Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • C07D491/12—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 three hetero rings
  • C07D491/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
• U.S. Pat. No. 4,468,400 describes tricyclic imidazo[1,2-a]pyridines with various ring systems fused to the imidazopyridine parent structure, which should be suitable for the treatment of peptic ulcers.
• International Patent Application WO 95/27714 discloses certain substituted tricyclic imidazo[1,2-a]pyridines which are said to reversibly inhibit gastric acid secretion and to be useful in the prevention and treatment of gastrointestinal inflammatory diseases.
• International Patent Application WO 98/42707 discloses tetrahydroimidazo[1,2-h][1,7]naphthyridines which shall be suitable for the prevention and treatment of gastrointestinal diseases.
• WO 98/54188 describes fused dihydropyrans, which are said to be suitable for the treatment of peptic ulcer disorders.
• German Offenlegungsschrift 43 08 095 certain prodrug derivatives of pharmaceutically active agents with hydroxyl groups are disclosed.
• the invention relates to compounds of the formula 1
• R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl
• R2 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl or 2-4C-alkynyl,
• R3 is hydrogen, halogen, trifluoromethyl, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b,
• one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R4′, or in which R4a and R4b together are O (oxygen),
• R4′ is a radical from which a hydroxyl group is formed under physiological conditions
• one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R5′, or in which R5a and R5b together are O (oxygen),
• R5′ is a radical from which a hydroxyl group is formed under physiological conditions
• R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl,
• R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy and
• X is O (oxygen) or NH
• R3a is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R3b is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R3a and R3b together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino or morpholino radical,
• 1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and the methyl radical.
• Hydroxy-1-4C-alkyl represents abovementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl radical, the 2-hydroxyethyl radical and the 3-hydroxypropyl radical.
• Halogen within the meaning of the invention is bromine, chlorine or fluorine.
• 2-4C-Alkenyl represents straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl radical, 3-butenyl radical, 1-propenyl radical and the 2-propenyl radical (allyl radical).
• 2-4C-Alkynyl represents straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl radical, 3-butynyl radical and preferably the 2-propynyl radical (propargyl radical).
• 1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, Examples which may be mentioned are the butoxy radical, isobutoxy radical, sec-butoxy radical, tert-butoxy radical, propoxy radical, isopropoxy radical and preferably the ethoxy radical and methoxy radical.
• 1-4C-alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl radical, the methoxyethyl radical and the butoxyethyl radical.
• Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by a fluoro-1-4C-alkoxy radical.
• Fluoro-1-4C-alkoxy in this case represents one of the abovementioned 1-4C-alkoxy radicals which is completely or partly substituted by fluorine.
• Examples of 1-4C-alkoxy completely or partly substituted by fluorine which may be mentioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy radical, the 2-trifluormethyl-2-propoxy radical, the 1,1,1-trifluoro-2-propoxy radical, the perfluoro-tert-butoxy radical, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy radical, the 4,4,4-trifluoro-1-butoxy radical, the 2,2,3,3,3-pentafluoropropoxy radical, the perfluoroethoxy radical, the 1,2,2-trifluoroethoxy radical, in particular the 1,1,2,2-tetrafluoroethoxy radical, the 2,2,2-trifluoroethoxy radical, the trifluormethoxy radical and preferably the difluoromethoxy radical.
• 1-4C-Alkoxy-1-4C-alkoxy represents one of the abovementioned 1-4C-alkoxy radicals which is substituted by a further 1-4C-alkoxy radical.
• examples which may be mentioned are the radicals 2-(methoxy)ethoxy (CH 3 —O—CH 2 —CH 2 —O—) and 2-(ethoxy)ethoxy (CH 3 —CH 2 —O—CH 2 —CH 2 —O—).
• 1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals.
• An example which may be mentioned is the acetyl radical.
• 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom.
• An example which may be mentioned is the acetoxy radical (CH 3 CO—O—).
• a radical from which a hydroxyl group is formed under physiological conditions is understood as meaning a radical —OR′, from which the group R′ is removed hydrolytically in the human or animal body with formation of the radical —OH and the nontoxic compound R′OH.
• the radical R′ can thus also be designated as a hydroxy protective group or as a “prodrug” radical.
• Such hydroxy protective groups or “prodrug” radicals are known, inter alia, from the patent applications and patents DE 4308095, WO 95114016, EP 694547, WO 95/11884, WO 94/05282 and U.S. Pat. No. 5,432,183.
• radicals R′ having the general structure—C(O)R, —C(O)NRaRb, —P(O)ORaORb or —S(O) 2 OR can be mentioned, where R, Ra and Rb are any desired organic radicals or optionally hydrogen.
• R4′ and R5′ have a common hydroxy protective group R′, which can then have, for example, one of the structures —CRaRb—, —CRa(ORb)—, —C(ORa)(ORb)— or —P(O)OR—.
• 1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl radical (CH 3 O—C(O)—) and the ethoxycarbonyl radical (CH 3 CH 2 O—C(O)—).
• 1-4C-Alkoxycarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the ethoxycarbonylamino radical and the methoxycarbonylamino radical.
• 1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy-1-4C-alkoxy radicals is bonded.
• Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl radical (CH 3 —O—CH 2 CH 2 —O—CO—) and the 2-(ethoxy)ethoxycarbonyl radical (CH 3 CH 2 —O—CH 2 CH 2 —O—CO—).
• 1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino radical and the 2-(ethoxy)ethoxycarbonylamino radical.
• Radicals R′ to be mentioned in the context of the invention are the groups to be emphasized by way of example
• alk is 1-7C-alkylene
• R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by halogen, carboxyl, hydroxyl, sulfo (—SO 3 H), sulfamoyl (—SO 2 NH 2 ), carbamoyl (—CONH 2 ), 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
• R9 is hydrogen or 1-4C-alkyl
• R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1 -4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl and
• R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy.
• 1-7C-Alkylene represents straight-chain or branched 1-7C-alkylene radicals, for example the methylene radical (—CH 2 —), ethylene radical (—CH 2 CH 2 —), trimethylene radical (—CH 2 CH 2 CH 2 —), tetramethylene radical (—CH 2 CH 2 CH 2 CH 2 —), 1,2-dimethylethylene radical [—CH(CH 3 )—CH(CH 3 )—], 1,1-dimethylethylene radical [—C(CH 3 ) 2 —CH 2 —], 2,2-dimethylethylene radical [—CH 2 —C(CH 3 ) 2 —], isopropylidene radical [—C(CH 3 ) 2 —], 1-methylethylene radical [—CH(CH 3 )—CH 2 —], pentamethylene radical (—CH 2 CH 2 CH 2 CH 2 —), hexamethylene radical (—CH 2 CH 2 CH 2 CH 2 CH 2 —) and the heptamethylene radical (—CH 2 CH
• 1-10C-Alkyl within the meaning of the present invention represents straight-chain, branched or cyclic alkyl radicals having 1 to 10 carbon atoms.
• Examples which may be mentioned are the menthyl radical, neomenthyl radical, isomenthyl radical, neoisomenthyl radical, octyl radical, isooctyl radical (6-methylheptyl radical), heptyl radical, isoheptyl radical (5-methylhexyl radical), hexyl radical, isohexyl radical (4-methylpentyl radical), neohexyl radical (3,3-dimethylbutyl radical), pentyl radical, isopentyl radical (3-methylbutyl radical), neopentyl radical (2,2-dimethylpropyl radical), butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropy
• radicals R′ to be mentioned as particularly to be emphasized by way of example are the groups —C(O)—N(CH 3 ) 2 , —C(O)—N(C 2 H 5 ) 2 , —C(O)—NHC 2 H 5 , —C(O)—CH 2 CH 2 NH 2 , —C(O)—(CH 2 ) 3 NH 2 , —C(O)—C(CH 3 ) 2 NH 2 , —C(O)—CH 2 N(CH 3 ) 2 , —C(O)—CH(NH 2 )—CH(CH 3 ) 2 , —C(O)—CH(NH 2 )CH(CH 3 )C 2 H 5 , —C(O)—(CH 2 ) 6 C(O)N(CH 3 )CH 2 CH 2 SO 3 H, —P(O)(OH) 2 , —S(O) 2 NH 2 , —C(O)—NH 2 ,
• Pharmacologically intolerable salts which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
• the compounds according to the invention and their salts if they are isolated, for example, in crystalline form, can contain various amounts of solvents.
• the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
• the compounds of the formula I have at least two chiral centers.
• the invention relates to all conceivable stereoisomers in any desired mixing ratio with one another, including the pure enantiomers, which are a preferred subject of the invention.
• One embodiment (embodiment a) of the invention are compounds of the formula 1 in which R3 is hydrogen.
• a further embodiment (embodiment b) of the invention are compounds of the formula 1 in which R3 is halogen.
• a further embodiment (embodiment c) of the invention are compounds of the formula 1 in which R3 is carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b.
• a preferred radical R1 by way of example is the methyl radical.
• Preferred radicals R2 by way of example are the hydroxymethyl radical and in particular the methyl radical.
• R3 in the context of the present invention is preferably hydrogen, halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl
• R3 is hydrogen, halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b,
• one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R4a and R4b together are O (oxygen),
• one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R5a and R5b together are O (oxygen),
• R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl,
• R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy and
• X is O (oxygen) or NH
• R3a is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R3b is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R3a and R3b together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino or morpholino radical,
• R′ is selected from the group consisting of
• alk is 1-7C-alkylene
• R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by halogen, carboxyl, hydroxyl, sulfo (—SO 3 H), sulfamoyl (—SO 2 NH 2 ), carbamoyl (—CONH 2 ), 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
• R9 is hydrogen or 1-4C-alkyl
• R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl and
• R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,
• one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical—OR′, or in which R4a and R4b together are O (oxygen),
• one of the substituents R5a and R5b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R5a and R5b together are O (oxygen),
• R6 is hydrogen
• R7 is hydrogen
• X is O (oxygen) or NH
• R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R3b is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R′ is selected from the group consisting of
• alk is 1-7C-alkylene
• R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by carboxyl or sulfo (—SO 3 H),
• R9 is hydrogen or 1-4C-alkyl
• R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluormethyl and
• R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R1 is methyl
• R2 is methyl
• R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,
• one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
• one of the substituents R5a and R5b is hydrogen and the other is the radical —OR′,
• R6 is hydrogen
• R7 is hydrogen
• X is O (oxygen) or NH
• R3a is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and
• R3b is hydrogen, methyl or ethyl
• R′ is selected from the group consisting of
• alk is 1-7C-alkylene
• R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by carboxyl or sulfo (—SO 3 H),
• R9 is hydrogen or 1-4C-alkyl
• R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or trifluoro-methyl and
• R11 is hydrogen or halogen
• Preferred compounds of the invention are those of the formula 1*,
• R1 is methyl
• R2 is methyl
• R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,
• one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
• R5a is the radical —OR′
• R5b is hydrogen
• R6 is hydrogen
• R7 is hydrogen
• X is O (oxygen) or NH
• R3a is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and
• R3b is hydrogen, methyl or ethyl
• R′ is selected from the group consisting of
• alk is 1-4C-alkylene
• R8 is hydrogen, 1-4C-alkyl or menthyl
• R9 is hydrogen or 1-4C-alkyl
• R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or trifluoro-methyl and
• R11 is hydrogen or halogen
• Preferred compounds of embodiment a of the invention are those of the formula 1* in which R3 is hydrogen.
• Preferred compounds of embodiment b of the invention are those of the formula 1* in which R3 is chlorine or fluorine.
• Preferred compounds of embodiment c of the invention are those of the formula 1* in which R3 is hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b.
• the compounds according to the invention can thus be prepared as described by way of example in the following examples, or using analogous process steps starting from corresponding starting compounds (see, for example, WO 98/42707, WO 98/54188, EP-A-299470 or Kaminski et al., J. Med. Chem. 1985, 28, 876-892 and Angew. Chem. 1996, 108, 589-591).
• the starting compounds are known or they can be prepared in an analogous manner to the known compounds.
• the compounds according to the invention can be prepared, for example, according to the following reaction schemes.
• the group Y in the above compound 3 is a suitable leaving group, for example a halogen atom, preferably chlorine.
• the acylation is carried out in a manner habitual to the person skilled in the art, preferably using bis(trimethylsilyl)sodium amide or -potassium amide if the leaving group is a chlorine atom.
• oxidation following the acylation is likewise carried out under conditions customary per se using chloranil, atmospheric oxygen or manganese dioxide as an oxidant.
• auxiliary acid for the subsequent protective group removal and cyclization, certain conditions have to be fulfilled with respect to the auxiliary acid to be used.
• formic acid is employed as an auxiliary acid.
• the starting materials to be used are 3-hydroxy-3-phenylpropionic acid derivatives (appropriately protected on the hydroxyl group) in which Y (analogously to the above scheme) is a suitable leaving group.
• the above scheme 2 likewise, by way of example, is an enantioselective synthesis.
• Y is again a suitable leaving group, for example a methoxy group.
• the isolation and purification of the substances according to the invention are carried out in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on suitable support material.
• Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added.
• a suitable solvent e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added.
• the salts are obtained by filtering, reprecipitating, precipitating with anonsolvent for the addition salt or by evaporating the solvent.
• Salts obtained can be converted by alkalization or by acidification into the free compounds, from which salts can in turn be prepared. In this manner, pharmacologically nontolerable salts can be converted into pharmacologically tolerable salts.
• the pure enantiomers in particular the pure enantiomers of the formula 1*, which are a preferred subject of the invention, can be obtained in a manner familiar to the person skilled in the art, for example by enantioselective synthesis (see, for example, the scheme), by chromatographic separation on chiral separating columns, by derivatization with chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group, by salt formation with chiral acids, subsequent resolution of the salts and release of the desired compound from the salt, or by (fractional) crystallization from a suitable solvent.
• Trans products obtained e.g.
• acidic conditions e.g. in 2 equivalents of acid, such as sulfuric acid
• cis products can be converted into the corresponding trans products.
• the cis and trans products are separated, for example, by chromatography or by crystallization.
• the starting compounds of the formula 2 can be prepared starting from compounds known from the literature or with analogous use of processes known from the literature (e.g. Kaminski et al., J. Med. Chem. 1985, 28, 876-892), for example according to the general scheme 3 below:
• the reaction to give the compound 4 is carried out in a manner such as is known to the person skilled in the art.
• the reaction of 4 to 5 can be carried out in various ways, for example using the Heck reaction (with Pd(II), carbon monoxide and ethanol) or by metallation in the 6-position (with lithium or magnesium) and subsequent Grignard reaction.
• the metallation also offers the possibility of introducing other desired groups R3 in position 6, for example fluorine, chlorine or the carboxyl group.
• the debenzylation/reduction of the compound 5 is likewise carried out in a manner known per se, for example using hydrogen/Pd(0). If compounds where R3 ⁇ —CO—NR5R6 are desired, an appropriate derivatization can be carried out in a manner known per se (conversion of an ester into an amide) at the stage of the compound 5 or after the debenzylation/reduction.
• the title compound is obtained as a colorless viscous oil by reaction of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with 3-nitrobenzoyl chloride analogously to example 6.
• the title compound is obtained as a yellowish foam by reaction of (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with N,N-diethylcarbamoyl chloride analogously to example 8.
• a mixture of 31.8 g of 2-amino-3,5-dibromopyridine, 22 g of 3-bromo-2-butanone and 350 ml of tetrahydrofuran is heated to reflux for 9 days, and the precipitate formed is filtered off and dried in vacuo. It is then suspended in 1 l of water and adjusted to pH 8 using 6 molar aqueous sodium hydroxide solution. The precipitate formed here is filtered off and washed with water. 28 g of the title compound of melting point above 90° C. (sintering) are obtained.
• the catalyst is then filtered off, the filter cake is washed with 200 ml of methanol, the filtrate is concentrated to dryness in vacuo, the residue is stirred with 200 ml of chloroform and insoluble material is filtered off. The filter cake is washed well with 150 ml of chloroform and the filtrate is concentrated to dryness in vacuo. 142 g of the title compound of melting point 178-9° C. (2-propanol) are obtained.
• 6 g of the title compound are obtained as a colorless powder of melting point 108-110° C. after purification on silica gel according to example L, method a, starting from (7S,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine.
• the compounds of the formula 1 and their salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals, in particular humans.
• the compounds according to the invention are distinguished by a high selectivity, an advantageous duration of action, a particularly good enteral activity, the absence of significant side effects and a large therapeutic breadth.
• Gastric and intestinal protection in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions, and of gastric acid-related diseases in mammals including man (such as, for example, gastric ulcers, duodenal ulcers, gastritis, hyperacidic or medicament-related functional gastropathy, reflux esophagitis, Zollinger-Ellison syndrome, heartburn), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori ), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics), chemicals (e.g. ethanol), gastric acid or stress situations.
• microorganisms e.g. Helicobacter pylori
• bacterial toxins e.g. certain antiinflammatories and antirheumatics
• chemicals e.g. ethanol
• the compounds according to the invention surprisingly prove to be markedly superior to the compounds known from the prior art in various models in which the antiulcerogenic and the antisecretory properties are determined.
• the compounds of the formula 1 and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.
• the invention therefore further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
• the invention likewise comprises the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.
• the invention furthermore comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
• the invention further relates to medicaments which contain one or more compounds of the formula 1 and/or their pharmacologically tolerable salts.
• the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
• a pharmaceutical administration form e.g. a delayed-release form or an enteric form
• excipients and vehicles are suitable for the desired pharmaceutical formulations.
• solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or in particular permeation promoters and complexing agents (e.g. cyclodextrins).
• the active compounds can be administered orally, parenterally or percutaneously.
• the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other pharmaceutical groups.
• tranquillizers for example from the benzodiazepines group, e.g. diazepam
• spasmolytics e.g. bietamiverine or camylofine
• anticholinergics e.g. oxyphencyclimine or phencarbamide
• local anesthetics e.g. tetracaine or procaine
• enzymes for example from the benzodiazepines group, e.g. diazepam
• spasmolytics e.g. bietamiverine or camylofine
• anticholinergics e.g. oxyphencyclimine or phencarbamide
• local anesthetics e.g. tetracaine or procaine
• also enzymes e.g. tetracaine or procaine
• H 2 blockers e.g. cimetidine, ranitidine
• H + /K + ATPase inhibitors e.g. omeprazole, pantoprazole
• peripheral anticholinergics e.g.
• pirenzepine pirenzepine, telenzepine
• gastric antagonists with the aim of potentiating the main action in the additive or superadditive sense and/or of eliminating or lowering the side effects, or furthermore the combination with antibacterially active substances (such as cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of Helicobacter pylori .
• antibacterially active substances such as cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts
• antibacterially active combination components examples include meziocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combinations thereof (e.g. clarithromycin+metronidazole).
• the body temperature of the animals was kept at a constant 37.8-38° C. by means of infrared irradiation and heating pads (automatic, step-free control via a rectal temperature sensor).

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