromatic ring, whereby the linkage can occur either over an aromatic or a hydrated ring; anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18 ring atoms, especially up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or 0 and the linkage can occur either over an aromatic or a hydrated ring;
is selected from
X\p / Ar1
(G6) O* \Ar2
wherein X can have the above meanings and
.Ar-'- and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl; and whereby aromatic ring systems in the substituents R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, Ar1 and Ar2 and/or in ring systems = C R8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C^-Cg-alkyl, trifluoromethyl, C3-C8- cycloalkyl, benzyl, phenyl, hydroxy, C_-Cg-hydroxyalkyl, C]_- Cg-alkoxy, C -Cg-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, Cχ-Cg-alkylthio, phenylthio, sulfo, carboxy, C2~C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C -Cg-aminoalkyl, mono-C -Cg-alkylamino, di- (Cχ-Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different groups, selected from hydroxy, carboxy, C2~C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C -Cg-alkyl) amino;
the cis- and trans-isomers, E- and Z-isomers of the above defined compounds , especially in the case that A is a cyclopropane ring or D contains one or more double bonds, including the corresponding enantiomers, diastereomers and other isomers of the above defined compounds, optionally in pure form or as their racemic and/or non-racemic mixtures;
the tautomers of the above defined compounds, in the optional case that G represents or contains a heterocyclic aromatic ring with simultaneous substitution by free hydroxy, mercapto or amino groups; as well as the corresponding
acid addition salts of the above defined compounds including their hydrates and solvates.
3. Compounds according to claims 1 or 2 according to the general formula (I)
Figure imgf000178_0001
wherein the substituents have the following meaning:
R is selected from hydrogen, halogen, cyano, C -Cg-alkyl, trifluoromethyl, ethinyl, hydroxy, C^-C^-alkoxy, benzyloxy, C -C4~alkyl- thio, C2-C5-alkoxycarbonyl, aminocarbonyl, C3-C9- dialkylaminocarbonyl, carboxy, phenoxy, phenylthio and pyridyloxy;
R2 is selected from hydrogen, fluorine, chorine, bromine, C -C4-alkyl, trifluoromethyl, hydroxy, C -C4~alkoxy;
R3 is selected from hydrogen, C_-C3~alkyl, allyl, hydroxy, C_-C3~alkoxy and benzyloxy;
k is 0 or 1,
A is selected from
C -Cg-alkylene, optionally substituted once or twice by Cχ-C3~alkyl, hydroxy, fluorine or phenyl;
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, and
1, 2-cyclopropylene;
C2-Cg-alkenylene, optionally substituted once or twice by C -C3~alkyl, phenyl, hydroxy and/or fluorine; C4-Cg-Alkadienylene, optionally substituted once or twice by methyl or fluorine;
1, 3, 5-hexatrienylene, optionally substituted by methyl or fluorine, and
ethinylene
D is selected from
C3-C 2~alkylene, optionally substituted once or twice by C_-C3~alkyl, hydroxy or phenyl;
C3-C 2-alkenylene, optionally substituted once or twice by C -C3~alkyl, hydroxy or phenyl;
C3-C]_2~alkinyle e, optionally substituted once or twice by Cχ-C3-alkyl, hydroxy or phenyl, and
C3-C_2_alkylene, C3-Ci2~alkenylene or C3-C╬╣_2~alkinylene, wherein one to three methylene units are isosterically replaced by 0, S, NH, N(CH3), N(C0CH3), N(S02CH3), CO or S02;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
has the meaning
(CR9R10)m R IG1)
whereby m is the number 0 or 1,
R8 is selected from benzyl, diphenylmethyl, phenyl; benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluoroenyl, oxof luoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, bound directly or over a methylene group;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, dihydrobenzof uryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzo isoxazolyl, oxobenzoisoxazolinyl, benzo thiazolyl, oxobenzothiazolinyl, be zo isothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolinyl, dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, 1, l-dioxo-l-thia-2-aza-acenaphthenyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, oxodihydrophenanthridinyl , dihydrobenzoisochinolinyl , oxodihydrobenzosoquinolinyl, phenothiazinyl, dihydrodibenzooxepinyl , oxodihydrodibenzooxepinyl , benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzo thiepinyl, oxodihydrothienobenzo- thiepinyl, dihydrodibenzo thiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzo thiepinyl , dibenzoazepinyl, dihydrodibenzoazepinyl , oxodihydrodibenzoazepinyl , octahydrodibenzoazepinyl , ben zocycloheptapyr idyl, oxobenzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl , oxodihydropyridobenzoazepinyl, dihydropyridobenzo- diazepinyl , oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl , dihydropyridobenzooxepinyl , dihydropyridobenzooxazepinyl, oxodihydropyridobenzo- oxazepinyl , dihydrodibenzothiazepinyl, oxodihydrodibenzo thiazepinyl , dihydropyridobenzo- thiazepinyl or oxodihydropyridobenzothiazepinyl , bound directly or over a methylene group;
is selected from hydrogen, C -Cg-alkyl , C3-Cg-alkenyl, C2 _Cg-alkinyl , C3-
Cs-cycloalkyl; benzyl, phenyl; azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, hexahydroazepinyl, piperazinyl, morpholinyl or hexahydrodiazepinyl ;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iso-thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, triazinyl, bound directly or over a methylene group
indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluoroenyl, oxofluoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl , oxodihydrodibenzocycloheptenyl, bound directly or over a methylene group;
benzofuryl, benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoiso- thiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, quinolinyl, isoquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, carbazolyl, pyridoindolyl, dihydrobenzoisoquinolinyl, phenothiazinyl, bound directly or over a methylene group;
R10 is synonymous with R9, but is selected independently thereof, or is hydroxy;
is the grouping
CR8R9 !G2;
which is bound to D over a double bond, wherein R8 and R9 have the above meaning, or whereby the grouping =CR8R9 can also be a ring system bound over the carbon atom, selected from indanyl, indenyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl , dihydrodibenzocycloheptenyl ; indolinyl, isoindolinyl, oxoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroacridinyl , dihydrodibenzooxepinyl , dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzo- cycloheptapyridinyl, pyridobenzoazepinyl, dihydropyrido- benzoazepinyl , oxodihydropyridobenzooxepinyl , dihydropyridobenzothiepinyl ;
G3 is selected from X (CH2)n (CR99RR1100))m or m ΓÇö R8 (G3a NR8R9 (G3b)
whereby m and the substituents R8, R9 and R10 can have the above defined meanings and
n is the number 0 or 1,
X has the meaning NR-H, 0 or S, whereby
RU is selected from hydrogen, C -C3~alkyl, allyl, propinyl, benzyl and phenyl, or the grouping
NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (4H)- dihydrobenzooxazine, (4H) -dihydrobenzothiazine, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo- [c] azepine, ( IH) -tetrahydrobenzo [d] azepine, (5H)- tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo- [b] thiazepine, 1,2,3, -tetrahydro-9H-pyrido [3,4- b]indole, carbazole, tetrahydrocarbazolee, 1, 1-di-oxo-l- thia-2-aza-acenaphthene, (10H) -dihydroacridine, (10H)- dihydrophenanthridine, 1,2,3, 4-tetrahydroacridanone, (10H) -phenoxazine, (10H) -phenothiazine, dihydrobenzo [d, e] iso-quinoline, (5H) -dibenzoazepine, (5H) -dihydrodibenzoazepine, (5H) -octahydrodi- benzoazepine, (5H) -dihydrodibenzodiazepine, (5H)- benzo [b] pyrido [f] azepine, (5H) -dihydrobenzo [b] pyrido- [f] azepine, ( 11H) -dihydrodibenzo [b, e] oxazepine, (11H)- dihydrodibenzo [b, e] thiazepine, (10H) -dihydrodibenzo- [b, f] oxazepine, (10H) -dihydrodibenzo [b, f] thiazepine, (5H) -tetrahydrodibenzoazocine, (11H) - dihydrobenzo [e]pyrido [b] -1, 4-diazepin-6-one or (11H)- dihydrobenzo [b] pyrido [e] -1, 4-diazepin-5-one;
G4 is selected from -NR11 C (CR9R10)
II m R£ !G4a) o or
-NR 11 C NR8R9
II !G4b) z
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or -^C-CO-N<) , whereby m and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above meanings with the proviso that the residues
Figure imgf000184_0001
cannot be identical, and
is selected from methylene, ethylene, ethenylene, cyclopropylene or represents a bond, and
has the meaning 0 or S;
has the meaning
-NR 11 SO- R 12
(G5)
wherein R11 has the above meaning, and
is selected from phenyl, indenyl, naphthyl, anthryl; furyl, thienyl, thiazolyl, pyridyl, indolyl, benzothienyl or quinolinyl; G6 is selected from
Figure imgf000185_0001
wherein X can have the above meanings and
Ar^ and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl;
and whereby aromatic ring systems in the substituents R1, R3, R8, R9, R10, R11, R12, Ar1 and Ar2 and/or in ring systems =CR8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, C3-C8- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl, Cχ~
Cg-alkoxy, Cχ-Cg-Alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, Cχ-Cg-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C]_-Cg-aminoalkyl, mono-C -Cg-alkylamino, di-
(C -Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, ethylenedioxy .
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2~C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (C -Cg-alkyl) amino .
4. Compounds according to one of claims 1 to 3 according to the general formula (I)
Figure imgf000186_0001
wherein the substituents have the following meanings:
Rl is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, C^-C^-alkoxy, phenoxy, methylthio, ethylthio, methoxycarbonyl, aminocarbonyl and carboxy;
R2 is selected from hydrogen, chlorine, methyl, hydroxy and methoxy;
R3 is hydrogen;
is 0,
is selected from
C2-Cg-alkylene, optionally substituted once or twice by hydroxy or fluorine;
C2~Cg-alkylene, wherein a methylene unit is isosterically replaced by 0, S, or CO, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group;
C2-Cg-alkenylene, optionally substituted by methyl and/or fluorine;
C4-Cg-alkadienylene, optionally substituted by methyl;
ethinylene; is selected from
C3-C]_o~ lkylene, optionally substituted by methyl, hydroxy or phenyl;
C3-Cχo_a-lkenyle e, optionally substituted by methyl, hydroxy or phenyl;
C3-C o~alkinylene, optionally substituted by hydroxy or phenyl;
C3-C]_o~alkylene, C3-C o~alkenylene or C3-Cχo~alkinylene, wherein, respectively, a methylene unit is isosterically replaced by 0, NH, N(CH3), or CO, or an ethylene group is isosterically replaced by a group NH-CO and/or CO-NH, or a propylene group isosterically replaced by a group NH-CO-NH or NH-CO-O and/or 0-CO-NH;
G is selected from Gl, G2, G3, G4, G5 or G6 with the proviso that G must contain at least one aromatic ring, whereby
G1 has the meaning
(CR9R10)m R8 (Gl) whereby m is the number 0 or 1,
R8 is selected from benzyl, diphenylmethyl, phenyl;
indanyl, indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluoroenyl, oxofluoroenyl, anthryl, dihydroanthryl, oxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, bound directly or over a methylene group; furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroi idazopyridyl, thienopyrimidinyl, chromanonyl, quinolyl, isoquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazoleyl, pyridoindolyl, 1,1-dioxo-l- thia-2-aza-acenaphthenyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, dihydrobenzoisoquinolinyl, oxodihydrobenzoisoquinolinyl, dihydrodibenzooxepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl, benzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl , dihydropyridobenzodiazepinyl, oxodihydropyridobenzodiazepinyl, dihydropyridobenzooxepinyl or dihydrodibenzothiazepinyl, bound directly or over a methylene group;
is selected from hydrogen, C -C3-alkyl, C3-C8~cycloalkyl, benzyl, phenyl, indanyl, indenyl, naphthyl, anthryl; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiadiazolyl, triazolyl, pyridyl,
benzofuryl, benzothienyl, indolyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoimidazolyl and benzotriazolyl; R10 is synonymous with R9, but is selected independently thereof, or can be hydroxy;
G2 is the grouping
= CR8R9 (G2)
which is bound to D over a double bond, wherein R8 and R9 have the above meaning, or whereby the grouping =CR8R9 can also be a ring system bound over the carbon atom, selected from indanyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl ; indolinyl, isoindolinyl, oxoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroacridinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzoeyelohepta- pyridinyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, oxodihydropyridobenzo- oxepinyl, dihydropyridobenzothiepinyl;
G3 is selected from
ΓÇö X ΓÇö (CH2)nΓÇö (CRRlO)m R8 (G3a) or NR8R9 (G3b)
whereby m and the substituents R8, R9 and R10 can have the above defined meanings and
n is the number 0 or 1,
X has the meaning NR 1, 0 or S, whereby R11 is selected from hydrogen, C -C3-alkyl, benzyl and phenyl, or the grouping NR8R9 can also be a nitrogen heterocycle bound over the nitrogen atom selected from indoline, isoindoline, (IH) -dihydroquinoline, (1H)- tetrahydroquinoline, (2H) -tetrahydroisoquinoline, (1H)- tetrahydrobenzo [b] azepine, (IH) -tetrahydrobenzo-
[c] azepine, ( IH) -tetrahydrobenzo [d] azepine, (5H)- tetrahydrobenzo [b] oxazepine, (5H) -tetrahydrobenzo-
[b] thiazepine, carbazole, 1, l-dioxo-l-thia-2-aza- acenaphthene, ( 10H) -dihydroacridine, (10H)- dihydrophenanthridine, dihydrobenzo [d, e] isoquinoline,
(5H) -dihydrodibenzoazepine, (5H) -dihydrodibenzodiazepine, (5H) -dihydrobenzo [b] pyrido [f] azepine, (11H)- dihydrodibenzo [b, e] oxazepine, (11H) -dihydrodibenzo [b, e] - thiazepine, (10H) -dihydrodibenzo [b, f] oxazepine, (10H)- dihydrodibenzo [b, f] thiazepine, (5H) - tetrahydrodibenzoazocine, (11H) -dihydrobenzo-
[e]pyrido [b] -1, 4-diazepin-6-one or (11H) -dihydrobenzo-
[b] pyrido [e] -1, 4-diazepin-5-one;
G4 is selected from
ΓÇöNR11ΓÇö C ΓÇö Y ΓÇö (CR9RlO)m ΓÇö R8 (G4a)
or
Figure imgf000190_0001
with the proviso that the structural element D G cannot contain a total of more than 1 amide grouping (>N-CO-C - or - C-CO-N<) , whereby rn and the substituents R8, R9, R10, R11 and the grouping NR8R9 can have the above meanings with the proviso that the residues
Figure imgf000191_0001
cannot be identical, and
Y is selected from methylene, ethenylene, or represents a bond, and
Z has the meaning 0 or S;
has the meaning
-NR 11 SO, >12
( G5 )
wherein RU has the above meaning, and
R12 is selected from phenyl, naphthyl, anthryl; thienyl, pyridyl, benzothienyl or quinolinyl;
G^ is selected from
Figure imgf000191_0002
wherein X can have the above meanings and
Ar1 and Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl;
and whereby aromatic ring systems in the substituents R1,
R3, R8, R9, R10, R11, R12, Ar1 and Ar2 and/or in ring systems =CR8R9 and NR8R9 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C -Cg-alkyl, trifluoromethyl, C3-C8- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl, Cχ~ Cg-alkoxy, Cχ-Cg-Alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, Cχ-Cg-alkylthio, phenylthio, sulfo, carboxy, C2~C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, Cχ-Cg-aminoalkyl, mono-C -Cg-alkylamino, di- (C -Cg-alkyl) amino and, for two adjacent residues on the aromatic ring, methylenedioxy and
whereby alkyl and cycloalkyl residues in the Group G can be substituted by one or two of the same or different residues, selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (Cχ-Cg-alkyl) amino .
5. Compounds according to one of claims 1 to 4 according to the general formula (I)
Figure imgf000192_0001
wherein the substituents have the following meanings:
R! is selected from hydrogen, fluorine, methyl, trifluoromethyl, ethylthio;
R2 is hydrogen;
R3 is hydrogen;
k is 0, A is selected from ethylene or butylene, optionally substituted by hydroxy or one or two fluorine atoms, or OCH2, SCH2,
ethenylene or 1, 3-butadienylene;
D is selected from
C3~C -alkylene, optionally substituted by hydroxy or phenyl;
C3-C8-alkenylene, optionally substituted by phenyl,
C3-C8_alkinylene; or
C3-C8~alkylene, C3~C8-alkenyle e or C3-C8~alkinylene, in which one or two methylene units are isosterically replaced by 0, NH or CO;
G is selected from cyclopentylphenyImethylene, cyclohexylphenylmethyl, cyclohexylhydroxyphenyl ethyl , diphenylmethyl , diphenylhydroxymethyl, diphenylmethylene, diphenylethyl, diphenylhydroxy ethyl, diphenylethylene, triphenylmethyl, triphenylethyl, triphenylhydroxyethyl, triphenylethylene, naphthylmethylene, naphthyl, tetrahydronaphthyl, hydroxytetrahydronaphthyl, tetrahydronaphthylidene, fluoroenyl, hydroxyfluoroenyl, fluoroenylidene, tetrahydrobenzocycloheptenyl, hydroxytetrahydrobenzocycloheptenyl, tetrahydrobenzocycloheptenylidene, dihydrodibenzocycloheptenyl, hydroxydihydrodibenzo- cycloheptenyl, dihydrodibenzocycloheptenylidene;
phenyl-thienylmethyl, phenyl-thienylhydroxymethyl, phenyl-thienylmethylene, dithienylmethyl, dithienylhydroxymethyl, dithienylmethylene, phenyl- furylmethyl, phenyl-furyl-hydroxymethyl, phenyl- furylmethylene, phenyl-pyridylmethyl, phenyl- pyridylhydroxymethyl, phenyl-pyridyImethylene; tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzocycloheptapyridinyl, benzocycloheptapyridinylidene, dihydrobenzocycloheptapyridinyl, dihydrobenzocycloheptapyridinylidene, dihydrodibenzooxepinyl, dihydrodibenzooxepinylidene, dihydrodibenzothiepinyl, dihydrodibenzothiepinylidene;
phenylpyrrolyl, diphenylpyrrolyl, phenylthienyl, diphenyl-thienyl, phenylpyrazolyl, diphenylpyrazolyl, phenylimidazolyl, diphenylimidazolyl, phenylpyridyl, diphenylpyridyl, indolyl, oxoindolinyl, benzoimidazolyl, oxobenzoimidazolyl, benzothiazolyl, oxobenzothiazolyl, benzoisothiazolyl, benzooxazolyl, oxobenzooxazolyl, benzotriazolyl;
diphenylmethylamino, diphenylmethyl-methylamino, dibenzylamino, benzylphenylamino, cyclohexylphenylamino, triphenylmethylamino, biphenylylamino, diphenylamino; N- indolinyl, N-isoindolinyl, N-tetrahydroquinolinyl, N- tetrahydrobenzazepinyl, N-phenyl- tetrahydrobenzoazepinyl, N-l, l-dioxo-l-thia-2-aza- acenaphthenyl, N-1H, 3H-benzo [de] -isoquinolinyl, N- dihydrodibenzoazepinyl ;
diphenylmethyloxy, diphenylmethylthio;
diphenylacetylamino, diphenylacetyl-phenylamino, diphenylpropionylamino, diphenylacryloylamino, naphthylacetylamino, furoylacrylamino, benzoylamino, naphthoylamino, oxofluoroenylcarbonylamino, furoylamino;
diphenylmethylaminocarbonylamino, dibenzylaminocarbonylamino, naphthyImethylaminocarbonylamino, dibenzylaminocarbonylamino, biphenylylaminocarbonylamino, naphthylaminocarbonylamino, benzylphenylaminocarbonylamino, diphenylaminocarbonyl- amino; diphenylaminocarbonyl-phenylamino; dipheny1furylaminocarbonylamino, indolinyl-N-carbonyl- amino, isoindolinyl-N-carbonylamino, IH, 3H- benzo [de] isoquinolinyl-N-carbonylamino, tetrahydrobenzoazepinyl-N-carbonylamino, phenyl- tetrahydrobenzoazepinyl-N-carbo-nylamino, dihydrodibenzoazepin-N-carbonylamino, di ydrobenzopyridoazepinyl-N-carbonylamino;
tolylsulfonylamino, naphthylsulfonylamino, diphenylphosphinoylamino and diphenylphosphinoyloxy,
and whereby aromatic ring systems in G can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, Cχ-Cg-alkyl, trifluoromethyl, C3-C8- cycloalkyl, benzyl, phenyl, hydroxy, Cχ-Cg-hydroxyalkyl , C ~
Cg-alkoxy, Cχ-Cg-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C -Cg-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7- carboxyalkenyl, C2-C7~alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C -Cg-aminoalkyl, mono-Cχ-Cg-alkylamino, di-
(C -Cg-alkyl) amino and for two adjacent residues on the aromatic ring, methylenedioxy, and
whereby alkyl and cycloalkyl residues in the group G can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2~C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C -Cg-alkylamino and di- (Cχ-Cg-alkyl) amino .
6. Compounds of the general formula (I) according to one of claims 1-6, characterized in that they are present in the form of the following compounds:
(1) ) N- [8, 8-bis- (4-fluorophenyl) -octyl] -3-pyridin-3-yl-acryl- amide┬╗hydrochloride
(2) N- [ 6- (3, 3-diphenyl-ureido) -hexyl] -3-pyridin-3-yl- acrylamide (3) N- [4- (1-phenyl-l, 2, 4, 5-tetrahydrobenzo [d] azepin-3-yl) - butyl] -3-pyridin-3-yl-acrylamide
(4) N- (8, 8-diphenyl-octyl) -3-pyridin-3-yl-acrylamide
(5) N- (8-hydroxy-8, 8-diphenyl-octyl) -3-pyridin-3-yl- acrylamide
(6) N- [4- (3, 3-diphenyl-ureido) -butyl] -3-pyridin-3-yl- acrylamide
(7) N-[4- (IH, 3H-benzo[de]isoquinolin-2-yl) -butyl ] -3-pyridin- 3-yl-acrylamide
(8) N- [6- (10, 11-dihydrodibenzo [b, f] azepin-5-yl- carbonylamino) -hexyl] -3-pyridin-3-yl-acrylamide
(9) 3-pyridin-3-yl-N- [6- (tosylamino) -hexyl] -acrylamide
(10) N- [4- (1, l-dioxo-l-thia-2-aza-acenaphthylen-2-yl) -butyl] - 3-pyridin-3-yl-acrylamide
(11) N- ( 6-hydroxy-6, 6-diphenyl-hexyl ) -3-pyridin-3-yl- acrylamide
( 12 ) N- ( 6, 6-diphenyl-hex-5-enyl) -3-pyridin-3-yl-acrylamide
(13) N- [4- (4, 5-diphenyl-imidazol-l-yl) -butyl] -3-pyridin-3-yl- acrylamide
(14) N- [4- (trans-2-phenyl-cyclopropyl-carbonylamino) -butyl] - 3-pyridin-3-yl-acrylamide
(15) N- (5-hydroxy-5, 5-diphenyl-pentyl) -3-pyridin-3-yl- acrylamide
(16) N- (7-phenyl-heptyl) -3-pyridin-3-yl-acrylamide
(17) N- (4-diphenylacetylamino-butyl) -3-pyridin-3-yl- acrylamide ( 18 ) N- [4- (benzhydryl-amino) -butyl] -3-pyridin-3-yl-acrylamide and
(19) N-(4-{[2- (benzhydrylmethylamino) -ethyl] -methylamino }- butyl) -3-pyridin-3-yl-acrylamide .
7. Method for the production of the compounds of formula (I)
Figure imgf000197_0001
according to one of claims 1-6, characterized in that according to method (A), compounds of the formula (I) are obtained in the manner that carboxylic acids of formula (II),
wherein R1, R.2, A and k have the meanings given above or their reactive derivatives are reacted with compounds of formula (III)
H N-
R (III) wherein D, G and R3 are defined above, for example in the form of their active esters, anhydrides acid halides, especially acid chlorides, or simple lower alkyl esters as free bases or acid addition salts, optionally in the presence of condensation agents, for example carbodiimides, in a suitable, preferably inert solvent or polar aprotic solvent or solvent mixture, as well as, optionally, in the presence of an auxiliary base in the form of a carbonate or organic amine, at a reaction temperature especially between -40┬░C and 180┬░C, preferably between -10┬░C and 130┬░C; or according to method (B) , compounds of formula wherein G corresponds to the meanings of G3a, G4, G5 or G6, and, optionally X is equal to NR11, can be produced that compounds of formula (IV)
Figure imgf000198_0001
are reacted with suitable alkylation or arylation agents and/or carboxylic acid, carbamic acid, thiocarbamic acid, sulfonic acid or phosphinic acid derivatives of formula (Va] to (Ve),
L (CH2)n (CR9R10)m Re (Va)
Figure imgf000198_0002
Figure imgf000198_0003
SO, ┬╗12 (Vd)
Figure imgf000198_0004
wherein each L represents a suitable nucleofuge, or
according to method (Bl), compounds of formula (I), wherein G has the meanings of G3a with X = NRH according to the above definition, can also be produced in the manner that compounds of formula (IV) are reacted in a suitable inert solvent and/or solvent mixture with a suitable alkylation and/or arylation agent of formula (Va) , wherein m, n, R8, R9 and R10 are defined as above and the leaving group L can be a reactive derivative of an alcohol, for example a halogen atom, or sulfonic acid ester, whereby the reaction preferably takes place in the presence of bases as named above in method (A) and, in the case of the use of compounds of formula (Va) in the form of their chlorides or bromides as starting products, the reaction can be accelerated by addition of alkali metal iodides such as sodium iodide or potassium iodide and whereby the reaction temperature can vary, especially between 0┬░C and 180┬░C, preferably between 20┬░C and 130┬░C; or
according to method (B2), compounds of formula (I), wherein G has the meaning G4 to G6 according to the above definition, can also be produced in that starting products of formula (IV) are reacted with a carboxylic acid, thiocarbamic acid carbamic acid, sulfonic acid and/or phosphinic acid of formula (VIb) to (Vie),
HO C Y (CR9R10)m R8 (vib)
O
HO C NR8R9 (vie)
Z
HO S02 R12 (VId)
Figure imgf000199_0001
wherein , Y, Z, R8, R9, R10, R12, Ar1, Ar2 and optionally the group NR R9 have the above meanings or with their derivatives capable of reaction, preferably in the presence of auxiliary bases in solvents and under conditions as they are described in method (A) , or
according to method (B3) , compounds of formula (I), wherein G represents a carbamoyl residue according to the definition G4b with Z = 0, i.e. is a group -NR 11 NR8R9
O
can also be produced in the manner that compounds of formula (IV), wherein X = NR11 are reacted to an intermediate product with a carbonyl group transmitter, preferably with a bis- trichloromethy carbonate (triphosgene) or carbonyldiimidazole, especially in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base and, subsequently, without purification or isolation of the intermediate product, this is reacted with a primary or secondary amine of formula (VII),
H NR8R9 (VII)
wherein R8 and R9 or optionally the residue NR8R9 have the meanings according to the above definitions, whereby the temperature for the first partial reaction can lie especially between -40┬░C and 50┬░C, preferably at 0┬░C to 30┬░C, and, for the second partial reaction, between 0┬░C and 150┬░C, preferably in the range of 20┬░C to 120┬░C, and whereby compounds of formula (I) wherein G represents a thiocarbamoyl residue according to the definition G4b with Z = S, i.e. is a group
NR11 C NR8R9
II s
can be produced in an identical manner from the starting compounds of the formulas (IV) and (VII) in that thiocarbonyldiimidazole or thiophosgene is used as a thiocarbonyl group transmitter, or
according to method (B4) , compounds of formula (I), wherein G represents a carbamoyl residue or thiocarbamoyl residue according to the definition G4b with R9 = hydrogen, i.e. is a group NR1 1 C NHR8
II z
can be produced in the manner, that the starting compounds of formula (IV), wherein X = R l are reacted with an isocyanate or isothiocyanate of formula (VIII),
Z = C=N ΓÇö R8 (VIII)
wherein R8 has the meanings defined above, preferably in absolute, inert solvents as they are considered in the above method (B3) , especially at a reaction temperature which can vary in the range of -20┬░C to 150┬░C, preferably at 20┬░C to 100┬░C.
8. Compound or compound mixture according to one of claims 1 to 6 for use in a therapeutic method for treatment of the human or animal body or in a corresponding diagnosis method.
9. Compound or compound mixture according to claim 8 for use in a therapeutic or diagnostic method, characterized in that these uses are in connection with cancerostatic or cytostatic anti-proliferative or immunosuppressive treatment or inhibition of abnormal cell growth and/or preventing the formation of metastases, optionally in connection with suitable pharmaceutically acceptable adjuvants and carriers and/or one or more further active ingredients.
10. Use of one or more compounds according to one of claims 1 to 6 for the production of a medicament for the treatment of the human or animal body in the medical indications named above in claim 9.
11. Medicament with an amount of one or more active ingredients according to claim 1 to 6 optionally in connection with a pharmaceutically acceptable carrier, next to toxicologically safe adjuvants, optionally in combination with other active ingredients.
12. A method for the production of a medicament according to claim 11, characterized in that one or more compounds according to one or more of claims 1 to 6 are processed to finished medical forms with suitable pharmacologically acceptable carriers and adjuvants.
13. Medicament according to claim 11, characterized in that it i╬╡ present in a solid, peroral administrable form as a tablet, capsule, coated tablet, or as a liquid, peroral administrable solution, suspension, effervescent tablet, in the form of tabs or sachets, optionally in sustained action, and/or in gastric fluid-resistant form.
14. Medicaments according to claim 11, characterized in that it is present in the form of a suitable injection or infusion preparation together with suitable pharmaceutically acceptable carriers and adjuvants, optionally in sustained action form and or as a parenteral depot medicinal form or implant or is used in the form of a concentrate, powder or lyophilisate and the parenteral dilution agent is optionally manufactured in the packaging separately therefrom, so that the mixing of components contained therein with a common parenterally applicable dilution agent is possible immediately before use .
15. Medicament according to claim 11, characterized in that it is present in the form of an inhalation therapeutic agent, for example, in the form of a spray together with suitable pharmaceutically acceptable propellants, carriers and adjuvants .
16. Medicament according to claim 11, characterized in that it is present in the form of a transdermal therapeutic system for systemic treatment .
17. Medicament according to claim 11, characterized in that it is present in the form of a gastrointestinal therapeutic system (GITS) for systemic treatment.
18. Medicament according to claim 11, characterized in that it is present in the form of a salve, suspension, emulsion, a balm or plaster or in the form of an externally applicable solution.
19. Medicament according to claim 15 for administration by means of a controlled dosage aerosol or in the form of a dry powder dosage formulation.
20. Medicament according to claim 11, characterized in that it is present in the form of a rectal, genital, or transurethral administration emulsion, a solution, a liposomal solution, an implant, suppository or a capsule.
21. Medicament according to claim 11, characterized in that it is present in the form of a composition capable of being applied nasally, otologically or ophthalmologically .
22. Medicament according to one of the claims 11 or 13, characterized in that it is present in the form of a buccally applicable form.
23. Medicament according to one of the claims 11, 13 to 15, and 19, characterized in that a dosage unit for single administration contains 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 1, 2, 5, 10, 20, 25, 30, 50, 75, 100, 200, 300, 400, 500, 600 or 800 mg active ingredient according to the claims 1 to 6.
24. Medicament according to claim 15, characterized in that the pharmaceutically acceptable carrier and/or diluent is a propellant aerosol .
25. Medicament according to claim 15 or 24, characterized in that the propellant aerosol is tetrafluoroethane and/or heptafluoropropane and/or propane, butane, or dimethyl ether or mixtures thereof .
26. Medicament according to one of the claims 15, 24 or 25, characterized in that the propellant aerosol contains surface active adjuvants.
27. Medicament according to one of the claims 11 or 15, characterized in that it contains glucose and/or lactose as a dry powder dosage.
28. Substance or substance mixture according to one of the claims 8 or 9 , characterized in that the therapeutic use occurs in combination with a further cytostatic agent or immunosuppressive agent.
29. Use of one or more compounds according to one of claims 1 to 6 or 8 for treatment of the human or animal body in the medical indications named in claim 9 as well as a diagnostic agent .
30. Medicament according to one of the claims 11 and 13 to 27, characterized in that it is present in combination with a further cytostatic agent or immunosuppressive agent, optionally in the form of separate dosage units in the pharmaceutical package.
31. Use of one or more compounds according to one of claims 1 to 6 for treatment of the human or animal body in the medical indications named in claim 9.
PCT/EP1998/008272 1997-12-17 1998-12-16 Aryl-substituted pyridylalkane, alkene, and alkine carboxamides useful as cytostatic and immunosuppressive agents WO1999031064A1 (en)

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US11584766B2 (en) 2018-02-05 2023-02-21 The Trustees Of Indiana University Nicotinamide phosphoribosyltransferase inhibitors and methods for use of the same
US12030901B2 (en) 2018-02-05 2024-07-09 The Trustees Of Indiana University Nicotinamide phosphoribosyltransferase inhibitors and methods for use of the same

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JP4838934B2 (en) 2011-12-14
DE69830855D1 (en) 2005-08-18
ES2246073T3 (en) 2006-02-01
EP1042291B1 (en) 2005-07-13
US7320993B1 (en) 2008-01-22
DE69830855T2 (en) 2006-05-24
ZA9811240B (en) 1999-06-08
PT1042291E (en) 2005-11-30
JP2002508357A (en) 2002-03-19
AU2274099A (en) 1999-07-05
DE19756261A1 (en) 1999-07-01
EP1042291A1 (en) 2000-10-11
ATE299495T1 (en) 2005-07-15

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