WO2012152915A1 - Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy - Google Patents

Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy Download PDF

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Publication number
WO2012152915A1
WO2012152915A1 PCT/EP2012/058760 EP2012058760W WO2012152915A1 WO 2012152915 A1 WO2012152915 A1 WO 2012152915A1 EP 2012058760 W EP2012058760 W EP 2012058760W WO 2012152915 A1 WO2012152915 A1 WO 2012152915A1
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alkyl
crc
benzo
benzyl
tetrahydro
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PCT/EP2012/058760
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French (fr)
Inventor
Wilhelm Amberg
Udo Lange
Michael Ochse
Frauke Pohlki
Berthold Behl
Mario Mezler
Wilfried Hornberger
Charles W. Hutchins
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Abbott Gmbh & Co. Kg
Abbott Laboratories
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Priority to CA2834712A priority Critical patent/CA2834712A1/en
Priority to JP2014509754A priority patent/JP2014513145A/en
Priority to EP12723134.8A priority patent/EP2707358A1/en
Priority to CN201280023049.8A priority patent/CN103702983A/en
Priority to MX2013013223A priority patent/MX2013013223A/en
Publication of WO2012152915A1 publication Critical patent/WO2012152915A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • Benzazepine derivatives Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
  • the present invention relates to benzazepine derivatives, pharmaceutical compositions comprising such benzazepine derivatives, and the use of such benzazepine derivatives for therapeutic purposes.
  • the benzazepine derivatives are GlyT1 inhibitors.
  • Dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease and bipolar disorder.
  • CNS central nervous system
  • a large number of studies in animal models lend support to the NMDA hypofunction hypothesis of schizophrenia.
  • NMDA receptor function can be modulated by altering the availability of the co-agonist glycine.
  • This approach has the critical advantage of maintaining activity-dependent activation of the NMDA receptor because an increase in the synaptic concentration of glycine will not produce an activation of NMDA receptors in the absence of glutamate. Since syn- aptic glutamate levels are tightly maintained by high affinity transport mechanisms, an increased activation of the glycine site will only enhance the NMDA component of activated synapses.
  • GlyT1 and GlyT2 Two specific glycine transporters, GlyT1 and GlyT2 have been identified and shown to belong to the Na/CI-dependent family of neurotransmitter transporters which includes taurine, gamma-aminobutyric acid (GABA), proline, monoamines and orphan transporters.
  • GlyT1 and GlyT2 have been isolated from different species and shown to have only 50% identity at the amino acid level. They also have a different pattern of expression in mammalian central nervous system, with GlyT2 being expressed in spinal cord, brainstem and cerebellum and GlyT1 present in these regions as well as forebrain areas such as cortex, hippocampus, septum and thalamus.
  • GlyT2 has been reported to be expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1 appears to be preferentially expressed by glial cells.
  • GlyT1 blockade of GlyT1 with the potent inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])- sarcosine (NFPS) potentiates NMDA receptor activity and NMDA receptor-dependent long-term potentiation in rat.
  • NFPS sarcosine
  • Glycine transporter inhibitors are already known in the art, for example:
  • the present invention relates to benzazepine derivatives of the formula (I)
  • R is R 1 -W-A 1 -Q-Y-A 2 -X 1 - or -CN;
  • R 1 is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl, trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyi, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl, alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl, dialkylaminocarbonyl- aminoalkyl, alkylsulfonylaminoalkyi, (optionally substituted arylalkyi) aminoalkyi, optionally substituted arylalkyi, optionally substituted heterocyclylalkyl, cycloalkyl, al- kylcarbonyl, alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl,
  • W is -NR - or a bond
  • a 1 is optionally substituted alkylene or a bond;
  • Q is -S(0) 2 - or -C(O)-;
  • Y is -NR 9 - or a bond; is optionally substituted alkylene, alkylene-CO-, -CO-alkylene, alkylene-O-alkylene, alkylene-NR 10 -alkylene, optionally substituted alkenylene, optionally substituted al- kynylene, optionally substituted arylene, optionally substituted heteroarylene or a bond; is -0-, -NR 11 -, -S-, optionally substituted alkylene, optionally substituted alkenylen, optionally substituted alkynylene; is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl, -CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated alkoxy, alkoxycarbonyl, al
  • R 3 is hydrogen, halogen, alkyi or alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;
  • X 2 is -0-, -NR 6 -, -S-, >CR 12a R 12b or a bond
  • X 3 is -0-, -NR 7 -, -S-, >CR 13a R 13b or a bond
  • R 5 is optionally substituted aryl, optionally substituted cycloalkyi or optionally substituted heterocyclyl;
  • R 6 is hydrogen or alkyi;
  • R 7 is hydrogen or alkyi
  • R 8 is hydrogen or alkyi
  • R 9 is hydrogen, alkyi, cycloalkyi, aminoalkyi, optionally substituted arylalkyi or heterocyclyl; or
  • R 9 is alkylene that is bound to a carbon atom in A 2 and A 2 is alkylene or to a carbon atom in X 1 and X 1 is alkylene;
  • R 10 is hydrogen, alkyi or alkylsulfonyl;
  • R 11 is hydrogen or alkyi, or R 9 , R 11
  • R 12a is hydrogen, optionally substituted alkyi, alkylaminoalkyi, dialkylaminoalkyi, hetero- cyclylalkyl, optionally substituted aryl or hydroxy;
  • R 12b is hydrogen or alkyi, or
  • carbonyl or optionally substituted alkylene wherein one -CH 2 - of alkylene may be replaced by an oxygen atom or -NR 14 -; is hydrogen, optionally substituted alkyi, alkylaminoalkyi, dialkylaminoalkyi, hetero- cyclylalkyl, optionally substituted aryl or hydroxy; is hydrogen or alkyi, or
  • R 14 is hydrogen or alkyi
  • R 15 is hydrogen or alkyi
  • the present invention relates to benzazepine derivatives having the formula (la)
  • R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • the present invention relates to benzazepine derivatives of formula (I) wherein R is -CN, i.e. benzazepine derivatives having the formula (lb)
  • R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • benzazepine derivative is used herein to denote in particular benzazepines and benzazepine derivatives wherein the fused heterocyclic ring contains a further het- eroatom.
  • Said compounds of formula (I), i.e., the benzazepine derivatives of formula (I) and their physiologically tolerated salts, are glycine transporter inhibitors and thus useful as pharmaceuticals.
  • the compounds of formula (I) display good to moderate metabolic stability.
  • the present invention thus further relates to the compounds of formula (I) for use in therapy.
  • the present invention also relates to pharmaceutical compositions which comprise a carrier and a compound of formula (I).
  • said compounds i.e., the benzazepine derivatives and their physiologically tolerated salts, are inhibitors of the glycine transporter GlyT1.
  • the present invention thus further relates to the compounds of formula (I) for use in inhibiting the glycine transporter.
  • the present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 and corresponding methods of inhibiting the glycine transporter GlyT1 .
  • Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are known to be useful in treating a variety of neurologic and psychiatric disorders.
  • the present invention thus further relates to the compounds of formula (I) for use in treating a neurologic or psychiatric disorder.
  • the present invention further relates to the compounds of formula (I) for use in treating pain.
  • the present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating a neurologic or psychiatric disorder and correspond- ing methods of treating said disorders.
  • the present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating pain and corresponding methods of treating pain.
  • the present invention further relates to benzazepines derivatives of formula (II):
  • L is an amino-protecting group
  • Y is NR 9
  • a 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are defined as herein.
  • the benzazepine derivatives of the formula (I) of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enanti- omers, diastereomers and tautomers of the compounds of formula (I) and/or of their salts.
  • an enantiomer of the benzazepine derivatives of the present invention has the following fo
  • R, R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • an enantiomer of the benzazepine derivatives of the present invention has the following formula:
  • R, R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • physiologically tolerated salts of the benzazepine derivatives of the formula (I) are especially acid addition salts with physiologically tolerated acids.
  • suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C 1 -C 4 -alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic ac- ids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid.
  • physiologically tolerated salts of the benzazepine derivatives also include salts of a physiologically tolerated anion with an benzazepine derivatives wherein one or more than one nitrogen atom is quaternized, e.g. with an alkyl residue (e.g. methyl or ethyl).
  • the present invention moreover relates to compounds of formula (I) as defined herein, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 12 C by 13 C, 14 N by 15 N, 16 0 by 18 0) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.
  • stable, non-radioactive isotope e.g., hydrogen by deuterium, 12 C by 13 C, 14 N by 15 N, 16 0 by 18 0
  • at least one hydrogen atom has been replaced by a deuterium atom.
  • such compounds contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds (I).
  • Stable isotopes are nonradioactive isotopes which contain one or more additional neutron than the normally abundant isotope of the respective atom.
  • Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non-deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
  • Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol.
  • Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process.
  • Deuterium tracers such as deuterium-labeled drugs and doses, in some cases repeatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 1 14: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet Gynecol. 1981 139: 948).
  • any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.
  • the weight percentage of hydrogen in a mammal indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201 : 357).
  • enrichment Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment.
  • the amount of enrichment include from about 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21 , 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71 , 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • the hydrogens present on a particular organic compound have different capacities for exchange with deuterium.
  • Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient.
  • Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D 2 S0 4 /D 2 0.
  • deuterium atoms may be incorporated in various combinations during the syn- thesis of compounds of the invention.
  • Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.
  • Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant pro- cedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut,
  • the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
  • the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
  • substituted means that a radical is substituted with 1 , 2 or 3, especially 1 , substituent which are in particular selected from the group consist- ing of halogen, C-
  • -C 4 -Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, C 2 -C -alkyl such as ethyl, n-propyl, iso-propyl, n- butyl, 2-butyl, iso-butyl or tert-butyl.
  • -C 2 -Alkyl is methyl or ethyl
  • -C 3 -alkyl is additionally n-propyl or isopropyl.
  • CrC 6 -Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include methyl, C 2 -C 4 -alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 - dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,2-trimethylpropyl, 1 ,2,
  • Halogenated Ci-C -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least one, e.g.
  • 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethyl, diha- logenomethyl, trihalogenomethyl, (R)-l-halogenoethyl, (S)-l -halogenoethyl, 2- halogenoethyl, 1 , 1 -dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl, (R)-1 - halogenopropyl, (S)-l -halogenopropyl, 2-halogenopropyl, 3-halogenopropyl, 1 , 1 - dihalogenopropyl, 2,2-dihalogenopropyl, 3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl, (R)-2-halogeno-1-methylethyl, (S)
  • C 6 -Ci2-Aryl-CrC 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 6 -Ci 2 -aryl, such as in benzyl.
  • Hydroxy-CrC 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two hydroxyl groups, such as in hydroxy- methyl, (R)-l-hydroxyethyl, (S)-l -hydroxyethyl, 2-hydroxyethyl, (R)-l -hydroxypropyl, (S)- 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl, (S)-2- hydroxy-1 -methylethyl, 2-hydroxy-1 -(hydroxymethyl)ethyl, (R)-l-hydroxybutyl, (S)-1 - hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.
  • Ci-C 6 -Alkoxy-CrC 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4, in particular 1 or 2 carbon atoms, such as in methoxymethyl, (R)-l -methoxyethyl, (S)-l-methoxyethyl, 2-methoxyethyl, (R)-l-methoxypropyl, (S)-l-methoxypropyl, 2- methoxypropyl, 3-methoxypropyl, (R)-2-methoxy-1-methylethyl, (S)-2-methoxy-1 - methylethyl, 2-methoxy-1-(methoxymethyl)ethyl, (R)-l -methoxybutyl
  • Amino-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by an amino group, such as in aminomethyl, 2-aminoethyl.
  • Ci-C 6 -Alkylamino-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C 6 - alkylamino group, in particular by a Ci-C 4 -alkylamino group, such as in methylami- nomethyl, ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl, n- butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl or tert-butylaminomethyl.
  • Di-Ci-C 6 -Alkylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-Ci-C 6 - Alkylamino group, in particular by a di-Ci-C 4 -alkylamino group, such as in dimethylami- nomethyl.
  • Ci-C 6 -Alkylcarbonylamino-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C 6 - alkylcarbonylamino group, in particular by a C 1 -C 4 -alkylcarbonylamino group, such as in methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl, 2- butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl or tert- butylcarbonylaminomethyl.
  • C 1 -C 6 -Alkylaminocarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C 6 -alkylaminocarbonylamino group, in particular by a Ci-C 4 -alkylaminocarbonylamino group, such as in methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl, n- propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl, n- butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl, iso- butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl
  • Di-Ci-C 6 -alkylaminocarbonylamino-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-Ci-C 6 -alkylaminocarbonylamino group, in particular by a di-Ci-C 4 -alkylaminocarbo- nylamino group, such as in dimethylaminocarbonylaminomethyl, dimethylaminocarbonyl- aminoethyl, dimethylaminocarbonylaminon-propyl.
  • Ci-C 6 -Alkylsulfonylamino-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C 6 - alkylsulfonylamino group, in particular by a Ci-C 4 -alkylsulfonylamino group, such as in methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl, iso- propylsulfonylaminomethyl, n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl, iso- butylsulfonylaminomethyl or tert-butylsul
  • (C6-Ci2-Aryl-Ci-C 6 -alkyl)amino-Ci-C4 alkyl is a straight-chain or branched alkyl group hav- ing 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a (C 6 -Ci2-aryl-Ci-C 6 -alkyl)amino group, in particular a (C 6 -Ci2-aryl-Ci-C2-alkyl)amino group, such as in benzylaminomethyl.
  • C 3 -Ci2-Heterocyclyl-Ci-C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 3 -Ci 2 - heterocyclyl, such as in N-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.
  • C 3 -C 12 -Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbon atoms.
  • 3 to 6 carbon atoms form the cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cyclic structure may be unsubstituted or may carry 1 , 2, 3 or 4 C1-C4 alkyl radicals, preferably one or more methyl radicals.
  • CrC 6 -Alkylcarbonyl is a radical of the formula R-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.
  • Halogenated Ci-C 6 -alkylcarbonyl is CrC 6 -alkylcarbonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • Examples include fluoromethylcar- bonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are 1 , 1 , 1- trifluoroeth-2-ylcarbonyl, 1 , 1 , 1 -trifluoroprop-3-ylcarbonyl.
  • C 6 -Ci2-Arylcarbonyl is a radical of the formula R-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein.
  • R is an aryl radical having from 6 to 12 carbon atoms as defined herein.
  • Examples include benzoyl.
  • CrC 6 -Alkoxycarbonyl is a radical of the formula R-O-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methoxycarbonyl and tert-butyloxycarbonyl.
  • Halogenated Ci-C 6 -alkoxycarbonyl is a CrC 6 -alkoxycarbonyl as defined herein, wherein at least one, e.g.
  • C 6 -Ci 2 -Aryloxycarbonyl is a radical of the formula R-O-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenoxycarbonyl.
  • Cyano is -C ⁇ N.
  • Aminocarbonyl is NH 2 C(0)-.
  • Ci-C 6 -Alkylaminocarbonyl is a radical of the formula R-NH-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methylaminocarbonyl.
  • (Halogenated Ci-C 4 -alkyl)aminocarbonyl is a Ci-C 4 -alkylaminocarbonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different hydrogen atoms.
  • C 6 -Ci 2 -Arylaminocarbonyl is a radical of the formula R-NH-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylami- nocarbonyl.
  • C 2 -C 6 -Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1 -propen-1-yl, 2-propen-2-yl, methallyl(2- methylprop-2-en-1 -yl) and the like.
  • C 3 -C 5 -Alkenyl is, in particular, allyl, 1-methylprop-2-en- 1-yl, 2-buten-1 -yl, 3-buten-1 -yl, methallyl, 2-penten-1-yl, 3-penten-1 -yl, 4-penten-1-yl, 1 - methylbut-2-en-1 -yl or 2-ethylprop-2-en-1-yl.
  • C 2 -C 6 -Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1 -yl, 2-propyn-2-yl and the like.
  • C 3 -C 5 -Alkynyl is, in particular, 2-propyn-1 -yl, 2-butyn-1-yl, 3-butyn-1 -yl, 2-pentyn-1 -yl, 3-pentyn-1 -yl, 4- pentyn-1 -yl.
  • Ci-C 4 -Alkylene is straight-chain or branched alkylene group having from 1 to 4 carbon atoms. Examples include methylene and ethylene. A further example is propylene.
  • C 2 -C 4 -Alkenylene is straight-chain or branched alkenylene group having from 2 to 4 carbon atoms.
  • C 2 -C 4 -Alkynylene is straight-chain or branched alkynylene group having from 2 to 4 carbon atoms. Examples include propynylene.
  • C 6 -Ci 2 -Aryl is a 6- to 12-membered, in particular 6- to 10-membered, aromatic cyclic radi- cal. Examples include phenyl and naphthyl.
  • C 3 -Ci 2 -Arylene is an aryl diradical. Examples include phen-1 ,4-ylene and phen-1 ,3-ylene.
  • C-i-C 6 -Alkoxy is a radical of the formula R-0-, wherein R is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms.
  • R is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms.
  • Examples include meth- oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy), tert.-butoxy pentyloxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2- dimethylpropoxy, 1 -ethylpropoxy, hexyloxy, 1 , 1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 1- methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1 , 1- dimethylbutyloxy, 1
  • Halogenated Ci-C 6 -alkoxy is a straight-chain or branched alkoxy group having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethoxy, dihalogenomethoxy, trihalogenomethoxy, (R)-l -halogenoethoxy, (S)-l -halogenoethoxy, 2-halogenoethoxy, 1 , 1 - dihalogenoethoxy, 2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1- halogenopropoxy, (S)-l-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy, 1 , 1 - dihalogenopropoxy, 2,2-dihalogenopropoxy
  • Particular examples include the fluorinated C C 4 alkoxy groups as defined, such as trifluoromethoxy.
  • CrC 6 -Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by hydroxy. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2- hydroxyethoxy and the like.
  • Ci-C 6 -Alkoxy-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by one or two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include methoxymethoxy, 2-methoxyethoxy, 1 - methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1 -methyl-1 -methoxyethoxy, eth- oxymethoxy, 2-ethoxyethoxy, 1 -ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1 - methyl-1-ethoxyethoxy and the like.
  • Amino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon at- oms as defined herein, wherein one hydrogen atom is replaced by an amino group. Examples include 2-aminoethoxy.
  • Ci-C 6 -Alkylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include methylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy, iso- propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy, iso- butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy, 2- (ethylamino)ethoxy, 2-(n-propylamino)ethoxy, 2-(iso-propylamino)ethoxy, 2-(n- butylamino)ethoxy, 2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy, 2-(tert- butylamino)ethoxy.
  • Di-Ci-C 6 -alkylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a di- alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include dimethylaminomethoxy, diethylaminomethoxy, N-methyl-N- ethylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy, 2-(N-methyl-N- ethylamino)ethoxy.
  • Ci-C 6 -Alkylcarbonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an al- kylcarbonylamino group wherein the alkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include methylcarbonylaminomethoxy, ethyl- carbonylaminomethoxy, n-propylcarbonylaminomethoxy, iso- propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy, 2- butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy, tert-butylcarbonyl- aminomethoxy, 2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy, 2-(n- propylcarbonylamino)ethoxy, 2-(iso-propylcarbonylamino)ethoxy, 2-(n- butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonyl- amino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.
  • C 6 -Ci 2 -Arylcarbonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 - C- 12 -arylcarbonylamino group as defined herein.
  • Examples include 2- (benzoylamino)ethoxy.
  • Ci-C 6 -Alkoxycarbonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy, iso- propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy, 2- butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy, tert- butoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonyl- amino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy, 2-(iso- butoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.
  • C 2 -C 6 -Alkenyloxy is a radical of the formula R-0-, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms.
  • R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy (2-propen-1 -yloxy), 1-propen-1 -yloxy, 2-propen-2-yloxy, methal- lyloxy (2-methylprop-2-en-1 -yloxy) and the like.
  • C 3 -C 5 -Alkenyloxy is, in particular, allyloxy, 1-methylprop-2-en-1 -yloxy, 2-buten-1 -yloxy, 3-buten-1 -yloxy, methallyloxy, 2-penten-1 - yloxy, 3-penten-1 -yloxy, 4-penten-1 -yloxy, 1 -methylbut-2-en-1 -yloxy or 2-ethylprop-2-en-1 - yloxy.
  • C 6 -Ci 2 -Aryl-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -Ci 2 -aryl group as defined herein. Examples include benzyloxy.
  • Ci-C 6 -Alkylsulfonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkyl- sulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy, 2- [(2-methylpropyl)sulfonylamino]ethoxy.
  • (Halogenated Ci-C 6 -alkyl)sulfonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein the alkyl group is halogenated. Examples include 2- (trifluoromethylsulfonylamino)ethoxy.
  • C 6 -Ci2-Arylsulfonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 - arylsulfonylamino group as defined herein.
  • Examples include 2- (phenylsulfonylamino)ethoxy, 2-(naphthylsulfonylamino)ethoxy.
  • (C 6 -C 1 2-Aryl-C 1 -C6-alkyl)sulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is re- placed by a (Ce-C ⁇ -aryl-CrCe-alky sulfonylamino group, preferably by a (Ce-C ⁇ -aryl-C C 2 -alkyl)sulfonylamino group.
  • Examples include 2-(benzylsulfonylamino)ethoxy.
  • C 3 -Ci2-Heterocyclylsulfonylamino-Ci-C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -Ci 2 -heterocyclylsulfonylamino group as defined herein.
  • Examples include 2- (pyridin-3-yl-sulfonylamino)ethoxy.
  • C 3 -C 12 -Heterocyclyl-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -C-
  • Examples include 2-(N-pyrrolidinyl)ethoxy, 2-(N- morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.
  • CrC 2 -Alkylenedioxo is a radical of the formula -0-R-0-, wherein R is a straight-chain or branched alkylene group having from 1 or 2 carbon atoms as defined herein. Examples include methylenedioxo.
  • C 6 -Ci 2 -Aryloxy is a radical of the formula R-0-, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxy.
  • C 3 -Ci 2 -Heterocyclyloxy is a radical of the formula R-0-, wherein R is a C 3 -Ci 2 -heterocyclyl group having from 3 to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples include pyridin-2-yloxy.
  • CrC 6 -Alkylthio is a radical of the formula R-S-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • Examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3- methylbutylthio, 2,2-dimethylpropylthio, 1 -ethylpropylthio, hexylthio, 1 , 1- dimethylpropylthio, 1 ,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3- methylpentylthio, 4-methylpentylthio, 1 ,1 -dimethylbutylthio, 1 ,
  • Halogenated C-i-C 6 -alkylthio is a radical of the formula R-S-, wherein R is a halogenated alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • R is a halogenated alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include halogenomethylthio, dihalogenomethylthio, trihalogenomethylthio, (R)- 1-halogenoethylthio, (S)-l -halogenoethylthio, 2-halogenoethylthio, 1 , 1- dihalogenoethylthio, 2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio, (R)-1- halogenopropylthio, (S)-l -halogenopropylthio, 2-halogenopropylthio, 3- halogeno
  • CrC 6 -Alkylsulfinyl is a radical of the formula R-S(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include me- thylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1 -methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1- ethylpropylsulfinyl, hexylsulfinyl, 1 , 1 -dimethylpropylsulfinyl, 1 ,2-dimethylprop
  • CrC 6 -Alkylsulfonyl is a radical of the formula R-S(0) 2 -, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1 - methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2- dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1 ,1 -dimethylpropylsulfonyl, 1 ,2-dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl
  • Halogenated CrC 6 -alkyl)sulfonyl is a CrC 6 -alkylsulfonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • C 6 -Ci 2 -Arylsulfonyl is a radical of the formula R-S(0) 2 -, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonyl.
  • (C 6 -C 12 -Aryl-C 1 -C 4 -alkyl)sulfonyl is a radical of the formula R-S(0) 2 -, wherein R is a C 6 - Ci 2 -aryl-Ci-C 4 -alkyl radical, in particular a C 6 -Ci 2 -aryl-Ci-C 2 -alkyl radical as defined herein. Examples include benzylsulfonyl.
  • C 3 -C 12 -Heterocyclylsulfonyl is a radical of the formula R-S(0) 2 -, wherein R is C 3 -C 12 - heterocyclyl as defined herein.
  • Aminosulfonyl is NH 2 -S(0) 2 -.
  • Ci-C 6 -Alkylaminosulfonyl is a radical of the formula R-NH-S(0) 2 - wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.
  • R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, iso- propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl, tert-butylaminosulfonyl.
  • Di-Ci-C 6 -alkylaminosulfonyl is a radical of the formula RR'N-S(0) 2 - wherein R and R' are independently of each other an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminosulfonyl, diethylaminosul- fonyl, N-methyl-N-ethylaminosulfonyl.
  • C 6 -Ci 2 -Arylaminosulfonyl is a radical of the formula R-NH-S(0) 2 - wherein R is an aryl radical having from 6 to 12, preferably 6 carbon atoms as defined herein.
  • Amino is NH 2 .
  • CrC 6 -Alkylamino is a radical of the formula R-NH- wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino, tert-butylamino.
  • Ci-C 6 -alkyl is a Ci-C 6 -alkylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • -C 6 -alkylamino is a radical of the formula RR'N- wherein R and R' are independently of each other an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.
  • Di-(halogenated C"i-C 6 -alkyl)amino is a di-C"i-C 6 -alkylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • -C 6 -Alkylcarbonylamino is a radical of the formula R-C(0)-NH-, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein.
  • Examples include acetamido (methylcarbonylamino), propionamido, n-butyramido, 2- methylpropionamido (isopropylcarbonylamino), 2,2-dimethylpropionamido and the like.
  • (Halogenated Ci-C 6 -alkyl)carbonylamino is a Ci-C 6 -alkylcarbonylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • C 6 -Ci2-Arylcarbonylamino is a radical of the formula R-C(0)-NH-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylcar- bonylamino.
  • C 2 -C 6 -Alkenylamino is a radical of the formula R-NH-, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms.
  • R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms.
  • Examples include vinylamino, allylamino (2-propen-1-ylamino), 1 -propen-1-ylamino, 2-propen-2- ylamino, methallylamino (2-methylprop-2-en-1 -ylamino) and the like.
  • C 3 -C 5 -Alkenylamino is, in particular, allylamino, 1-methylprop-2-en-1 -ylamino, 2-buten-1 -ylamino, 3-buten-1 - ylamino, methallylamino, 2-penten-1-ylamino, 3-penten-1 -ylamino, 4-penten-1 -ylamino, 1- methylbut-2-en-1 -ylamino or 2-ethylprop-2-en-1 -ylamino.
  • CrC 6 -Alkylsulfonylamino is a radical of the formula R-S(0) 2 -NH-, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, iso- propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino, iso-butylsulfonylamino, tert-butylsulfonylamino.
  • (Halogenated Ci-C 6 alkyl)sulfonylamino is a Ci-C 6 -alkylsulfonylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
  • C 6 -C 12 -Arylsulfonylamino is a radical of the formula R-S(0) 2 -NH-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsul- fonylamino. Nitro is -N0 2 .
  • C 3 -C 12 -Heterocyclyl is a 3- to 12-membered heterocyclic radical including a saturated heterocyclic radical, which generally has 3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring forming atoms, and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7 ring forming atoms.
  • the heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound).
  • Preferred heterocyclic radicals comprise 1 nitrogen atom as ring member atom and optionally 1 , 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N.
  • preferred heterocyclic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1 , 2 or 3 further nitrogen atoms as ring members.
  • C 3 -Ci 2 -heterocyclyl examples include: C- or N-bound 3-4-membered, saturated rings, such as
  • N-bound, 5-membered, saturated rings such as
  • N-bound, 6-membered, saturated rings such as
  • pyridin-2-yl pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2- yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4- triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,4,5-tetrazin-3-yl;
  • N-bound, 5-membered, heteroaromatic rings such as
  • pyrrol-1 -yl pyrazol-1-yl, imidazol-1 -yl, 1 ,2,3-triazol-1 -yl, 1 ,2,4-triazol-1 -yl, tetrazol-1 -yl.
  • Heterocyclyl also includes bicyclic heterocycles, which comprise one of the described 5- or 6-membered heterocyclic rings and a further anellated, saturated or unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a futher anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring being saturated or unsaturated or aromatic.
  • bicyclic heterocycles which comprise one of the described 5- or 6-membered heterocyclic rings and a further anellated, saturated or unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a futher anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring being saturated or unsaturated or aromatic.
  • C 3 -Ci2-Heteroarylene is a heteroaryl diradical. Examples include pyrid-2,5-ylene and pyrid-2,4-ylene.
  • the variables R, R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 preferably have the following meanings which, when taken alone or in combination, represent particular embodiments of the benzazepine derivatives of the formula (I) or any other formula disclosed herein.
  • a is 1 , 2 or 3
  • b is 1 , 2, 3, 4, 5, 6 or 7 and c is 1.
  • R 2 these may be the same or different radicals.
  • R 3 these may be the same or different radicals.
  • R is cyano
  • R is R 1 -W-A 1 -Q-Y-A 2 -X 1 - and R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • R 1 is hydrogen, d-Ce-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or n- pentyl), C 3 -Ci2-cycloalkyl-Ci-C 4 -alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclo- hexylmethyl), halogenated ( Ce-alkyl (e.g.
  • d-C 6 -alkylcarbonyl CrC 6 -alkoxycarbonyl, halogenated Ci-C 6 - alkoxycarbonyl, C 6 -Ci2-aryloxycarbonyl, aminocarbonyl, Ci-C 6 -alkylaminocarbonyl, (halogenated Ci-C 4 -alkyl)aminocarbonyl, C 6 -Ci2-arylaminocarbonyl, C 2 -C 6 -alkenyl (e.g. prop- 1 ,2-en-1-yl), C 2 -C 6 -alkynyl, optionally substituted C 6 -Ci 2 -aryl (e.g.
  • Ci-C 6 -alkoxy e.g. tert-butyloxy
  • CrC 6 -alkoxy e.g. tert-butyloxy
  • C C 6 -hydroxyalkoxy Ci-C 6 -alkoxy-CrC 4 -alkoxy, amino-Ci-C 4 -alkoxy
  • Ci-C 6 -alkylamino-Ci- C 4 -alkoxy di-Ci-C 6 -alkylamino-Ci-C 4 -alkoxy
  • Ci-C 6 -alkylcarbonylamino-Ci-C 4 -alkoxy C 6 - Ci2-arylcarbonylamino-Ci-C 4 -alkoxy
  • Ci-C 6 -alkoxycarbonylamino-Ci-C 4 -alkoxy C 6 -Ci 2 - aryl-CrC -alkoxy
  • Ci-C 6 -alkyl dimethylamino
  • di-(halogenated Ci-C 6 -alkyl)amino Ci-C 6 - alkylcarbonylamino, (halogenated C"
  • R 1 is CrC 6 -alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl or n- pentyl), C 3 -Ci 2 -cycloalkyl-CrC 4 -alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclo- hexylmethyl), halogenated Ci-C 6 -alkyl (e.g.
  • amino-Ci-C 4 -alkyl amino-Ci-C 4 -alkyl, Ci-C 6 -alkylamino-Ci-C 4 -alkyl, di-Ci-C 6 - alkylamino-Ci-C 4 -alkyl, Ci-C 6 -alkyloxycarbonylamino-Ci-C 4 -alkyl, Ci-C 6 - alkylaminocarbonylamino-Ci-C 4 -alkyl, C 6 -Ci 2 -aryl-Ci-C 4 -alkyl, C 3 -Ci 2 -cycloalkyl (e.g.
  • cyclopropyl or cyclobutyl C 2 -C 6 -alkenyl (e.g. prop-1 ,2-en-1 -yl), optionally substituted C 6 - Ci 2 -aryl (e.g. phenyl), hydroxy, Ci-C 6 -alkylamino, (halogenated Ci-C 6 -alkyl)amino, di-Cr C 6 -alkylamino or optionally substituted C 3 -Ci 2 -heterocyclyl (e.g.
  • R 1 is CrC 6 -alkyl (e.g. ethyl or n-propyl), C 3 -Ci2-cycloalkyl-Ci-C 4 -alkyl (e.g. cyclopropylmethyl), C 3 -Ci 2 -cycloalkyl (e.g. cyclobutyl), or optionally substituted C 3 -Ci 2 - heterocyclyl (e.g. 3-pyridyl, 1 -methyl-1 ,2-diazol-4-yl, 1 -methyl-1 ,3-diazol-4-yl, 3-oxetanyl, 1 -methyl-pyrrol-3-yl).
  • C 3 -Ci2-cycloalkyl-Ci-C 4 -alkyl e.g. cyclopropylmethyl
  • C 3 -Ci 2 -cycloalkyl e.g. cyclobutyl
  • substituted C 6 -Ci 2 -aryl in particular includes C 6 -Ci 2 -aryl, such as phenyl or naphthyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, d-C 4 -alkyl, Ci-C 4 -haloalkyl, cyano, Ci-C 4 -alkoxy, CrC 4 -haloalkoxy, amino, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, morpholino and piperidinyl.
  • the same ap- plies to substituted C 6 -Ci 2 -aryl in substituted C 6 -Ci 2 -aryl-Ci-C 4 -alkyl.
  • substituted C 3 -Ci 2 -heterocyclyl in particular includes C 3 -C-
  • W is -NR 8 - and Y is a bond.
  • W is a bond and Y is -NR 9 -.
  • W is a bond and Y is a bond, especially if R 1 is a nitrogen-bound radical, e.g. nitrogen- bound heterocyclyl such as piperazinyl or morpholinyl.
  • Q is -S(0) 2 -. According to an alternative embodiment, Q is -C(O)-.
  • -W-A 1 -Q-Y- is -W-A 1 -S(0) 2 -NR 9 -, -NR 8 -S(0) 2 -, -A 1 - S(0) 2 - or -S(0) 2 -.
  • -W-A 1 -Q-Y- is -W-A 1 -CO- NR 9 - or -NR 8 -CO-.
  • a 1 is optionally substituted CrC 4 -alkylene or a bond.
  • substituted Ci- C 4 -alkylene in particular includes CrC 4 -alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, CrC 4 -alkyl and cyano.
  • a 1 is a bond. If A 1 is C C 4 -alkylene, W is preferably -NR 8 -.
  • a 2 is optionally substituted CrC 4 -alkylene (e.g. 1 ,2-ethylene), Ci-C 4 -alkylene-CO-, -CO- C C 4 -alkylene, Ci-C 4 -alkylene-0-CrC 4 -alkylene, Ci-C 4 -alkylene-NR 10 -Ci-C 4 -alkylene, optionally substituted C 6 -Ci 2 -arylene, optionally substituted C 6 -Ci 2 -heteroarylene or a bond. Additionally, A 2 may be optionally substituted C 2 -C 4 -alkenylen or optionally substituted C 2 -C 4 -alkynylene.
  • a 2 is optionally substituted CrC 4 -alkylene (e.g. 1 ,2- ethylene). More preferably, A 2 is CrC 4 -alkylene (e.g. 1 ,2-ethylene).
  • a 2 is optionally substituted C 6 -Ci 2 -arylene, in particular C 6 -Ci 2 -arylene selected from the group consisting of phen-1 ,4-ylene and phen-1 ,3-ylene, or optionally substituted C 6 -Ci 2 -heteroarylene, in particular C 6 -Ci 2 -heteroarylene selected from the group consisting of pyrid-2,5-ylene and pyrid-2,4-ylene.
  • X 1 is preferably optionally substituted Ci-C 4 -alkylene.
  • X 1 is in particular optionally substituted C 2 -C 4 -alkenylene or optionally substituted C 2 -C 4 -alkynylene.
  • substituted C 1 -C 4 -alkylene in particular includes C 1 -C 4 -alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, d- C 4 -alkyl, C 1 -C 4 -haloalkyl and cyano.
  • substituted C 2 -C 4 -alkenylene or substituted C 2 -C 4 -alkynylene in particular includes C 2 -C 4 -alkenylene or C 2 -C 4 -alkynylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and cyano.
  • substituted C 6 -Ci 2 -arylene in particular includes C 6 -Ci 2 -arylene substituted with 1 , 2 or 3 substituents selected from the group consisting of C 1 -C 4 -alkyl, C-
  • substituents selected from the group consisting of C 1 -C 4 -alkyl, C-
  • substituted C 6 -Ci 2 -heteroarylene in particular includes C 6 -Ci 2 - heteroarylene substituted with 1 , 2 or 3 substituents selected from the group consisting of CrC 4 -alkyl, CrC 4 -haloalkyl, CrC 4 -alkoxycarbonyl, cyano, Ci-C 4 -alkoxy, CrC 4 -haloalkoxy, CrC 4 -alkylsulfonyl, amino, Ci-C 4 -alkylamino, Ci-C 4 -dialkylamino, C 6 -Ci 2 -arylamino and C 3 -Ci 2 -heterocyclyl (e.g, morpholino or piperidinyl).
  • substituents selected from the group consisting of CrC 4 -alkyl, CrC 4 -haloalkyl, CrC 4 -alkoxycarbonyl, cyano, Ci-C 4 -alkoxy, CrC 4
  • X 1 is -0-, -NR 11 -, -S- or optionally substituted Ci-C 4 -alkylene (e.g. -CH 2 -, 1 ,2-ethylene or 1 ,3-popylene).
  • substituted CrC 4 -alkylene in particular includes Cr C 4 -alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C 4 -alkyl, CrC 4 -haloalkyl and cyano.
  • X 1 may be optionally substituted C 2 -C 4 -alkenylen or optionally substituted C 2 -C 4 -alkynylene (e.g. propynylene).
  • substituted C 2 -C 4 -alkenylene or substituted C 2 -C 4 -alkynylene in particular includes C 2 -C 4 -alkenylene or C 2 -C 4 -alkynylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, CrC 4 -alkyl, Ci-C 4 -haloalkyl and cyano.
  • X 1 is -0-, -NR 11 , -S-. More preferably, X 1 is -0-.
  • a 2 is a bond and X 1 is optionally substituted Ci-C 4 - alkylene, optionally substituted C 2 -C 4 -alkenylene or optionally substituted C 2 -C 4 - alkynylene.
  • R 1 -W-A 1 -Q-Y-A 2 -X 1 - is R 1 -S(0) 2 -NH-A 2 -X 1 -, R 1 -NH- S(0) 2 -A 2 -X 1 -, R 1 -C(0)-NH-A 2 -X 1 - or R 1 -NH-C(0)-A 2 -X 1 -.
  • the structural element -Y-A 2 -X 1 - comprises at least 2, 3 or 4 atoms in the main chain. According to further particular embodiments the structural element -Y-A 2 -X 1 - has up to 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4 atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.
  • -Y-A 2 -X 1 - is -Ci-C 4 -alkylene-0- or -NR 9 -Ci- C 4 -alkylene-0-, with -Y-A 2 -X 1 - preferably having 2 to 6, 3 to 5 and especially 4 atoms in the main chain.
  • Particular examples of -Y-A 2 -X 1 - include -(CH 2 ) 3 -0- and -NR 9 -(CH 2 ) 2 -0-.
  • R 9 is as defined herein and preferably R 9 is hydrogen, C-
  • R 9 is Ci-C 4 -alkylene that is bound to a carbon atom in A 2 which is C-i-C 4 -alkylene.
  • -Y-A 2 -X 1 - is -NR 9 -C-
  • R 9 is as defined herein and preferably R 9 is hydrogen, CrC 6 -alkyl (e.g. methyl or ethyl) or C 3 -C-
  • R 9 is Ci-C 4 -alkylene that is bound to a carbon atom in X 1 which is CrC 4 -alkylene.
  • -Y-A 2 -X 1 - is -NR 9 -C 2 -C 4 -alkenylene- or -NR 9 - C 2 -C 4 -alkynylene- (e.g. -NH-CH 2 -C ⁇ C-), with -Y-A 2 -X 1 - preferably having 2 to 6, 3 to 5 and especially 4 atoms in the main chain.
  • R 9 is as defined herein and preferably is R 9 is hydrogen, d-C 6 -alkyl (e.g. methyl or ethyl) or C 3 -Ci 2 -cycloalkyl (e.g. cyclopropyl or cyclobutyl). If A is a heterocyclic ring, this embodiment of -Y-A 2 -X 1 - is particularly suitable.
  • -Y-A 2 -X 1 - is -Ci-C 4 -alkylene- (e.g. -(CH 2 ) 2 -), with -Y-A 2 -X 1 - preferably having 2 to 6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain. If A is a heterocyclic ring, this embodiment of -Y-A 2 -X 1 - is particularly suitable.
  • the structural motif -Y-A 2 -X 1 as disclosed herein is bound to Q being -S(0) 2 - or -C(O)-.
  • Particular examples for this embodiment include heterocyclic compounds of the invention wherein R is R 1 -S(0) 2 -Y-A 2 -X 1 or R 1 - C(0)-Y-A 2 -X 1 .
  • radical R and in particular the radical R 1 -W-A 1 -Q-Y-A 2 -X 1 - may, in principle, be bound to the 6-, 7- , 8, or 9-position of the benzazepine skeleton:
  • R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • Benzazepine derivatives having the radical R 1 -W-A 1 -Q-Y-A 2 -X 1 - (or the radical -CN) in the 7-, 8-, 9-position are preferred.
  • benzazepine derivatives having the radical R 1 -W-A 1 -Q-Y-A 2 -X 1 - (or the radical -CN) in the 8-position.
  • the benzazepine derivatives of the invention may have one or more than one further substituent bound to the benzene ring. In these positions, the skeleton of the benzazepine derivatives may thus be substituted with one or more than one radical R 2 . If there is more than one radical R 2 , these may be the same or different radicals. In particular, in 6-, 7-, 8- and/or 9-position, the benzazepine skeleton may be substituted with one or more than one radical R 2 .
  • the benzazepine derivatives of the invention may therefore be represented by one of the following formulae:
  • R 2a , R 2b , R 2c , R 2d independently have one of the meanings given for R 2 , and R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • R 2 is hydrogen, halogen (e.g. fluorine), Ci-C 6 -alkyl, halogenated CrC 4 -alkyl, hydroxy-d- C 4 -alkyl, -CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C C 6 -alkoxy, halogenated CrC 6 -alkoxy, CrC 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -Ci 2 -aryl- CrC 4 -alkoxy, CrCe-alkylcarbonyloxy, CrCe-alkylthio, CrCe-alkylsulfinyl, C C 6 - alkylsulfonyl, aminosulfonyl, amino, Ci-C 6 -alkylamino, C 2 -C 6 -alken
  • An optionally substituted 5- or 6-membered ring that is formed by two radicals R 2 together with the ring atoms of A to which they are bound is, for instance, a benzene ring.
  • substituted C 6 -Ci 2 -aryl in particular includes C 6 -Ci 2 -aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen and CrC 4 -alkyl, Ci-C 4 -haloalkyl, cyano, CrC 4 -alkoxy and Ci-C 4 -haloalkoxy.
  • substituted C 3 -Ci 2 -heterocyclyl in particular includes C 3 -C-
  • R 2 is hydrogen, halogen (e.g. fluorine) or Ci-C 6 -alkoxy.
  • R 2 is hydrogen or halogen (e.g. fluorine).
  • the benzazepine derivatives of the invention have one of the following formulae:
  • R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein.
  • articularly preferred are benzazepine derivatives of the following formula:
  • R 1 , W, A 1 , Q, Y, A 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein, with R 2 preferably being halogen, in particular fluorine.
  • a 3 is -CH 2 -, -0-, -NR 16 -, or -S-. If A 3 is -CH 2 -, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[c]azepines. If A 3 is -0-, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[f][1 ,4]oxazepines. If A 3 is -NR 16 -, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[e][1 ,4]diazepines.
  • a 3 is -S-, the compounds of formula (I) are referred to as 6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptenes. According to a particular embodiment, A 3 is -CH 2 -, -O- or -S-.
  • the benzazepine derivatives of the invention may be substituted with one or more than one radical R 3 . If there is more than one radical R 3 , these may be the same or different radicals.
  • the benzazepine derivatives of the invention may therefore be represented by the following formula:
  • a 3 is -CR 3a R 3b -, -0-, -NR 16 -, or -S;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g independently have one of the meanings given for R 3 ;
  • R, R 2 , R 3 , R 4 , X 2 , X 3 , R 5 , R 16 are as defined herein.
  • R 3 is hydrogen, halogen, C-i-C 6 -alkyl, C-i-C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group.
  • R 3 is hydrogen or CrC 6 -alkyl.
  • R 3 is hydrogen.
  • R 4 is hydrogen, d-C 6 -alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C 3 -Ci 2 -cycloalkyl-Ci- C 4 -alkyl (e.g. cyclopropylmethyl), halogenated Ci-C 4 -alkyl (e.g.
  • fluoromethylcarbonyl difluoromethylcarbonyl, trifluoromethylcarbonyl, 1 , 1 , 1-trifluoroeth-2-ylcarbonyl or 1 , 1 , 1-trifluoroprop-3-ylcarbonyl), C 6 -Ci 2 -arylcarbonyl (e.g. phenylcarbonyl), CrC 4 -alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl), C 6 - C 12 -aryloxycarbonyl (e.g.
  • R 4 is hydrogen, d-d-alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C 3 -C 12 - cycloalkyl-CrC 4 -alkyl (e.g. cyclopropylmethyl), halogenated CrC 4 -alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl), amino-C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl (e.g.
  • cyclopropyl CH 2 CN, CrC 4 -alkylcarbonyl (e.g. methylcarbonyl or isopropylcarbonyl), (halogenated C 1 -C 4 -alkyl)carbonyl (e.g. fluoromethylcarbonyl, difluoromethylcarbonyl or trifluoromethylcarbonyl), C 6 -Ci 2 -arylcarbonyl (e.g. phenylcarbonyl), CrC 4 -alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl), C 6 -C 12 -aryloxycarbonyl (e.g.
  • R 4 is hydrogen, d-d-alkyl (e.g. methyl, ethyl or n-propyl), C 3 -d 2 -cycloalkyl (e.g. cyclopropyl) or C 3 -d 2 -cycloalkyl-d-C 4 -alkyl (e.g. cyclopropylmethyl).
  • X 2 is -0-, -NR 6 -, -S-, >CR 12a R 12b or a bond.
  • X 2 is >CR 12a R 12b .
  • X 3 is -0-, -NR 7 -, -S-, >CR 13a R 13b or a bond.
  • X 3 is a bond.
  • R 12a is hydrogen, optionally substituted d-C 6 -alkyl, d-C 6 -alkylamino-d-C 4 -alkyl, di-d- C 6 -alkylamino-d-C 4 -alkyl, C 3 -d 2 -heterocyclyl-d-C 6 -alkyl, optionally substituted C 6 -d 2 - aryl or hydroxy.
  • R 12a is hydrogen or d-C 6 -alkyl.
  • R 13a is hydrogen, optionally substituted d-C 6 -alkyl, Ci-C 6 -alkylamino-d-d-alkyl, di-d- C 6 -alkylamino-Crd-alkyl, C 3 -d 2 -heterocyclyl-d-C 6 -alkyl, optionally substituted C 6 -Ci 2 - aryl or hydroxy.
  • R 13a is hydrogen or d-C 6 -alkyl.
  • substituted CrC 6 -alkyl in particular includes CrC 6 -alkyl substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, hydroxy, CrC 4 -alkoxy and amino.
  • substituted C 6 -Ci 2 -aryl in particular includes C 6 -Ci 2 -aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of CrC 4 -alkyl, Ci-C 4 -haloalkyl, cyano, CrC 4 -alkoxy and Ci-C 4 -haloalkoxy.
  • R 12b is hydrogen or Ci-C 6 -alkyl. According to a particular embodiment, R 12b is hydrogen.
  • R 13b is hydrogen or Ci-C 6 -alkyl. According to a particular embodiment, R 13b is hydrogen.
  • R 12a and R 12b , or R 13a and R 13b together are together are carbonyl or, preferably, optionally substituted Ci-C 4 -alkylene (e.g. 1 ,3-propylene), wherein one -CH 2 - of d- C 4 -alkylene may be replaced by an oxygen atom or -NR 14 -.
  • Ci-C 4 -alkylene e.g. 1 ,3-propylene
  • substituted C C 4 -alkylene in particular includes CrC 4 -alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, cyano, C-i-C 4 -alkoxy and C C 4 - haloalkoxy.
  • R 12a is Ci-C 6 -alkyl and R 12b is hydrogen or CrC 6 - alkyl, or R 13a is Ci-C 6 -alkyl and R 13b is hydrogen or C C 6 -alkyl. According to a further particular embodiment, R 12a is hydrogen and R 12b is hydrogen, or R 13a is hydrogen and R 13b is hydrogen.
  • R 12a and R 12b together are optionally substituted 1 ,3-propylene, or R 13a and R 13b together are optionally substituted 1 ,3-propylene.
  • R 5 is optionally substituted C 6 -Ci 2 -aryl (e.g. phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chlorophenyl; 3-cyanophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4-dichlorophenyl or 3,4- dichlorophenyl,), optionally substituted C 3 -Ci 2 -cycloalkyl (e.g. cyclohexyl) or optionally substituted C 3 -Ci 2 -heterocyclyl.
  • C 3 -Ci 2 -cycloalkyl
  • substituted C 3 -Ci 2 -cycloalkyl in particular includes C 3 -Ci 2 -cycloalkyl, such as cyclopropyl or cyclohexyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, optionally substituted CrC 6 -alkyl, halogenated CrC 6 -alkyl, CN, hydroxy, Ci-C 6 -alkoxy, halogenated CrC 6 -alkoxy, amino, Ci-C 6 -alkylamino, di-CrC 6 - alkylamino and C 3 -Ci 2 -heterocyclyl.
  • substituents selected from the group consisting of halogen, optionally substituted CrC 6 -alkyl, halogenated CrC 6 -alkyl, CN, hydroxy, Ci-C 6 -alkoxy, halogenated CrC 6 -alkoxy, amino, Ci-C 6 -alky
  • substituted C 6 -Ci 2 -aryl in particular includes C 6 -Ci 2 -aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen (e.g. F, CI, Br), optionally substituted CrC 6 -alkyl (e.g. methyl), halogenated Ci-C 6 - alkyl (e.g. trifluoromethyl), CN, hydroxy, CrC 6 -alkoxy (e.g.
  • halogen e.g. F, CI, Br
  • optionally substituted CrC 6 -alkyl e.g. methyl
  • halogenated Ci-C 6 - alkyl e.g. trifluoromethyl
  • CN hydroxy, CrC 6 -alkoxy
  • substituted C 3 -Ci 2 -heterocyclyl in particular includes C 3 -C-
  • C 3 -Ci 2 -heterocyclyl in particular is C 3 -Ci 2 -heteroaryl.
  • R 5 is optionally substituted C 6 -Ci 2 -aryl, in particular as in the benzazepine de- rivatives of the formula:
  • R, R 2 , A 3 , R 3 , R 4 , X 2 , X 3 are as defined herein, and
  • R 17a , R 17b , R 17c , R 17d , R 17e independently are hydrogen, halogen (e.g. F, CI or Br), optionally substituted CrC 6 -alkyl (e.g. methyl), halogenated CrC 6 -alkyl (e.g. trifluoromethyl), CN, hydroxy, Ci-C 6 -alkoxy (e.g. methoxy), amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino or C 3 -Ci 2 -heterocyclyl.
  • halogen e.g. F, CI or Br
  • optionally substituted CrC 6 -alkyl e.g. methyl
  • halogenated CrC 6 -alkyl e.g. trifluoromethyl
  • CN hydroxy
  • Ci-C 6 -alkoxy e.g. methoxy
  • amino Ci-C 6 -alkylamino
  • R 5 is optionally substituted C 6 -Ci 2 -heteroaryl, in particular as in the benzazepine derivatives of the formula:
  • R, R 2 , A 3 , R 3 , R 4 , X 2 , X 3 are as defined herein, and
  • R 17b , R 17c , R 17d , R 17e independently are hydrogen, halogen (e.g. F, CI or Br), optionally substituted CrC 6 -alkyl (e.g. methyl), halogenated CrC 6 -alkyl (e.g. trifluoromethyl), CN, hydroxy, Ci-C 6 -alkoxy (e.g. methoxy), amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino or C 3 - C 12 -heterocyclyl.
  • halogen e.g. F, CI or Br
  • optionally substituted CrC 6 -alkyl e.g. methyl
  • halogenated CrC 6 -alkyl e.g. trifluoromethyl
  • CN hydroxy
  • Ci-C 6 -alkoxy e.g. methoxy
  • amino Ci-C 6 -alkylamino, di-Ci-
  • the invention relates to benzazepine derivatives of the formula:
  • R, R 2 , A 3 ,R 3 , R 4 , R 5 are as defined herein, R 5 preferably being optionally substituted aryl and in particular optionally substituted phenyl as disclosed herein.
  • substituted C C 6 -alkyl in particular includes d-C 6 -alkyl, especially C 1 -C 4 -alkyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of hydroxy, CrC 6 -alkoxy, amino, Ci-C 6 -alkylamino, di-CrCe- alkylamino and C 3 -C 12 -heterocyclyl (e.g. morpholinyl or piperidinyl).
  • substituents selected from the group consisting of hydroxy, CrC 6 -alkoxy, amino, Ci-C 6 -alkylamino, di-CrCe- alkylamino and C 3 -C 12 -heterocyclyl (e.g. morpholinyl or piperidinyl).
  • R 17a , R 17b , R 17d , R 17e are hydrogen and R 17c is different from hydrogen (para-mono-substitution).
  • R 17a , R 17c , R 17d , R 17e are hydrogen and R 17b is different from hydrogen (meta-mono-substitution).
  • R 17b , R 17c , R 17d , R 17e are hydrogen and R 17a is different from hydrogen (meta-ortho-substitution).
  • C 3 -Ci 2 -heterocyclyl in particular includes morpholinyl, imidazolyl and pyrazolyl.
  • R 6 is hydrogen or CrC 6 -alkyl.
  • R 6 is hydrogen.
  • R 7 is hydrogen or CrC 6 -alkyl.
  • R 7 is hydrogen.
  • R 8 is hydrogen or CrC 6 -alkyl. Preferably, R 8 is hydrogen.
  • R 9 is hydrogen, d-C 6 -alkyl (e.g. methyl or ethyl), C 3 -Ci 2 -cycloalkyl (e.g. cyclopropyl), amino-CrCe-alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 3 -C 12 -heterocyclyl (e.g. 3-azetidinyl).
  • R 9 is hydrogen or CrC 6 -alkyl (e.g. methyl or ethyl).
  • R 9 and R 1 together are CrC 4 -alkylene (e.g. 1 ,3-1 ,2- ethylene or propylene) so as that R 9 and R 1 together with the atom in Q to which R 1 is bound and the nitrogen atom to which R 9 is bound form an heterocyclic ring having, in particular, 4, 5 or 6 ring member atoms (including the nitrogen atom and Q).
  • W and A 1 both being a bond such a ring may be represented by the following partial structure:
  • a 2 , X 1 , Q is as defined herein (e.g. S(0) 2 ) and n is 0, 1 , 2, 3 or 4.
  • R 9 is CrC 4 -alkylene (e.g. methylene or 1 ,3- propylene) that is bound to a carbon atom in A 2 and A 2 is Ci-C 4 -alkylene so that R 9 and at least part of A 2 together with the nitrogen atom to which R 9 is bound form an N-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen atom).
  • a ring may be represented by the following partial structure:
  • R N wherein R 1 , W, A 1 , Q and X 1 are as defined herein, p is 1 or 2, r is 0, 1 or 2 and q is 0, 1 or 2.
  • X 1 preferably is -0-.
  • p is 0, r is 3 and q is 1 , with X 1 preferably being -0-.
  • R 9 is CrC 4 -alkylene (e.g. methylene or 1 ,3- propylene) that is bound to a carbon atom in X 1 and X 1 is CrC 4 -alkylene (e.g. 1 ,2- ethylene) so that R 9 and at least part of X 1 together with the nitrogen atom to which R 9 is bound form an N-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen atom).
  • a 2 being a bond
  • such a ring may be represented by the following partial structure:
  • R 10 is hydrogen, C-
  • R 10 is hydrogen.
  • R 11 is hydrogen or C-
  • R 11 is hydrogen.
  • R 9 , R 11 together are C 1 -C 4 -alkylene (e.g. ethylene).
  • R 14 is hydrogen or C-
  • R 14 is hydrogen.
  • R 15 is hydrogen or C-
  • R 15 is hydrogen.
  • R 16 is hydrogen or C-
  • R 16 is hydrogen or C-
  • R is R 1 -W-A 1 -Q-Y-A 2 -X 1 -;
  • R 1 is CrC 6 -alkyl (e.g. ethyl or n-propyl), C 3 -Ci2-cycloalkyl-Ci-C 4 -alkyl (e.g. cyclopro- pylmethyl), C 3 -Ci 2 -cycloalkyl (e.g. cyclobutyl), or optionally substituted C3-C12- heterocyclyl (e.g. 3-pyridyl, 1 -methyl-1 ,2-diazol-4-yl, 1 -methyl-1 ,3-diazol-4-yl, 3- oxetanyl, 1 -methyl-pyrrol-3-yl);
  • W is a bond
  • a 1 is a bond
  • Q is -S(0) 2 -; Y is -NR - or a bond;
  • a 2 is CrC 4 -alkylene (e.g. 1 ,2-ethylene) or a bond;
  • X 1 is -O- or optionally substituted C 1 -C 4 -alkylene (e.g. methylene, 1 ,2-ethylene or 1 ,3- propylene);
  • R 2 is hydrogen or halogen (e.g. fluorine);
  • a 3 is -CH 2 -, -0-, -NR 16 , or -S-;
  • R 3 is hydrogen
  • R 4 is hydrogen, d-C 6 -alkyl (e.g. methyl, ethyl or n-propyl), C 3 -Ci 2 -cycloalkyl (e.g. cyclopropyl) or or C 3 -Ci2-cycloalkyl-Ci-C 4 -alkyl (e.g. cyclopropylmethyl);
  • X 2 is >CR 12a R 12b ;
  • X 3 is a bond
  • R 5 is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4- chlorophenyl) or optionally substituted pyridyl (e.g. 2-pyridyl);
  • phenyl e.g. phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4- chlorophenyl
  • pyridyl e.g. 2-pyridyl
  • R 9 is hydrogen, or
  • R 9 is CrC 4 -alkylene (e.g. methylene) that is bound to a carbon atom in X 1 and X 1 is C C 4 -alkylene (e.g. 1 ,2-ethylene);
  • R 12a is hydrogen
  • R is hydrogen; or together are C 1 -C 4 -alkylene (e.g. 1 ,3-propylene);
  • R 16 is hydrogen or C-
  • Table 8 Compounds of the formula (Id) wherein R 2 is 7-F, R 3 is hydrogen, R 17 is 3-F and the combination of R 1 , -Y-A 2 -X 1 -, >CR 12a R 12b , A 3 , R 4 for a compound in each case corresponds to one line of Table A (A-1 to A-448).
  • Table 9 Compounds of the formula (Id) wherein R 2 is 7-F, R 3 is hydrogen, R 17 is 3-F and the combination of R 1 , -Y-A 2 -X 1 -, >CR 12a R 12b , A 3 , R 4 for a compound in each case corresponds to one line of Table A (A-1 to A-448).
  • Table 9 Compounds of the formula (Id) wherein R 2 is 7-F, R 3 is hydrogen, R 17 is 3-F and the combination of R 1 , -Y-A 2 -X 1 -, >CR 12a R 12b , A 3 , R 4 for a
  • A-41 1 . -NH- -CH 2 - -0- -CH 2 CH 2 CH 3 -
  • Further particular compounds of the present invention are the individual benzazepine derivatives of the formula (Id) as listed in tables 1 to 12 and physiologically tolerated salts thereof wherein the radical R 1 -S(0) 2 -Y-A 2 -X 1 - is replaced by the radical -CN.
  • Further particular compounds of the present invention are the benzazepine derivatives disclosed in preparation examples and physiologically tolerated salts thereof. These include for each preparation example the exemplified compound as well as the correspond- ing free base and any other physiologically tolerated salts of the free base (if the exemplified compound is a salt), or any physiologically tolerated salt of the free base (if the exemplified compound is a free base). These further include enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
  • the compounds of the formula (I) can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of compounds of formula (I) are outlined in the following schemes. The process depicted in scheme 1 is useful for obtaining benzazepine precursors of the general formula 3, wherein X 1 is -O- or -S- and A 3 is optionally substituted alkylene (e.g. - CH 2 -).
  • the compound of general formula 1 readily undergoes enamine alkylation to give the enamine 2 and after subsequent hydrolysis the compound of general formula 3.
  • L 1 represents an alkyl substituent (e.g. Me, Et, Bn).
  • the process depicted in scheme 1 is also useful for obtaining benzazepines, wherein X 1 is optionally substituted alkylene.
  • L 1 is a group that represents, or can be converted into, the desired side chain R 1 -W-A 1 -Q-Y-A 2 -.
  • L 1 Me, Et, Bn, or tBuMe 2 Si
  • the process depicted in scheme 6 is useful for obtaining benzazepines, wherein X is - NR 11 -, A 2 is optionally substituted alkylene, Y is -NR 9 -, and Q is -S(0) 2 .
  • the compound of general formula 33 readily undergoes alkylation to give the compound of general formula 34.
  • Deprotection leads to compounds of the general formula 35, which are converted via well known amide coupling reactions to the corresponding compounds of general formula 36 (e.g. EDC, DMAP).
  • Amides of the gen- eral formula 36 undergo cyclization to imines of the formula 37 under Vilsmeier reaction conditions (e.g. POCI 3 , SOCI 2 , oxalyl chloride; see Chem. Ind. 1973, 870, Indian J. Chem., Sect. B (37B), 1998, 965, and Advances in Organic Chemistry (9), Pt. 1 , 1976, 225 ).
  • the acid addition salts of the benzazepine derivatives of formula (I) are prepared in a customary manner by mixing the free base with a corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
  • a lower alcohol such as methanol, ethanol or propanol
  • an ether such as methyl tert-butyl ether or diisopropyl ether
  • a ketone such as acetone or methyl ethyl ketone
  • an ester such as ethyl acetate.
  • L is an amino-protecting group
  • Y is NR 9
  • a 2 , X 1 , R 2 , A 3 , R 3 , R 4 , X 2 , X 3 , R 5 are defined as herein are useful as intermediates in the preparation of GlyT1 inhibitors, in particular those of formula (I).
  • Suitable amino-protecting groups are well known in the art such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • L is optionally substituted alkylcarbonyl (e.g., tert- butylcarbonyl), optionally substituted arylcarbonyl, optionally substituted arylalkycarbonyl (e.g., benzylcarbonyl), optionally substituted alkoxycarbonyl (e.g., methoxycarbonyl or tert-butyloxycarbonyl), optionally substituted aryloxycarbonyl (e.g. phenoxycarbonyl) or optionally substituted arylalkoxycarbonyl.
  • alkylcarbonyl e.g., tert- butylcarbonyl
  • arylalkycarbonyl e.g., benzylcarbonyl
  • alkoxycarbonyl e.g., methoxycarbonyl or tert-butyloxycarbonyl
  • aryloxycarbonyl e.g. phenoxycarbonyl
  • the compounds of the formula (I) are capable of inhibiting the activity of glycine transporter, in particular glycine transporter 1 (GlyT1 ).
  • hGlyT1 c_5_CHO cells can be used for measuring glycine uptake and its inhibition (IC 50 ) by a compound of formula (I).
  • compounds of the formula (I) are preferred which achieve effective inhibition at low concentrations.
  • compounds of the formula (I) are preferred which inhibit glycine transporter 1 (GlyT1 ) at a level of IC 50 ⁇ 1 ⁇ , more preferably at a level of IC 5 o ⁇ 0.5 ⁇ , particularly preferably at a level of IC 5 o ⁇ 0.2 ⁇ and most preferably at a level of IC 5 o ⁇ 0.1 ⁇ .
  • the compounds of formula (I) display good to moderate metabolic stability.
  • the metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001 , 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved.
  • the stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver.
  • the slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the com- pounds of the invention is increased.
  • Increased and/or longer-lasting active levels may lead to a better activity of the compound in therapeutic treatment.
  • an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degra- dation in the liver (so-called first pass effect).
  • An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
  • compounds of the formula (I) are particularly preferred which display good to moderate metabolic stability towards human liver microsomes.
  • compounds of the formula (I) are preferred which display a microsomal clearance at a level of mCI ⁇ 1000 ⁇ /min/mg, more preferably at a level of mCI ⁇ 500 ⁇ /min/mg, particularly preferably at a level of mCI ⁇ 100 ⁇ /min/mg and most preferably at a level of mCI ⁇ 50 ⁇ /min/mg.
  • the compounds of the formula (I) according to the present invention are thus useful as pharmaceuticals.
  • the present invention therefore also relates to pharmaceutical compositions which com- prise an inert carrier and a compound of the formula (I).
  • the present invention also relates to the use of the compounds of the formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 , and to corresponding methods of inhibiting the glycine transporter GlyT1.
  • the NMDA receptor is central to a wide range of CNS processes, and its role in a variety of diseases in humans or other species has been described.
  • GlyT1 inhibitors slow the removal of glycine from the synapse, causing the level of synaptic glycine to rise. This in turn increases the occupancy of the glycine binding site on the NMDA receptor, which increases activation of the NMDA receptor following glutamate release from the presynaptic terminal.
  • Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus known to be useful in treating a variety of neurologic and psychiatric disorders.
  • glycine A receptors play a role in a variety of diseases in humans or other species.
  • Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus useful in treating a variety of neurologic and psychiatric disorders.
  • the present invention thus further relates to the use of the compounds of the formula (I) for the manufacture of a medicament for treating a neurologic or psychiatric disorder, and to corresponding methods of treating said disorders.
  • the disorder is associated with glycinergic or glu- tamatergic neurotransmission dysfunction.
  • the disorder is one or more of the following conditions or diseases: schizophrenia or a psychotic disorder including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance- induced psychotic disorder, including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alz- heimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or cognitive impairment including age related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disor- der, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder,
  • the disorder is pain, in particular chronic pain and especially neuropathic pain.
  • Chronic pain serves no protective biological function. Rather than being the symptom of tissue damage it is a disease in its own right. Chronic pain is unrelenting and not self-limiting and can persist for years, perhaps decades after the initial injury. Chronic pain can be refractory to multiple treatment regimes. Psychological symptoms associated with chronic pain include chronic anxiety, fear, depression, sleeplessness and impairment of social interaction. Chronic non-malignant pain is predominantly neuropathic in nature and involves damage to either the peripheral or central nervous systems.
  • Acute pain and chronic pain are caused by different neuro-physiological processes and therefore tend to respond to different types of treatments.
  • Acute pain can be somatic or visceral in nature. Somatic pain tends to be a well localised, constant pain and is described as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing or colicky in nature. Examples of acute pain include post-operative pain, pain associated with trauma and the pain of arthritis. Acute pain usually responds to treatment with opioids or non-steroidal anti-inflammatory drugs.
  • Chronic pain in contrast to acute pain, is described as burning, electric, tingling and shooting in nature. It can be continuous or paroxysmal in presentation.
  • the hallmarks of chronic pain are chronic allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus that normally does not ellicit a painful response, such as a light touch.
  • Hyperalgesia is an increased sensitivity to normally painful stimuli. Primary hyperalgesia occurs immediately within the area of the injury. Secondary hyperalgesia occurs in the undam- aged area surrounding the injury.
  • chronic pain examples include complex regional pain syndrome, pain arising from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension-type headache, pain arising from mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic disease, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain arising as a conse- quence of or associated with stress or depressive illness.
  • opioids are cheap and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity.
  • doses of opioids which can be administered are limited by nausea, emesis, con- stipation, pruritis and urinary retention, often resulting in patients electing to receive sub- optimal pain control rather than suffer these distressing side-effects.
  • these side-effects often result in patients requiring extended hospitalisation.
  • Opioids are highly addictive and are scheduled drugs in many territories.
  • the compounds of formula (I) are particularly useful in the treatment of schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and postpartum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including Attention-Deficit/Hyperactivity Disorder, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.
  • Particular cognitive disorders are dementia, delirium, amnestic disorders and cognitive impartment including age-related cognitive decline.
  • Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack.
  • Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • Particular neurologic disorders that can be treated with the compounds of of the formula (I) include in particular a cognitive disorder such as dementia, cognitive impairment, attention deficit hyperactivity disorder.
  • Particular psychiatric disorders that can be treated with the compounds of of the formula (I) include in particular an anxiety disorder, a mood disorder such as depression or a bipo- lar disorder, schizophrenia, a psychotic disorder.
  • the use according to the invention of the compounds of the formula (I) involves a method.
  • an effective quantity of one or more compounds or the formula (I), as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being.
  • a mammal in particular a human being.
  • Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
  • the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other drugs or drug-containing preparations.
  • the invention also relates to the manufacture of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being.
  • the compounds of the formula (I) are customarily administered in the form of pharmaceutical compositions which comprise an inert carrier (e.g. a pharmaceutically acceptable excipient) together with at least one compound according to the invention and, where appropriate, other drugs.
  • an inert carrier e.g. a pharmaceutically acceptable excipient
  • These compositions can, for example, be administered orally, rectally, transdermal ⁇ , subcutaneously, intravenously, intramuscularly or intranasally.
  • suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar- coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops.
  • Implanted release devices can also be used for administering inhibitors according to the invention.
  • liposomes or microspheres can also be used for administering inhibitors according to the invention.
  • the compounds according to the invention are option- ally mixed or diluted with one or more carriers (excipients).
  • Carriers can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
  • Suitable carriers are listed in the specialist medicinal monographs.
  • the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirri- tants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refat- ting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils.
  • auxiliary substances such as wetting agents; emulsifying and suspending
  • a formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV- Editio-Cantor-Verlag, 1996.
  • the compounds of formula (I) may also be suitable for combination with other therapeutic agents.
  • the present invention also provides:
  • a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient;
  • kits-of-parts for use in the treatment of a disorder, disease or condition as defined herein comprising a first dosage form comprising a compound of formula (I) and one or more further dosage forms each comprising one or more further therapeutic agents for simultaneous therapeutic administration,
  • the combination therapies of the invention may be administered adjunctively.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) and at least one further therapeutic agent are within the scope of the current invention.
  • a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such com- binations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention further provides at least one antipsychotic agent for adjunctive therapeutic administra- tion for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one antipsychotic agent.
  • the invention further provides the use of a combination of compounds of formula (I) and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides a combination of compounds of formula (I) and at least one antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disor- der.
  • the invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder.
  • the invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilis- ing or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
  • Antipsychotic agents include both typical and atypical antipsychotic drugs.
  • antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothix- ene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benziso- thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroin
  • tradenames and suppliers of selected antipsychotic drugs are as follows: clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename
  • THORAZINE® from SmithKline Beecham (GSK)
  • fluphenazine available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Phar- maceutical Partners, Pasadena
  • thiothixene available under the tradename NAVANE®, from Pfizer
  • trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2- (trifluoro- methyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman
  • perphenazine available under the tradename TRILAFON®; from Schering
  • thioridazine available under the tradename MELLARIL®; from Novartis, Rox- ane, HiTech, Teva, and Alpharma
  • molindone available under the tradename MOBAN®, from Endo
  • loxapine available under the tradename LOXITANE(D; from Watson
  • benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used.
  • Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRI N®), chlor- prothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename Pl- POTRIL®), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRI N®
  • chlor- prothixene available under the tradename TARACTAN®
  • the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease to a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides the use of at least one agent suitable for the treat- ment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for adjunc- tive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufac- ture of a medicament for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Dis- ease.
  • the invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides compounds of formula (I) for use for simultaneous therapeutic administra- tion with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration with compounds of for- mula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • the invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
  • agents suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease include, but are not limited to: cholinesterase inhibitors, agents targeting nicotinic or muscarinic acethylcholine receptors, NMDA receptors, amyloid formation, mitochondrial dysfunctions, disease associated cal- pain activity, neuroinflamation, tumor necrosis factor receptors, NF-kappaB, peroxisome proliferator activator receptor gamma, Apolipoprotein E variant 4 (ApoE4), disease- associated increase of the HPA axis, epileptic discharges, vascular dysfunction, vascular risk factors, and oxidative stress.
  • Suitable cholinesterase inhibitors which may be used in combination with the compounds of the inventions include for example tacrine, donepezil, galantamine and rivastigmine.
  • Suitable NMDA receptors targeting agents which may be used in combination with the compounds of the inventions include for example memantine.
  • Suitable agents affecting increased HPA axis activity which may be used in combination with the compounds of the inventions include for example CRF1 antagonists or V1 b antagonists.
  • the invention provides a method of treatment of pain by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain.
  • the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain.
  • the invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain.
  • the invention provides a method of treatment of pain by adjunctive therapeutic administration of at least one agent suitable for the treatment of pain to a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for adjunctive therapeutic administration for the treat- ment of pain in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention further provides at least one agent suitable for the treatment of pain for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I).
  • the invention provides a method of treatment of pain by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of pain.
  • the invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of pain.
  • the invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain for simultaneous therapeutic administration in the treatment of pain.
  • the invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain.
  • the invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain.
  • the invention further provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain.
  • the invention further provides at least one agent suitable for the treatment of pain for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain.
  • agents suitable for the treatment of pain include, but are not limited to: NSAIDs (Nonsteroidal Antiinflammatory Drugs), anti- convulsant drugs such as carbamazepine and gabapentin, sodium channel blockers, antidepressant drugs, cannabinoids and local anaesthetics.
  • NSAIDs Nonsteroidal Antiinflammatory Drugs
  • anti- convulsant drugs such as carbamazepine and gabapentin
  • sodium channel blockers such as sodium channel blockers
  • antidepressant drugs such as cannabinoids and local anaesthetics.
  • Suitable agents used in combination with the compounds of the inventions include for example celecoxib, etoricoxib, lumiracoxib, paracetamol, tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion, gabapentin, pregabalin, lamotrigine, fentanyl, pare- coxib, nefopam, remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil, pethidine, diamorphine and butorphanol.
  • antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as cognitive enhancers.
  • antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents,
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • the compounds were characterized by mass spectrometry, generally recorded via HPLC- MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
  • Example 1 (for reference purposes): 1 -Benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H- benzo[c]azepine
  • N-(2-(1 -Benzyl-2, 3,4, 5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H-pyrazole- 4-sulfonamide was prepared in analogy to example 2 using 1 -methyl-1 H-pyrazole-4- sulfonyl chloride in place of 1 -methyl-1 H-imidazole-4-sulfonyl chloride.
  • Example 7 1 -Methyl- 1 H-pyrazole-4-sulfonic acid [2-(1 -benzyl-2-methyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin- -yloxy)-ethyl]-amide
  • Example 1 Ethanesulfonic acid [2-(1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy)-ethyl]-amide
  • Example 19 1-Methyl-1 H-pyrazole-4-sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro- 1 H-benzo-[c]azepin-8-ylmethyl]-amide
  • Example 20 1 -Methyl-1 H-imidazole-4-sulfonic acid ⁇ 2-[1 -(3-fluoro-benzyl)-2,3,4,5- tetrahydro-1 H-benzo[c]azepin-8-yloxy]-ethyl ⁇ -amide
  • Example 21 1-Methyl-1 H-pyrazole-4-sulfonic acid ⁇ 2-[1 -(3-fluoro-benzyl)-2,3,4,5- tetrahydro-1 H-benzo[c]azepin-8-yloxy]-ethyl ⁇ -amide
  • Example 24 C-Cyclopropyl-N- ⁇ 2-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl ⁇ -methanesulfonamide
  • Example 25 Ethanesulfonic acid ⁇ 2-[1-(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl ⁇ -amide
  • Example 26 1-Methyl-1 H-pyrazole-4-sulfonic acid [1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydr 1 H-benzo[c]azepin-8-ylmethyl]-amide
  • Example 28 C-Cyclopropyl-N-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin- 8-ylmethyl)-methanesulfonamide
  • Example 32 Propane-1 -sulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8- ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
  • Example 33 Ethanesulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8- ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
  • Example 35 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetra-hyd benzo[c]azepin-8-ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
  • Example 36 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetrahyd benzo[c]azepin-8-ylmethyl)-methyl-amide
  • Example 37 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-propyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- lmethyl)-amide
  • Example 38 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-methyl-2,3,4,5-tetrahyd 1 H-benzo[c]azepin-8-ylmethyl)-amide
  • Example 39 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-ethyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-ylmethyl)-amide
  • Example 41 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-7-fluoro-2,3,4,5-tetrahyd 1 H-benzo[c]azepin-8-ylmethyl)-amide
  • Example 42 Ethanesulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin- 8-ylmethyl)-amide; compound with trifluoro-acetic acid
  • Example 44 N-(1-Benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)-C- cyclopropyl-methanesulfonamide; compound with (E)-but-2-enedioic acid
  • Example 45 1 -Methyl-1 H-imidazole-4-sulfonic acid [2-(1 -benzyl-7-fluoro-2, 3,4,5- tetrahydro-1 H-benzo[c]
  • Example 47 1-Methyl-1 H-imidazole-4-sulfonic acid [5-(1 -methyl-1 -phenyl-ethyl)-2, 3,4,5- tetrahydro-benzo
  • Example 48 1-Methyl-1 H-imidazole-4-sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]
  • Example 49 1-Methyl-1 H-pyrazole-4-sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-amide
  • Example 50 Ethanesulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro-benzo[f][1 ,4]oxazepin-7- yloxy)-ethyl]-amide
  • Example 51 Propane-1 -sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-amide
  • Human GlyTI c expressing recombinant hGlyT1 c_5_CHO cells were plated at 20,000 cells per well in 96 well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured to sub-confluency for 24 h.
  • the culture medium was aspirated and the cells were washed once with 100 ⁇ HBSS (Gibco BRL, #14025-050) with 5 mM L-Alanine (Merck #1007).
  • HBSS buffer 80 ⁇ HBSS buffer were added, followed by 10 ⁇ inhibitor or vehicle (10% DMSO) and 10 ⁇ [ 3 H]-glycine (TRK71 , Amersham Biosciences) to a final concentration of 200 nM for initiation of glycine uptake.
  • the plates were placed in a Wal- lac Microbeta (PerkinElmer) and continuously counted by solid phase scintillation spectrometry during up to 3 hours. Nonspecific uptake was determined in the presence of 10 ⁇ Org24598.
  • IC 50 calculations were made by four-parametric logistic nonlinear regres- sion analysis (GraphPad Prism) using determinations within the range of linear increase of [ 3 H]-glycine incorporation between 60 and 120 min.
  • Radioligand binding to human GlyTI c transporter-expressing membranes was determined as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.
  • Metabolic stability was determined as follows:
  • test substance 0.5 ⁇ test substance was preincubated together with human liver microsomes (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37°C for 5 min. The reaction was started by adding NADPH ( 1 .0 mM). After 0, 5, 10, 15, 20 and 30 min, 65 ⁇ aliquots were removed, and the reaction was immediately stopped and cooled with twice the amount of ethanol. The samples were frozen until analyzed. The remaining concentration of undegraded test substance was determined by LC MSMS.
  • the half-life (T1/2) was determined from the gradient of the signal of test sub- stance/unit time plot, allowing to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time.
  • R, R 2 , R 3 , R 4 , X 2 , X 3 , R 5 are as defined herein for the benzazepine derivatives, or a physiologically tolerated salt thereof; pharmaceutical compositions comprising such compounds; and the use of such compounds for therapeutic purposes.
  • the compounds are GlyT1 inhibitors.
  • isoindoline derivatives and their physiologically tolerated salts can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of isoindoline derivatives of formula (A) are outlined in the following schemes.
  • the following examples serve to explain the invention relating to the isoindoline derivatives without limiting it.
  • the compounds were characterized by mass spectrometry, generally recorded via MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
  • Example A3 [2-(3-Benzyl-1 -oxo-2,3-dihydro-1 H-isoindol-5-yloxy)-ethyl]-carbamic acid tert-butyl ester
  • Example A12 N-[2-[3-benzyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl]oxyethyl]-1-methyl- pyrazole-4-sulfonamide
  • Example A13 N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4- sulfonamide; 2,2,2-trifluoroacetic acid
  • Example A15 N-[2-[3-benzyl-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]oxyethyl]-1-methyl- pyrazole-4-sulfonamide; 2,2,2-trifluoroacetic acid
  • Example A16 N-[2-[3-benzyl-2-(oxetan-3-yl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole sulfonamide; 2,2,2-trifluoroacetic acid
  • Example A17 N-[2-(3-benzyl-3-methyl-1 -oxo-isoindolin-5-yl)oxyethyl]-1 -cyclopropyl- methanesulfonamide

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Abstract

The present invention relates to benzazepine derivatives of the formula (I) or a physiologically tolerated salt thereof. The present invention also relates to pharmaceutical compositions comprising such benzazepine derivatives, and the use of such benzazepine derivatives for therapeutic purposes.

Description

Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
Background of the Invention
The present invention relates to benzazepine derivatives, pharmaceutical compositions comprising such benzazepine derivatives, and the use of such benzazepine derivatives for therapeutic purposes. The benzazepine derivatives are GlyT1 inhibitors. Dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease and bipolar disorder. A large number of studies in animal models lend support to the NMDA hypofunction hypothesis of schizophrenia.
NMDA receptor function can be modulated by altering the availability of the co-agonist glycine. This approach has the critical advantage of maintaining activity-dependent activation of the NMDA receptor because an increase in the synaptic concentration of glycine will not produce an activation of NMDA receptors in the absence of glutamate. Since syn- aptic glutamate levels are tightly maintained by high affinity transport mechanisms, an increased activation of the glycine site will only enhance the NMDA component of activated synapses.
Two specific glycine transporters, GlyT1 and GlyT2 have been identified and shown to belong to the Na/CI-dependent family of neurotransmitter transporters which includes taurine, gamma-aminobutyric acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2 have been isolated from different species and shown to have only 50% identity at the amino acid level. They also have a different pattern of expression in mammalian central nervous system, with GlyT2 being expressed in spinal cord, brainstem and cerebellum and GlyT1 present in these regions as well as forebrain areas such as cortex, hippocampus, septum and thalamus. At the cellular level, GlyT2 has been reported to be expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1 appears to be preferentially expressed by glial cells. These expression studies have led to the suggestion that GlyT2 is predominantly responsible for glycine uptake at glycinergic synapses whereas GlyT1 is involved in monitoring glycine concentration in the vicinity of NMDA receptor expressing synapses. Recent functional studies in rat have shown that blockade of GlyT1 with the potent inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])- sarcosine (NFPS) potentiates NMDA receptor activity and NMDA receptor-dependent long-term potentiation in rat. Molecular cloning has further revealed the existence of three variants of GlyT1 , termed GlyT-1 a, GlyT-1 b and GlyT-1 c, each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions.
The physiological effects of GlyT1 in forebrain regions together with clinical reports showing the beneficial effects of GlyT1 inhibitor sarcosine in improving symptoms in schizophrenia patients suggest that selective GlyT1 inhibitors represent a new class of antipsychotic drugs.
Glycine transporter inhibitors are already known in the art, for example:
Figure imgf000003_0001
Figure imgf000004_0001
78
Figure imgf000004_0002
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
O
Figure imgf000009_0001
Figure imgf000010_0001
(see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1 , 43-53; Harsing L.G. et al., Current Medicinal Chemistry, 2006, 13, 1017-1044; Javitt D.C., Molecular Psychiatry (2004) 9, 984-997; Lindsley, C.W. et al., Current Topics in Medicinal Chemis- try, 2006, 6, 771-785; Lindsley C.W. et al., Current Topics in Medicinal Chemistry, 2006, 6, 1883-1896).
It was one object of the present invention to provide further glycine transporter inhibitors. Summary of the Invention
The present invention relates to benzazepine derivatives of the formula (I)
Figure imgf000011_0001
wherein
R is R1-W-A1-Q-Y-A2-X1- or -CN; R1 is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl, trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyi, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl, alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl, dialkylaminocarbonyl- aminoalkyl, alkylsulfonylaminoalkyi, (optionally substituted arylalkyi) aminoalkyi, optionally substituted arylalkyi, optionally substituted heterocyclylalkyl, cycloalkyl, al- kylcarbonyl, alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl, amino- carbonyl, alkylaminocarbonyl, (halogenated alkyl)aminocarbonyl, arylaminocar- bonyl, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated alkoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, dialkylami- noalkoxy, alkylcarbonylaminoalkoxy, arylcarbonylaminoalkoxy, alkoxycarbonylami- noalkoxy, arylalkoxy, alkylsulfonylaminoalkoxy, (halogenated alkyl)sulfonylamino- alkoxy, arylsulfonylaminoalkoxy, (arylalkyl)sulfonylaminoalkoxy, heterocyclylsulfon- ylaminoalkoxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, alkylthio, halogenated alkylthio, alkylamino, (halogenated alkyl)amino, dialkylamino, di-(halogenated al- kyl)amino, alkylcarbonylamino, (halogenated alkyl)carbonylamino, arylcarbonyl- amino, alkylsulfonylamino, (halogenated alkyl)sulfonylamino, arylsulfonylamino or optionally substituted heterocyclyl;
W is -NR - or a bond;
A1 is optionally substituted alkylene or a bond; Q is -S(0)2- or -C(O)-; Y is -NR9- or a bond; is optionally substituted alkylene, alkylene-CO-, -CO-alkylene, alkylene-O-alkylene, alkylene-NR10-alkylene, optionally substituted alkenylene, optionally substituted al- kynylene, optionally substituted arylene, optionally substituted heteroarylene or a bond; is -0-, -NR11-, -S-, optionally substituted alkylene, optionally substituted alkenylen, optionally substituted alkynylene; is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl, -CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated alkoxy, alkoxycarbonyl, al- kenyloxy, arylalkoxy, alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino- sulfonyl, amino, alkylamino, alkenylamino, nitro or optionally substituted heterocyclyl, or two radicals R2 together with the ring atoms of A to which they are bound form a 5- or 6-membered ring; is -CH2-, -0-, -NR16-, or -S-;
R3 is hydrogen, halogen, alkyi or alkoxy, or two radicals R3 together with the carbon atom to which they are attached form a carbonyl group;
R4 is hydrogen, alkyi, cycloalkylalkyi, halogenated alkyi, hydroxyalkyi, alkoxyalkyi, aminoalkyi, CH2CN, arylalkyi, cycloalkyi, -CHO, alkylcarbonyl, (halogenated al- kyl)carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, al- kenyl, -C(=NH)NH2, -C(=NH)NHCN, alkylsulfonyl, arylsulfonyl, amino, -NO or het- erocyclyl;
X2 is -0-, -NR6-, -S-, >CR12aR12b or a bond; X3 is -0-, -NR7-, -S-, >CR13aR13b or a bond;
R5 is optionally substituted aryl, optionally substituted cycloalkyi or optionally substituted heterocyclyl; R6 is hydrogen or alkyi;
R7 is hydrogen or alkyi;
R8 is hydrogen or alkyi;
R9 is hydrogen, alkyi, cycloalkyi, aminoalkyi, optionally substituted arylalkyi or heterocyclyl; or
R9, R1
together are alkylene; or
R9 is alkylene that is bound to a carbon atom in A2 and A2 is alkylene or to a carbon atom in X1 and X1 is alkylene; R10 is hydrogen, alkyi or alkylsulfonyl; R11 is hydrogen or alkyi, or R9, R11
together are alkylene,
R12a is hydrogen, optionally substituted alkyi, alkylaminoalkyi, dialkylaminoalkyi, hetero- cyclylalkyl, optionally substituted aryl or hydroxy; R12b is hydrogen or alkyi, or
R12b
together are carbonyl or optionally substituted alkylene, wherein one -CH2- of alkylene may be replaced by an oxygen atom or -NR14-; is hydrogen, optionally substituted alkyi, alkylaminoalkyi, dialkylaminoalkyi, hetero- cyclylalkyl, optionally substituted aryl or hydroxy; is hydrogen or alkyi, or
R13b
together are carbonyl or optionally substituted alkylene, wherein one -CH2- of alkylene may be replaced by an oxygen atom or -NR15-; R14 is hydrogen or alkyi;
R15 is hydrogen or alkyi; and
R16 is hydrogen, alkyi, cycloalkylalkyi, halogenated alkyi, hydroxyalkyi, alkoxyalkyi, ami- noalkyl, CH2CN, arylalkyl, cycloalkyl, -CHO, alkylcarbonyl, (halogenated al- kyl)carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, al- kenyl, -C(=NH)NH2, -C(=NH)NHCN, alkylsulfonyl, arylsulfonyl, amino, -NO or het- erocyclyl, or a physiologically tolerated salt thereof. Thus, the present invention relates to benzazepine derivatives having the formula (la)
Figure imgf000015_0001
wherein R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
Further, the present invention relates to benzazepine derivatives of formula (I) wherein R is -CN, i.e. benzazepine derivatives having the formula (lb)
Figure imgf000015_0002
wherein R2, A3, R3, R4, X2, X3, R5 are as defined herein.
Thus, the term benzazepine derivative is used herein to denote in particular benzazepines and benzazepine derivatives wherein the fused heterocyclic ring contains a further het- eroatom. Said compounds of formula (I), i.e., the benzazepine derivatives of formula (I) and their physiologically tolerated salts, are glycine transporter inhibitors and thus useful as pharmaceuticals. The compounds of formula (I) display good to moderate metabolic stability.
The present invention thus further relates to the compounds of formula (I) for use in therapy. The present invention also relates to pharmaceutical compositions which comprise a carrier and a compound of formula (I).
In particular, said compounds, i.e., the benzazepine derivatives and their physiologically tolerated salts, are inhibitors of the glycine transporter GlyT1.
The present invention thus further relates to the compounds of formula (I) for use in inhibiting the glycine transporter. The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 and corresponding methods of inhibiting the glycine transporter GlyT1 .
Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are known to be useful in treating a variety of neurologic and psychiatric disorders.
The present invention thus further relates to the compounds of formula (I) for use in treating a neurologic or psychiatric disorder. The present invention further relates to the compounds of formula (I) for use in treating pain.
The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating a neurologic or psychiatric disorder and correspond- ing methods of treating said disorders. The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating pain and corresponding methods of treating pain.
The present invention further relates to benzazepines derivatives of formula (II):
Figure imgf000016_0001
wherein L is an amino-protecting group, Y is NR9, and A2, X1, R2, A3, R3, R4, X2, X3, R5 are defined as herein. Detailed description of the Invention
Provided that the benzazepine derivatives of the formula (I) of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enanti- omers, diastereomers and tautomers of the compounds of formula (I) and/or of their salts.
According to one embodiment, an enantiomer of the benzazepine derivatives of the present invention has the following fo
Figure imgf000017_0001
wherein R, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
According to another embodiment, an enantiomer of the benzazepine derivatives of the present invention has the following formula:
Figure imgf000017_0002
wherein R, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
The physiologically tolerated salts of the benzazepine derivatives of the formula (I) are especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic ac- ids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other utilizable acids are described, e.g., in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of the benzazepine derivatives also include salts of a physiologically tolerated anion with an benzazepine derivatives wherein one or more than one nitrogen atom is quaternized, e.g. with an alkyl residue (e.g. methyl or ethyl). The present invention moreover relates to compounds of formula (I) as defined herein, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 12C by 13C, 14N by 15N, 160 by 180) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom. Of course, such compounds contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds (I).
Stable isotopes (e.g., deuterium, 13C, 15N, 180) are nonradioactive isotopes which contain one or more additional neutron than the normally abundant isotope of the respective atom. Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non-deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999). Incorporation of a heavy atom particularly substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This effect is usually insignificant if the label is placed at a metabolically inert position of the molecule.
Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to "kinetic isotope effect". A reaction involving breaking a C--D bond can be up to 700 percent slower than a similar reaction involving breaking a C--H bond. If the C--D bond is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If a deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C--D bond is the rate limiting step. There is evidence to suggest that whenever cleavage of an aliphatic C--H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway a process called "metabolic switching".
Deuterium tracers, such as deuterium-labeled drugs and doses, in some cases repeatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 1 14: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.
The weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201 : 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).
Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment. Examples of the amount of enrichment include from about 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21 , 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71 , 75, 79, 84, 88, 92, 96, to about 100 mol %.
The hydrogens present on a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient. Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D2S04/D20. Alternatively, deuterium atoms may be incorporated in various combinations during the syn- thesis of compounds of the invention. Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention. Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant pro- cedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut,
21 (1 1 ), 1 1 16 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications W01997010223, WO2005099353, W01995007271 , WO2006008754; US Patent Nos. 7538189; 7534814; 7531685;
7528131 ; 7521421 ; 7514068; 751 1013; and US Patent Application Publication Nos.
20090137457; 20090131485; 20090131363; 200901 18238; 200901 1 1840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471 , the methods are hereby incorporated by reference.
The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.
Unless indicated otherwise, the term "substituted" means that a radical is substituted with 1 , 2 or 3, especially 1 , substituent which are in particular selected from the group consist- ing of halogen, C-|-C4-alkyl, hydroxy-C-|-C4-alkyl, C3-C12-heterocyclyl-alkyl, C-|-C4-alkoxy- CrC4-alkyl, amino-Ci-C4-alkyl, Ci-C4-alkenyl, OH, SH, CN, CF3, 0-CF3, COOH, 0-CH2- COOH, Ci-Ce-alkoxy, C C6-alkylthio, C3-C7-cycloalkyl, COO-Ci-C6-alkyl, CONH2, CONH- CrC6-alkyl, S02NH-C C6-alkyl, CON-(Ci-C6-alkyl)2, S02N-(C C6-alkyl)2, NH2, NH-Ci-C6- alkyl, N-(Ci-C6-alkyl)2, NH-(C C4-alkyl- C6-Ci2-aryl), NH-CO-C C6-alkyl, NH-S02-C C6- alkyl, S02-C C6-alkyl, C6-Ci2-aryl, 0-C6-Ci2-aryl, 0-CH2-C6-Ci2-aryl, CONH-C6-Ci2-aryl, S02NH-C6-Ci2-aryl, CONH-C3-Ci2-heterocyclyl, S02NH-C3-Ci2-heterocyclyl, S02-C6-Ci2- aryl, NH-S02-C6-Ci2-aryl, NH-CO-C6-Ci2-aryl, NH-S02-C3-Ci2-heterocyclyl, NH-CO-C3- Ci2-heterocyclyl and C3-Ci2-heterocyclyl, wherein aryl and heterocyclyl in turn may be unsubstituted or substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, CrC4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C -haloalkoxy.
The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine. C-|-C4-Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, C2-C -alkyl such as ethyl, n-propyl, iso-propyl, n- butyl, 2-butyl, iso-butyl or tert-butyl. C-|-C2-Alkyl is methyl or ethyl, C-|-C3-alkyl is additionally n-propyl or isopropyl. CrC6-Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include methyl, C2-C4-alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 - dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 , 1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1- ethyl-1-methylpropyl and 1 -ethyl-2-methylpropyl.
Halogenated Ci-C -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethyl, diha- logenomethyl, trihalogenomethyl, (R)-l-halogenoethyl, (S)-l -halogenoethyl, 2- halogenoethyl, 1 , 1 -dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl, (R)-1 - halogenopropyl, (S)-l -halogenopropyl, 2-halogenopropyl, 3-halogenopropyl, 1 , 1 - dihalogenopropyl, 2,2-dihalogenopropyl, 3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl, (R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1 -methylethyl, (R)-2,2-dihalogeno-1- methylethyl, (S)-2,2-dihalogeno-1-methylethyl, (R)-1 ,2-dihalogeno-1-methylethyl, (S)-1 ,2- dihalogeno-1 -methylethyl, (R)-2,2,2-trihalogeno-1 -methylethyl, (S)-2,2,2-trihalogeno-1 - methylethyl, 2-halogeno-1 -(halogenomethyl)ethyl, 1 -(dihalogenomethyl)-2,2- dihalogenoethyl, (R)-l-halogenobutyl, (S)-l-halogenobutyl, 2-halogenobutyl, 3- halogenobutyl, 4-halogenobutyl, 1 , 1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3- dihalogenobutyl, 4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Particular examples include the fluorinated C1-C4 alkyl groups as defined, such as trifluoromethyl. C6-Ci2-Aryl-CrC4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C6-Ci2-aryl, such as in benzyl. Hydroxy-CrC4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two hydroxyl groups, such as in hydroxy- methyl, (R)-l-hydroxyethyl, (S)-l -hydroxyethyl, 2-hydroxyethyl, (R)-l -hydroxypropyl, (S)- 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl, (S)-2- hydroxy-1 -methylethyl, 2-hydroxy-1 -(hydroxymethyl)ethyl, (R)-l-hydroxybutyl, (S)-1 - hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.
Ci-C6-Alkoxy-CrC4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4, in particular 1 or 2 carbon atoms, such as in methoxymethyl, (R)-l -methoxyethyl, (S)-l-methoxyethyl, 2-methoxyethyl, (R)-l-methoxypropyl, (S)-l-methoxypropyl, 2- methoxypropyl, 3-methoxypropyl, (R)-2-methoxy-1-methylethyl, (S)-2-methoxy-1 - methylethyl, 2-methoxy-1-(methoxymethyl)ethyl, (R)-l -methoxybutyl, (S)-l -methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, ethoxymethyl, (R)-l -ethoxyethyl, (S)-1- ethoxyethyl, 2-ethoxyethyl, (R)-l-ethoxypropyl, (S)-l-ethoxypropyl, 2-ethoxypropyl, 3- ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methylethyl, 2-ethoxy-1- (ethoxymethyl)ethyl, (R)-l-ethoxybutyl, (S)-l -ethoxybutyl, 2-ethoxybutyl, 3-ethoxybutyl, 4- ethoxybutyl.
Amino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by an amino group, such as in aminomethyl, 2-aminoethyl.
Ci-C6-Alkylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C6- alkylamino group, in particular by a Ci-C4-alkylamino group, such as in methylami- nomethyl, ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl, n- butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl or tert-butylaminomethyl.
Di-Ci-C6-Alkylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-Ci-C6- Alkylamino group, in particular by a di-Ci-C4-alkylamino group, such as in dimethylami- nomethyl. Ci-C6-Alkylcarbonylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C6- alkylcarbonylamino group, in particular by a C1-C4-alkylcarbonylamino group, such as in methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl, 2- butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl or tert- butylcarbonylaminomethyl.
C1-C6-Alkylaminocarbonylamino-C1-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C6-alkylaminocarbonylamino group, in particular by a Ci-C4-alkylaminocarbonylamino group, such as in methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl, n- propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl, n- butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl, iso- butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.
Di-Ci-C6-alkylaminocarbonylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-Ci-C6-alkylaminocarbonylamino group, in particular by a di-Ci-C4-alkylaminocarbo- nylamino group, such as in dimethylaminocarbonylaminomethyl, dimethylaminocarbonyl- aminoethyl, dimethylaminocarbonylaminon-propyl. Ci-C6-Alkylsulfonylamino-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a Ci-C6- alkylsulfonylamino group, in particular by a Ci-C4-alkylsulfonylamino group, such as in methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl, iso- propylsulfonylaminomethyl, n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl, iso- butylsulfonylaminomethyl or tert-butylsulfonylaminomethyl.
(C6-Ci2-Aryl-Ci-C6-alkyl)amino-Ci-C4 alkyl is a straight-chain or branched alkyl group hav- ing 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a (C6-Ci2-aryl-Ci-C6-alkyl)amino group, in particular a (C6-Ci2-aryl-Ci-C2-alkyl)amino group, such as in benzylaminomethyl. C3-Ci2-Heterocyclyl-Ci-C4-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C3-Ci2- heterocyclyl, such as in N-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl. C3-C12-Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure may be unsubstituted or may carry 1 , 2, 3 or 4 C1-C4 alkyl radicals, preferably one or more methyl radicals. Carbonyl is >C=0.
CrC6-Alkylcarbonyl is a radical of the formula R-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.
Halogenated Ci-C6-alkylcarbonyl is CrC6-alkylcarbonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms. Examples include fluoromethylcar- bonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are 1 , 1 , 1- trifluoroeth-2-ylcarbonyl, 1 , 1 , 1 -trifluoroprop-3-ylcarbonyl.
C6-Ci2-Arylcarbonyl is a radical of the formula R-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include benzoyl. CrC6-Alkoxycarbonyl is a radical of the formula R-O-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methoxycarbonyl and tert-butyloxycarbonyl. Halogenated Ci-C6-alkoxycarbonyl is a CrC6-alkoxycarbonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms. C6-Ci2-Aryloxycarbonyl is a radical of the formula R-O-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenoxycarbonyl.
Cyano is -C≡N. Aminocarbonyl is NH2C(0)-.
Ci-C6-Alkylaminocarbonyl is a radical of the formula R-NH-C(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methylaminocarbonyl.
(Halogenated Ci-C4-alkyl)aminocarbonyl is a Ci-C4-alkylaminocarbonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different hydrogen atoms. C6-Ci2-Arylaminocarbonyl is a radical of the formula R-NH-C(O)-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylami- nocarbonyl.
C2-C6-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1 -propen-1-yl, 2-propen-2-yl, methallyl(2- methylprop-2-en-1 -yl) and the like. C3-C5-Alkenyl is, in particular, allyl, 1-methylprop-2-en- 1-yl, 2-buten-1 -yl, 3-buten-1 -yl, methallyl, 2-penten-1-yl, 3-penten-1 -yl, 4-penten-1-yl, 1 - methylbut-2-en-1 -yl or 2-ethylprop-2-en-1-yl. C2-C6-Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1 -yl, 2-propyn-2-yl and the like. C3-C5-Alkynyl is, in particular, 2-propyn-1 -yl, 2-butyn-1-yl, 3-butyn-1 -yl, 2-pentyn-1 -yl, 3-pentyn-1 -yl, 4- pentyn-1 -yl. Ci-C4-Alkylene is straight-chain or branched alkylene group having from 1 to 4 carbon atoms. Examples include methylene and ethylene. A further example is propylene.
C2-C4-Alkenylene is straight-chain or branched alkenylene group having from 2 to 4 carbon atoms. C2-C4-Alkynylene is straight-chain or branched alkynylene group having from 2 to 4 carbon atoms. Examples include propynylene.
C6-Ci2-Aryl is a 6- to 12-membered, in particular 6- to 10-membered, aromatic cyclic radi- cal. Examples include phenyl and naphthyl.
C3-Ci2-Arylene is an aryl diradical. Examples include phen-1 ,4-ylene and phen-1 ,3-ylene.
Hydroxy is -OH.
C-i-C6-Alkoxy is a radical of the formula R-0-, wherein R is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms. Examples include meth- oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy), tert.-butoxy pentyloxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2- dimethylpropoxy, 1 -ethylpropoxy, hexyloxy, 1 , 1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 1- methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1 , 1- dimethylbutyloxy, 1 ,2-dimethylbutyloxy, 1 ,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3- dimethylbutyloxy, 3,3-dimethylbutyloxy, 1 -ethylbutyloxy, 2-ethylbutyloxy, 1 , 1 ,2- trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1 -ethyl-2- methylpropoxy.
Halogenated Ci-C6-alkoxy is a straight-chain or branched alkoxy group having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethoxy, dihalogenomethoxy, trihalogenomethoxy, (R)-l -halogenoethoxy, (S)-l -halogenoethoxy, 2-halogenoethoxy, 1 , 1 - dihalogenoethoxy, 2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1- halogenopropoxy, (S)-l-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy, 1 , 1 - dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy, 3,3,3- trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy, (S)-2-halogeno-1-methylethoxy, (R)- 2,2-dihalogeno-1-methylethoxy, (S)-2,2-dihalogeno-1-methylethoxy, (R)-1 ,2-dihalogeno-1- methylethoxy, (S)-1 ,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1 -methylethoxy, (S)-2,2,2-trihalogeno-1 -methylethoxy, 2-halogeno-1 -(halogenomethyl)ethoxy, 1 -(dihaloge- nomethyl)-2,2-dihalogenoethoxy, (R)-l -halogenobutoxy, (S)-l -halogenobutoxy, 2- halogenobutoxy, 3-halogenobutoxy, 4-halogenobutoxy, 1 , 1 -dihalogenobutoxy, 2,2- dihalogenobutoxy, 3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy, etc. Particular examples include the fluorinated C C4 alkoxy groups as defined, such as trifluoromethoxy. CrC6-Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by hydroxy. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2- hydroxyethoxy and the like.
Ci-C6-Alkoxy-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by one or two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxymethoxy, 2-methoxyethoxy, 1 - methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1 -methyl-1 -methoxyethoxy, eth- oxymethoxy, 2-ethoxyethoxy, 1 -ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1 - methyl-1-ethoxyethoxy and the like.
Amino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon at- oms as defined herein, wherein one hydrogen atom is replaced by an amino group. Examples include 2-aminoethoxy.
Ci-C6-Alkylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy, iso- propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy, iso- butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy, 2- (ethylamino)ethoxy, 2-(n-propylamino)ethoxy, 2-(iso-propylamino)ethoxy, 2-(n- butylamino)ethoxy, 2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy, 2-(tert- butylamino)ethoxy.
Di-Ci-C6-alkylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a di- alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminomethoxy, diethylaminomethoxy, N-methyl-N- ethylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy, 2-(N-methyl-N- ethylamino)ethoxy. Ci-C6-Alkylcarbonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an al- kylcarbonylamino group wherein the alkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylcarbonylaminomethoxy, ethyl- carbonylaminomethoxy, n-propylcarbonylaminomethoxy, iso- propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy, 2- butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy, tert-butylcarbonyl- aminomethoxy, 2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy, 2-(n- propylcarbonylamino)ethoxy, 2-(iso-propylcarbonylamino)ethoxy, 2-(n- butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonyl- amino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.
C6-Ci2-Arylcarbonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C6- C-12-arylcarbonylamino group as defined herein. Examples include 2- (benzoylamino)ethoxy.
Ci-C6-Alkoxycarbonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy, iso- propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy, 2- butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy, tert- butoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonyl- amino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy, 2-(iso- butoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.
C2-C6-Alkenyloxy is a radical of the formula R-0-, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy (2-propen-1 -yloxy), 1-propen-1 -yloxy, 2-propen-2-yloxy, methal- lyloxy (2-methylprop-2-en-1 -yloxy) and the like. C3-C5-Alkenyloxy is, in particular, allyloxy, 1-methylprop-2-en-1 -yloxy, 2-buten-1 -yloxy, 3-buten-1 -yloxy, methallyloxy, 2-penten-1 - yloxy, 3-penten-1 -yloxy, 4-penten-1 -yloxy, 1 -methylbut-2-en-1 -yloxy or 2-ethylprop-2-en-1 - yloxy.
C6-Ci2-Aryl-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C6-Ci2-aryl group as defined herein. Examples include benzyloxy.
Ci-C6-Alkylsulfonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkyl- sulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy, 2- [(2-methylpropyl)sulfonylamino]ethoxy. (Halogenated Ci-C6-alkyl)sulfonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein the alkyl group is halogenated. Examples include 2- (trifluoromethylsulfonylamino)ethoxy.
C6-Ci2-Arylsulfonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C6-C12- arylsulfonylamino group as defined herein. Examples include 2- (phenylsulfonylamino)ethoxy, 2-(naphthylsulfonylamino)ethoxy.
(C6-C12-Aryl-C1-C6-alkyl)sulfonylamino-C1-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is re- placed by a (Ce-C^-aryl-CrCe-alky sulfonylamino group, preferably by a (Ce-C^-aryl-C C2-alkyl)sulfonylamino group. Examples include 2-(benzylsulfonylamino)ethoxy.
C3-Ci2-Heterocyclylsulfonylamino-Ci-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C3-Ci2-heterocyclylsulfonylamino group as defined herein. Examples include 2- (pyridin-3-yl-sulfonylamino)ethoxy.
C3-C12-Heterocyclyl-C1-C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C3-C-|2- heterocyclyl group as defined herein. Examples include 2-(N-pyrrolidinyl)ethoxy, 2-(N- morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.
CrC2-Alkylenedioxo is a radical of the formula -0-R-0-, wherein R is a straight-chain or branched alkylene group having from 1 or 2 carbon atoms as defined herein. Examples include methylenedioxo.
C6-Ci2-Aryloxy is a radical of the formula R-0-, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxy. C3-Ci2-Heterocyclyloxy is a radical of the formula R-0-, wherein R is a C3-Ci2-heterocyclyl group having from 3 to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples include pyridin-2-yloxy.
CrC6-Alkylthio is a radical of the formula R-S-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3- methylbutylthio, 2,2-dimethylpropylthio, 1 -ethylpropylthio, hexylthio, 1 , 1- dimethylpropylthio, 1 ,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3- methylpentylthio, 4-methylpentylthio, 1 ,1 -dimethylbutylthio, 1 ,2-dimethylbutylthio, 1 ,3- dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1 - ethylbutylthio, 2-ethylbutylthio, 1 , 1 ,2-trimethylpropylthio, 1 ,2,2-trimethylpropylthio, 1 -ethyl- 1 -methylpropyl and 1-ethyl-2-methylpropyl.
Halogenated C-i-C6-alkylthio is a radical of the formula R-S-, wherein R is a halogenated alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include halogenomethylthio, dihalogenomethylthio, trihalogenomethylthio, (R)- 1-halogenoethylthio, (S)-l -halogenoethylthio, 2-halogenoethylthio, 1 , 1- dihalogenoethylthio, 2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio, (R)-1- halogenopropylthio, (S)-l -halogenopropylthio, 2-halogenopropylthio, 3- halogenopropylthio, 1 ,1 -dihalogenopropylthio, 2,2-dihalogenopropylthio, 3,3-dihalo- genopropylthio, 3,3,3-trihalogenopropylthio, (R)-2-halogeno-1 -methylethylthio, (S)-2- halogeno-1 -methylethylthio, (R)-2,2-dihalogeno-1 -methylethylthio, (S)-2,2-dihalogeno-1- methylethylthio, (R)-1 ,2-dihalogeno-1-methylethylthio, (S)-1 ,2-dihalogeno-1 - methylethylthio, (R)-2,2,2-trihalogeno-1-methylethylthio, (S)-2,2,2-trihalogeno-1- methylethylthio, 2-halogeno-1 -(halogenomethyl)ethylthio, 1 -(dihalogenomethyl)-2,2- dihalogenoethylthio, (R)-1 -halogenobutylthio, (S)-1 -halogenobutylthio, 2- halogenobutylthio, 3-halogenobutylthio, 4-halogenobutylthio, 1 , 1 -dihalogenobutylthio, 2,2- dihalogenobutylthio, 3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio, 4,4,4- trihalogenobutylthio, etc. Particular examples include the fluorinated Ci-C4 alkylthio groups as defined, such as trifluoromethylthio.
CrC6-Alkylsulfinyl is a radical of the formula R-S(O)-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include me- thylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1 -methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1- ethylpropylsulfinyl, hexylsulfinyl, 1 , 1 -dimethylpropylsulfinyl, 1 ,2-dimethylpropylsulfinyl, 1- methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1 , 1-dimethylbutylsulfinyl, 1 ,2-dimethylbutylsulfinyl, 1 ,3-dimethylbutylsulfinyl, 2,2- dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1- ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1 , 1 ,2-trimethylpropylsulfinyl, 1 ,2,2- trimethylpropylsulfinyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
CrC6-Alkylsulfonyl is a radical of the formula R-S(0)2-, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1 - methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2- dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1 ,1 -dimethylpropylsulfonyl, 1 ,2-dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3- methylpentylsulfonyl, 4-methylpentylsulfonyl, 1 ,1 -dimethylbutylsulfonyl, 1 ,2- dimethylbutylsulfonyl, 1 ,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3- dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1 -ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1 , 1 ,2-trimethylpropylsulfonyl, 1 ,2,2-trimethylpropylsulfonyl, 1 -ethyl-1 -methylpropyl and 1 - ethyl-2-methylpropyl. (Halogenated CrC6-alkyl)sulfonyl is a CrC6-alkylsulfonyl as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C6-Ci2-Arylsulfonyl is a radical of the formula R-S(0)2-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonyl.
(C6-C12-Aryl-C1-C4-alkyl)sulfonyl is a radical of the formula R-S(0)2-, wherein R is a C6- Ci2-aryl-Ci-C4-alkyl radical, in particular a C6-Ci2-aryl-Ci-C2-alkyl radical as defined herein. Examples include benzylsulfonyl.
C3-C12-Heterocyclylsulfonyl is a radical of the formula R-S(0)2-, wherein R is C3-C12- heterocyclyl as defined herein.
Aminosulfonyl is NH2-S(0)2-.
Ci-C6-Alkylaminosulfonyl is a radical of the formula R-NH-S(0)2- wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, iso- propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl, tert-butylaminosulfonyl.
Di-Ci-C6-alkylaminosulfonyl is a radical of the formula RR'N-S(0)2- wherein R and R' are independently of each other an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminosulfonyl, diethylaminosul- fonyl, N-methyl-N-ethylaminosulfonyl.
C6-Ci2-Arylaminosulfonyl is a radical of the formula R-NH-S(0)2- wherein R is an aryl radical having from 6 to 12, preferably 6 carbon atoms as defined herein. Amino is NH2. CrC6-Alkylamino is a radical of the formula R-NH- wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino, tert-butylamino.
(Halogenated Ci-C6-alkyl)amino is a Ci-C6-alkylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
Di-C"|-C6-alkylamino is a radical of the formula RR'N- wherein R and R' are independently of each other an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino. Di-(halogenated C"i-C6-alkyl)amino is a di-C"i-C6-alkylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C"|-C6-Alkylcarbonylamino is a radical of the formula R-C(0)-NH-, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein.
Examples include acetamido (methylcarbonylamino), propionamido, n-butyramido, 2- methylpropionamido (isopropylcarbonylamino), 2,2-dimethylpropionamido and the like.
(Halogenated Ci-C6-alkyl)carbonylamino is a Ci-C6-alkylcarbonylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C6-Ci2-Arylcarbonylamino is a radical of the formula R-C(0)-NH-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylcar- bonylamino.
C2-C6-Alkenylamino is a radical of the formula R-NH-, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinylamino, allylamino (2-propen-1-ylamino), 1 -propen-1-ylamino, 2-propen-2- ylamino, methallylamino (2-methylprop-2-en-1 -ylamino) and the like. C3-C5-Alkenylamino is, in particular, allylamino, 1-methylprop-2-en-1 -ylamino, 2-buten-1 -ylamino, 3-buten-1 - ylamino, methallylamino, 2-penten-1-ylamino, 3-penten-1 -ylamino, 4-penten-1 -ylamino, 1- methylbut-2-en-1 -ylamino or 2-ethylprop-2-en-1 -ylamino. CrC6-Alkylsulfonylamino is a radical of the formula R-S(0)2-NH-, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, iso- propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino, iso-butylsulfonylamino, tert-butylsulfonylamino.
(Halogenated Ci-C6 alkyl)sulfonylamino is a Ci-C6-alkylsulfonylamino as defined herein, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by 1 , 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C6-C12-Arylsulfonylamino is a radical of the formula R-S(0)2-NH-, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsul- fonylamino. Nitro is -N02.
C3-C12-Heterocyclyl is a 3- to 12-membered heterocyclic radical including a saturated heterocyclic radical, which generally has 3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring forming atoms, and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7 ring forming atoms. The heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclic radicals comprise 1 nitrogen atom as ring member atom and optionally 1 , 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N. Likewise preferred heterocyclic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1 , 2 or 3 further nitrogen atoms as ring members.
Examples of C3-Ci2-heterocyclyl include: C- or N-bound 3-4-membered, saturated rings, such as
2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1 -azetidinyl, 2-azetidinyl, 3- azetidinyl;
C-bound, 5-membered, saturated rings, such as
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetra- hydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl, tet- rahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1 ,2-oxathiolan-3-yl, 1 ,2-oxathiolan-4-yl, 1 ,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1 ,2-dithiolan-3-yl, 1 ,2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tet- rahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1 ,3-dioxolan-2-yl, 1 ,3- dioxolan-4-yl, 1 ,3-oxathiolan-2-yl, 1 ,3-oxathiolan-4-yl, 1 ,3-oxathiolan-5-yl, 1 ,3-dithiolan-2- yl, 1 ,3-dithiolan-4-yl, 1 ,3,2-dioxathiolan-4-yl; C-bound, 6-membered, saturated rings, such as
tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3- yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4- yl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3-dioxan-5-yl, 1 ,4-dioxan-2-yl, 1 ,3-dithian-2-yl, 1 ,3- dithian-4-yl, 1 ,3-dithian-5-yl, 1 ,4-dithian-2-yl, 1 ,3-oxathian-2-yl, 1 ,3-oxathian-4-yl, 1 ,3- oxathian-5-yl, 1 ,3-oxathian-6-yl, 1 ,4-oxathian-2-yl, 1 ,4-oxathian-3-yl, 1 ,2-dithian-3-yl, 1 ,2- dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetra hydro- 1 ,3- oxazin-2-yl, tetrahydro-1 ,3-oxazin-4-yl, tetrahydro-1 ,3-oxazin-5-yl, tetrahydro-1 ,3-oxazin- 6-yl, tetrahydro-1 , 3-thiazin-2-yl, tetrahydro-1 , 3-thiazin-4-yl, tetrahydro-1 ,3-thiazin-5-yl, tetrahydro-1 ,3-thiazin-6-yl, tetrahydro-1 , 4-thiazin-2-yl, tetrahydro-1 ,4-thiazin-3-yl, tetrahydro-1 , 4-oxazin-2-yl, tetrahydro-1 ,4-oxazin-3-yl, tetrahydro-1 , 2-oxazin-3-yl, tetra hydro- 1 ,2- oxazin-4-yl, tetrahydro-1 ,2-oxazin-5-yl, tetrahydro-1 ,2-oxazin-6-yl;
N-bound, 5-membered, saturated rings, such as
tetrahydropyrrol-1-yl (pyrrolidin-1-yl), tetra hyd ropy razol-1 -y I, tetrahydroisoxazol-2-yl, tetra- hydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;
N-bound, 6-membered, saturated rings, such as
piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1 -yl (piperazin-1 -yl), hexahydro- pyridazin-1 -yl, tetrahydro-1 , 3-oxazin-3-yl, tetrahydro-1 , 3-thiazin-3-yl, tetrahydro-1 ,4- thiazin-4-yl, tetrahydro-1 , 4-oxazin-4-yl (morpholin-1-yl), tetrahydro-1 , 2-oxazin-2-yl;
C-bound, 5-membered, partially unsaturated rings, such as
2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl, 2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2,5-dihydro-1 H-pyrrol-2-yl, 2,5- dihydro-1 H-pyrrol-3-yl, 4,5-dihydro-1 H-pyrrol-2-yl, 4,5-dihydro-1 H-pyrrol-3-yl, 3,4-dihydro- 2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H- pyrrol-3-yl, 4,5-dihydro-1 H-pyrazol-3-yl, 4,5-dihydro-1 H-pyrazol-4-yl, 4,5-dihydro-1 H- pyrazol-5-yl, 2,5-dihydro-1 H-pyrazol-3-yl, 2,5-dihydro-1 H-pyrazol-4-yl, 2,5-dihydro-1 H- pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, 2,3- dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5- dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl, 2,5- dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl, 2,3- dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro- 1 H-imidazol-2-yl, 4,5-dihydro-1 H-imidazol-4-yl, 4,5-dihydro-1 H-imidazol-5-yl, 2,5-dihydro- 1 H-imidazol-2-yl, 2,5-dihydro-1 H-imidazol-4-yl, 2,5-dihydro-1 H-imidazol-5-yl, 2,3-dihydro- 1 H-imidazol-2-yl, 2,3-dihydro-1 H-imidazol-4-yl, 4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol- 4-yl, 4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5- dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-
2- yl, 2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl, 2,3-dihydro- thiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1 ,3-dioxol-2-yl, 1 ,3-dioxol-4-yl, 1 ,3-dithiol-2-yl, 1 ,3- dithiol-4-yl, 1 ,3-oxathiol-2-yl, 1 ,3-oxathiol-4-yl, 1 ,3-oxathiol-5-yl;
C-bound, 6-membered, partially unsaturated rings, such as
2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl, 2H-3,4-dihydropyran-4-yl, 2H-3,4- dihydropyran-3-yl, 2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4- dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran-3-yl, 2H-3,4- dihydrothiopyran-2-yl, 1 ,2,3,4-tetrahydropyridin-6-yl, 1 ,2,3,4-tetrahydropyridin-5-yl,
1.2.3.4- tetrahydropyridin-4-yl, 1 ,2,3,4-tetra-hydropyridin-3-yl, 1 ,2,3,4-tetrahydropyridin-2- yl, 2H-5,6-dihydropyran-2-yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6- dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl, 2H-5,6- dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl, 2H-5,6- dihydrothiopyran-6-yl, 1 ,2,5,6-tetrahydropyridin-2-yl, 1 ,2,5,6-tetrahydropyridin-3-yl,
1 ,2,5,6-tetrahydropyridin-4-yl, 1 ,2,5,6-tetrahydropyridin-5-yl, 1 ,2,5,6-tetrahydropyridin-6-yl,
2.3.4.5- tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2,3,4, 5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-
, 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1 ,4- dihydropyridin-2-yl, 1 ,4-dihydropyridin-3-yl, 1 ,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H- pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-
3- yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1 ,2-dihydropyridin-2-yl, 1 ,2- dihydro-pyridin-3-yl, 1 ,2-dihydropyridin-4-yl, 1 ,2-dihydropyridin-5-yl, 1 ,2-dihydro-pyridin-6- yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl, 3,4- dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl,
2.5- d ihyd ropy rid in-4-yl , 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 2,3-dihydropyridin- 2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3- dihydropyridin-6-yl, 2H-5,6-dihydro-1 ,2-oxazin-3-yl, 2H-5,6-dihydro-1 ,2-oxazin-4-yl, 2H-
5.6- dihydro-1 ,2-oxazin-5-yl, 2H-5,6-dihydro-1 ,2-oxazin-6-yl, 2H-5,6-dihydro-1 ,2-thiazin-3- yl, 2H-5,6-dihydro-1 ,2-thiazin-4-yl, 2H-5,6-dihydro-1 ,2-thiazin-5-yl, 2H-5,6-dihydro-1 ,2- thiazin-6-yl, 4H-5,6-dihydro-1 ,2-oxazin-3-yl, 4H-5,6-dihydro-1 ,2-oxazin-4-yl, 4H-5,6-di- hydro-1 ,2-oxazin-5-yl, 4H-5,6-dihydro-1 ,2-oxazin-6-yl, 4H-5,6-dihydro-1 ,2-thiazin-3-yl, 4H- 5,6-dihydro-1 ,2-thiazin-4-yl, 4H-5,6-dihydro-1 ,2-thiazin-5-yl, 4H-5,6-dihydro-1 ,2-thiazin-6- yl, 2H-3,6-dihydro-1 ,2-oxazin-3-yl, 2H-3,6-dihydro-1 ,2-oxazin-4-yl, 2H-3,6-dihydro-1 ,2- oxazin-5-yl, 2H-3,6-dihydro-1 ,2-oxazin-6-yl, 2H-3,6-dihydro-1 ,2-thiazin-3-yl, 2H-3.6- dihydro-1 ,2-thiazin-4-yl, 2H-3,6-dihydro-1 ,2-thiazin-5-yl, 2H-3,6-dihydro-1 ,2-thiazin-6-yl, 2H-3,4-dihydro-1 ,2-oxazin-3-yl, 2H-3,4-dihydro-1 ,2-oxazin-4-yl, 2H-3,4-dihydro-1 ,2- oxazin-5-yl, 2H-3,4-dihydro-1 ,2-oxazin-6-yl, 2H-3,4-dihydro-1 ,2-thiazin-3-yl, 2H-3.4- dihydro-1 ,2-thiazin-4-yl, 2H-3,4-dihydro-1 ,2-thiazin-5-yl, 2H-3,4-dihydro-1 ,2-thiazin-6-yl,
2.3.4.5- tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5- tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl,
3.4.5.6- tetrahydropyridazin-4-yl, 1 ,2,5,6-tetrahydropyridazin-3-yl, 1 ,2,5,6- tetrahydropyridazin-4-yl, 1 ,2,5,6-tetra-hydropyridazin-5-yl, 1 ,2,5,6-tetrahydropyridazin-6-yl, 1 ,2,3,6-tetrahydro-pyridazin-3-yl, 1 ,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1 ,3- oxazin-2-yl, 4H-5,6-dihydro-1 ,3-oxazin-4-yl, 4H-5,6-dihydro-1 ,3-oxazin-5-yl, 4H-5,6- dihydro-1 ,3-oxazin-6-yl, 4H-5,6-dihydro-1 ,3-thiazin-2-yl, 4H-5,6-dihydro-1 ,3-thiazin-4-yl, 4H-5,6-dihydro-1 ,3-thiazin-5-yl, 4H-5,6-dihydro-1 ,3-thiazin-6-yl, 3,4,5-6- tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl, 1 ,2,3,4-tetrahydropyrazin-2-yl, 1 ,2,3,4-tetrahydropyrazin- 5-yl, 1 ,2,3,4-tetrahydro-pyrimidin-2-yl, 1 ,2,3,4-tetrahydropyrimidin-4-yl, 1 ,2,3,4- tetrahydropyrimidin-5-yl, 1 ,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1 ,4-thiazin-2-yl, 2,3- dihydro-1 ,4-thiazin-3-yl, 2,3-dihydro-1 ,4-thiazin-5-yl, 2,3-dihydro-1 ,4-thiazin-6-yl, 21-1-1 ,3- oxazin-2-yl, 2H-1 ,3-oxazin-4-yl, 2H-1 ,3-oxazin-5-yl, 2H-1 ,3-oxazin-6-yl, 2H-1 ,3-thiazin-2- yl, 2H-1 ,3-thiazin-4-yl, 2H-1 ,3-thiazin-5-yl, 2H-1 ,3-thiazin-6-yl, 4H-1 ,3-oxazin-2-yl, 41-1-1 ,3- oxazin-4-yl, 4H-1 ,3-oxazin-5-yl, 4H-1 ,3-oxazin-6-yl, 4H-1 ,3-thiazin-2-yl, 4H-1 ,3-thiazin-4- yl, 4H-1 ,3-thiazin-5-yl, 4H-1 ,3-thiazin-6-yl, 6H-1 ,3-oxazin-2-yl, 6H-1 ,3-oxazin-4-yl, 6H-1.3- oxazin-5-yl, 6H-1 ,3-oxazin-6-yl, 6H-1 ,3-thiazin-2-yl, 6H-1 ,3-oxazin-4-yl, 6H-1 ,3-oxazin-5- yl, 6H-1 ,3-thiazin-6-yl, 2H-1 ,4-oxazin-2-yl, 2H-1 ,4-oxazin-3-yl, 2H-1 ,4-oxazin-5-yl, 2H-1 ,4- oxazin-6-yl, 2H-1 ,4-thiazin-2-yl, 2H-1 ,4-thiazin-3-yl, 2H-1 ,4-thiazin-5-yl, 2H-1 ,4-thiazin-6- y|, 4H-1 ,4-oxazin-2-yl, 4H-1 ,4-oxazin-3-yl, 4H-1 ,4-thiazin-2-yl, 4H-1 ,4-thiazin-3-yl, 1 ,4- dihydropyridazin-3-yl, 1 ,4-dihydropyridazin-4-yl, 1 ,4-dihydropyridazin-5-yl, 1 ,4- dihydropyridazin-6-yl, 1 ,4-dihydropyrazin-2-yl, 1 ,2-dihydropyrazin-2-yl, 1 ,2-dihydropyrazin- 3-yl, 1 ,2-dihydropyrazin-5-yl, 1 ,2-dihydropyrazin-6-yl, 1 ,4-dihydropyrimidin-2-yl, 1 ,4- dihydropyrimidin-4-yl, 1 ,4-dihydropyrimidin-5-yl, 1 ,4-dihydropyrimidin-6-yl, 3,4- dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or 3,4- dihydropyrimidin-6-yl; N-bound, 5-membered, partially unsaturated rings, such as
2,3-dihydro-1 H-pyrrol-1 -yl, 2,5-dihydro-1 H-pyrrol-1 -yl, 4,5-dihydro-1 H-pyrazol-1-yl, 2,5- dihydro-1 H-pyrazol-1-yl, 2,3-dihydro-1 H-pyrazol-1 -yl, 2,5-dihydroisoxazol-2-yl, 2,3- dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1 H- imidazol-1-yl, 2,5-dihydro-1 H-imidazol-1 -yl, 2,3-dihydro-1 H-imidazol-1-yl, 2,3- dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl; N-bound, 6-membered, partially unsaturated rings, such as
1 ,2,3,4-tetrahydropyridin-1-yl, 1 ,2,5,6-tetrahydropyridin-1-yl, 1 ,4-dihydro-pyridin-1-yl, 1 ,2- dihydropyridin-1 -yl, 2H-5,6-dihydro-1 ,2-oxazin-2-yl, 2H-5,6-dihydro-1 ,2-thiazin-2-yl, 2H- 3,6-dihydro-1 ,2-oxazin-2-yl, 2H-3,6-dihydro-1 ,2-thiazin-2-yl, 2H-3,4-dihydro-1 ,2-oxazin-2- yl, 2H-3,4-dihydro-1 ,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1 ,2,5,6- tetrahydropyridazin-1 -yl, 1 ,2,5,6-tetrahydropyridazin-2-yl, 1 ,2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl, 1 ,2,3,4-tetrahydropyrazin-1-yl, 1 ,2,3,4- tetrahydropyrimidin-1 -yl, 1 ,2,3,4-tetrahydropyrimidin-3-yl, 2,3-dihdro-1 ,4-thiazin-4-yl, 2H- 1 ,2-oxazin-2-yl, 2H-1 ,2-thiazin-2-yl, 4H-1 ,4-oxazin-4-yl, 4H-1 ,4-thiazin-4-yl, 1 ,4- dihydropyridazin-1-yl, 1 ,4-dihydropyrazin-1 -yl, 1 ,2-dihydropyrazin-1-yl, 1 ,4- dihydropyrimidin-1 -yl or 3,4-dihydropyrimidin-3-yl;
C-bound, 5-membered, heteroaromatic rings, such as
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, isoxa- zol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imida- zol-2-yl, imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thia- zol-5-yl, 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4,-oxadiazol-5- yl, 1 ,3,4-oxadiazol-2-yl, 1 ,2,3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,3,4-thiadiazolyl-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl, tetrazol-5- yi;
C-bound, 6-membered, heteroaromatic rings, such as
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2- yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4- triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,4,5-tetrazin-3-yl;
N-bound, 5-membered, heteroaromatic rings, such as
pyrrol-1 -yl, pyrazol-1-yl, imidazol-1 -yl, 1 ,2,3-triazol-1 -yl, 1 ,2,4-triazol-1 -yl, tetrazol-1 -yl.
Heterocyclyl also includes bicyclic heterocycles, which comprise one of the described 5- or 6-membered heterocyclic rings and a further anellated, saturated or unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a futher anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring being saturated or unsaturated or aromatic. These include quinolinyl, isoquinolinyl, indolyl, indol- izinyl, isoindolyl, indazolyl, benzofuryl, benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl and benzimidazolyl. Examples of 5- or 6-membered heteroaromatic compounds comprising an anellated cycloalkenyl ring include dihydroindolyl, dihydroindoliz- inyl, dihydroisoindolyl, dihydrochinolinyl, dihydroisoquinolinyl, chromenyl and chromanyl. C3-Ci2-Heteroarylene is a heteroaryl diradical. Examples include pyrid-2,5-ylene and pyrid-2,4-ylene.
With respect to the compounds' capability of inhibiting glycine transporter 1 , the variables R, R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 preferably have the following meanings which, when taken alone or in combination, represent particular embodiments of the benzazepine derivatives of the formula (I) or any other formula disclosed herein. In said formula (I), there may be one or more than one substituent R, R2 and/or R3. More particularly, there may be up to 3 substituents R2, and up to 7 substituents R3. Preferably there is one substituent R and 1 , 2 or 3 substituents R2. Formula (I) may thus be depicted as follows:
Figure imgf000038_0001
wherein a is 1 , 2 or 3, b is 1 , 2, 3, 4, 5, 6 or 7 and c is 1. If there is more than one radical R2, these may be the same or different radicals. If there is more than one radical R3, these may be the same or different radicals.
According to one embodiment, R is cyano.
Preferably, R is R1-W-A1-Q-Y-A2-X1- and R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
R1 is hydrogen, d-Ce-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or n- pentyl), C3-Ci2-cycloalkyl-Ci-C4-alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclo- hexylmethyl), halogenated ( Ce-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1 -yl or 3,3,3- trifluoroprop-1 -yl), tri-(Ci-C4-alkyl)-silyl-Ci-C4-alkyl (e.g. tnmethylsilylethyl), hydroxy-CrC4- alkyl, C1-C6-alkoxy-C1-C4-alkyl (e.g. ethoxyethyl), amino-C1-C4-alkyl, C-i-Ce-alkylamino-Cr C4-alkyl, di-Ci-C6-alkylamino-Ci-C4-alkyl, Ci-C6-alkylcarbonylamino-Ci-C4-alkyl, CrC6- alkyloxycarbonylamino-C1-C4-alkyl, C1-C6-alkylaminocarbonylamino-C1-C4-alkyl, di-C-|-C6- alkylaminocarbonylamino-Ci-C4-alkyl, Ci-C6-alkylsulfonylamino-Ci-C4-alkyl, (optionally substituted C6-C12-aryl-C1-C6-alkyl)amino-C1-C4-alkyl, optionally substituted C6-C12-aryl- CrC4-alkyl, optionally substituted C3-Ci2-heterocyclyl-Ci-C4-alkyl, C3-Ci2-cycloalkyl (e.g. cyclopropyl or cyclobutyl), d-C6-alkylcarbonyl, CrC6-alkoxycarbonyl, halogenated Ci-C6- alkoxycarbonyl, C6-Ci2-aryloxycarbonyl, aminocarbonyl, Ci-C6-alkylaminocarbonyl, (halogenated Ci-C4-alkyl)aminocarbonyl, C6-Ci2-arylaminocarbonyl, C2-C6-alkenyl (e.g. prop- 1 ,2-en-1-yl), C2-C6-alkynyl, optionally substituted C6-Ci2-aryl (e.g. phenyl, 2- methylphenyl), hydroxy, Ci-C6-alkoxy (e.g. tert-butyloxy), halogenated CrC6-alkoxy, C C6-hydroxyalkoxy, Ci-C6-alkoxy-CrC4-alkoxy, amino-Ci-C4-alkoxy, Ci-C6-alkylamino-Ci- C4-alkoxy, di-Ci-C6-alkylamino-Ci-C4-alkoxy, Ci-C6-alkylcarbonylamino-Ci-C4-alkoxy, C6- Ci2-arylcarbonylamino-Ci-C4-alkoxy, Ci-C6-alkoxycarbonylamino-Ci-C4-alkoxy, C6-Ci2- aryl-CrC -alkoxy, CrCe-alkylsulfonylamino-CVC -alkoxy, (halogenated C^-C6- alkyl)sulfonylamino-Ci-C4-alkoxy, C6-Ci2-arylsulfonylamino-Ci-C4-alkoxy, (C6-Ci2-aryl-Cr C6-alkyl)sulfonylamino-C-|-C4-alkoxy, C3-C12-heterocyclylsulfonylamino-C-|-C4-alkoxy, C3- Ci2-heterocyclyl-Ci-C4-alkoxy, C6-Ci2-aryloxy, C3-Ci2-heterocyclyloxy, CrC6-alkylthio, halogenated CrCe-alkylthio, CrCe-alkylamino, (halogenated C Ce-alkylamino, d\-C -C6- alkylamino (e.g. dimethylamino), di-(halogenated Ci-C6-alkyl)amino, Ci-C6- alkylcarbonylamino, (halogenated C"|-C6-alkyl)carbonylamino, C6-C12-arylcarbonylamino, Ci-C6-alkylsulfonylamino, (halogenated Ci-C6-alkyl)sulfonylamino, C6-Ci2- arylsulfonylamino or optionally substituted C3-C12-heterocyclyl (e.g. 3-pyridyl, 2-thienyl, 4- methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1 ,2-diazol- 4-yl, 1-methyl-1 ,2-diazol-4-yl, 1 -ethyl-1 ,2-diazol-4-yl, 1 -difluormethyl-1 ,2-diazol-4-yl, 2- methyl-1 ,3-diazol-4-yl, 1 -methyl-1 ,3-diazol-4-yl, 2-methyl-1 ,3-thiazol-5-yl, 2,4-dimethyl-1 ,3- thiazol-5-yl, 3-pyrrolidinyl, 1-methyl-pyrrol-3-yl, 2-pyridyl, 1 -methyl-1 , 2-diazol-3-yl, 1- methyl-3-trifluoromethyl-1 ,2-diazol-4-yl, 1 , 2-dimethyl-1 ,3-diazol-4-yl, 5-methylisoxazol-3-yl or 1 -methyl-1 , 2,4-triazol-3-yl). Preferably, R1 is CrC6-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl or n- pentyl), C3-Ci2-cycloalkyl-CrC4-alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclo- hexylmethyl), halogenated Ci-C6-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1 -yl or 3,3,3- trifluoroprop-1 -yl), tri-(CrC4-alkyl)-silyl-Ci-C4-alkyl (e.g. trimethylsilylethyl), Ci-C6-alkoxy- Ci-C4-alkyl (e.g. ethoxyethyl), amino-Ci-C4-alkyl, Ci-C6-alkylamino-Ci-C4-alkyl, di-Ci-C6- alkylamino-Ci-C4-alkyl, Ci-C6-alkyloxycarbonylamino-Ci-C4-alkyl, Ci-C6- alkylaminocarbonylamino-Ci-C4-alkyl, C6-Ci2-aryl-Ci-C4-alkyl, C3-Ci2-cycloalkyl (e.g.
cyclopropyl or cyclobutyl), C2-C6-alkenyl (e.g. prop-1 ,2-en-1 -yl), optionally substituted C6- Ci2-aryl (e.g. phenyl), hydroxy, Ci-C6-alkylamino, (halogenated Ci-C6-alkyl)amino, di-Cr C6-alkylamino or optionally substituted C3-Ci2-heterocyclyl (e.g. 3-pyridyl, 2-thienyl, 4- methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1 ,2-diazol- 4-yl, 1 -methyl-1 , 2-diazol-4-yl, 1 -ethyl-1 ,2-diazol-4-yl, 1 -difluormethyl-1 ,2-diazol-4-yl, 2- methyl-1 ,3-diazol-4-yl, 1 -methyl-1 , 3-diazol-4-yl, 2-methyl-1 ,3-thiazol-5-yl, 2,4-dimethyl-1 ,3- thiazol-5-yl or 3-pyrrolidinyl). In particular, R1 is CrC6-alkyl (e.g. ethyl or n-propyl), C3-Ci2-cycloalkyl-Ci-C4-alkyl (e.g. cyclopropylmethyl), C3-Ci2-cycloalkyl (e.g. cyclobutyl), or optionally substituted C3-Ci2- heterocyclyl (e.g. 3-pyridyl, 1 -methyl-1 ,2-diazol-4-yl, 1 -methyl-1 ,3-diazol-4-yl, 3-oxetanyl, 1 -methyl-pyrrol-3-yl).
In connection with R1, substituted C6-Ci2-aryl in particular includes C6-Ci2-aryl, such as phenyl or naphthyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, d-C4-alkyl, Ci-C4-haloalkyl, cyano, Ci-C4-alkoxy, CrC4-haloalkoxy, amino, C1-C4-alkylamino, C1-C4-dialkylamino, morpholino and piperidinyl. The same ap- plies to substituted C6-Ci2-aryl in substituted C6-Ci2-aryl-Ci-C4-alkyl.
In connection with R1, substituted C3-Ci2-heterocyclyl in particular includes C3-C-|2- heterocyclyl, such as pyridyl, thienyl, diazolyl, quinolinyl, piperidinyl, piperazinyl or mor- pholinyl, pyrrolyl, isoxazolyl and triazolyl being further examples of such C3-Ci2- heterocyclyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C4-alkyl, CrC4-haloalkyl, CrC4-alkoxycarbonyl, cyano, CrC4-alkoxy, Ci-C4- haloalkoxy, C1-C4-alkylsulfonyl, amino, C1-C4-alkylamino, C1-C4-dialkylamino, C6-C12- arylamino and C3-Ci2-heterocyclyl (e.g., morpholino or piperidinyl). The same applies to substituted C3-C12-heteroaryl in substituted C3-C12-heteroaryl-C1-C4-alkyl.
According to one embodiment, W is -NR8- and Y is a bond. According to an alternative embodiment, W is a bond and Y is -NR9-. According to a further alternative embodiment, W is a bond and Y is a bond, especially if R1 is a nitrogen-bound radical, e.g. nitrogen- bound heterocyclyl such as piperazinyl or morpholinyl.
According to one embodiment, Q is -S(0)2-. According to an alternative embodiment, Q is -C(O)-.
According to a particular embodiment, -W-A1-Q-Y- is -W-A1-S(0)2-NR9-, -NR8-S(0)2-, -A1- S(0)2- or -S(0)2-. According to a further particular embodiment, -W-A1-Q-Y- is -W-A1-CO- NR9- or -NR8-CO-.
A1 is optionally substituted CrC4-alkylene or a bond. In connection with A1, substituted Ci- C4-alkylene in particular includes CrC4-alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, CrC4-alkyl and cyano. Preferably, A1 is a bond. If A1 is C C4-alkylene, W is preferably -NR8-.
A2 is optionally substituted CrC4-alkylene (e.g. 1 ,2-ethylene), Ci-C4-alkylene-CO-, -CO- C C4-alkylene, Ci-C4-alkylene-0-CrC4-alkylene, Ci-C4-alkylene-NR10-Ci-C4-alkylene, optionally substituted C6-Ci2-arylene, optionally substituted C6-Ci2-heteroarylene or a bond. Additionally, A2 may be optionally substituted C2-C4-alkenylen or optionally substituted C2-C4-alkynylene. Preferably, A2 is optionally substituted CrC4-alkylene (e.g. 1 ,2- ethylene). More preferably, A2 is CrC4-alkylene (e.g. 1 ,2-ethylene). Alternatively, it is preferred that A2 is optionally substituted C6-Ci2-arylene, in particular C6-Ci2-arylene selected from the group consisting of phen-1 ,4-ylene and phen-1 ,3-ylene, or optionally substituted C6-Ci2-heteroarylene, in particular C6-Ci2-heteroarylene selected from the group consisting of pyrid-2,5-ylene and pyrid-2,4-ylene. If A2 is a bond, X1 is preferably optionally substituted Ci-C4-alkylene. Alternatively, if A2 is a bond, X1 is in particular optionally substituted C2-C4-alkenylene or optionally substituted C2-C4-alkynylene.
In connection with A2, substituted C1-C4-alkylene in particular includes C1-C4-alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, d- C4-alkyl, C1-C4-haloalkyl and cyano. In connection with A2, substituted C2-C4-alkenylene or substituted C2-C4-alkynylene in particular includes C2-C4-alkenylene or C2-C4-alkynylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and cyano. In connection with A2, substituted C6-Ci2-arylene in particular includes C6-Ci2-arylene substituted with 1 , 2 or 3 substituents selected from the group consisting of C1-C4-alkyl, C-|-C4- haloalkyl, CrC4-alkoxycarbonyl, cyano, CrC4-alkoxy, CrC4-haloalkoxy, C1-C4- alkylsulfonyl, amino, C1-C4-alkylamino, C1-C4-dialkylamino, C6-C12-arylamino and C3-C12- heterocyclyl (e.g., morpholino or piperidinyl).
In connection with A2, substituted C6-Ci2-heteroarylene in particular includes C6-Ci2- heteroarylene substituted with 1 , 2 or 3 substituents selected from the group consisting of CrC4-alkyl, CrC4-haloalkyl, CrC4-alkoxycarbonyl, cyano, Ci-C4-alkoxy, CrC4-haloalkoxy, CrC4-alkylsulfonyl, amino, Ci-C4-alkylamino, Ci-C4-dialkylamino, C6-Ci2-arylamino and C3-Ci2-heterocyclyl (e.g, morpholino or piperidinyl).
X1 is -0-, -NR11-, -S- or optionally substituted Ci-C4-alkylene (e.g. -CH2-, 1 ,2-ethylene or 1 ,3-popylene). In connection with X1, substituted CrC4-alkylene in particular includes Cr C4-alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C4-alkyl, CrC4-haloalkyl and cyano. Additionally, X1 may be optionally substituted C2-C4-alkenylen or optionally substituted C2-C4-alkynylene (e.g. propynylene). In connection with X1, substituted C2-C4-alkenylene or substituted C2-C4-alkynylene in particular includes C2-C4-alkenylene or C2-C4-alkynylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, CrC4-alkyl, Ci-C4-haloalkyl and cyano. Preferably, X1 is -0-, -NR11, -S-. More preferably, X1 is -0-. Alternatively, it is pre- ferred if X1 is optionally substituted CrC4-alkylene (e.g. -CH2-, 1 ,2-ethylene or 1 ,3- propylene).
According to a particular embodiment, A2 is a bond and X1 is optionally substituted Ci-C4- alkylene, optionally substituted C2-C4-alkenylene or optionally substituted C2-C4- alkynylene.
According to a particular embodiment, R1-W-A1-Q-Y-A2-X1- is R1-S(0)2-NH-A2-X1-, R1-NH- S(0)2-A2-X1-, R1-C(0)-NH-A2-X1- or R1-NH-C(0)-A2-X1-.
According to a particular embodiment, the structural element -Y-A2-X1- comprises at least 2, 3 or 4 atoms in the main chain. According to further particular embodiments the structural element -Y-A2-X1- has up to 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4 atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.
According to a further particular embodiment, -Y-A2-X1- is -Ci-C4-alkylene-0- or -NR9-Ci- C4-alkylene-0-, with -Y-A2-X1- preferably having 2 to 6, 3 to 5 and especially 4 atoms in the main chain. Particular examples of -Y-A2-X1- include -(CH2)3-0- and -NR9-(CH2)2-0-. In this particular embodment, R9 is as defined herein and preferably R9 is hydrogen, C-|-C6- alkyl (e.g. methyl or ethyl) or C3-Ci2-cycloalkyl (e.g. cyclopropyl), or R9 is Ci-C4-alkylene that is bound to a carbon atom in A2 which is C-i-C4-alkylene.
According to a further particular embodiment, -Y-A2-X1- is -NR9-C-|-C4-alkylene- (e.g. -NH- CH2-, -NH-(CH2)2- or -NH-(CH2)3-), with -Y-A2-X1- preferably having 2 to 6, 2 to 5, 2 to 4 and especially 2, 3 or 4 atoms in the main chain. In this particular embodment, R9 is as defined herein and preferably R9 is hydrogen, CrC6-alkyl (e.g. methyl or ethyl) or C3-C-|2- cycloalkyl (e.g. cyclopropyl); or R9 is Ci-C4-alkylene that is bound to a carbon atom in X1 which is CrC4-alkylene. According to a further particular embodiment, -Y-A2-X1- is -NR9-C2-C4-alkenylene- or -NR9- C2-C4-alkynylene- (e.g. -NH-CH2-C≡C-), with -Y-A2-X1- preferably having 2 to 6, 3 to 5 and especially 4 atoms in the main chain. In this particular embodment, R9 is as defined herein and preferably is R9 is hydrogen, d-C6-alkyl (e.g. methyl or ethyl) or C3-Ci2-cycloalkyl (e.g. cyclopropyl or cyclobutyl). If A is a heterocyclic ring, this embodiment of -Y-A2-X1- is particularly suitable.
According to a further particular embodiment, -Y-A2-X1- is -Ci-C4-alkylene- (e.g. -(CH2)2-), with -Y-A2-X1- preferably having 2 to 6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain. If A is a heterocyclic ring, this embodiment of -Y-A2-X1- is particularly suitable. According to a further particular embodiment, the structural motif -Y-A2-X1 as disclosed herein is bound to Q being -S(0)2- or -C(O)-. Particular examples for this embodiment include heterocyclic compounds of the invention wherein R is R1-S(0)2-Y-A2-X1 or R1- C(0)-Y-A2-X1.
The radical R and in particular the radical R1-W-A1-Q-Y-A2-X1- may, in principle, be bound to the 6-, 7- , 8, or 9-position of the benzazepine skeleton:
R1— W— A— Q— Y— A— X1
Figure imgf000043_0001
In said formulae, R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
Further particular examples include benzazepine derivatives of the above formulae wherein the radical R1-W-A1-Q-Y-A2-X1- is replaced by the radical -CN.
Benzazepine derivatives having the radical R1-W-A1-Q-Y-A2-X1- (or the radical -CN) in the 7-, 8-, 9-position are preferred.
Particularly preferred are benzazepine derivatives having the radical R1-W-A1-Q-Y-A2-X1- (or the radical -CN) in the 8-position.
In addition to the radical R1-W-A1-Q-Y-A2-X1- (or the radical -CN), the benzazepine derivatives of the invention may have one or more than one further substituent bound to the benzene ring. In these positions, the skeleton of the benzazepine derivatives may thus be substituted with one or more than one radical R2. If there is more than one radical R2, these may be the same or different radicals. In particular, in 6-, 7-, 8- and/or 9-position, the benzazepine skeleton may be substituted with one or more than one radical R2. The benzazepine derivatives of the invention may therefore be represented by one of the following formulae:
Figure imgf000044_0001
Figure imgf000045_0001
or by corresponding formulae wherein the radical R1-W-A1-Q-Y-A2-X1- is replaced by the radical -CN,
wherein R2a, R2b, R2c, R2d independently have one of the meanings given for R2, and R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein.
R2 is hydrogen, halogen (e.g. fluorine), Ci-C6-alkyl, halogenated CrC4-alkyl, hydroxy-d- C4-alkyl, -CN, C2-C6-alkenyl, C2-C6-alkynyl, optionally substituted C6-C12-aryl, hydroxy, C C6-alkoxy, halogenated CrC6-alkoxy, CrC6-alkoxycarbonyl, C2-C6-alkenyloxy, C6-Ci2-aryl- CrC4-alkoxy, CrCe-alkylcarbonyloxy, CrCe-alkylthio, CrCe-alkylsulfinyl, C C6- alkylsulfonyl, aminosulfonyl, amino, Ci-C6-alkylamino, C2-C6-alkenylamino, nitro or optionally substituted C3-C12-heterocyclyl, or two radicals R2 together with the ring atoms to which they are bound form a 5- or 6 membered ring.
An optionally substituted 5- or 6-membered ring that is formed by two radicals R2 together with the ring atoms of A to which they are bound is, for instance, a benzene ring.
In connection with R2, substituted C6-Ci2-aryl in particular includes C6-Ci2-aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen and CrC4-alkyl, Ci-C4-haloalkyl, cyano, CrC4-alkoxy and Ci-C4-haloalkoxy.
In connection with R2, substituted C3-Ci2-heterocyclyl in particular includes C3-C-|2- heterocyclyl, such as morpholinyl, pyrrolidinyl and piperidinyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, Ci-C4-alkoxy and Ci-C4-haloalkoxy. Preferably, R2 is hydrogen, halogen (e.g. fluorine) or Ci-C6-alkoxy. In particular, R2 is hydrogen or halogen (e.g. fluorine). According to a particular embodiment, the benzazepine derivatives of the invention have one of the following formulae:
Figure imgf000046_0001
Figure imgf000046_0002
or a corresponding formula wherein the radical R1-W-A1-Q-Y-A2-X1- is replaced by the radical -CN,
wherein R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein. articularly preferred are benzazepine derivatives of the following formula:
Figure imgf000047_0001
wherein R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined herein, with R2 preferably being halogen, in particular fluorine.
A3 is -CH2-, -0-, -NR16-, or -S-. If A3 is -CH2-, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[c]azepines. If A3 is -0-, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[f][1 ,4]oxazepines. If A3 is -NR16-, the compounds of formula (I) are referred to as 2,3,4,5-tetrahydro-1 H-benzo[e][1 ,4]diazepines. If A3 is -S-, the compounds of formula (I) are referred to as 6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptenes. According to a particular embodiment, A3 is -CH2-, -O- or -S-.
In 1 -, 3-, 4- and/or 5-position, the benzazepine derivatives of the invention may be substituted with one or more than one radical R3. If there is more than one radical R3, these may be the same or different radicals. The benzazepine derivatives of the invention may therefore be represented by the following formula:
Figure imgf000047_0002
wherein A3 is -CR3aR3b-, -0-, -NR16-, or -S; R3a, R3b, R3c, R3d, R3e, R3f, R3g independently have one of the meanings given for R3; and R, R2, R3, R4, X2, X3, R5, R16 are as defined herein.
R3 is hydrogen, halogen, C-i-C6-alkyl, C-i-C6-alkoxy, or two radicals R3 together with the carbon atom to which they are attached form a carbonyl group. Preferably, R3 is hydrogen or CrC6-alkyl. In particular, R3 is hydrogen. R4 is hydrogen, d-C6-alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C3-Ci2-cycloalkyl-Ci- C4-alkyl (e.g. cyclopropylmethyl), halogenated Ci-C4-alkyl (e.g. 2-fluoroethyl or 2,2,2- trifluoroethyl), hydroxy-CrC4-alkyl, CrC6-alkoxy-Ci-C4-alkyl, amino-Ci-C4-alkyl, C6-Ci2- aryl-Ci-C4-alkyl, C3-Ci2-cycloalkyl (e.g. cyclopropyl), CH2CN, -CHO, Ci-C4-alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl or isopropylcarbonyl), (halogenated d-d- alkyl)carbonyl (e.g. fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 1 , 1 , 1-trifluoroeth-2-ylcarbonyl or 1 , 1 , 1-trifluoroprop-3-ylcarbonyl), C6-Ci2-arylcarbonyl (e.g. phenylcarbonyl), CrC4-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl), C6- C12-aryloxycarbonyl (e.g. phenoxycarbonyl), d-d-alkylaminocarbonyl, C2-C6-alkenyl, - C(=NH)NH2, -C(=NH)NHCN, C C6-alkylsulfonyl, C6-Ci2-arylsulfonyl, amino, -NO or C3- C12-heterocyclyl (e.g. 3-oxetanyl).
Preferably, R4 is hydrogen, d-d-alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C3-C12- cycloalkyl-CrC4-alkyl (e.g. cyclopropylmethyl), halogenated CrC4-alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl), amino-C1-C4-alkyl, C6-C12-aryl-C1-C4-alkyl, C3-C12-cycloalkyl (e.g. cyclopropyl), CH2CN, CrC4-alkylcarbonyl (e.g. methylcarbonyl or isopropylcarbonyl), (halogenated C1-C4-alkyl)carbonyl (e.g. fluoromethylcarbonyl, difluoromethylcarbonyl or trifluoromethylcarbonyl), C6-Ci2-arylcarbonyl (e.g. phenylcarbonyl), CrC4-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl), C6-C12-aryloxycarbonyl (e.g. phenoxycar- bonyl), -C(=NH)NH2, -C(=NH)NHCN, Ci-C6-alkylsulfonyl, amino, -NO or C3-Ci2- heterocyclyl (e.g. 3-oxetanyl).
In particular, R4 is hydrogen, d-d-alkyl (e.g. methyl, ethyl or n-propyl), C3-d2-cycloalkyl (e.g. cyclopropyl) or C3-d2-cycloalkyl-d-C4-alkyl (e.g. cyclopropylmethyl).
X2 is -0-, -NR6-, -S-, >CR12aR12b or a bond. Preferably, X2 is >CR12aR12b.
X3 is -0-, -NR7-, -S-, >CR13aR13b or a bond. Preferably, X3 is a bond. Thus, it is preferred if X2 is >CR12aR12b and X3 is a bond.
R12a is hydrogen, optionally substituted d-C6-alkyl, d-C6-alkylamino-d-C4-alkyl, di-d- C6-alkylamino-d-C4-alkyl, C3-d2-heterocyclyl-d-C6-alkyl, optionally substituted C6-d2- aryl or hydroxy. Preferably, R12a is hydrogen or d-C6-alkyl.
R13a is hydrogen, optionally substituted d-C6-alkyl, Ci-C6-alkylamino-d-d-alkyl, di-d- C6-alkylamino-Crd-alkyl, C3-d2-heterocyclyl-d-C6-alkyl, optionally substituted C6-Ci2- aryl or hydroxy. Preferably, R13a is hydrogen or d-C6-alkyl. In connection with R12a and R13a, substituted CrC6-alkyl in particular includes CrC6-alkyl substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, hydroxy, CrC4-alkoxy and amino. In connection with R12a and R13a, substituted C6-Ci2-aryl in particular includes C6-Ci2-aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of CrC4-alkyl, Ci-C4-haloalkyl, cyano, CrC4-alkoxy and Ci-C4-haloalkoxy.
R12b is hydrogen or Ci-C6-alkyl. According to a particular embodiment, R12b is hydrogen.
R13b is hydrogen or Ci-C6-alkyl. According to a particular embodiment, R13b is hydrogen.
Alternatively, R12a and R12b, or R13a and R13b, together are together are carbonyl or, preferably, optionally substituted Ci-C4-alkylene (e.g. 1 ,3-propylene), wherein one -CH2- of d- C4-alkylene may be replaced by an oxygen atom or -NR14-.
In connection with R12a and R12b, or R13a and R13b, substituted C C4-alkylene in particular includes CrC4-alkylene substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, C-i-C4-alkoxy and C C4- haloalkoxy.
According to a particular embodiment, R12a is Ci-C6-alkyl and R12b is hydrogen or CrC6- alkyl, or R13a is Ci-C6-alkyl and R13b is hydrogen or C C6-alkyl. According to a further particular embodiment, R12a is hydrogen and R12b is hydrogen, or R13a is hydrogen and R13b is hydrogen.
According to a further particular embodiment, R12a and R12b together are optionally substituted 1 ,3-propylene, or R13a and R13b together are optionally substituted 1 ,3-propylene.
R5 is optionally substituted C6-Ci2-aryl (e.g. phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chlorophenyl; 3-cyanophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4-dichlorophenyl or 3,4- dichlorophenyl,), optionally substituted C3-Ci2-cycloalkyl (e.g. cyclohexyl) or optionally substituted C3-Ci2-heterocyclyl.
In connection with R5, substituted C3-Ci2-cycloalkyl in particular includes C3-Ci2-cycloalkyl, such as cyclopropyl or cyclohexyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, optionally substituted CrC6-alkyl, halogenated CrC6-alkyl, CN, hydroxy, Ci-C6-alkoxy, halogenated CrC6-alkoxy, amino, Ci-C6-alkylamino, di-CrC6- alkylamino and C3-Ci2-heterocyclyl.
In connection with R5, substituted C6-Ci2-aryl in particular includes C6-Ci2-aryl, such as phenyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen (e.g. F, CI, Br), optionally substituted CrC6-alkyl (e.g. methyl), halogenated Ci-C6- alkyl (e.g. trifluoromethyl), CN, hydroxy, CrC6-alkoxy (e.g. methoxy), halogenated Ci-C6- alkoxy, amino, Ci-C6-alkylamino, di-Ci-C6-alkylamino and C3-Ci2-heterocyclyl. In connection with R5, substituted C3-Ci2-heterocyclyl in particular includes C3-C-|2- heterocyclyl substituted with 1 , 2 or 3 substituents selected from the group consisting of halogen, optionally substituted CrC6-alkyl, halogenated Ci-C6-alkyl, CN, hydroxy, Ci-C6- alkoxy, halogenated C-i-C6-alkoxy, amino, C"i-C6-alkylamino, di-C"i-C6-alkylamino and C3- Ci2-heterocyclyl.
In connection with R5, C3-Ci2-heterocyclyl in particular is C3-Ci2-heteroaryl.
Preferably, R5 is optionally substituted C6-Ci2-aryl, in particular as in the benzazepine de- rivatives of the formula:
Figure imgf000050_0001
wherein R, R2, A3, R3, R4, X2, X3 are as defined herein, and
R17a, R17b, R17c, R17d, R17e independently are hydrogen, halogen (e.g. F, CI or Br), optionally substituted CrC6-alkyl (e.g. methyl), halogenated CrC6-alkyl (e.g. trifluoromethyl), CN, hydroxy, Ci-C6-alkoxy (e.g. methoxy), amino, Ci-C6-alkylamino, di-Ci-C6-alkylamino or C3-Ci2-heterocyclyl.
It is also prefered if R5 is optionally substituted C6-Ci2-heteroaryl, in particular as in the benzazepine derivatives of the formula:
Figure imgf000051_0001
wherein R, R2, A3, R3, R4, X2, X3 are as defined herein, and
R17b, R17c, R17d, R17e independently are hydrogen, halogen (e.g. F, CI or Br), optionally substituted CrC6-alkyl (e.g. methyl), halogenated CrC6-alkyl (e.g. trifluoromethyl), CN, hydroxy, Ci-C6-alkoxy (e.g. methoxy), amino, Ci-C6-alkylamino, di-Ci-C6-alkylamino or C3- C12-heterocyclyl.
According to a particular embodiment, the invention relates to benzazepine derivatives of the formula:
Figure imgf000051_0002
wherein R, R2, A3,R3, R4, R5 are as defined herein, R5 preferably being optionally substituted aryl and in particular optionally substituted phenyl as disclosed herein.
In connection with R5 or R17a, R17b, R17c, R17d, R17e, substituted C C6-alkyl in particular includes d-C6-alkyl, especially C1-C4-alkyl, substituted with 1 , 2 or 3 substituents selected from the group consisting of hydroxy, CrC6-alkoxy, amino, Ci-C6-alkylamino, di-CrCe- alkylamino and C3-C12-heterocyclyl (e.g. morpholinyl or piperidinyl).
According to a particular embodiment, R17a, R17b, R17d, R17e are hydrogen and R17c is different from hydrogen (para-mono-substitution).
According to a further particular embodiment, R17a, R17c, R17d, R17e are hydrogen and R17b is different from hydrogen (meta-mono-substitution). According to a further particular embodiment, R17b, R17c, R17d, R17e are hydrogen and R17a is different from hydrogen (meta-ortho-substitution). In connection with R17a, R17b, R17c, R17d, R17e, C3-Ci2-heterocyclyl in particular includes morpholinyl, imidazolyl and pyrazolyl.
R6 is hydrogen or CrC6-alkyl. Preferably, R6 is hydrogen. R7 is hydrogen or CrC6-alkyl. Preferably, R7 is hydrogen.
R8 is hydrogen or CrC6-alkyl. Preferably, R8 is hydrogen.
R9 is hydrogen, d-C6-alkyl (e.g. methyl or ethyl), C3-Ci2-cycloalkyl (e.g. cyclopropyl), amino-CrCe-alkyl, optionally substituted C6-C12-aryl-C1-C4-alkyl or C3-C12-heterocyclyl (e.g. 3-azetidinyl). Preferably, R9 is hydrogen or CrC6-alkyl (e.g. methyl or ethyl).
According to a particular embodiment, R9 and R1 together are CrC4-alkylene (e.g. 1 ,3-1 ,2- ethylene or propylene) so as that R9 and R1 together with the atom in Q to which R1 is bound and the nitrogen atom to which R9 is bound form an heterocyclic ring having, in particular, 4, 5 or 6 ring member atoms (including the nitrogen atom and Q). With W and A1 both being a bond, such a ring may be represented by the following partial structure:
Figure imgf000052_0001
wherein A2, X1, Q is as defined herein (e.g. S(0)2) and n is 0, 1 , 2, 3 or 4.
According to a further particular embodiment, R9 is CrC4-alkylene (e.g. methylene or 1 ,3- propylene) that is bound to a carbon atom in A2 and A2 is Ci-C4-alkylene so that R9 and at least part of A2 together with the nitrogen atom to which R9 is bound form an N-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen atom). Such a ring may be represented by the following partial structure:
R N wherein R1, W, A1, Q and X1 are as defined herein, p is 1 or 2, r is 0, 1 or 2 and q is 0, 1 or 2. In this particular embodiment, X1 preferably is -0-. Particular combinations of p, r and q include p=1 , r=0, q=1 ; and p=1 , r=0, q=0. Alternatively, p is 0, r is 3 and q is 1 , with X1 preferably being -0-.
According to a further particular embodiment, R9 is CrC4-alkylene (e.g. methylene or 1 ,3- propylene) that is bound to a carbon atom in X1 and X1 is CrC4-alkylene (e.g. 1 ,2- ethylene) so that R9 and at least part of X1 together with the nitrogen atom to which R9 is bound form an N-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen atom). With A2 being a bond, such a ring may be represented by the following partial structure:
Figure imgf000053_0001
wherein R1, W, A1 and Q are as defined herein, p is 1 or 2, r is 0, 1 or 2 and q is 0, 1 or 2. Particular combinations of p, r and q include p=1 , r=0, q=0.
R10 is hydrogen, C-|-C6-alkyl or C-|-C6-alkylsulfonyl. Preferably, R10 is hydrogen. R11 is hydrogen or C-|-C6-alkyl. Preferably, R11 is hydrogen. Alternatively, R9, R11 together are C1-C4-alkylene (e.g. ethylene). R14 is hydrogen or C-|-C6-alkyl. Preferably, R14 is hydrogen. R15 is hydrogen or C-|-C6-alkyl. Preferably, R15 is hydrogen.
R16 is hydrogen or C-|-C6-alkyl. Preferably, R16 is hydrogen or C-|-C6-alkyl (e.g. methyl).
Particular embodiments of benzazepine derivatives of the invention result if
R is R1-W-A1-Q-Y-A2-X1-;
R1 is CrC6-alkyl (e.g. ethyl or n-propyl), C3-Ci2-cycloalkyl-Ci-C4-alkyl (e.g. cyclopro- pylmethyl), C3-Ci2-cycloalkyl (e.g. cyclobutyl), or optionally substituted C3-C12- heterocyclyl (e.g. 3-pyridyl, 1 -methyl-1 ,2-diazol-4-yl, 1 -methyl-1 ,3-diazol-4-yl, 3- oxetanyl, 1 -methyl-pyrrol-3-yl);
W is a bond;
A1 is a bond;
Q is -S(0)2-; Y is -NR - or a bond;
A2 is CrC4-alkylene (e.g. 1 ,2-ethylene) or a bond;
X1 is -O- or optionally substituted C1-C4-alkylene (e.g. methylene, 1 ,2-ethylene or 1 ,3- propylene);
R2 is hydrogen or halogen (e.g. fluorine);
A3 is -CH2-, -0-, -NR16, or -S-;
R3 is hydrogen;
R4 is hydrogen, d-C6-alkyl (e.g. methyl, ethyl or n-propyl), C3-Ci2-cycloalkyl (e.g. cyclopropyl) or or C3-Ci2-cycloalkyl-Ci-C4-alkyl (e.g. cyclopropylmethyl);
X2 is >CR12aR12b;
X3 is a bond;
R5 is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4- chlorophenyl) or optionally substituted pyridyl (e.g. 2-pyridyl);
R9 is hydrogen, or
R9 is CrC4-alkylene (e.g. methylene) that is bound to a carbon atom in X1 and X1 is C C4-alkylene (e.g. 1 ,2-ethylene);
R12a is hydrogen;
312b
R is hydrogen; or together are C1-C4-alkylene (e.g. 1 ,3-propylene); and
R16 is hydrogen or C-|-C6-alkyl (e.g. methyl).
Further particular compounds of the present invention are the individual benzazepine derivatives of the formula (Id) as listed in the following tables 1 to 12 and physiologically tol erated salts thereof:
Figure imgf000054_0001
Table 1 Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is hydrogen and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448). Table 2
Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is 3-F and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corre- sponds to one line of Table A (A-1 to A-448). Table 3
Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is 3-CI and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corre- sponds to one line of Table A (A-1 to A-448). Table 4
Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is 3-CF3 and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448). Table 5
Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is 4-F and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corre- sponds to one line of Table A (A-1 to A-448). Table 6
Compounds of the formula (Id) wherein R2 is hydrogen, R3 is hydrogen, R17 is 4-CI and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corre- sponds to one line of Table A (A-1 to A-448). Table 7
Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is hydrogen and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448).
Table 8 Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is 3-F and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448). Table 9
Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is 3-CI and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448). Table 10
Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is 3-CF3 and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448). Table 1 1
Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is 4-F and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448).
Table 12
Compounds of the formula (Id) wherein R2 is 7-F, R3 is hydrogen, R17 is 4-CI and the combination of R1, -Y-A2-X1-, >CR12aR12b, A3, R4 for a compound in each case corresponds to one line of Table A (A-1 to A-448).
R1 -Y-A2-X1- > C R12aR12b A3 R4
A-1 . -NH- -CH2- -CH2- -H
(CH2)3-
A-2. -NH- -CH2- -CH2- -H
0* (CH2)3-
A-3. -NH- -CH2- -CH2- -H
(CH2)3-
Figure imgf000057_0001
Figure imgf000058_0001
R1 -Y-A2-X1- > C R12aR12b Α3 R4
A-24. -NH-CH2- -CH2- -CH2- -H
A-25. -NH-CH2- -CH2- -CH2- -H
A-26. -NH-CH2- -CH2- -CH2- -H
A-27. -NH-CH2- -CH2- -CH2- -H
Figure imgf000059_0001
A-28. -NH-CH2- -CH2- -CH2- -H
A-29. -NH- -CH2- -H
X (CH2)3- k
A-30. -NH- -CH2- -H
(CH2)3-
A-31. -NH- -CH2- -H
(CH2)3-
A-32. -NH- -CH2- -H
(CH2)3-
A-33. -NH- -CH2- -H
(CH2)3-
V
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
R1 -Y-A2-X1- > C R12aR12b A3 R4
A-74. -NH- -CH2- -CH2- -CH3
(CH2)2-
A-75. -NH- -CH2- -CH2- -CH3
(CH2)2-
A-76. -NH- -CH2- -CH2- -CH3
(CH2)2-
A-77. -NH- -CH2- -CH2- -CH3
(CH2)2-
A-78. -NH-CH2- -CH2- -CH2- -CH3
X
k
A-79. -NH-CH2- -CH2- -CH2- -CH3
A-80. -NH-CH2- -CH2- -CH2- -CH3
A-81. -NH-CH2- -CH2- -CH2- -CH3
A-82. -NH-CH2- -CH2- -CH2- -CH3
A-83. -NH-CH2- -CH2- -CH2- -CH3
Figure imgf000064_0001
Figure imgf000065_0001
R1 -Y-A2-X1- > C R12aR12b Α3 R4
A-95. -NH- -CH2- -CH3
(CH2)2-0-
A-96. -NH- -CH2- -CH3
(CH2)2-0-
A-97. -NH- -CH2- -CH3
(CH2)2-0-
A-98. -NH- -CH2- -CH3
(CH2)2-0-
A-99. -NH- -CH2- -CH3
X (CH2)2- k
A-100. -NH- -CH2- -CH3
(CH2)2-
A-101 . -NH- -CH2- -CH3
(CH2)2-
A-102. -NH- -CH2- -CH3
(CH2)2-
A-103. lf -NH- -CH2- -CH3
(CH2)2-
Y
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
R1 -Y-A2-X1- > C R12aR12b A3 R4
A-187. -NH- -CH2- -CH2- -CH2CH2CH3-
(CH2)2- CH2CH3
A-188. -NH- -CH2- -CH2- -CH2CH2CH3
(CH2)2-
A-189. -NH- -CH2- -CH2- -CH2CH2CH3
(CH2)2-
A-190. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-191 . -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-192. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-193. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-194. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-195. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
A-196. -NH-CH2- -CH2- -CH2- -CH2CH2CH3
Figure imgf000076_0001
R1 -Y-A2-X1- > C R12aR12b Α3 R4
A-207. -NH- -CH2- -CH2CH2CH3
(CH2)2-0-
A-208. -NH- -CH2- -CH2CH2CH3
(CH2)2-0-
A-209. -NH- -CH2- -CH2CH2CH3
(CH2)2-0-
A-210. -NH- -CH2- -CH2CH2CH3
(CH2)2-0-
A-21 1 . -NH- -CH2- -CH2CH2CH3
X (CH2)2- k
A-212. -NH- -CH2- -CH2CH2CH3
(CH2)2-
A-213. -NH- -CH2- -CH2CH2CH3
(CH2)2-
A-214. -NH- -CH2- -CH2CH2CH3
(CH2)2-
A-215. lf -NH- -CH2- -CH2CH2CH3
(CH2)2-
Y
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
R1 -Y-A2-X1- > C R12aR12b A3 R4
A-299. -NH- -CH2- -0- -CH3
(CH2)2-
A-300. -NH- -CH2- -0- -CH3
(CH2)2-
A-301 . -NH- -CH2- -0- -CH3
(CH2)2-
A-302. -NH-CH2- -CH2- -0- -CH3
A-303. -NH-CH2- -CH2- -0- -CH3
A-304. -NH-CH2- -CH2- -0- -CH3
A-305. -NH-CH2- -CH2- -0- -CH3
A-306. -NH-CH2- -CH2- -0- -CH3
A-307. -NH-CH2- -CH2- -0- -CH3
A-308. -NH-CH2- -CH2- -0- -CH3
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
R1 -Y-A2-X1- > C R12aR12b A3 R4
A-41 1 . -NH- -CH2- -0- -CH2CH2CH3-
(CH2)2- CH2CH3
A-412. -NH- -CH2- -0- -CH2CH2CH3
(CH2)2-
A-413. -NH- -CH2- -0- -CH2CH2CH3
(CH2)2-
A-414. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-415. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-416. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-417. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-418. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-419. -NH-CH2- -CH2- -0- -CH2CH2CH3
A-420. -NH-CH2- -CH2- -0- -CH2CH2CH3
Figure imgf000098_0001
R1 -Y-A2-X1- > C R12aR12b Α3 R4
A-431. -NH- -0- -CH2CH2CH3
(CH2)2-0-
A-432. -NH- -0- -CH2CH2CH3
(CH2)2-0-
A-433. -NH- -0- -CH2CH2CH3
(CH2)2-0-
A-434. -NH- -0- -CH2CH2CH3
(CH2)2-0-
A-435. -NH- -0- -CH2CH2CH3
X (CH2)2- k
A-436. -NH- -0- -CH2CH2CH3
(CH2)2-
A-437. -NH- -0- -CH2CH2CH3
(CH2)2-
A-438. -NH- -0- -CH2CH2CH3
(CH2)2-
A-439. lf -NH- -0- -CH2CH2CH3
(CH2)2-
Y
Figure imgf000100_0001
Further particular compounds of the present invention are the individual benzazepine derivatives of the formula (Id) as listed in tables 1 to 12 and physiologically tolerated salts thereof wherein the radical R1-S(0)2-Y-A2-X1- is replaced by the radical -CN. Further particular compounds of the present invention are the benzazepine derivatives disclosed in preparation examples and physiologically tolerated salts thereof. These include for each preparation example the exemplified compound as well as the correspond- ing free base and any other physiologically tolerated salts of the free base (if the exemplified compound is a salt), or any physiologically tolerated salt of the free base (if the exemplified compound is a free base). These further include enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
The compounds of the formula (I) can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of compounds of formula (I) are outlined in the following schemes. The process depicted in scheme 1 is useful for obtaining benzazepine precursors of the general formula 3, wherein X1 is -O- or -S- and A3 is optionally substituted alkylene (e.g. - CH2-).
Scheme 1 :
Figure imgf000101_0001
As shown in scheme 1 , the compound of general formula 1 readily undergoes enamine alkylation to give the enamine 2 and after subsequent hydrolysis the compound of general formula 3.
In scheme 1 , the variables X2, X3, R5 are as defined herein, and L1 represents an alkyl substituent (e.g. Me, Et, Bn).
The process depicted in scheme 1 is also useful for obtaining benzazepines, wherein X1 is optionally substituted alkylene. In this case, L1 is a group that represents, or can be converted into, the desired side chain R1-W-A1-Q-Y-A2-.
Alternatively, compounds of formula 3 can be prepared as described in scheme 2. Scheme 2:
Figure imgf000102_0001
As shown in scheme 2, the compound of general formula 4 readily undergoes alkylation to give the compound of general formula 5. Conversion to the acid chloride and subsequent ring closure with ethylene in the presence of a Lewis acid (e.g. AICI3) affords compound 3 (e.g. J. Het. Chem., 23 (2), 343, 1986 and Bioorg. Med. Chem. Let, 17 (22), 6160, 2007).
In scheme 2, the variables X1, X2, X3, R5 are as defined herein and L1 and L2 are suitable protecting groups (e.g. L1 = Me, Et, Bn). Compounds 3 can be further converted to com- pounds of the general formula (I).
The process depicted in scheme 3 is useful for obtaining bezazepines, wherein X1 is -O- or -S-, A3 is optionally substituted alkylene (e.g. -CH2-), Y is -NR9-, and Q is -S(0)2. Scheme 3:
Figure imgf000103_0001
Compounds of the general formula 3 readily undergo condensation reactions to the corresponding mixtures of E- and Z-oxims 4. The oxims can be transferred into the tosylates, which subsequently undergo a Beckmann rearrangement to give a mixture of lactames of the general formula 5 and 6 (e.g. Org. Lett. 2, 2373, 2000). Alternatively, the Beckmann rearrangement can be carried out under acidic conditions to convert the oxims 4 directly to the lactames 5 and 6. Lactames 5 and 6 can be separated (e.g. flash chromatography). Lactames 5 can be converted to the amines of the general formula 7 using LiAIH4 or other well known reducing agents (BH3 Me2S). Protection of the amino group with a suitable protecting group (e.g. L2 = COOEt) leads to compounds of the general formula 8.
In scheme 3, the variables R1, W, A1, R2, R3, R4, X2, X3, R5, R9, A2 are as defined herein and L1 and L2 are suitable protecting groups (e.g. L1= Me, Et, Bn, or tBuMe2Si; L2= COOtBu or COOEt).
The process depicted in scheme 4 is useful for obtaining benzazepines, wherein X1 is methylene, A2 is a bond, Y is -NR9-, and Q is -S(0)2.
Scheme 4:
Figure imgf000105_0001
Instead of the triflate 18, the corresponding bromide, iodide, or nonaflate can be used to prepare compound 19.
In scheme 4, the variables R1, W, A1, R2, R3, R4, X2, X3, R5, R9 are as defined herein, and L1 and L2 are a suitable protecting group (e.g. L1= Me, Et, Bn, or tBuMe2Si; L2 = COO'Bu or COOEt). The process depicted in scheme 5 is useful for obtaining benzazepines, wherein X1 is optionally substituted alkylene, A2 is optionally substituted alkylene or a bond, Y is -NR9-, and Q is -S(0)2. Scheme 5:
Figure imgf000106_0001
Instead of the trifluoroborate 24, the corresponding 9-borabicyclo[3.3.1]non-9-yl derivative can be used to prepare compound 25.
In scheme 5, the variables R1, W, A1, R2, R3, R4, X2, X3, R5, R9 are as defined herein, and L2 is a suitable protecting group (e.g. L2 = COO'Bu or COOEt). The process depicted in scheme 6 is useful for obtaining benzazepines, wherein X is - NR11-, A2 is optionally substituted alkylene, Y is -NR9-, and Q is -S(0)2.
Scheme 6:
Figure imgf000107_0001
In scheme 6, the variables R1, W, A1, R11, R2, R3, R4, X2, X3, R5, R9 are as defined herein, and L2 and L4 are a suitable protecting group (e.g. L2, L4 = COO'Bu or COOEt).
The process depicted in scheme 7 is useful for obtaining benzoxazepine precursors of the general formula 39, wherein X1 is -O- or -S- and A3 is -0-.
Scheme 7:
Figure imgf000107_0002
33 34
Figure imgf000107_0003
As shown in scheme 7, the compound of general formula 33 readily undergoes alkylation to give the compound of general formula 34. Deprotection leads to compounds of the general formula 35, which are converted via well known amide coupling reactions to the corresponding compounds of general formula 36 (e.g. EDC, DMAP). Amides of the gen- eral formula 36 undergo cyclization to imines of the formula 37 under Vilsmeier reaction conditions (e.g. POCI3, SOCI2, oxalyl chloride; see Chem. Ind. 1973, 870, Indian J. Chem., Sect. B (37B), 1998, 965, and Advances in Organic Chemistry (9), Pt. 1 , 1976, 225 ). Reduction of imins of the general formula 37 (e.g. with NaBH4) readily gives the corresponding amines of general formula 38. Protection of the free amine with a suitable protecting group (e.g. L2 = COO'Bu) yields compounds of the general formula 39. Introduction of the various side chains is performed as already described for the benzazepine derivatives in schemes 4 to 6.
In scheme 7, the variables R2, R3, R4, X2, X3, R5 are as defined herein, L represents an alkyl substituent (e.g. Me, Et, Bn) and and L2 is a suitable protecting group (e.g. L2 = COO'Bu or COOEt).
The process depicted in scheme 7 is also useful for obtaining benzazepines derivatives of formula (I), wherein A3 is -S-, or NR16.
The acid addition salts of the benzazepine derivatives of formula (I) are prepared in a customary manner by mixing the free base with a corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
The benzazepines derivatives of formula (II):
Figure imgf000108_0001
wherein L is an amino-protecting group, Y is NR9, and A2, X1, R2, A3, R3, R4, X2, X3, R5 are defined as herein are useful as intermediates in the preparation of GlyT1 inhibitors, in particular those of formula (I). Suitable amino-protecting groups are well known in the art such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
According to a particular embodiment, L is optionally substituted alkylcarbonyl (e.g., tert- butylcarbonyl), optionally substituted arylcarbonyl, optionally substituted arylalkycarbonyl (e.g., benzylcarbonyl), optionally substituted alkoxycarbonyl (e.g., methoxycarbonyl or tert-butyloxycarbonyl), optionally substituted aryloxycarbonyl (e.g. phenoxycarbonyl) or optionally substituted arylalkoxycarbonyl.
The compounds of the formula (I) are capable of inhibiting the activity of glycine transporter, in particular glycine transporter 1 (GlyT1 ).
The utility of the compounds in accordance with the present invention as inhibiting the glycine transporter activity, in particular GlyT1 activity, may be demonstrated by methodology known in the art. For instance, human GlyTI c expressing recombinant
hGlyT1 c_5_CHO cells can be used for measuring glycine uptake and its inhibition (IC50) by a compound of formula (I).
Amongst the compounds of the formula (I) those are preferred which achieve effective inhibition at low concentrations. In particular, compounds of the formula (I) are preferred which inhibit glycine transporter 1 (GlyT1 ) at a level of IC50 < 1 μΜοΙ, more preferably at a level of IC5o < 0.5 μΜοΙ, particularly preferably at a level of IC5o < 0.2 μΜοΙ and most preferably at a level of IC5o < 0.1 μΜοΙ.
The compounds of formula (I) display good to moderate metabolic stability. The metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001 , 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved. The stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver. The slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the com- pounds of the invention is increased. Increased and/or longer-lasting active levels may lead to a better activity of the compound in therapeutic treatment. In addition, an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degra- dation in the liver (so-called first pass effect). An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
Amongst the compounds of the formula (I) those are particularly preferred which display good to moderate metabolic stability towards human liver microsomes.. In particular, compounds of the formula (I) are preferred which display a microsomal clearance at a level of mCI < 1000 μΙ/min/mg, more preferably at a level of mCI < 500 μΙ/min/mg, particularly preferably at a level of mCI < 100 μΙ/min/mg and most preferably at a level of mCI < 50 μΙ/min/mg.
The compounds of the formula (I) according to the present invention are thus useful as pharmaceuticals.
The present invention therefore also relates to pharmaceutical compositions which com- prise an inert carrier and a compound of the formula (I).
The present invention also relates to the use of the compounds of the formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 , and to corresponding methods of inhibiting the glycine transporter GlyT1.
The NMDA receptor is central to a wide range of CNS processes, and its role in a variety of diseases in humans or other species has been described. GlyT1 inhibitors slow the removal of glycine from the synapse, causing the level of synaptic glycine to rise. This in turn increases the occupancy of the glycine binding site on the NMDA receptor, which increases activation of the NMDA receptor following glutamate release from the presynaptic terminal. Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus known to be useful in treating a variety of neurologic and psychiatric disorders. Further, glycine A receptors play a role in a variety of diseases in humans or other species. Increasing extracellular glycine concentrations by inhibiting glycine trans- port may enhance the activity of glycine A receptors. Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus useful in treating a variety of neurologic and psychiatric disorders. The present invention thus further relates to the use of the compounds of the formula (I) for the manufacture of a medicament for treating a neurologic or psychiatric disorder, and to corresponding methods of treating said disorders. According to a particular embodiment, the disorder is associated with glycinergic or glu- tamatergic neurotransmission dysfunction.
According to a further particular embodiment, the disorder is one or more of the following conditions or diseases: schizophrenia or a psychotic disorder including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance- induced psychotic disorder, including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alz- heimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or cognitive impairment including age related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disor- der, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, depend- ence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and pre- menstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including attention-deficit hyperactivity disorder (ADHD) and conduct disorder; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinson- ism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic- induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disor- ders associated with muscular spasticity or weakness including tremors; dyskinesias [including tremor (such as rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocy- tosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia)]; urinary incontinence; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders including insomnia and narcolepsy.
According to a further particular embodiment, the disorder is pain, in particular chronic pain and especially neuropathic pain.
Pain can be classified as acute and chronic pain. Acute pain and chronic pain differ in their etiology, pathophysiology, diagnosis and treatment. Acute pain, which occurs following tissue injury, is self-limiting, serves as an alert to ongoing tissue damage and following tissue repair it will usually subside. There are minimal psychological symptoms associated with acute pain apart from mild anxiety. Acute pain is nociceptive in nature and occurs following chemical, mechanical and thermal stimulation of A-delta and C-polymodal pain receptors.
Chronic pain, on the other hand, serves no protective biological function. Rather than being the symptom of tissue damage it is a disease in its own right. Chronic pain is unrelenting and not self-limiting and can persist for years, perhaps decades after the initial injury. Chronic pain can be refractory to multiple treatment regimes. Psychological symptoms associated with chronic pain include chronic anxiety, fear, depression, sleeplessness and impairment of social interaction. Chronic non-malignant pain is predominantly neuropathic in nature and involves damage to either the peripheral or central nervous systems.
Acute pain and chronic pain are caused by different neuro-physiological processes and therefore tend to respond to different types of treatments. Acute pain can be somatic or visceral in nature. Somatic pain tends to be a well localised, constant pain and is described as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing or colicky in nature. Examples of acute pain include post-operative pain, pain associated with trauma and the pain of arthritis. Acute pain usually responds to treatment with opioids or non-steroidal anti-inflammatory drugs.
Chronic pain, in contrast to acute pain, is described as burning, electric, tingling and shooting in nature. It can be continuous or paroxysmal in presentation. The hallmarks of chronic pain are chronic allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus that normally does not ellicit a painful response, such as a light touch. Hyperalgesia is an increased sensitivity to normally painful stimuli. Primary hyperalgesia occurs immediately within the area of the injury. Secondary hyperalgesia occurs in the undam- aged area surrounding the injury. Examples of chronic pain include complex regional pain syndrome, pain arising from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension-type headache, pain arising from mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic disease, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain arising as a conse- quence of or associated with stress or depressive illness.
Although opioids are cheap and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity. In addition the doses of opioids which can be administered are limited by nausea, emesis, con- stipation, pruritis and urinary retention, often resulting in patients electing to receive sub- optimal pain control rather than suffer these distressing side-effects. Furthermore, these side-effects often result in patients requiring extended hospitalisation. Opioids are highly addictive and are scheduled drugs in many territories. The compounds of formula (I) are particularly useful in the treatment of schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and postpartum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including Attention-Deficit/Hyperactivity Disorder, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance. Particular cognitive disorders are dementia, delirium, amnestic disorders and cognitive impartment including age-related cognitive decline.
Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
Particular neurologic disorders that can be treated with the compounds of of the formula (I) include in particular a cognitive disorder such as dementia, cognitive impairment, attention deficit hyperactivity disorder.
Particular psychiatric disorders that can be treated with the compounds of of the formula (I) include in particular an anxiety disorder, a mood disorder such as depression or a bipo- lar disorder, schizophrenia, a psychotic disorder.
Within the context of the treatment, the use according to the invention of the compounds of the formula (I) involves a method. In this method, an effective quantity of one or more compounds or the formula (I), as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other drugs or drug-containing preparations.
The invention also relates to the manufacture of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being. Thus, the compounds of the formula (I) are customarily administered in the form of pharmaceutical compositions which comprise an inert carrier (e.g. a pharmaceutically acceptable excipient) together with at least one compound according to the invention and, where appropriate, other drugs. These compositions can, for example, be administered orally, rectally, transdermal^, subcutaneously, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar- coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.
When producing the compositions, the compounds according to the invention are option- ally mixed or diluted with one or more carriers (excipients). Carriers (excipients) can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
Suitable carriers (excipients) are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirri- tants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refat- ting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV- Editio-Cantor-Verlag, 1996.
The compounds of formula (I) may also be suitable for combination with other therapeutic agents.
Thus, the present invention also provides:
i) a combination comprising a compound of formula (I) with one or more further therapeutic agents;
ii) a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient;
iii) the use of a combination as defined in i) above in the manufacture of a medicament for treating or preventing a disorder, disease or condition as defined herein;
iv) a combination as defined in i) above for use in treating or preventing a disorder, dis- ease or condition as defined herein;
v) a kit-of-parts for use in the treatment of a disorder, disease or condition as defined herein, comprising a first dosage form comprising a compound of formula (I) and one or more further dosage forms each comprising one or more further therapeutic agents for simultaneous therapeutic administration,
vi) a combination as defined in i) above for use in therapy; vii) a method of treatment or prevention of a disorder, disease or condition as defined herein comprising administering an effective amount of a combination as defined in i) above;
viii) a combination as defined in i) above for treating or preventing a disorder, disease or condition as defined herein.
The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) and at least one further therapeutic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component. The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such com- binations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one antipsychotic agent for adjunctive therapeutic administra- tion for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides a combination of compounds of formula (I) and at least one antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disor- der. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder. The invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder.
In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilis- ing or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
Antipsychotic agents include both typical and atypical antipsychotic drugs. Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothix- ene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benziso- thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename
THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Phar- maceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE®, from Pfizer); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2- (trifluoro- methyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman); perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Rox- ane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE(D; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used. Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRI N®), chlor- prothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename Pl- POTRIL®), ziprasidone, and hoperidone.
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treat- ment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for adjunc- tive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufac- ture of a medicament for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Dis- ease. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administra- tion with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration with compounds of for- mula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
Examples of agents suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease that are useful in the present invention include, but are not limited to: cholinesterase inhibitors, agents targeting nicotinic or muscarinic acethylcholine receptors, NMDA receptors, amyloid formation, mitochondrial dysfunctions, disease associated cal- pain activity, neuroinflamation, tumor necrosis factor receptors, NF-kappaB, peroxisome proliferator activator receptor gamma, Apolipoprotein E variant 4 (ApoE4), disease- associated increase of the HPA axis, epileptic discharges, vascular dysfunction, vascular risk factors, and oxidative stress. Suitable cholinesterase inhibitors which may be used in combination with the compounds of the inventions include for example tacrine, donepezil, galantamine and rivastigmine.
Suitable NMDA receptors targeting agents which may be used in combination with the compounds of the inventions include for example memantine.
Suitable agents affecting increased HPA axis activity which may be used in combination with the compounds of the inventions include for example CRF1 antagonists or V1 b antagonists. In a further aspect therefore, the invention provides a method of treatment of pain by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. In a further aspect, the invention provides a method of treatment of pain by adjunctive therapeutic administration of at least one agent suitable for the treatment of pain to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for adjunctive therapeutic administration for the treat- ment of pain in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of pain for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides a method of treatment of pain by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of pain. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of pain. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain for simultaneous therapeutic administration in the treatment of pain. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain. The invention further provides at least one agent suitable for the treatment of pain for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain.
Examples of agents suitable for the treatment of pain that are useful in the present invention include, but are not limited to: NSAIDs (Nonsteroidal Antiinflammatory Drugs), anti- convulsant drugs such as carbamazepine and gabapentin, sodium channel blockers, antidepressant drugs, cannabinoids and local anaesthetics.
Suitable agents used in combination with the compounds of the inventions include for example celecoxib, etoricoxib, lumiracoxib, paracetamol, tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion, gabapentin, pregabalin, lamotrigine, fentanyl, pare- coxib, nefopam, remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil, pethidine, diamorphine and butorphanol.
It will be appreciated by those skilled in the art that the compounds according to the inven- tion may advantageously be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as cognitive enhancers. Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide. Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine. Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
The following examples serve to explain the invention without limiting it.
The compounds were characterized by mass spectrometry, generally recorded via HPLC- MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
Preparation Examples
Example 1 (for reference purposes): 1 -Benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H- benzo[c]azepine
1.1 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1 H)-one oxime
Figure imgf000123_0001
To a solution of 4.47 mmol of 1 -benzyl-7-methoxy-3,4-dihydronaphthalen-2(1 H)-one in 15 ml ethanol were added 5.59 mmol hydroxylamine hydrochloride (dissolved in 3 ml water). The solution was stirred at 65°C for 1 .5 h. The mixture was cooled to RT and concen- trated. The residue was dissolved in methyl tert-butylether and washed with water (2x), dried over MgS04 and filtered. Evaporation of the solvent gave 1.29 g of 1-benzyl-7- methoxy-3,4-dihydronaphthalen-2(1 H)-one oxime (mixture of E- and Z-isomer, 100 %).
ESI-MS [M+H+] = 282 Calculated for Ci8H19N02 = 281
1.2 1-Benzyl-8-methoxy-4,5-dihydro-1 H-benzo[c]azepin-3(2H)-one
Figure imgf000123_0002
To a solution of 8.46 mmol of p-toluenesulfonylchloride, 8.4 mmol triethylamine and 0.16 mmol of dimethylaminopyridine in 5 ml of dichloromethane was added a solution of 945 mg of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1 H)-one oxime in 5 ml dichloromethane. The solution was stirred at room temperature over night. The mixture was diluted with dichloromethane and washed with water and saturated NaHC03 solution. The combined organic layers were dried over MgS04 and filtered. Evaporation of the solvent gave 1.9 g of crude material that was purified by flash chromatography to yield 637 mg of the desired isomer 1 -benzyl-8-methoxy-4,5-dihydro-1 H-benzo[c]azepin-3(2H)-one (67%) and 248 mg of its regioisomer 1-benzyl-8-methoxy-4,5-dihydro-1 H-benzo[d]azepin-2(3H)- one (26 %).
ESI-MS [M+H+] = 282 Calculated for Ci8H19N02 = 281 1.3 1-Benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H-benzo[c]azepine
Figure imgf000124_0001
To a solution of 2.17 mmol of 1 -benzyl-8-methoxy-4,5-dihydro-1 H-benzo[c]azepin-3(2H)- one in tetrahydrofuran under nitrogen atmosphere was added 3.25 mmol of lithiumalumi- numhydride as 1 M solution in tetrahydrofuran. The solution was heated to reflux and stirred for 1.5 h. The mixture was cooled to room temperature and water (1 ml) was carefully added. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was extracted with acidified water (acidified with 1 M HCI, 4x). To the combined aqueous phase was added NaOH (50%) until basic and ethyl acetate. The suspension was filtered over celite. The residue was washed with water and ethyl acetate. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgS04 and filtered. Evaporation of the solvent gave 439 mg of crude material that was purified by flash chromatography to yield 399 mg of 1 -benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H-benzo[c]azepine (69%).
ESI-MS [M+H+] = 268 Calculated for d8H2i NO = 267
Example 2: N-(2-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1-methyl- 1 H-imidazole-4-sulfonamide
2.1 Ethyl 1 -benzyl-8-methoxy-4,5-dihydro-1 H-benzo[c]azepine-2(3H)-carboxylate
Figure imgf000124_0002
To a solution of 0.97 mmol of 1 -benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H-benzo[c]azepine in 10 ml dichloromethane under nitrogene atmosphere were added 1 .17 mmol dimethyl amino pyridine and 1.12 mmol ethyl carbonochloridate and the mixture was stirred at room temperature for 1 h. The mixture was diluted with methylenechloride and washed with saturated NH4CI solution and brine. The combined organic layers were dried over MgS04 and filtered. Evaporation of the solvent gave 248 mg of 1-benzyl-8-methoxy- 2,3,4,5-tetrahydro-1 H-benzo[c]azepine (75 %).
ESI-MS [M+H+] = 340 Calculated for C21 H25NO3 = 339
2.2 Ethyl 1 -benzyl-8-hydroxy-4,5-dihydro-1 H-benzo[c]azepine-2(3H)-carboxylate
Figure imgf000125_0001
To a solution of 0.73 mmol 1 -benzyl-8-methoxy-2,3,4,5-tetrahydro-1 H-benzo[c]azepine in 7 ml dichloromethylene under nitrogen atmosphere were added 2.20 mmol borontribro- mide (1 M solution in dichloromethane) at 0°C and stirred for 2 h. To the mixture was added saturated solution of NaHC03. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgS04 and filtered. Evaporation of the solvent gave 242 mg of 1 1-benzyl-8- hydroxy-4,5-dihydro-1 H-benzo[c]azepine-2(3H)-carboxylate (100 %).
ESI-MS [M+H+] = 326 Calculated for C2oH23N03 = 325
2.3 ethyl 2-(1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethylcarbamate
Figure imgf000125_0002
To a suspension of 1 .88 mmol sodium hydride (60% in mineral oil) in 2 ml dimethyl acetamide under nitrogene atmosphere was added a solution of 0.74 mmol 1 1 -benzyl-8- hydroxy-4,5-dihydro-1 H-benzo[c]azepine-2(3H)-carboxylate in 5 ml dimethyl acetamide at room temperature and stirred for 1 h. Then, a solution of 2.23 mmol tert-butyl 2- bromoethylcarbamate in 1 ml dimethyl acetamide was added and the mixture was stirred at room temperature for 2 d. 1.88 mmol of sodium hydride were added followed by 2.23 mmol of tert-butyl 2-bromoethylcarbamate in 1 ml dimethyl acetamide. The mixture was stirred at room temperature for additional 4 d. 1.88 mmol of sodium hydride were added followed by 2.23 mmol of tert-butyl 2-bromoethylcarbamate in 1 ml dimethyl acetamide. The mixture was stirred at room temperature for additional 2 d. The mixture was poured onto water and extracted with diethyl ether (3x). The combined organic layers were washed with water, dried over MgS04 and filtered. Evaporation of the solvent gave 1 .17 g mg of crude material that was purified by flash chromatography to yield 359 mg of ethyl 2- (1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethylcarbamate (100 %).
ESI-MS [M+-Boc] = 369 Calculated for C27H36N205 = 468
Ethyl 8-(2-aminoethoxy)-1 -benzyl-4,5-dihydro-1 H-benzo[c]azepi
carboxylate
Figure imgf000126_0001
To a solution of 0.46 mmol of ethyl 2-(1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy)ethylcarbamate in 3 ml dichloromethane were added 4.57 mmol of a 5-6 N solution of HCI in isopropanol. The mixture was stirred at room temperature over night. The mixture was heated to 40°C and stirred for additional 2 h. The solvent was evaporated to give 151 mg of crude 2-(1 -benzyl-2-(ethoxycarbonyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy)ethanaminium chloride (82 %).
ESI-MS [M++H] = 369 Calculated for C22H28N203 = 368 2.5 Ethyl 1-benzyl-8-(2-(1 -methyl-1 H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1 H- benzo[c]azepine-2(3H)-carboxylate
Figure imgf000126_0002
To a solution of 0.12 mmol 2-(1-benzyl-2-(ethoxycarbonyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy)ethanaminium chloride in 3 ml dichloromethane were added 0.33 mmol dimethylaminopyridine and 0.17 mmol 1-methyl-1 H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature over night. The mixture was diluted with ethyl acetate and washed with NH4CI solution (2x), water (1x), and brine (1 x). The organic layer was dried over MgS04 and filtered. Evaporation of the solvent gave 66 mg of crude material that was purified by flash chromatography to yield 60 mg of ethyl 1 -benzyl-8-(2- (1-methyl-1 H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1 H-benzo[c]azepi
carboxylate (95 %).
ESI-MS [M+H+] = 513 Calculated for C26H32N4O5S = 512
N-(2-(1-Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H- imidazole-4-sulfonamide
Figure imgf000127_0001
0.1 1 mmol of ethyl 1-benzyl-8-(2-(1 -methyl-1 H-imidazole-4-sulfonamido)ethoxy)-4, 5- dihydro-1 H-benzo[c]azepine-2(3H)-carboxylate were dissolved in a solution of potassium hydroxide in ethanol (20 %). The solution was heated in the microwave at 100°C for 3 h. The mixture was diluted with brine and extracted with ethyl acetate (3x). The combined organic layers were concentrated in vacuo to give 96 mg of crude material that was purified by flash chromatography to yield 37 mg of N-(2-(1-benzyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H-imidazole-4-sulfonamide (77 %).
ESI-MS [M+H+] = 441 Calculated for C23H28N4O3S = 440
Example 3: N-(2-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1-methyl- 1 H-pyrazole-4-sulfonamide
Figure imgf000127_0002
N-(2-(1 -Benzyl-2, 3,4, 5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H-pyrazole- 4-sulfonamide was prepared in analogy to example 2 using 1 -methyl-1 H-pyrazole-4- sulfonyl chloride in place of 1 -methyl-1 H-imidazole-4-sulfonyl chloride.
ESI-MS [M+H+] = 441 Calculated for C23H28N4O3S = 440 Example 4: N-(2-(1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1- cyclopropylmethanesulfonamide
Figure imgf000128_0001
N-(2-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 - cyclopropylmethanesulfonamide was prepared in analogy to example 2 using
cyclopropylmethanesulfonyl chloride in place of 1 -methyl-1 H-imidazole-4-sulfonyl chloride.
ESI-MS [M+H+] = 415 Calculated for C23H30N2O3S = 414 Example 5 (for reference purposes only): 5-(1-(4-Chlorophenyl)cyclobutyl)-7-methoxy- 2,3,4,5-tetrahydrobenzo[f][1 ,4]oxazepine hydrochloride
5.1 1 -(4-Chlorophenyl)-N-(2-(4-methoxyphenoxy)ethyl)cyclobutanecarboxamide
Figure imgf000128_0002
To a solution of 5.74 mmol of 2-(3-methoxy-phenyl)-ethylamine and 10.97 mmol of 4- dimethylaminopyridine in 400 ml dichloromethane were added 5.22 mmol 1 -(4-chloro- phenyl)-cyclobutanecarboxylic acid and the mixture was cooled to 4°C. EDC was added and the mixture was allowed to warm to room temperature within 45 min. The mixture was stirred at room temperature for additional 60 h. The organic phase was washed with water (3x) and brine, dried over Na2S04, and filtered. Evaporation of the solvent gave the crude material, which was purified by flash chromatography to yield 1 .87 g of 1 -(4-chlorophenyl)- N-(2-(4-methoxyphenoxy)ethyl)cyclobutanecarboxamide (99 %).
ESI-MS [M+H+] = 360 Calculated for C2oH22CIN03 = 359
5.2 5-(1-(4-Chlorophenyl)cyclobutyl)-7-methoxy-2,3-dihydrobenzo[f][1 ,4]oxazepine
Figure imgf000129_0001
To a solution of 2.92 mmol of 1 -(4-chlorophenyl)-N-(2-(4-methoxyphenoxy)ethyl)cyclo- butanecarboxamide in 2 ml acetonitrile were added 1 14.78 mmol POCI3 and the mixture was stirred in the microwave at 135°C for 2 h. The mixture was concentrated and the resi- due was dissolved in ethyl acetate. The organic phase was washed with water (3x) and brine, dried over Na2S04, and filtered and concentrated to give 0.8 g of a light yellow solid. The crude material was purified by flash chromatography to yield 0.15 g of 5-(1 -(4- chlorophenyl)cyclo-butyl)-7-methoxy-2,3-dihydrobenzo[f][1 ,4]oxazepine (15 %). 5.3 5-(1-(4-Chlorophenyl)cyclobutyl)-7-methoxy-2,3,4,5- tetrahydrobenzo[f][1 ,4]oxazepine hydrochloride
Figure imgf000129_0002
To a solution of 0.51 mmol of 5-(1-(4-chlorophenyl)cyclo-butyl)-7-methoxy-2,3- dihydrobenzo[f][1 ,4]oxazepine in 5 ml methanol and 0.1 ml water were added 1 .00 mmol sodium borohydride and the mixture was stirred at room temperature over night. The mixture was concentrated and the residue was dissolved in methylene chloride and water was added. The phases were separated using a Chromabond® PTS column. The aqueous phase was extracted with methylene chloride (1 x). The combined organic phases were dried over Na2S04, and filtered and concentrated to give 0.18 g of a crude material, which was purified by flash chromatography. To the combined fractions was added a solution of hydrogen chloride in 2-propanol and concentrated. The residue was dissolved in methanol and concentrated (2x). The material was further purified by flash chromatography to yield 14 mg of 5-(1-(4-chlorophenyl)cyclobutyl)-7-methoxy-2, 3,4,5- tetrahydrobenzo[f][1 ,4]oxazepine hydrochloride as a white solid (HCI-salt, 15 %).
ESI-MS [M+H+] = 344 Calculated for C2oH22CI1N02 = 343 Example 6: 1-Methyl-1 H-imidazole-4-sulfonic acid [2-(1 -benzyl-2-methyl-2,3,4,5- tetrahydro-1 H-be
Figure imgf000130_0001
ESI-MS [M+H+] = 455 Calculated for C24H30N4O3S = 454
Example 7: 1 -Methyl- 1 H-pyrazole-4-sulfonic acid [2-(1 -benzyl-2-methyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin- -yloxy)-ethyl]-amide
Figure imgf000130_0002
ESI-MS [M+H+] = 455 Calculated for C24H30N4O3S = 454
Example 8: Propane-1 -sulfonic acid {2-[1 -(4-chlorobenzyl)-2,3,4,5-tetrahydr<
benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000130_0003
ESI-MS [M+H+] = 437 Calculated for C22H29CIN2O3S = 437
Example 9: Ethanesulfonic acid {2-[1-(4-chlorobenzyl)-2,3,4,5-tetrahyd
benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000131_0001
ESI-MS [M+H+] = 423 Calculated for C21 H27CIN2O3S = 423
Example 10: Propane-1 -sulfonic acid [2-(1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin- 8-yloxy)-ethyl]-amide
Figure imgf000131_0002
ESI-MS [M+H+] = 403 Calculated for C22H30N2O3S = 403
Example 1 1 : Ethanesulfonic acid [2-(1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy)-ethyl]-amide
Figure imgf000131_0003
ESI-MS [M+H+] = 389 Calculated for C21 H28N2O3S = 388
Example 12: N-{2-[1 -(4-Chlorobenzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin
ethyl}-C-cyclopropyl-methanesulfonamide
Figure imgf000132_0001
The 1 R- and 1 S-enantiomers have been prepared but the absolute configuration has not been assigned to the individual compounds. ESI-MS [M+H+] = 449/451 Calculated for C23H29CIN2O3S = 449
Example 13: N-{2-[1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy]-ethyl}-C- cyclopropyl-methanesulfonamide
Figure imgf000132_0002
The 1 R- and 1 S-enantiomers have been prepared but the absolute configuration has not been assigned to the individual compounds.
ESI-MS [M+H+] Calculated for C23H30N2O3S = 415
Example 14: Propane-1 -sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetra-hydro-1 H- benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000132_0003
ESI-MS ΓΜ+ΗΊ = 407 Calculated for C21 H27CIN2O2S = 407 Example 15: N-[1 -(4-Chloro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl]-C- cyclopropyl-methanesulfonamide
Figure imgf000133_0001
ESI-MS [M+H+] = 419 Calculated for C22H27CIN2O2S = 419
Example 16: Ethanesulfonic acid [1-(4-chloro-benzyl)-2,3,4,5-tetra-hyd
benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000133_0002
ESI-MS [M+H+] = 393 Calculated for C20H25CIN2O2S = 393
Example 17: Cyclobutanesulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetra-hyd
benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000133_0003
ESI-MS [M+H+] = 419 Calculated for C22H27CIN2O2S = 419 Example 18: 1-Methyl-1 H-imidazole-4-sulfonic acid [1 -(4-chloro-benzyl)-2, 3,4,5- tetrahydro-1 H-benzo-[c]azepin-8-ylmethyl]-amide
Figure imgf000134_0001
ESI-MS [M+H+] = 445 Calculated for C22H25CIN4O2S = 445
Example 19: 1-Methyl-1 H-pyrazole-4-sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro- 1 H-benzo-[c]azepin-8-ylmethyl]-amide
Figure imgf000134_0002
ESI-MS [M+H+] = 445 Calculated for C22H25CIN4O2S = 445
Example 20: 1 -Methyl-1 H-imidazole-4-sulfonic acid {2-[1 -(3-fluoro-benzyl)-2,3,4,5- tetrahydro-1 H-benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000134_0003
ESI-MS [M+H+] = 459 Calculated for C23H27FN4O3S = 458
Example 21 : 1-Methyl-1 H-pyrazole-4-sulfonic acid {2-[1 -(3-fluoro-benzyl)-2,3,4,5- tetrahydro-1 H-benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000135_0001
ESI-MS [M+H+] = 459 Calculated for C23H27FN4O3S = 458
Example 22: 1-Methyl-1 H-imidazole-4-sulfonic acid [1-(3-fluoro-benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000135_0002
ESI-MS [M+H+] = 429 Calculated for C22H25FN402S = 428
Example 23: Propane-1 -sulfonic acid {2-[1-(3-fluoro-benzyl)-2,3,4,5-tetrahydr
benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000135_0003
ESI-MS [M+H+] = 421 Calculated for C22H29FN203S = 421
Example 24: C-Cyclopropyl-N-{2-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-methanesulfonamide
Figure imgf000136_0001
Example 25: Ethanesulfonic acid {2-[1-(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide
Figure imgf000136_0002
ESI-MS [M+H+] = 407 Calculated for C2iH27FN203S = 407
Example 26: 1-Methyl-1 H-pyrazole-4-sulfonic acid [1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydr 1 H-benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000136_0003
Example 27: Propane-1 -sulfonic acid [1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000137_0001
ESI-MS [M+H+] = 391 Calculated for C21 H27FN2O2S = 390
Example 28: C-Cyclopropyl-N-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin- 8-ylmethyl)-methanesulfonamide
Figure imgf000137_0002
ESI-MS [M+H+] = 403 Calculated for C22H27FN2O2S = 403
Example 29: Ethanesulfonic acid [1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 \
benzo[c]azepin-8-ylmethyl]-amide
Figure imgf000137_0003
ESI-MS [M+H+] = 377 Calculated for C20H25FN2O2S = 376 Example 30: N-(1-Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)-C- cyclopropyl-methane-sulfonamide H
Figure imgf000138_0001
Example 31 : Cyclobutanesulfonic acid (1-benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
Figure imgf000138_0002
ESI-MS [M+H+] = 395 Calculated for C22H28N202S = 385
Example 32: Propane-1 -sulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8- ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
Figure imgf000138_0003
ESI-MS [M+H+] = 373 Calculated for C2iH28N202S = 373
Example 33: Ethanesulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8- ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
Figure imgf000139_0001
Example 34: 1-Methyl-1 H-pyrazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetra-hydro-1 H- benzo[c]aze
Figure imgf000139_0002
ESI-MS [M+H+] = 41 1 Calculated for C22H26N4O3S = 41 1
Example 35: 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetra-hyd benzo[c]azepin-8-ylmethyl)-amide; compound with (E)-buten-2-enedioic acid
Figure imgf000139_0003
Example 36: 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetrahyd benzo[c]azepin-8-ylmethyl)-methyl-amide
Figure imgf000140_0001
ESI-MS [M+H+] = 425 Calculated for C23H28N4O2S = 425
Example 37: 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-propyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- lmethyl)-amide
Figure imgf000140_0002
ESI-MS [M+H+] = 453 Calculated for C25H32N4O2S = 453
Example 38: 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-methyl-2,3,4,5-tetrahyd 1 H-benzo[c]azepin-8-ylmethyl)-amide
Figure imgf000140_0003
ESI-MS [M+H+] = 425 Calculated for C23H28N4O2S = 425
Example 39: 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2-ethyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-ylmethyl)-amide
Figure imgf000140_0004
ESI-MS [M+H+] = 439 Calculated for C24H30N4O2S = 439 Example 40: 1-Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-ethyl-amide
Figure imgf000141_0001
ESI-MS [M+H+] = 439 Calculated for C24H30N4O2S = 439
Example 41 : 1 -Methyl-1 H-imidazole-4-sulfonic acid (1-benzyl-7-fluoro-2,3,4,5-tetrahyd 1 H-benzo[c]azepin-8-ylmethyl)-amide
Figure imgf000141_0002
ESI-MS [M+H+] = 429 Calculated for C22H25FN4O2S = 428
Example 42: Ethanesulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin- 8-ylmethyl)-amide; compound with trifluoro-acetic acid
Figure imgf000141_0003
ESI-MS [M+H+] = 354 Calculated for C20H25FN2O2S = 376
Example 43: Ethanesulfonic acid [2-(1-benzyl-7-fluoro-2,3,4,5-tetrahydro
[c]azepin-8-yloxy)-ethyl]-amide
Figure imgf000142_0001
ESI-MS [M+H+] = 407 Calculated for C21 H27FN2O3S = 406
Example 44: N-(1-Benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)-C- cyclopropyl-methanesulfonamide; compound with (E)-but-2-enedioic acid
Figure imgf000142_0002
ESI-MS [M+H+] = 403 Calculated for C22H27FN2O2S = 403
Example 45: 1 -Methyl-1 H-imidazole-4-sulfonic acid [2-(1 -benzyl-7-fluoro-2, 3,4,5- tetrahydro-1 H-benzo[c]
Figure imgf000142_0003
ESI-MS [M+H+] = 459 Calculated for C23H27FN4O3S = 459
Example 46: N-[2-(1 -Benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)-ethyl]- C-cyclopropyl-methanesulfonamide
Figure imgf000143_0001
ESI-MS [M+H+] = 433 Calculated for C23H29FN2O3S =
Example 47: 1-Methyl-1 H-imidazole-4-sulfonic acid [5-(1 -methyl-1 -phenyl-ethyl)-2, 3,4,5- tetrahydro-benzo
Figure imgf000143_0002
ESI-MS [M+H+] = 440 Calculated for C23H28N4O3S = 441
Example 48: 1-Methyl-1 H-imidazole-4-sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]
Figure imgf000143_0003
ESI-MS [M+H+] = 443 Calculated for C22H26N4O4S = 444
Example 49: 1-Methyl-1 H-pyrazole-4-sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-amide
Figure imgf000144_0001
ESI-MS [M+H+] = 443 Calculated for C22H26N404S = 444
Example 50: Ethanesulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro-benzo[f][1 ,4]oxazepin-7- yloxy)-ethyl]-amide
Figure imgf000144_0002
ESI-MS [M+H+] = 391 Calculated for C2oH26N204S = 390
Example 51 : Propane-1 -sulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-amide
Figure imgf000144_0003
ESI-MS [M+H+] = 405 Calculated for C2iH28N204S = 404
Example 52: Cyclobutanesulfonic acid [2-(5-benzyl-2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-amide
Figure imgf000144_0004
ESI-MS [M+H+] = 417 Calculated for C22H28N204S = 417 Example 53: N-[2-(5-Benzyl-2,3,4,5-tetrahydro-benzo[f][1 ,4]oxazepin-7-yloxy)-ethyl]-C- cyclopropyl-methanesulfonamide
Figure imgf000145_0001
ESI-MS [M+H+] = 417 Calculated for C22H28 2O4S = 417
The following compounds were obtained or can be obtained using the procedures described herein.
1-Methyl-1 H-imidazole-4- sulfonic acid [2-(1 -benzyl-2- methyl-2,3,4,5-tetrahydro-
1 H-benzo[c]azepin ethyl]-amide
1-Methyl-1 H-pyrazole-4- sulfonic acid [2-(1 -benzyl-2- methyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy)- ethyl]-amide
Propane-1 -sulfonic acid [2- (1-benzyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy)- ethyl]-amide
Figure imgf000145_0002
Ethanesulfonic acid [2-(1 - benzyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy)- ethyl]-amide
Propane-1 -sulfonic acid (1- benzyl-2,3,4,5-tetrahydro- 1 H-benzo[c]-azepin-8- ylmethyl)-amide
Ethanesulfonic acid (1 - benzyl-2,3,4,5-tetrahydro- 1 H-benzo[c]-azepin-8- ylmethyl)-amide
N-(1-Benzyl-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-
C-cyclopropyl-methane- sulfonamide
Figure imgf000146_0001
8
1-Methyl-1 H-imidazole-4- sulfonic acid (1-benzyl- 2,3,4,5-tetra-hydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
Figure imgf000146_0002
1-Methyl-1 H-pyrazole-4- sulfonic acid (1-benzyl- 2,3,4,5-tetra-hydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
1-Methyl-1 H-imidazole-4- sulfonic acid (1-benzyl-2- methyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- ylmethyl)-amide
Figure imgf000147_0001
1 1
1-Methyl-1 H-pyrazole-4- sulfonic acid (1-benzyl-2- methyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- ylmethyl)-amide
1-benzyl-2,3,4,5-tetrahydro- 1 H-benzo[c]azepine-8- carbonitrile
N-[2-(1-Benzyl-7-fluoro-
2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy)- ethyl]-C-cyclopropyl- methanesulfonamide
Figure imgf000147_0002
Propane-1 -sulfonic acid [2-
(1-benzyl-7-fluoro-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-yloxy)- ethyl]-amide
Ethanesulfonic acid [2-(1 - benzyl-7-fluoro-2,3,4,5- tetrahydro-1 H-benzo- [c]azepin-
8-yloxy)-ethyl]-amide
Propane-1 -sulfonic acid (1- benzyl-7-fluoro-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
Ethanesulfonic acid (1 - benzyl-7-fluoro-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
N-(1 -Benzyl-7-fluoro-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-
C-cyclopropyl- methanesulfonamide
Figure imgf000148_0001
1-Methyl-1 H-imidazole-4- sulfonic acid (1-benzyl-7- fluoro-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
1-Methyl-1 H-pyrazole-4- sulfonic acid (1-benzyl-7- fluoro-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)- amide
Figure imgf000149_0001
Propane-1 -sulfonic acid {2- [1 -(4-fluoro-benzyl)-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-yloxy]- ethyl}-amide
Ethanesulfonic acid {2-[1 -(4- fluoro-benzyl)-2, 3,4,5- tetrahydro-1 H- benzo[c]azepin-8-yloxy]- ethyl}-amide
Figure imgf000149_0002
1-Methyl-1 H-imidazole-4- sulfonic acid [1 -(4-fluoro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- ylmethyl]-amide
Figure imgf000149_0003
Propane-1 -sulfonic acid [1 - (4-chloro-benzyl)-2,3,4,5- tetra-hydro-1 H- benzo[c]azepin-8-ylmethyl]-
Figure imgf000150_0001
amide
Ethanesulfonic acid [1 -(4- chloro-benzyl)-2,3,4,5-tetra- hydro-1 H-benzo[c]azepin-8- ylmethyl]-amide
N-[1-(4-Chloro-benzyl)-
2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]-
C-cyclopropyl- methanesulfonamide
1-Methyl-1 H-imidazole-4- sulfonic acid [1 -(4-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo-[c]azepin-8- ylmethyl]-amide
Figure imgf000150_0002
1-Methyl-1 H-pyrazole-4- sulfonic acid [1 -(4-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo-[c]azepin-8- ylmethyl]-amide
Figure imgf000150_0003
Propane-1 -sulfonic acid (1- pyridin-2-yl-methyl-2,3,4,5- tetrahydro-I H- benzo[c]azepin-8-ylmethyl)- amide
Ethanesulfonic acid (1 - pyridin-2-yl-methyl-2,3,4,5- tetrahydro-I H- benzo[c]azepin-8-ylmethyl)- amide
C-Cyclopropyl-N-(1 -pyridin-
2-ylmethyl-2,3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)- methanesulfonamide
1-Methyl-1 H-imidazole-4- sulfonic acid {2-[1 -(4-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
1-Methyl-1 H-pyrazole-4- sulfonic acid {2-[1 -(4-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
Figure imgf000151_0001
1-Methyl-1 H-imidazole-4- sulfonic acid {2-[1 -(3-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
1-Methyl-1 H-pyrazole-4- sulfonic acid {2-[1 -(3-chloro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
1-Methyl-1 H-imidazole-4- sulfonic acid {2-[1 -(3-fluoro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
1-Methyl-1 H-pyrazole-4- sulfonic acid {2-[1 -(3-fluoro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8-yloxy]- ethyl}-amide
Figure imgf000152_0001
Propane-1 -sulfonic acid [1 - (4-f I u oro-benzy I )-2 , 3 ,4, 5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]- amide
Ethanesulfonic acid [1 -(4- fluoro-benzyl)-2, 3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]- amide
C-Cyclopropyl-N-[1 -(4- fluoro-benzyl)-2, 3,4,5- tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]- methanesulfonamide
1-Methyl-1 H-imidazole-4- sulfonic acid [1 -(4-fluoro- benzyl)-2,3,4,5-tetrahydro- 1 H-benzo[c]azepin-8- ylmethyl]-amide
Figure imgf000153_0001
Biological testing 1. [3H]-Glycine uptake into recombinant CHO cells expressing human GlyT1 :
Human GlyTI c expressing recombinant hGlyT1 c_5_CHO cells were plated at 20,000 cells per well in 96 well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured to sub-confluency for 24 h. For glycine uptake assays the culture medium was aspirated and the cells were washed once with 100 μΙ HBSS (Gibco BRL, #14025-050) with 5 mM L-Alanine (Merck #1007). 80 μΙ HBSS buffer were added, followed by 10 μΙ inhibitor or vehicle (10% DMSO) and 10 μΙ [3H]-glycine (TRK71 , Amersham Biosciences) to a final concentration of 200 nM for initiation of glycine uptake. The plates were placed in a Wal- lac Microbeta (PerkinElmer) and continuously counted by solid phase scintillation spectrometry during up to 3 hours. Nonspecific uptake was determined in the presence of 10 μΜ Org24598. IC50 calculations were made by four-parametric logistic nonlinear regres- sion analysis (GraphPad Prism) using determinations within the range of linear increase of [3H]-glycine incorporation between 60 and 120 min.
2. Radioligand binding assays using recombinant CHO cell membranes expressing human GlyT1 :
Radioligand binding to human GlyTI c transporter-expressing membranes was determined as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.
3. Metabolic stability
Metabolic stability was determined as follows:
0.5 μΜ test substance was preincubated together with human liver microsomes (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37°C for 5 min. The reaction was started by adding NADPH ( 1 .0 mM). After 0, 5, 10, 15, 20 and 30 min, 65 μΙ aliquots were removed, and the reaction was immediately stopped and cooled with twice the amount of ethanol. The samples were frozen until analyzed. The remaining concentration of undegraded test substance was determined by LC MSMS. The half-life (T1/2) was determined from the gradient of the signal of test sub- stance/unit time plot, allowing to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCI) was calculated from mCI = ln2/T1/2 / (content of microsomal protein in mg/ml) χ 1000 (modified from references: Di, The Society for Biomolecular Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N 1 1 , 1350-1359).
The following results were obtained with the compounds disclosed in the examples:
Example radioligand binding Kiapp [nmol] human mCI [μΙ/min/mg]
1 > 10000 < 50
2 < 100 < 50
3 < 10 < 50
4 < 100 < 50
5 < 10000 < 250
6 < 10 < 150 < 10 < 200
< 1000 < 250
< 10000 < 100
< 100 < 50
< 1000 < 50* < 1000 < 150
< 10000 < 150* < 100 < 50
< 1000 < 50
< 1000 < 50
< 10000 < 100
< 10000 < 50
< 1000 < 100
< 1000 < 50
< 100 < 100
< 10 < 50
< 10 < 100
< 10 < 50
< 100 < 150
< 100 < 100
< 1000 < 50
< 10 < 50
< 1000 < 100
< 100 < 50
< 1000 < 50
< 100 < 50
< 100 < 100
< 1000 < 100
< 10000 < 50
< 10 < 50
< 10 < 50
< 100 < 50
< 10 < 300
< 100 < 100
< 100 < 150
< 100 < 50
< 10 < 50
< 1000 < 50
< 1000 < 50 44 < 100 < 50
45 < 100 < 50
46 < 100 < 50
47 < 10000 -
48 < 100 < 50
49 < 100 < 50
50 < 10000 < 50
51 < 1000 < 100
52 < 1000 < 100
53 < 1000 < 100
*(1R)/(1S)
Further, the present application relates to isoindoline derivatives of the formula (A):
Figure imgf000157_0001
wherein R, R2, R3, R4, X2, X3, R5 are as defined herein for the benzazepine derivatives, or a physiologically tolerated salt thereof; pharmaceutical compositions comprising such compounds; and the use of such compounds for therapeutic purposes. The compounds are GlyT1 inhibitors.
The isoindoline derivatives and their physiologically tolerated salts can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of isoindoline derivatives of formula (A) are outlined in the following schemes.
Scheme 1 .
Figure imgf000157_0002
Scheme 2.
Figure imgf000158_0001
Scheme 3.
Figure imgf000158_0002
The following examples serve to explain the invention relating to the isoindoline derivatives without limiting it. The compounds were characterized by mass spectrometry, generally recorded via MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
Preparation Examples
The following compounds were obtained using the procedures described herein.
Example A1 : N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4- sulfonamide
Figure imgf000159_0001
ESI-MS [M+H+] =427 Calculated for C2i H22N404S= 426
Example A2: N-[(3-benzyl-1-oxo-isoindolin-5-yl)methyl]-1 -methyl-imidazole-4-sulfonamide
H
Figure imgf000159_0002
ESI-MS [M+H+] = 397 Calculated for C2oH2oN403S = 396
Example A3: [2-(3-Benzyl-1 -oxo-2,3-dihydro-1 H-isoindol-5-yloxy)-ethyl]-carbamic acid tert-butyl ester
Figure imgf000160_0001
ESI-MS [M+H+] = 383 Calculated for C22H26N204 = 382
Example A4: N-[(3-benzylisoindolin-5-yl)methyl]-1-methyl-imidazole-4-sulfonamide
H
Figure imgf000160_0002
ESI-MS [M+H+] = 383 Calculated for C20H22 4O2S = 382
Example A5: N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide
H
Figure imgf000160_0003
ESI-MS [M+H+] = 413 Calculated for C2i H24N403S = 412 ExampleA6: N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1 -methyl-pyrazole-4- sulfonamide
Figure imgf000161_0001
ESI-MS [M+H+] = 427 Calculated for C21 H22N4O4S = 426
Example A7: N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide
H
Figure imgf000161_0002
ESI-MS [M+H+] = 413 Calculated for C21 H24N4O3S = 412
Example A8: N-[2-(3-benzyl-3-methyl-1 -oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole- 4-sulfonamide
Figure imgf000162_0001
ESI-MS [M+H+] = 441 Calculated for C22H24N4O4S = 440
Example A9: N-[2-(3-benzyl-3-methyl-1 -oxo-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4- sulfonamide
H
Figure imgf000162_0002
ESI-MS [M+H+] = 441 Calculated for C22H24N404S = 440
Example A10: N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4- sulfonamide
Figure imgf000163_0001
ESI-MS [M+H+] = 427 Calculated for C22H26N403S = 426 Example A1 1 : N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4- sulfonamide
Figure imgf000163_0002
ESI-MS [M+H+] = 427 Calculated for C22H26N403S = 426
Example A12: N-[2-[3-benzyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl]oxyethyl]-1-methyl- pyrazole-4-sulfonamide
Figure imgf000163_0003
ESI-MS [M+H+] Calculated for C23H23F3N4O4S = 509
Example A13: N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4- sulfonamide; 2,2,2-trifluoroacetic acid
Figure imgf000164_0001
ESI-MS [M+H+] = 427 Calculated for C22H26N4O3S = 426 Example A14: N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4- sulfonamide; 2,2,2-trifluoroacetic acid
Figure imgf000164_0002
ESI-MS [M+H+] = 427 Calculated for C22H26N4O3S = 426
Example A15: N-[2-[3-benzyl-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]oxyethyl]-1-methyl- pyrazole-4-sulfonamide; 2,2,2-trifluoroacetic acid
Figure imgf000165_0001
ESI-MS [M+H+] = 495 Calculated for C23H25F3N4O3S = 494
Example A16: N-[2-[3-benzyl-2-(oxetan-3-yl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole sulfonamide; 2,2,2-trifluoroacetic acid
Figure imgf000165_0002
ESI-MS [M+H+] = 469 Calculated for C24H28N4O4S = 468
Example A17: N-[2-(3-benzyl-3-methyl-1 -oxo-isoindolin-5-yl)oxyethyl]-1 -cyclopropyl- methanesulfonamide
Figure imgf000165_0003
ESI-MS [M+H+] = 415 Calculated for C22H26N2O4S = 414 Example A18: N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-cyclopropyl- methanesulfonamide; 2,2,2-trifluoroacetic acid
Figure imgf000166_0001
ESI-MS [M+H+] = 401 Calculated for C22H28N2O3S = 400
Example A19: N-[2-(3-benzyl-6-fluoro-1-oxo-isoindolin-5-yl)oxyethyl]-1 -methyl-imidazole- 4-sulfonamide
H
Figure imgf000166_0002
ESI-MS [M+H+] = 443 Calculated for C21 H21 FN4O4S = 444
Example A20: N-(2-(3-benzyl-6-fluoro-2-methylisoindolin-5-yloxy)ethyl)-1-cyclopropyl- methanesulfonamide
Figure imgf000167_0001
ESI-MS [M+H+] = 419 Calculated for C22H27FN2O3S = 418

Claims

aim:
Benzazepine derivatives of the formula (I )
Figure imgf000168_0001
wherein
R is R1-W-A1-Q-Y-A2-X1- or -CN;
R1 is hydrogen, CrC6-alkyl, C3-Ci2-cycloalkyl-Ci-C4-alkyl, halogenated CrC6-alkyl, tri- (C 1 -C4-a I ky I )-s i ly I -Ci -C4-a I ky I , hydroxy-CrC4-alkyl, Ci-C6-alkoxy-Ci-C4-alkyl, amino- CrC4-alkyl, Ci-C6-alkylamino-Ci-C4-alkyl, di-Ci-C6-alkylamino-Ci-C4-alkyl, CrC6- alkylcarbonylamino-Ci-C4-alkyl, Ci-C6-alkyloxycarbonylamino-Ci-C4-alkyl, CrC6- alkylaminocarbonylamino-Ci-C4-alkyl, di-Ci-C6-alkylaminocarbonylamino-Ci-C4- alkyl, Ci-C6-alkylsulfonylamino-Ci-C4-alkyl, (optionally substituted C6-Ci2-aryl-Ci- C6-alkyl)amino-Ci-C4-alkyl, optionally substituted C6-Ci2-aryl-Ci-C4-alkyl, optionally substituted C3-Ci2-heterocyclyl-Ci-C4-alkyl, C3-Ci2-cycloalkyl, CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, halogenated CrC6-alkoxycarbonyl, C6-Ci2-aryloxycarbonyl, aminocarbonyl, Ci-C6-alkylaminocarbonyl, (halogenated Ci-C4- alkyl)aminocarbonyl, C6-Ci2-arylaminocarbonyl, C2-C6-alkenyl, C2-C6-alkynyl, optionally substituted C6-Ci2-aryl, hydroxy, CrC6-alkoxy, halogenated CrC6-alkoxy, CrC6-hydroxyalkoxy, Ci-C6-alkoxy-Ci-C4-alkoxy, amino-Ci-C4-alkoxy, Ci-C6- alkylamino-Ci-C4-alkoxy, di-Ci-C6-alkylamino-Ci-C4-alkoxy, Ci-C6- alkylcarbonylamino-Ci-C4-alkoxy, C6-Ci2-arylcarbonylamino-Ci-C4-alkoxy, Ci-C6- alkoxycarbonylamino-Ci-C4-alkoxy, C6-Ci2-aryl-Ci-C4-alkoxy, Ci-C6- alkylsulfonylamino-Ci-C4-alkoxy, (halogenated Ci-C6-alkyl)sulfonylamino-Ci-C4- alkoxy, C6-Ci2-arylsulfonylamino-Ci-C4-alkoxy, (C6-Ci2-aryl-Ci-C6- alkyl)sulfonylamino-Ci-C4-alkoxy, C3-Ci2-heterocyclylsulfonylamino-Ci-C4-alkoxy, C3-Ci2-heterocyclyl-Ci-C4-alkoxy, C6-Ci2-aryloxy, C3-Ci2-heterocyclyloxy, Ci-C6- alkylthio, halogenated CrC6-alkylthio, Ci-C6-alkylamino, (halogenated Ci-C6- alkyl)amino, di-Ci-C6-alkylamino, di-(halogenated Ci-C6-alkyl)amino, Ci-C6- alkylcarbonylamino, (halogenated Ci-C6-alkyl)carbonylamino, C6-Ci2- arylcarbonylamino, Ci-C6-alkylsulfonylamino, (halogenated CrC6- alkyl)sulfonylamino, C6-Ci2-arylsulfonylamino or optionally substituted C3-C12- heterocyclyl;
W is -N R8- or a bond;
A1 is optionally substituted CrC4-alkylene or a bond; Q is -S(0)2- or -C(O)-; Y is -N R9- or a bond;
A2 is optionally substituted CrC4-alkylene, CrC4-alkylene-CO-, -CO-CrC4-alkylene, Ci-C4-alkylene-0-Ci-C4-alkylene, Ci-C4-alkylene-N R10-Ci-C4-alkylene, optionally substituted C2-C4-alkenylen, optionally substituted C2-C4-alkynylene, optionally substituted C6-Ci2-arylene, optionally substituted C6-Ci2-heteroarylene or a bond;
X1 is -0-, -N R11-, -S-, optionally substituted CrC4-alkylene, optionally substituted C2- C4-alkenylen, optionally substituted C2-C4-alkynylene;
R2 is hydrogen, halogen, CrC6-alkyl, halogenated CrC4-alkyl, hydroxy-CrC4-alkyl, - CN , C2-C6-alkenyl, C2-C6-alkynyl, optionally substituted C6-Ci2-aryl, hydroxy, CrC6- alkoxy, halogenated CrC6-alkoxy, CrC6-alkoxycarbonyl, C2-C6-alkenyloxy, C6-Ci2- aryl-Ci-C4-alkoxy, CrC6-alkylcarbonyloxy, CrC6-alkylthio, CrC6-alkylsulfinyl, d- C6-alkylsulfonyl, aminosulfonyl, amino, Ci-C6-alkylamino, C2-C6-alkenylamino, nitro or optionally substituted C3-Ci2-heterocyclyl, or two radicals R2 together with the ring atoms of A to which they are bound form a 5- or 6 membered ring; is -CH2-, -0-, -NR1 -, or -S-; R3 is hydrogen, halogen, CrC6-alkyl or CrC6-alkoxy, or two radicals R3 together with the carbon atom to which they are attached form a carbonyl group;
R4 is hydrogen, CrC6-alkyl, C3-Ci2-cycloalkyl-Ci-C4-alkyl, halogenated CrC4-alkyl, hydroxy-CrC4-alkyl, Ci-C6-alkoxy-Ci-C4-alkyl, amino-Ci-C4-alkyl, CH2CN, C6-Ci2- aryl-Ci-C4-alkyl, C3-Ci2-cycloalkyl, -CHO, CrC4-alkylcarbonyl, (halogenated C1-C4- alkyl)carbonyl, C6-Ci2-arylcarbonyl, CrC4-alkoxycarbonyl, C6-Ci2-aryloxycarbonyl, d-Ce-alkylaminocarbonyl, C2-C6-alkenyl, -C(=NH)NH2, -C(=NH)NHCN, C C6- alkylsulfonyl, C6-Ci2-arylsulfonyl, amino, -NO or C3-Ci2-heterocyclyl;
X2 is -0-, -NR6-, -S-, >CR12aR12b or a bond;
X3 is -0-, -NR7-, -S-, >CR13aR13b or a bond;
R5 is optionally substituted C6-Ci2-aryl, optionally substituted C3-Ci2-cycloalkyl or optionally substituted C3-Ci2-heterocyclyl;
R6 is hydrogen or CrC6-alkyl;
R7 is hydrogen or CrC6-alkyl;
R8 is hydrogen or CrC6-alkyl;
R9 is hydrogen, CrC6-alkyl, C3-Ci2-cycloalkyl, amino-Ci-C6-alkyl, optionally substituted C6-Ci2-aryl-Ci-C4-alkyl or C3-Ci2-heterocyclyl; or
R9, R1
together are CrC4-alkylene; or
R9 is CrC4-alkylene that is bound to a carbon atom in A2 and A2 is CrC4-alkylene or to a carbon atom in X1 and X1 is CrC4-alkylene;
R10 is hydrogen, CrC6-alkyl or CrC6-alkylsulfonyl; R11 is hydrogen or CrC6-alkyl, or
R9, R11
together are CrC4-alkylene,
R12a is hydrogen, optionally substituted CrC6-alkyl, Ci-C6-alkylamino-Ci-C4-alkyl, di-Ci C6-alkylamino-Ci-C4-alkyl, C3-Ci2-heterocyclyl-Ci-C6-alkyl, optionally substituted C6-Ci2-aryl or hydroxy;
1 ?h
R is hydrogen or CrC6-alkyl, or R12a R12b
together are carbonyl or optionally substituted CrC4-alkylene, wherein one -CH2-
14
of CrC4-alkylene may be replaced by an oxygen atom or -NR -;
R13a is hydrogen, optionally substituted CrC6-alkyl, Ci-C6-alkylamino-Ci-C4-alkyl, di-Ci C6-alkylamino-Ci-C4-alkyl, C3-Ci2-heterocyclyl-Ci-C6-alkyl, optionally substituted C6-Ci2-aryl or hydroxy;
1
R is hydrogen or CrC6-alkyl, or
together are carbonyl or optionally substituted CrC4-alkylene, wherein one -CH2- of CrC4-alkylene may be replaced by an oxygen atom or -NR15-;
14
R is hydrogen or d-C6-alkyl; R15 is hydrogen or CrC6-alkyl; and
R16 is hydrogen, CrC6-alkyl, C3-Ci2-cycloalkyl-Ci-C4-alkyl, halogenated CrC4-alkyl, hydroxy-CrC4-alkyl, Ci-C6-alkoxy-Ci-C4-alkyl, amino-Ci-C4-alkyl, CH2CN , C6-Ci2- aryl-Ci-C4-alkyl, C3-Ci2-cycloalkyl, -CHO, CrC4-alkylcarbonyl, (halogenated Ci-C4 alkyl)carbonyl, C6-Ci2-arylcarbonyl, CrC4-alkoxycarbonyl, C6-Ci2-aryloxycarbonyl, d-Ce-alkylaminocarbonyl, C2-C6-alkenyl, -C(=NH)NH2, -C(=NH)NHCN, C C6- alkylsulfonyl, C6-Ci2-arylsulfonyl, amino, -NO or C3-Ci2-heterocyclyl, or a physiologically tolerated salt thereof.
Compound as claimed in claim 1 , wherein R is R1-W-A1-Q-Y-A2-X1-.
Compound as claimed in claim 1 or 2, wherein -Y-A2-X1- comprises at least 2, 3 or 4 atoms in the main chain.
Compound as claimed in any one of claims 1 to 3, wherein R1 is CrC6-alkyl, C3-C-|2- cycloalkyl-CrC4-alkyl, C3-Ci2-cycloalkyl, or optionally substituted C3-Ci2-heterocyclyl.
Compound as claimed in any one of claims 1 to 4, wherein A1 is a bond.
Compound as claimed in any one of claims 1 to 5, wherein W is a bond and Y is a bond.
Compound as claimed in any one of claims 1 to 5, wherein W is a bond and Y is -NR9-.
Compound as claimed in any one of claims 1 to 7, wherein X1 is -O- and A2 is CrC4- alkylene, or X1 is CrC4-alkylene and A2 is a bond.
Compound as claimed in any one of claims 1 to 8, wherein R1-W-A1-Q-Y-A2-X1- is R1- S(0)2-NR9-A2-X1- or R1-S(0)2-X1-.
Compound as claimed in any one of claims 1 to 9, having the formula
Figure imgf000172_0001
wherein R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined in any one of claims 1 to 9.
1 1 . Compound as claimed in any one of claims 1 to 10, wherein R2 is hydrogen or halogen.
12. Compound as claimed in claim 10 or 1 1 , having one of the formulae
Figure imgf000173_0001
wherein R1, W, A1, Q, Y, A2, X1, R2, A3, R3, R4, X2, X3, R5 are as defined in any of claims 1 to 1 1 .
13. Compound as claimed in any one of claims 1 to 12, wherein A3 is -CH2-, -0-, or -S-.
14. Compound as claimed in any one of claims 1 to 13, wherein R3 is hydrogen.
15. Compound as claimed in any one of claims 1 to 14, wherein R4 is hydrogen, CrC6-alkyl, or C3-Ci2-cycloalkyl.
16. Compound as claimed in any one of claims 1 to 15, wherein X2 is CR12aR12b.
17. Compound as claimed in any one of claims 1 to 16, wherein X3 is a bond.
18. Compound as claimed in any one of claims 1 to 17, wherein R12a is hydrogen or CrC6-
1 ?h
alkyl and R is hydrogen or CrC6-alkyl.
19. Compound as claimed in any one of claims 1 to 17, wherein R12a, R12b together are optionally substituted CrC4-alkylene.
20. Compound as claimed in any one of claims 1 to 19, wherein R5 is optionally substituted aryl.
21 . Compound as claimed in claim 20, having the formula
Figure imgf000174_0001
wherein R, R2, A3, R3, R4, X2, X3 are as defined in any one of claims 1 to 20; and
17a r-,17b .-,17c r->17d r^Me
independently are hydrogen, halogen, or halogenated CrC6-alkyl.
22 Compound as claimed in claim 20, having the formula
Figure imgf000175_0001
wherein R, R2, A3, R3, R4, X2, X3 are as defined in any one of claims 1 to 20; and
Figure imgf000175_0002
independently are hydrogen, halogen, or halogenated CrC6-alkyl.
23. Compound as claimed in any one of claims 1 to 22, wherein R is hydrogen or alkyl; or R9 is CrC4-alkylene that is bound to a carbon atom in X1 and X1 is CrC4-alkylene.
Compound as claimed in claim 1 , wherein
R is R1-W-A1-Q-Y-A2-X1-;
R1 is CrC6-alkyl, C3-Ci2-cycloalkyl-Ci-C4-alkyl, C3-Ci2-cycloalkyl, or optionally substituted C3-Ci2-heterocyclyl; is a bond; is a bond; is -S(0)2-; is -NR9- or a bond;
A is C C4-alkylene; is -O- or CrC4-alkylene; R2 is hydrogen or halogen;
A3 is -CH2-, -0-, -NR16, or -S-;
R3 is hydrogen;
R4 is hydrogen, C C6-alkyl, C3-Ci2-cycloalkyl or C3-Ci2-cycloalkyl-Ci-C4-alkyl;
X2 is CR12aR12b;
X3 is a bond;
R5 is optionally substituted phenyl or pyridyl;
R9 is hydrogen or alkyl; or
R9 is C C4-alkylene that is bound to a carbon atom in X1 and X1 is CrC4-alkylene;
R12a is hydrogen; and
R12b is hydrogen; or
R12a R1 b
together are CrC4-alkylene; and
R16 is hydrogen or C C6-alkyl.
Compound as claimed in claim 1 which is:
N-(2-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H- imidazole-4-sulfonamide;
N-(2-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 -methyl-1 H- pyrazole-4-sulfonamide N-(2-(1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)ethyl)-1 - cyclopropylmethanesulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid [2-(1 -benzyl-2-methyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy)-ethyl]-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid [2-(1 -benzyl-2-methyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy)ethyl]-amide;
Propane-1 -sulfonic acid [2-(1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)- ethyl]-amide;
Ethanesulfonic acid [2-(1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-yloxy)-ethyl]- amide;
Propane-1 -sulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8-ylmethyl)- amide;
Ethanesulfonic acid (1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]-azepin-8-ylmethyl)-amide; N-(1 -Benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)-C-cyclopropyl-methane- sulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid (1 -benzyl-2,3,4,5-tetra-hydro-1 H-benzo[c]azepin- 8-ylmethyl)-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid (1 -benzyl-2,3,4,5-tetra-hydro-1 H-benzo[c]azepin-8- ylmethyl)-amide;
1 -Methyl-1 H-imidazole-4-sulfonic acid (1 -benzyl-2-methyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid (1 -benzyl-2-methyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-amide;
1 -benzyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepine-8-carbonitrile;
N-p-il -Benzyl-y-fluoro^.S^.S-tetrahydro-I H-benzoMazepin-S-yloxy^ethy -C- cyclopropyl-methanesulfonamide;
Propane-1 -sulfonic acid [2-(1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy)-ethyl]-amide;
Ethanesulfonic acid [2-(1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo-[c]azepin-8- yloxy)-ethyl]-amide;
Propane-1 -sulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl)-amide;
Ethanesulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)- amide; N-(1 -Benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)-C-cyclopropyl- methanesulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid (1 -benzyl-7-fluoro-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl)-amide;
Propane-1 -sulfonic acid {2-[1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy]-ethyl}-amide;
Ethanesulfonic acid {2-[1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- yloxy]-ethyl}-amide;
1 -Methyl-1 H-imidazole-4-sulfonic acid [1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]-amide;
Propane-1 -sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetra-hydro-1 H-benzo[c]azepin-8- ylmethyl]-amide;
Ethanesulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetra-hydro-1 H-benzo[c]azepin-8- ylmethyl]-amide;
N-[1 -(4-Chloro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl]-C-cyclopropyl- methanesulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo- [c]azepin-8-ylmethyl]-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid [1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo- [c]azepin-8-ylmethyl]-amide;
Propane-1 -sulfonic acid (1 -pyridin-2-yl-methyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl)-amide;
Ethanesulfonic acid (1 -pyridin-2-yl-methyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl)-amide;
C-Cyclopropyl-N-(1 -pyridin-2-ylmethyl-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl)- methanesulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid {2-[1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid {2-[1 -(4-chloro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide;
1 -Methyl-1 H-imidazole-4-sulfonic acid {2-[1 -(3-chloro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide; 1 -Methyl-1 H-pyrazole-4-sulfonic acid {2-[1 -(3-chloro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide;
1 -Methyl-1 H-imidazole-4-sulfonic acid {2-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide;
1 -Methyl-1 H-pyrazole-4-sulfonic acid {2-[1 -(3-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yloxy]-ethyl}-amide;
Propane-1 -sulfonic acid [1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl]-amide;
Ethanesulfonic acid [1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8- ylmethyl]-amide;
C-Cyclopropyl-N-[1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-8-ylmethyl]- methanesulfonamide;
1 -Methyl-1 H-imidazole-4-sulfonic acid [1 -(4-fluoro-benzyl)-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-ylmethyl]-amide.
or a physiologically tolerated salt thereof.
26. The compound as claimed in any one of claims 1 to 25 for use in therapy.
27. Pharmaceutical composition which comprises a carrier and a compound of any one of claims 1 to 25.
28. A method for inhibiting the glycine transporter GlyT1 in a mammal in need thereof which comprises the administration of an effective amount of a compound of any one of claims 1 to 25.
29. The use of a compound of any one of claims 1 to 25 in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 .
30. A method for treating a neurologic or psychiatric disorder or pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 25.
31 . The use of a compound of any one of claims 1 to 25 in the manufacture of a medicament for treating a neurologic or psychiatric disorder or pain.
32. The compound of any one of claims 1 to 25 for use in a method of treating a neurologic or psychiatric disorder or pain. 33. The method, use or compound as claimed in any one of claims 35 to 39, wherein the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.
34. The method, use or compound as claimed in any one of claims 30 to 33, wherein the neurologic disorder is a cognitive disorder such as dementia, cognitive impairment, at- tention deficit disorder.
35. The method, use or compound as claimed in claim 34, wherein the attention deficit disorder is a the attention deficit disorder with hyperactivity. 36. The method, use or compound as claimed in any one of claims 30 to 33, wherein the psychiatric disorder is an anxiety disorder, a mood disorder such as depression, a bipolar disorder, schizophrenia, or a psychotic disorder.
37. Benzazepines derivatives of formula (II)
Figure imgf000180_0001
wherein L is an amino-protecting group, Y is NR9, and A2, X1, R2, A3, R3, R4, X2, X3, R5 are defined as in any one of claims 1 to 25.
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