EP1608662A1 - Guanidine derivatives and use thereof as neuropeptide ff receptor antagonists - Google Patents

Guanidine derivatives and use thereof as neuropeptide ff receptor antagonists

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Publication number
EP1608662A1
EP1608662A1 EP04722212A EP04722212A EP1608662A1 EP 1608662 A1 EP1608662 A1 EP 1608662A1 EP 04722212 A EP04722212 A EP 04722212A EP 04722212 A EP04722212 A EP 04722212A EP 1608662 A1 EP1608662 A1 EP 1608662A1
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European Patent Office
Prior art keywords
tetrahydro
guanidine
benzothiazol
formate
thiazolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP04722212A
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German (de)
French (fr)
Inventor
Eva Caroff
Matthias Steger
Oliver Valdenaire
Anja Fecher
Volker Breu
Kurt Hilpert
Heinz Fretz
Thomas Giller
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Publication of EP1608662A1 publication Critical patent/EP1608662A1/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to guanidine derivatives of the general formula
  • A is a chain of 3-6 optionally substituted C-
  • Atoms means one of which can be replaced by -N (R ') - or -0-;
  • R ' represents hydrogen or a substituent; the ring structure only the two double bonds of
  • Guanidine derivatives of the formula I which contain one or more centers of asymmetry can be used as optically pure enantiomers, as mixtures of enantiomers, for example racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers diastereomeric racemates or as mixtures of diastereomeric racemates.
  • the products defined at the beginning are partly known and partly new, and they have valuable pharmacodynamic properties in that they act as neuropeptide FF receptor antagonists.
  • the present invention relates to the use of the compounds of the formula I defined at the outset and the salts, esters, hydrates and solvates likewise defined at the outset as neuropeptide FF receptor antagonists or for the preparation of corresponding medicaments, in particular for the treatment of pain and hyperalgesia, withdrawal symptoms of alcohol, psychopharmaceutical and nicotine dependency and to improve or eliminate these dependencies, to regulate insulin release, food intake, memory functions, blood pressure, and the electrolyte and energy balance, and to treat urinary incontinence or to manufacture it appropriate drug.
  • the pain to be treated according to the invention can be chronic, acute, long-lasting or transient, and this pain can be of operative, traumatic or pathological origin; an advantage achieved according to the invention is the prevention of opioid tolerance and / or opioid dependence.
  • Neuropeptide FF Neuropeptide FF
  • NPFF neuropeptide FF
  • NPAF neuropeptide AF
  • NPAF neuropeptide AF
  • NPAF H-Ala- Gly-Glu-Gly-Leu-Ser-Ser-Pro Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH 2 [99588-52-0]
  • NPAF neuropeptide AF
  • NPAF neuropeptide AF
  • NPAF neuropeptide AF
  • NPAF neuropeptide AF
  • NPAF neuropeptide AF
  • NPAF H-Ala- Gly-Glu-Gly-Leu-Ser-Ser-Pro Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH 2 [99588-52-0]
  • a related octadecapeptide as Neurotransmitters of the central nervous system discovered in bovine brain
  • NPFF neuropeptide-binding protein
  • Antibodies increase analgesia caused by endogenous and exogenous opioids.
  • NPFF or NPFF analogs By direct injection of NPFF or NPFF analogs into the spinal cord (it), a prophylactic effect with long-lasting opioid-like analgesia and increased pain-relieving effects of morphine was obtained (Gouarderes et al., Eur. J. Pharmacol. 1993, 237 , 73-81; Kontinen and Kalso, Peptides 1995, 16, 973-977).
  • NPFF neuropeptide FF also appears to play a role in physiological processes such as insulin release, regulation of food intake, memory functions, blood pressure regulation and electrolyte balance play (Panula et. al., Prog. Neurobiol. 1996, 48, 461-487).
  • Nervous system such as the hypothalamus, medulla, and dorsal hearing of the spinal cord are restricted.
  • NPFF neuropeptide-like effects peripherally
  • GPCR G-protein coupled receptors
  • NPFF2 is identical to the receptor HLWAR77 originally described as orphan (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71).
  • NPFFl and NPFF2 could be characterized as specific receptors with affinities in the nanomolar and subnanomolar range for the two neuropeptides FF and AF.
  • NPFFl neuropeptide Y
  • NPY Y2 neuropeptide Y
  • cholecystokinin A NPY Yl
  • prolactin-releasing hormones Receptor NPY Y4.
  • NPFFl and NPFF2 were mainly detected in the central nervous system (CNS). In contrast, NPFF2 was found primarily in the spinal cord.
  • NPFF neuropeptides SF
  • NPVF neuropeptide VF
  • NPVF neuropeptide VF
  • NPFF-related peptides both localized on the so-called NPVF gene, bind to the NPFF1 receptor comparatively with higher affinity and selectivity than NPFF and NPAV.
  • the NPVF peptides also block morphine-induced analgesia in acute and inflammatory pain models to a greater extent than NPFF and underline the importance of the NPVF / FF1 system as part of an endogenous anti-opioid mechanism (Q. Liu et al., J. Biol. Chem. 2002, 276 (40), 36961).
  • NPFFl and NPFF2 receptors in addition to their original pain-modulating effects, could also have an influence on the storage and use of body energy (I. Lefrere et al., J. Biol. Chem. 2002, 277 (42), 39169).
  • the DesaminoTyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH 2 peptide has been described as the first NPFF receptor antagonist to counteract the NPFF effects. After icv injection, this peptide attenuated the withdrawal symptoms in the case of morphine dependence (Malin et al., Peptides 1991, 12, 1011-1014). However, this peptide showed no bioavailability in the central nervous system. Optimization of the tripeptide Pro-Gln-Arg-NH 2 in a combinatorial approach led to dansyl-Pro-Gln-Arg-NH 2 , or dansyl-Pro-Ser-Arg-NH 2 , both with improved
  • Arg-Tyr-amide peptoid BIBP3226 originally described as an NPY Yl selective receptor antagonist, showed an affinity for the human and rat NPFF1 receptor 10-60 times higher than for the corresponding NPFF2 receptors (Bonini et al., J. Biol. Chem 2000, 275 (50), 39324-31). From a series of compounds derived from the NPY Yl selective antagonist BIP3226, selective hNPFFl receptor antagonists were obtained which showed affinities of 40-80 nM (Mollereau et al., Europ. J. Pharmacol. 2002, 45, 245-56) ,
  • WO 02/24192 AI describes synthetic NPFF ligands of peptide structure, based on arginine as the central building block.
  • the products defined at the outset are potent and specific, low-molecular antagonists of neuropeptide FFl receptors with non-peptide or non-peptoid structures.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • canabinoids canabinoids
  • opioids canabinoids
  • morphine derivatives bind to the ⁇ -opioid receptor and have an analgesic effect.
  • Opioid binding to the ⁇ -opioid receptor is accompanied by the release of neuropeptide FF.
  • the released NPFF weakens the analgesic effect of the administered opioids and leads to tolerance towards opioids.
  • increasingly higher opioid doses have to be administered as a result of this tolerance, which can ultimately lead to serious side effects.
  • NPFF1 receptor mainly located in the central nervous system and the NPFF2 receptor predominantly in the spinal cord.
  • Activation of the NPFF2 receptors shows an opioid-like analgesic effect. Blocking the NPPFl receptors by an antagonist prevents the development of tolerance to opioids and additionally increases their effect.
  • the products defined there are partly known and partly new, and are distinguished by the valuable pharmacological property of blocking the interaction of neuropeptide FF with the neuropeptide FF1 receptor subtype.
  • one of the carbon atoms in chain A is / are substituted in formula I, then can one of the carbon atoms has one or two (geminal) identical or different substituents; or several of the carbon atoms can each carry one or two (geminal) identical or different substituents.
  • a together with the thiazole ring can form a cyclopentathiazole, benzothiazole, cycloheptathiazole, pyranothiazole, thiazolopyridine, thiazoloazepine or thiazolooxane skeleton which contains only the two double bonds of the thiazole building block, such as a 4, 5, 6, 7-tetrahydrobenzothiazole-, 5,6,7,8-tetrahydro-4H-cycloheptathiazole-, 5, 6-dihydro-4H-cyclopentathiazole-, 6, 7-dihydro-4H-pyrano [4, 3-d] thiazole-, or 5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-c] azepine backbone.
  • Alkanoyl alkenyl, alkoxy, alkoxyalkyl, alkoxyalkanoyl, alkoxyalkylcarbamoyl, alkoxyalkylthiocarbamoyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkanoyl, alkylamido, alkylaminocarbonyl, alkylarylamino, alkylcarbamoyl, alkylthiocarbamoyl, alkylcarbonyl
  • Dialkylaminoalkylamido Dialkylaminoalkanoyl, diarylamino, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, Haloalkylamido, haloalkanoyl, halo-alkylamino, heteroarylamino, Heteroarylamido, Heterocyclylalkylamido, heteroarylaminocarbonyl, Heteroaryloxycarbonylalkyl, Heteroaryloxycarbonylalkylamido, hetero- aryloxycarbonylalkanoyl, heterocyclyl, heterocyclylamino, Heterocyclylamido, heterocyclylalkyl, heterocyclylalkanoyl, Heterocyclylamido, heterocyclylalkyl, heterocyclylalkanoyl, Heterocyclylalkylamino, heterocyclylalkylamido,
  • Heteroarylalkyl heteroarylalkanoyl, heteroarylalkylamino, heteroarylalkylamido, heteroyclylalkylaminocarbonyl, heterocyclylalkoxycarbonylalkyl, heterocyclylalkoxycarbonylalkanoyl, heterocyclylalkoxycarbonylalkylamino, heterocyclylalkoxy
  • R x are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1, 1-dimethylpropyl, or phenyl.
  • Hydrogen are different, then they preferably mean methyl or another lower alkyl radical.
  • Another subgroup of the compounds of the formula I can be represented by the general formula
  • R ' is alkyl, alkanoyl, alkenyl, alkynyl, alkoxycarbonylalkyl, Alkoxycarbonylaminoalkanoyl, alkylcarbamoyl, Alkoxycarbonylalkylcarbamoyl, Alkoxycarbonylalkylthiocarbamoyl, alkylthiocarbamoyl, mono- or disubstituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, arylalkanoyl, arylcarbamoyl, alkoxyalkanoyl, alkylsulfonyl, arylthiocarbamoyl, aryloxycarbonylalkyl , Aryloxycarbonylalkanoyl, Aryloxycarbonylalkylcarbamoyl, Aryloxycarbonylalkylthio- carbamo
  • R ' is preferably methyl, ethyl, propyl, hexyl, 2, 2-dimethylpropionyl, cyclopropylmethyl, 2-
  • the present invention accordingly comprises these new substances as such and as therapeutic active substances; Processes for their manufacture;
  • one of the C atoms in chain A can carry one or two (ie geminal), identical or different, substituents; or several of the C atoms can each carry one or two (ie geminal), identical or different, substituents.
  • the substituent (s) can be selected from
  • substituent (s) can be selected from
  • Particularly preferred new fabrics are:
  • Also preferred new fabrics are:
  • alkyl denotes an unbranched or branched hydrocarbon radical of 1-8 C atoms.
  • Representative but not limiting examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl (or 2-
  • Methylpropyl n-pentyl (or n-amyl), isopentyl (or isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • the alkyl radical can carry one or more substituents which are independently selected from alkenyl, alkoxy, Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkoxyoxy, arylalkyloxyylylyloxy, Arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,
  • lower alkyl denotes alkyl groups with 1-4 C atoms.
  • Representative but not limiting examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like.
  • R a -R d denote substituents which are independently selected from hydrogen, alkyl, alkoxy, alkoxyalkyl, and the like.
  • Representative but not limiting examples of alkenyl are ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- Butenyl, 4-pentenyl, 5-hexenyl and the like.
  • alkylenedioxy denotes an -O (CH 2 ) n O group, in which n denotes 1 or 2, the O atoms being connected to two adjacent C atoms of the molecular backbone.
  • alkylenedioxy are methylenedioxy, ethylenedioxy and the like.
  • alkynyl denotes an unbranched or branched hydrocarbon radical of 2-8 C atoms, in which at least one carbon-carbon triple bond (R a -C ⁇ CR b ) is present.
  • R a and R b denote substituents which are selected independently of one another from hydrogen,
  • alkynyl alkenyl, alkoxy, alkoxyalkyl, and the like.
  • alkynyl are acetylenyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 2-pentynyl and the like.
  • alkoxy denotes an alkyl group that is linked via an oxygen bridge. Representative but not limiting examples of alkoxy are methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl alone or in combination, denotes an alkoxy group which is linked via an alkyl radical. Representative but not limiting examples of alkoxyalkyl are tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkoxycarbonyl denotes an alkoxy group which is linked via a carbonyl group.
  • Representative but not limiting examples of alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.
  • alkoxycarbonylalkyl denotes an alkoxycarbonyl group which is linked via an alkyl radical.
  • alkoxycarbonylalkyl are methoxycarbonylpropyl, ethoxycarbonylbutyl, 2-tert-
  • alkylcarbonyl alone or in combination, denotes an alkyl group which is linked via a carbonyl group. Representative but not limitative
  • alkylcarbonyl examples include acetyl, 1-oxopropyl, 2,2-
  • alkylcarbonylalkyl alone or in
  • alkylcarbonyl group which is linked via an alkyl group.
  • alkylcarbonylalkyl 2-oxopropyl, 3, 3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-
  • alkylcarbonyloxy denotes an alkylcarbonyl group which is linked via an oxygen bridge.
  • Representative but not limiting examples of alkylcarbonyloxy are acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy and the like.
  • alkylsulfinyl alone or in combination, denotes an alkyl group which is linked via a sulfinyl group.
  • Representative but not limiting examples of alkylsulfinyl are methylsulfinyl, ethylsulfinyl and the like.
  • alkylsulfinylalkyl denotes an alkylsulfinyl group which is linked via an alkyl group.
  • Representative but not limiting examples of alkylsulfinylalkyl are methylsulfinylmethyl, ethylsulfinylmethyl and the like.
  • alkylsulfonyl denotes an alkyl group which is linked via a sulfonyl group.
  • Representative but not limiting examples of alkylsulfonyl are methylsulfonyl, ethylsulfonyl and the like.
  • alkylsulfonylalkyl denotes an alkylsulfonyl group which is linked via an alkyl group.
  • Representative but not limiting examples of alkylsulfonylalkyl are methylsulfonylmethyl, ethylsulfonylmethyl and the like.
  • alkylthio denotes an alkyl group which is linked via a thio group.
  • Representative but not limiting examples of alkylthio are methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl and the like.
  • alkylthioalkyl denotes an alkylthio group linked through an alkyl group.
  • Representative but not limiting examples of alkylthioalkyl are methylsulfanyl-methyl, 2- (ethylsulfanyl) ethyl and the like.
  • amino denotes an -NR e R f group, where R e and R f are independently selected from hydrogen, alkyl, aryl, Arylalkyl, acyl, alkylcarbonyl, arylcarbonyl, carbamoyl, ureido, formyl, alkylsulfonyl, arylsulfonyl and the like.
  • aminoalkyl denotes an amino group which is linked via an alkyl group.
  • Representative but not limiting examples of aminoalkyl are aminomethyl, 2-aminoethyl, N-benzyl-N-methyl-aminomethyl, dimethylamino-methyl and the like.
  • aminocarbonyl denotes an amino group which is linked via a carbonyl group.
  • aminocarbonyl are dimethylaminocarbonyl, benzylaminocarbonyl, ethylaminocarbonyl and the like.
  • aminocarbonylalkyl alone or in
  • Combination refers to an aminocarbonyl group that is linked via an alkyl group.
  • aminocarbonylalkyl are 2-amino-2-oxoethyl, 2- (benzylamino) -2-oxoethyl, 2- (methylamino) -2-oxoethyl, 4-amino-4-oxobutyl, 4- (dimethylamino) -4-oxobutyl and the like
  • aryl denotes an aromatic carbocyclic group containing at least one aromatic ring, for example phenyl or biphenyl, or fused ring systems in which at least one ring is aromatic, for example 1,2,3,4 - tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl and the like.
  • the aryl group can carry one or more substituents which are independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,
  • arylalkenyl denotes an aryl group which is linked via an alkenyl group.
  • Representative but not limiting examples of arylalkenyl are 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2-ylethenyl and the like.
  • arylalkoxy denotes an aryl group which is linked via an alkoxy group.
  • Representative but non-limiting examples of arylalkoxy are 2-phenylethoxy, 5-phenylpentyloxy, 3-naphth-2-ylpropoxy and the like.
  • arylalkyl denotes an aryl group which is linked via an alkyl group.
  • the aryl group can be unsubstituted or substituted.
  • Representative but not limiting examples of arylalkyl are benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl and the like.
  • aryloxy denotes an aryl group that is linked via an oxygen bridge.
  • the aryl group can be unsubstituted or substituted.
  • Representative but not limiting examples of aryloxy are phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 3,4-dimethoxyphenoxy and the like.
  • the aryl group can be unsubstituted or substituted by definition.
  • carbamoyl alone or in combination, denotes a -C (0) NR e R f group.
  • thiocarbamoyl alone or in combination, denotes a -C (S) NR e R f group.
  • carbonyl alone or in combination, denotes a -C (0) group.
  • carboxyalkyl alone or in combination, denotes a carboxy group which is linked via an alkyl group.
  • Representative but not limiting examples of carboxyalkyl are carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and the like.
  • cyano alone or in combination, denotes a -C ⁇ N group.
  • cyanoalkyl alone or in combination, denotes a cyano group which is linked via an alkyl group.
  • Representative but not limiting examples of cyanoalkyl are cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and the like.
  • cycloalkyl alone or in combination, denotes a saturated cyclic
  • Hydrocarbon residue with 3-15 C atoms which can carry one or more substituents.
  • the substituents are selected independently of one another from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, arylyl, arylyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocarbonyl , Arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, ary
  • Cycloheptyl cyclooctyl.
  • one of the fused rings can be aromatic, such as 1-indanyl, 2-indanyl, tetrahydronaphthyl and the like.
  • cycloalkenyl and cycloalkynyl refer to cyclic hydrocarbon radicals which contain at least one carbon-carbon double or triple bond. Like the cycloalkyl radicals, these radicals can carry one or more substituents.
  • formylalkyl denotes a formyl group which is linked via an alkyl group.
  • Representative but not limiting examples of formylalkyl are formylmethyl, 2-formylethyl, and the like.
  • halo or halogen, alone or in combination, denotes fluorine, bromine, chlorine and iodine.
  • haloalkyl alone or in combination, denotes an alkyl group in which at least one
  • Hydrogen atom is replaced by halogen.
  • Representative but not limiting examples of haloalkyl are chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl and the like.
  • haloalkoxy denotes an alkoxy group in which at least one Hydrogen atom is replaced by halogen.
  • Representative but not limiting examples of haloalkoxy are chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy and the like.
  • heterocyclyl denotes a monocyclic, bicyclic or polycyclic ring system with up to 15 ring atoms, containing at least one heteroatom independently selected from nitrogen, oxygen, or sulfur, the ring (s) saturated, partially can be unsaturated or unsaturated or aromatic.
  • heterocyclyl are furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl , Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-
  • Dioxothiomorpholinyl benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl and the like.
  • the heterocylyl radicals may be selected from one another, where alkenyloxy may be one or more, wherein Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,
  • heteroaryl alone or in combination, is a special case of heterocyclyl and denotes a monocyclic, bicyclic or polycyclic ring system, in which the or at least one ring is heteroaromatic.
  • heterocyclylalkenyl denotes a heterocyclyl group which is linked via an alkenyl group.
  • Representative but not limiting examples of heterocyclylalkenyl are 2-pyrid-3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, 5-pyrid-4-ylpentylen-4-yl and the like.
  • heterocyclylalkoxy alone or in
  • Combination denotes a heterocyclyl group which is linked via an alkoxy group.
  • Representative but not limiting examples of heterocyclylalkoxy are 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy and the like.
  • heterocyclylalkyl denotes a heterocyclyl group which is linked via an alkyl group by definition.
  • heterocyclylalkyl 2-pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl and the like.
  • heterocyclyloxy denotes a heterocyclyl group which is linked via an oxygen bridge.
  • Representative but not limiting examples of heterocyclyloxy are pyrid-3-yloxy, quinolin-3-yloxy and the like.
  • hydroxy or "hydroxyl”, alone or in combination, denote an -OH group.
  • hydroxyalkyl alone or in combination, denotes an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group.
  • Representative but not limiting examples of hydroxyalkyl are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl and the like.
  • nitro alone or in combination, denotes a -N0 2 group.
  • oxy alone or in combination, denotes a -0- group.
  • Acid addition salts as pharmaceutically usable salts of acidic compounds of formula I with bases, as pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and as hydrates or solvates thereof.
  • bases as pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and as hydrates or solvates thereof.
  • the acid addition salts are made from the free bases by means of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. preferably hydrochloric acid or hydrobromic acid, or by means of organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, cit
  • Preferred salts with inorganic bases are, but not exclusively, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Preferred salts with organic bases are, but not exclusively, salts with primary, secondary and tertiary, if appropriate substituted amines, including all naturally occurring substituted amines, with cyclic amines and with basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like compounds of the formula I, which contain an acidic group, can also be present as zwitterions.
  • esters of compounds of the formula I containing hydroxyl or carboxy groups are also mentioned at the outset.
  • “Pharmaceutically usable esters” means that corresponding functional groups in compounds of the formula I are derivatized to ester groups in such a way that they are transformed back into their active form in vivo. On the one hand, COOH groups can be esterified.
  • suitable such esters are the alkyl and aralkyl esters. Preferred such esters are the methyl, ethyl, propyl, butyl and benzyl esters and the (R / S) -1- [(isopropoxycarbonyl) oxy] ethyl esters.
  • ethyl esters and the isomeric butyl esters are particularly preferred.
  • OH groups can be esterified.
  • examples of such compounds contain physiologically acceptable and metabolically labile ester groups, such as Methoxymethyl ester, methyl thiomethyl ester, pivaloyloxymethyl ester and similar ester groups.
  • Hamster cells (Chinese Hamster Ovary cells, CHOSP10) suitable for neuropeptide FF receptor binding studies, which each produce the NPFF1 or NPFF2 receptor, were grown under standard cell culture conditions.
  • the binding test was carried out in a final volume of 250 ⁇ l. 100 ⁇ l membrane buffer mix corresponding to 35 ⁇ g
  • Protein contents were mixed with 95 ⁇ l binding buffer (50 mM Tris pH 7.4, 60 mM NaCl, 0.1% protease free BSA, 0.01% NaN 3 ). After adding 5 ⁇ l of a concentration of test substance per measurement point, 0.2 nM 125 I-Tyrl-NPFF (NEN, NEX381) was added per measurement point in 50 ⁇ l. After incubating for 90 minutes at room temperature, the samples were aspirated through a GF / C filter (Millipore (MAHFC1H60)) and the filter was washed with ice-cold binding buffer with 3 times 300 ⁇ l (Packard Filtermate). After adding 55 ⁇ l
  • Microscint 40 (Packard 6013641) scintillation fluid the measuring points were quantified in the gamma counter (Packard, Top Count NXT).
  • Non-specific binding was determined in the presence of 1 ⁇ M unlabeled neuropeptide FF. Specific binding is defined as the difference between total and non-specific binding. IC 50 values are defined as the concentration of the antagonist which displaces 50% of the 12S I-labeled neuropeptide FF. This concentration is determined by linear regression analysis after logit / log transformation of the binding values.
  • Preferred compounds according to the invention show IC 50 values below 1000 nM in the receptor binding study described above, particularly preferred compounds show IC 50
  • the substances defined there are valuable for the treatment of pain, hypersensitivity to pain (hyperalgesia) and chronic, acute, long-lasting or temporary pain, due to their ability to block the neuropeptide FF receptors, these pains being operative, traumatic, or can be of pathological origin. Above all, they complement the common treatment methods for chronic pain with the advantage of preventing undesired opioid tolerance and / or opioid dependence.
  • the compounds can also be used to regulate insulin release, food intake, memory functions, blood pressure and the electrolyte and energy balance and to treat urinary incontinence.
  • the substances defined at the outset can be brought into suitable pharmaceutical dosage forms by methods which are generally known and familiar to any person skilled in the art.
  • dosage forms are, for example, tablets, coated tablets, dragees, capsules, injection solutions, etc.
  • Excipients and auxiliaries suitable for producing such pharmaceutical dosage forms are also generally known and familiar to any person skilled in the art.
  • these dosage forms can also contain further pharmacologically active compounds.
  • the dosage of the substances defined at the outset or of the dosage forms containing them must be adjusted by the attending physician to the respective needs of the patient.
  • a daily dose of 0.1-20 mg, preferably 0.5-5 mg of one of the substances defined at the beginning per kg of body weight of the patient should be appropriate.
  • the guanidine derivatives of the general formula I and the corresponding starting materials and intermediates can be prepared using methods known in organic synthesis and can be isolated and purified using known techniques such as precipitation, chromatography, crystallization, preparative reversed-phase HPLC, etc.
  • Any stereoisomer mixtures obtained, such as racemates, can be separated by generally customary methods, preferably by chromatography on a chiral phase.
  • 2-Imino-4-thiobiuret of the formula 3 is subjected to cyclocondensation, optionally splitting off the protective group attached to the nitrogen atom which may be present from the compound obtained, optionally substituting this nitrogen atom appropriately with an agent which gives off a radical R 'and optionally a basic compound obtained in a pharmaceutically usable acid addition salt, or a compound containing an acid group obtained in a pharmaceutically usable salt with a base, or a compound containing a hydroxyl or carboxy group obtained in one transferred pharmaceutically usable ester and optionally the product obtained is converted into a hydrate or solvate.
  • Guanidine derivatives of the formula I and the corresponding intermediates are carried out in solution using an organic solvent.
  • Protective groups are introduced and removed using typical methods known to those skilled in the art (T.W. Greene & P.G.M. Wuts in
  • cycloalkanones (1) can be halogenated to the carbonyl group in position ⁇ using known methods.
  • the subsequent cyclocondensation of ⁇ -halo-oxo compounds (2) with a thiourea derivative, such as. B. 2-imino-4-thiobiuret (3) takes place in a known manner and leads to the desired guanidine derivatives of the formula I (J. Med. Chem. 1991, 34 (3), 914-918; J. Med. Chem. 1994, 37 (8), 1189-1199).
  • heterocyclic oxo compounds (1) can be used in an analogous manner to the corresponding ones
  • Target compounds of Formula I are implemented. It should be noted here that an -NH group present in A of the starting product (cf. formula 4 below) should be provided with a common protective group (PG), see scheme 2 below:
  • PG common protective group
  • cyclic azaketones of the formula 4 required are known in some cases from the literature (Yokoo et al., Bull. Chem. Soc. Japan 1959, 29, 631; Griss et al., DE 2206385, published February 10, 1972) or can be analogous to the precursor for example N-07 can be manufactured.
  • the R 'radicals defined at the outset are known under known conditions by means of the corresponding R' releasing reagents, such as, for example, alkyl halides, carboxylic acid halides or anhydrides, or also carboxylic acids in the presence of coupling reagents and with base as Auxiliary reagent, chloroformates, sulfonyl halides, Isocyanates, isothiocyanates and the like. Reacted to the corresponding compound of formula III.
  • the corresponding R' releasing reagents such as, for example, alkyl halides, carboxylic acid halides or anhydrides, or also carboxylic acids in the presence of coupling reagents and with base as Auxiliary reagent, chloroformates, sulfonyl halides, Isocyanates, isothiocyanates and the like.
  • Suitable organic solvents are those which are inert under the chosen reaction conditions. These are preferably ethers, such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether; or alcohols, such as, for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; or hydrocarbons, such as benzene, toluene, xylene, hexane,
  • Cyclohexane or petroleum fractions or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene; or also ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoramide, acetonitrile, acetone or nitromethane. Mixtures of the solvents mentioned can also be used.
  • Bases that can be used for the processes described are generally inorganic or organic bases.
  • Alkali metal hydroxides for example sodium or potassium hydroxide
  • alkaline earth metal hydroxides for example barium hydroxide
  • alkali metal carbonates such as sodium carbonate or potassium carbonate
  • alkaline earth metal carbonates such as calcium carbonate, or alkali metal or
  • Alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium ert-butoxide, or organic amines, for example trialkyl -amines, such as triethylamine, or heterocyclic amines, such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine , N-methyl-piperidine or N-methylmorpholine. It is also possible to use alkali metals, such as sodium, or their hydrides, such as sodium hydride.
  • the bases mentioned can, where appropriate, be used as an acid-binding auxiliary.
  • Dehydrating reagents can serve as coupling reagents, for example carbodiimides such as
  • bases such as triethylamine or N-ethyl
  • Example C-01 Analogously to the preparation of Example C-01, the compounds according to Examples C-02 to C-73 in Table 3 are prepared starting from the corresponding ⁇ -bromo or ⁇ -chloro ketones.
  • N-butyllithium is added dropwise to a solution of diisopropylamine (5.5 mmol) in dry tetrahydrofuran which is cooled to 0 ° C. After the addition is complete
  • the title compound is implemented as a crude product without further characterization.
  • the title compound is implemented as a crude product without further characterization.
  • the title compound is implemented as a crude product without further characterization.
  • the title link is implemented as a raw product without further characterization.
  • the title compound is implemented as a crude product without further characterization.
  • 2-ethyl-2-methyl-cyclohexanone precursor for example C-27
  • the alkylation of 2-methylcyclohexanone with ethyl iodide is carried out in an analogous manner to that described above for the preparation of 2, 2-dimethyl-cyclohexanone.
  • Prep LC equipped with a Waters 600 controller, Waters 2767 sample manager, Waters 996 mass spectrometer and photodiode array detector).
  • Example C-31 the compounds of Examples C-32 to C-41 listed in Table 3 are obtained by reacting 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid with the corresponding amines in the presence a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
  • a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
  • Example C-31 Analogously to Example C-31, the compounds of Examples C-43 to C-46 listed in Table 3 are reacted with 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid with the corresponding amines in the presence a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
  • a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
  • the title compound is based on 4-phenyl-spiro [5.5] undecan-1-one instead of spiro [5.5] undecan-1-one in an analogous manner to N- (tetrahydro-benzothiazol-2-yl-4-spiro-cyclohexane ) -guanidine.
  • 4,4-diphenylcyclohexanone (precursor for example C-49) 4,4-diphenylcyclohexanone is prepared in an analogous manner to that described for the preparation of 4,4-dimethylcyclohexanone: t R 3.68 min (LC-1); IT I-
  • 1,4-dioxa-spiro [4.5] dec-7-en-8-yl-trifluoromethanesulfonic acid ester To a solution of lithium bis (trimethylsilyl) amide (IM in tetrahydrofuran, 1.1 mmol) in dry tetrahydrofuran, cooled to -78 ° C., 1,4-dioxa-spiro [4.5] decan-8-one (1 mmol) , dissolved in tetrahydrofuran (2 ml). The mixture is stirred for a further 1.5 hours at -78 ° C.
  • 8- (4-Fluoro-phenyl) -1, -dioxa-spiro [4.5] dec-7-ene is hydrogenated on Pd / C with hydrogen. After filtering off the catalyst through Celite and evaporating the solvent, 8- (4-fluorophenyl) -1, 4-dioxa-spiro [4.5] decane is obtained in quantitative yield: t R 3.65 min (LC-1); IT I-
  • Examples C-55 to C-66 are prepared in an analogous manner to that described above for the preparation of 4- (4-fluorophenyl) cyclohexanone.
  • Trimethyl- (4-phenyl-cyclohex-1-enyloxy) -silane (7.27 mmol) and tert-butyl chloride (7.85 mmol) are placed in dichloromethane under nitrogen and cooled to -45 ° C.
  • the reaction mixture is diluted with dichloromethane and washed with ice water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo.
  • Example N-02 Analogously to Example N-02, the compounds of Examples N-03 to N-10 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2- yl) -guanidine with the corresponding alkyl halides ("R 1 reagents").
  • N-Benzyl-azepan-3-one precursor for example N-07
  • N-benzylglycine ethyl ester (1.87 ml) and 5-bromovaleric acid ethyl ester (1.92 ml) are in Dimethylformamide (100 ml) dissolved and stirred in the presence of potassium carbonate (1.66 g) for 2 days at room temperature.
  • the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After drying over Sodium sulfate, the combined organic phases are evaporated.
  • Example N-II Analogously to Example N-II, the compounds of Examples N-13 to N-33 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2 - yl) -guanidine with the corresponding acid chlorides ("R'-reagents").
  • Example N-12 Analogously to Example N-12, the compounds of Examples N-19 to N-21 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, -c] pyridin-2 -yl ) -guanidine with the corresponding carboxylic acids ("R'-reagents”) in the presence of benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate as coupling reagent.
  • R'-reagents carboxylic acids
  • Example N-22 Analogously to Example N-22, the compound of Example N-23 listed in Table 4 is obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine made with butyl chloroformate ("R 'reagent").
  • Example N-24 Analogously to Example N-24, the compounds of Examples N-25 and N-26 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2 - yl) -guanidine with the corresponding sulfonyl chlorides ("R 1 reagents").
  • Example N-27
  • Dimethylformamide (0.5 ml) is added diisopropylethylamine (0.2 mmol) and after 5 min phenyl isocyanate (0.11 mmol).
  • the reaction mixture is at for 3 hours
  • Example N-27 the compounds of Examples N-28 and N-29 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2- yl) -guanidine dihydrochloride with the "R 1 reagents" tert-butyl isocyanate or pentyl isocyanate.
  • Benzylamine (0.1 mmol), dissolved in dimethylformamide (0.3 ml), is added under argon to a solution of 1'-thiocarbonyldiimidazole (0.1 mmol) in dimethylformamide (0.5 ml).
  • a solution of N- (4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) guanidine dihydrochloride 0.1 mmol
  • diisopropylethylamine (0.2 mmol ) added to the reaction mixture in dimethylformamide. This is stirred for a further 16 hours at room temperature and then quenched with saturated aqueous sodium carbonate solution.
  • Example N-30 Analogously to Example N-30, the compounds of Examples N-31 to N-33 listed in Table 4 are passed through
  • Preparative separations of substance mixtures are carried out on a preparative LC-MS system (Waters Prep LC-MS equipped with a Waters 600 controller, Waters 2767 sample manager, Waters 996 mass spectrometer and photodiode array detector).
  • An Xterra Prep MS C18 column (5 ⁇ m particle size, length 50 mm, diameter 19 mm) with a linear gradient of water / 0.06% formic acid (A) and acetonitrile / 0.06% formic acid (B) and a flow rate of 20 is used ml / min.
  • the ⁇ NMR spectra are on a Varian Oxford 300
  • Shift ⁇ is shifted in ppm downfield from the signal from tetramethylsilane as a reference, the residual signals from deuterated serve as internal standard
  • the compounds produced are analyzed by means of reversed-phase HPLC on a Waters Alliance
  • LC-1 GROM-SIL 120 ODS-4 HE HPLC column (particle size 3 ⁇ m, column length 30mm, diameter 2mm), with a linear gradient with water / 0.06% formic acid (A) and acetonitrile / 0.06% formic acid (B) from 5% to 95% B in 3 min. with a flow rate of 0.75 ml / min.
  • LC-2 XTerra MS C18 HPLC column (particle size 5 ⁇ m, column length 50 mm, diameter 2.1 mm), with a linear gradient with water / 0.06% formic acid (A) and
  • Acetonitrile / 0.06% formic acid (B) from 5% to 95% B in 2.5 min. with a flow rate of 0.75 ml / min.
  • Example structure name 9 ** . "Molecular (HPLC r Product weight Meth.) [M + H] [MH] -
  • N-02 TCO " - NH tetrahydro-thiazolo [5.4-1 bromohexane 282.18 / 280.33 281.4 (LC-1) vc] pyridin-2-yl) guanidine
  • N-31 isopropy amine _ no . .. _ .. 298.86 / 296.29 vv * 298.4 (LC-1)

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Abstract

The invention relates to guanidine derivatives of formula (I) where: A = a chain of 3-c6 carbon atoms, one of which can be replaced by -N(R')- or -O- and R' = H or a substituent, where the ring skeleton only contains both double bonds of the thiazole component, the pharmaceutically-acceptable acid addition salts of basic compounds of formula (I), the pharmaceutically-acceptable salts of compounds of formula (I),, comprising acid groups, with bases, the pharmaceutically-acceptable esters of hydroxy or carboxyl group containing compounds of formula (I) and the solvates or hydrates thereof, which are partly known and partly novel and exhibit a neuropeptide FF receptor antagonist effect. The above are suitable for the treatment of pain and hyperalgesia, withdrawal symptoms in alcohol, psychotropic and nicotine dependencies, for improvement or cure of said dependencies, for regulation of insulin excretion, food intake, memory functions, blood pressure, electrolyte and energy management and for treatment of urinary incontinence. The above can be produced using generally used methods and processed to give medicaments.

Description

GUANIDINDERIVATE UND IHRE VERWENDUNG ALS NEUROPEPTID FF REZEPTOR-ANTAGONISTENGUANID DERIVATIVES AND THEIR USE AS NEUROPEPTID FF RECEPTOR ANTAGONISTS
Die vorliegende Erfindung betrifft Guanidinderivate der allgemeinen FormelThe present invention relates to guanidine derivatives of the general formula
worinwherein
A eine Kette von 3-6 gegebenenfalls substituierten C-A is a chain of 3-6 optionally substituted C-
Atomen bedeutet, wovon eines durch -N(R')- oder -0- ersetzt sein kann; undAtoms means one of which can be replaced by -N (R ') - or -0-; and
R' Wasserstoff oder einen Substituenten bedeutet; wobei das Ringgerüst nur die beiden Doppelbindungen desR 'represents hydrogen or a substituent; the ring structure only the two double bonds of
T iazolbausteins enthält; pharmazeutisch verwendbare Säureadditionssalze von basischen Verbindungen der Formel I, pharmazeutisch verwendbare Salze von saure Gruppen enthaltendenContains T iazole component; pharmaceutically acceptable acid addition salts of basic compounds of formula I, pharmaceutically acceptable salts of acidic groups
Verbindungen der Formel I mit Basen, pharmazeutisch verwendbare Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I sowie Hydrate oderCompounds of the formula I with bases, pharmaceutically usable esters of hydroxyl or carboxy-containing compounds of the formula I and hydrates or
Solvate davon.Solvate of it.
Guanidinderivate der Formel I, welche eines oder mehrere Asymmetriezentren enthalten, können als optisch reine Enantiomere, als Mischungen von Enantiomeren, wie zum Beispiel Racemate, oder gegebenenfalls als optisch reine Diastereomere, als Mischungen von Diastereomeren, als diastereomere Racemate oder als Mischungen von diastereomeren Racematen vorliegen.Guanidine derivatives of the formula I which contain one or more centers of asymmetry can be used as optically pure enantiomers, as mixtures of enantiomers, for example racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers diastereomeric racemates or as mixtures of diastereomeric racemates.
Die eingangs definierten Produkte sind teilweise bekannt und teilweise neu, und sie zeichnen sich durch wertvolle pharmakodynamische Eigenschaften aus, indem sie als Neuropeptid FF Rezeptor-Antagonisten wirken.The products defined at the beginning are partly known and partly new, and they have valuable pharmacodynamic properties in that they act as neuropeptide FF receptor antagonists.
In einem ersten Aspekt betrifft die vorliegende Erfindung die Verwendung der eingangs definierten Verbindungen der Formel I sowie der eingangs ebenfalls definierten Salze, Ester, Hydrate und Solvate als Neuropeptid FF Rezeptor- Antagonsiten bzw. zur Herstellung entsprechender Arzneimittel, insbesondere zur Behandlung von Schmerz und Hyperalgesie, von Entzugserscheinungen bei Alkohol-, Psychopharmaka- und Nicotinabhangigkeit und zur Verbesserung oder Aufhebung dieser Abhängigkeiten, zur Regulierung der Insulin-Freisetzung, der Nahrungsauf ahme, von Gedächtnisfunktionen, des Blutdrucks, und des Elektrolyt- und Energiehaushaltes und zur Behandlung der Harninkontinenz bzw. zur Herstellung entsprechender Arzneimittel .In a first aspect, the present invention relates to the use of the compounds of the formula I defined at the outset and the salts, esters, hydrates and solvates likewise defined at the outset as neuropeptide FF receptor antagonists or for the preparation of corresponding medicaments, in particular for the treatment of pain and hyperalgesia, withdrawal symptoms of alcohol, psychopharmaceutical and nicotine dependency and to improve or eliminate these dependencies, to regulate insulin release, food intake, memory functions, blood pressure, and the electrolyte and energy balance, and to treat urinary incontinence or to manufacture it appropriate drug.
Die erfindungsgemäss zu behandelnden Schmerzen können chronisch, akut, lang andauernd oder vorübergehend sein, wobei diese Schmerzen operativen, traumatischen, oder pathologischen Ursprungs sein können; ein erfindungsgemäss erzielter Vorteil besteht in der Verhinderung von Opioidtoleranz und/oder Opioidabhängigkeit .The pain to be treated according to the invention can be chronic, acute, long-lasting or transient, and this pain can be of operative, traumatic or pathological origin; an advantage achieved according to the invention is the prevention of opioid tolerance and / or opioid dependence.
Bereits 1985 wurden Neuropeptid FF (NPFF; H-Phe-Leu-Phe- Gln-Pro-Gln-Arg-Phe-NH2 [99566-27-5] ) , ein Oktapeptid, und Neuropeptid AF (NPAF; H-Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro- Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH2 [99588-52-0] ) , ein verwandtes Oktadekapeptid, als Neurotransmittoren des zentralen Nervensystems in Rinderhirn entdeckt (Yang et al., Proc. Natl. Acad. Sei. USA 1985, 82(22), 7757-61) und ursprünglich als anti-opioide Peptide charakterisiert. Die carboxyterminal amidierten Neuropeptide wurden aufgrund ihrer Reaktivität mit anti-Phe-Met-Arg-Phe-NH2 Antiserum den FMRFamid-ähnlichen Peptiden zugeordnet. Beide Peptide zeigen schmerzmodulierende Eigenschaften, wobei das Oktapeptid eine höhere Wirksamkeit besitzt. Beide Peptide spielen sowohl bei der opioid-abhängigen Analgesie als auch der Entwicklung von Toleranz gegenüber Opioiden eine wichtige Rolle (Übersichtsartikel : Roumy and Zajac, Europ . J. Pharm. 1998, 345, 1-11; Panula et al . , Prog. Neurobiol . 1996, 48, 461-87) . Interessanterweise zeigt NPFF inNeuropeptide FF (NPFF; H-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH 2 [99566-27-5]), an octapeptide, and neuropeptide AF (NPAF; H-Ala- Gly-Glu-Gly-Leu-Ser-Ser-Pro Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH 2 [99588-52-0]), a related octadecapeptide, as Neurotransmitters of the central nervous system discovered in bovine brain (Yang et al., Proc. Natl. Acad. Sei. USA 1985, 82 (22), 7757-61) and originally characterized as anti-opioid peptides. The Due to their reactivity with anti-Phe-Met-Arg-Phe-NH 2 antiserum, carboxy-terminally amidated neuropeptides were assigned to the FMRFamide-like peptides. Both peptides show pain-modulating properties, the octapeptide being more effective. Both peptides play an important role both in opioid-dependent analgesia and the development of tolerance to opioids (review article: Roumy and Zajac, Europ. J. Pharm. 1998, 345, 1-11; Panula et al., Prog. Neurobiol 1996, 48, 461-87). Interestingly, NPFF shows in
Tierversuchen, abhängig von der Art der Verabreichung, sowohl anti-opioide als auch pro-opioide Wirkungen. So kann NPFF die akuten Effekte von Opioiden umkehren und eine gesteigerte Konzentration im Hirn ist möglicherweise verantwortlich für die Entwicklung von Opioid-Toleranz und Abhängigkeit. In Ratten, beispielsweise, erniedrigt die intracerebroventriculare (i.c.v.) Verabreichung von NPFF die nociceptive Schwelle und schwächt die durch Morphin induzierte Analgesie ab. Verabreichen von NPFF an morphin- tolerante Ratten verursacht Symptome vonAnimal testing, depending on the mode of administration, has both anti-opioid and pro-opioid effects. In this way, NPFF can reverse the acute effects of opioids and an increased concentration in the brain may be responsible for the development of opioid tolerance and addiction. In rats, for example, intracerebroventricular (i.c.v.) administration of NPFF lowers the nociceptive threshold and weakens morphine-induced analgesia. Administration of NPFF to morphine-tolerant rats causes symptoms of
Entzugserscheinungen. Der analgetische Effekt von Morphin in morphin-toleranten Ratten wurde nach i.c.v. Injektion von anti-NPFF IgG wieder hergestellt (Lake et al . , Neurosci. Lett . 1991, 132, 29-32). Immunoneutralisieren von NPFF durch intrathecal (i.t.) verabreichte anti-NPFFWithdrawal symptoms. The analgesic effect of morphine in morphine-tolerant rats was determined according to i.c.v. Injection of anti-NPFF IgG restored (Lake et al., Neurosci. Lett. 1991, 132, 29-32). Immunoneutralizing NPFF by intrathecal (i.t.) administered anti-NPFF
Antikörper erhöhen die durch endogene und exogene Opioide hervorgerufene Analgesie. Durch direkte Injektion von NPFF oder NPFF-Analoga ins Rückenmark (i.t.) wurde ein pro- opioder Effekt mit einer lang andauernden opioid-ähnlichen Analgesie und verstärkter schmerzlindernder Wirkung von Morphin erhalten (Gouarderes et al . , Eur. J. Pharmacol . 1993, 237, 73-81; Kontinen and Kalso, Peptides 1995, 16, 973-977) .Antibodies increase analgesia caused by endogenous and exogenous opioids. By direct injection of NPFF or NPFF analogs into the spinal cord (it), a prophylactic effect with long-lasting opioid-like analgesia and increased pain-relieving effects of morphine was obtained (Gouarderes et al., Eur. J. Pharmacol. 1993, 237 , 73-81; Kontinen and Kalso, Peptides 1995, 16, 973-977).
Weiteren Berichten zufolge scheint NPFF auch in physiologischen Vorgängen wie Insulin-Freisetzung, Regulierung der Nahrungsaufnahme, Gedächtnisfunktionen, Blutdruckregulierung und Elektrolythaushalt eine Rolle zu spielen (Panula et. al . , Prog. Neurobiol . 1996, 48, 461- 487) .According to further reports, NPFF also appears to play a role in physiological processes such as insulin release, regulation of food intake, memory functions, blood pressure regulation and electrolyte balance play (Panula et. al., Prog. Neurobiol. 1996, 48, 461-487).
In verschiedenen Säugerarten, wie Mensch, Ratte, Maus und Rind, wurde über die Entdeckung eines Genes berichtet, welches als gemeinsames Vorläuferprotein NPFF und NPAF kodiert, von dem die beiden aktiven Peptide schliesslich abgespalten werden (Perry et al . , FEBS Lett . 1997, 409, 426-30; Vilim et al . , Mol. Pharmacol . 1999, 55, 804-11). Im Menschen wird das Gen für diesen Vorläufer sowohl peripher in verschiedenen Organen als auch in Regionen des zentralen Nervensystems, vor allem im Cerebellum exprimiert (Elshourbagy et al . , J. Biol . Chem. 2000, 275 (34), 25965- 71) , währendem sich die Expression in Ratten ausschliesslich auf bestimmte Regionen des zentralenIn various mammals, such as humans, rats, mice and cattle, the discovery of a gene which encodes as a common precursor protein NPFF and NPAF, from which the two active peptides are ultimately cleaved, has been reported (Perry et al., FEBS Lett. 1997, 409, 426-30; Vilim et al., Mol. Pharmacol. 1999, 55, 804-11). In humans, the gene for this precursor is expressed both peripherally in various organs and in regions of the central nervous system, especially in the cerebellum (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71), whereas expression in rats is restricted to certain regions of the central
Nervensystems wie Hypothalamus, Medulla, und dorsalem Hörn des Rückenmarks beschränkt . Aufgrund des Nachweises von NPFF in menschlichem Blutplasma wird vermutet, dass die Peptide peripher zusätzlich für hormonähnliche Wirkungen verantwortlich sind (Sundblom et al . , Peptides 1998, 19, 1165-70) .Nervous system such as the hypothalamus, medulla, and dorsal hearing of the spinal cord are restricted. Based on the detection of NPFF in human blood plasma, it is assumed that the peptides are additionally responsible for hormone-like effects peripherally (Sundblom et al., Peptides 1998, 19, 1165-70).
In Gewebsproben von Mensch und Ratte wurden zwei G-Protein gekoppelte Rezeptoren (GPCR) , NPFFl und NPFF2 identifiziert (Bonini et al . , J. Biol. Chem. 2000, 275 (50), 39324-31;In human and rat tissue samples, two G-protein coupled receptors (GPCR), NPFFl and NPFF2 were identified (Bonini et al., J. Biol. Chem. 2000, 275 (50), 39324-31;
Kotani et al . , Br. J. Pharmacol. 2001, 133, 138-44), wobei NPFF2 identisch ist zum ursprünglich als orphan beschriebenen Rezeptor HLWAR77 (Elshourbagy et al . , J. Biol. Chem. 2000, 275 (34), 25965-71). NPFFl und NPFF2 konnten als spezifische Rezeptoren mit Affinitäten im nanomolaren und subnanomolaren Bereich für die beiden Neuropeptide FF und AF charakterisiert werden. NPFF bindet an NPFFl mit einer Bindungskonstante Kd = 1.13 nM und an NPFF2 mit Kd = 0.37 nM. Die Identität von NPFFl und NPFF2 liegt bei ca. 50%. Der Vergleich der Aminosäuresequenzen mit bekannten GPCRs zeigt eine 30-40%-ige Ähnlichkeit mit humanem Orexin-1, Orexin-2, Neuropeptid Y (NPY) Y2 , Cholecystokinin A, NPY Yl, Prolactin-releasing Hormone Rezeptor und NPY Y4. Die Verbreitung von NPFFl und NPFF2 in verschiedenen Gewebsproben von Mensch und Ratte wurde durch Nachweis der m-RNA mittels RT-PCR (reverse transcription- polynaerase chain reaction) bestimmt. NPFFl wurde dabei vorwiegend im Zentralen Nervensystem (ZNS) nachgewiesen. Im Gegensatz dazu, wurde NPFF2 vorwiegend im Rückenmark gefunden. Diese Befunde werden durch autoradiografische Methoden unter Verwendung von selektiven NPFFl und NPFF2 Radioliganden gestützt (Allard et al . , Brain Res . 1989, 500, 169-176; Neuroscience 1992, 49, 106-116; Gouarderes et al., Neuroscience 2002 115:2 349-61).Kotani et al. , Br. J. Pharmacol. 2001, 133, 138-44), where NPFF2 is identical to the receptor HLWAR77 originally described as orphan (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71). NPFFl and NPFF2 could be characterized as specific receptors with affinities in the nanomolar and subnanomolar range for the two neuropeptides FF and AF. NPFF binds to NPFFl with a binding constant Kd = 1.13 nM and to NPFF2 with Kd = 0.37 nM. The identity of NPFFl and NPFF2 is approximately 50%. The comparison of the amino acid sequences with known GPCRs shows a 30-40% similarity to human orexin-1, orexin-2, neuropeptide Y (NPY) Y2, cholecystokinin A, NPY Yl, prolactin-releasing hormones Receptor and NPY Y4. The spread of NPFFl and NPFF2 in different tissue samples from humans and rats was determined by detecting the m-RNA by means of RT-PCR (reverse transcription-polynaerase chain reaction). NPFFl was mainly detected in the central nervous system (CNS). In contrast, NPFF2 was found primarily in the spinal cord. These findings are supported by autoradiographic methods using selective NPFFl and NPFF2 radioligands (Allard et al., Brain Res. 1989, 500, 169-176; Neuroscience 1992, 49, 106-116; Gouarderes et al., Neuroscience 2002 115: 2 349-61).
Die als NPFF-verwandte Peptide beschriebenen Neuropeptide SF (NPSF, 37 Aminosäuren) und Neueropeptid VF (NPVF, Oktapeptid) , beide lokalisiert auf dem sogenannten NPVF- Gen, binden vergleichsweise mit höherer Affinität und Selektivität an den NPFFl Rezeptor als NPFF und NPAV. Die NPVF-Peptide blockieren ebenfalls die morphin-induzierte Analgesie in akuten und inflammatorischen Schmerzmodellen ausgeprägter als NPFF und unterstreichen die Wichtigkeit des NPVF/FF1 Systems als Teil eines endogenen anti-opioiden Mechanismus (Q. Liu et al . , J. Biol. Chem. 2002,276 (40), 36961) .The neuropeptides SF (NPSF, 37 amino acids) and new opeptide VF (NPVF, octapeptide) described as NPFF-related peptides, both localized on the so-called NPVF gene, bind to the NPFF1 receptor comparatively with higher affinity and selectivity than NPFF and NPAV. The NPVF peptides also block morphine-induced analgesia in acute and inflammatory pain models to a greater extent than NPFF and underline the importance of the NPVF / FF1 system as part of an endogenous anti-opioid mechanism (Q. Liu et al., J. Biol. Chem. 2002, 276 (40), 36961).
Das Vorkommen von funktionalen NPFFl und NPFF2 Rezeptoren in Adipocyten und die Wirkung von NPFF und NPAF auf Schlüsselstellen der Signalübertragung im adiposen Metabolismus deuten darauf hin, dass die beiden Peptide neben ihren ursprünglichen Schmerz modulierenden Effekten, zusätzlich einen Einfluss auf Speicherung und Verwendung von Kδrperenergie haben könnten (I. Lefrere et al . , J. Biol. Chem. 2002, 277 (42), 39169).The presence of functional NPFFl and NPFF2 receptors in adipocytes and the effect of NPFF and NPAF on key points of signal transmission in adipose metabolism indicate that the two peptides, in addition to their original pain-modulating effects, could also have an influence on the storage and use of body energy (I. Lefrere et al., J. Biol. Chem. 2002, 277 (42), 39169).
Das DesaminoTyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH2 Peptid wurde als erster, den NPFF Effekten entgegenwirkender NPFF- Rezeptor-Antagonist beschrieben. Nach i.c.v. Injektion hat dieses Peptid die Entzugserscheinungen bei Morphinabhängigkeit abgeschwächt (Malin et al . , Peptides 1991, 12, 1011-1014). Dieses Peptid zeigte jedoch keinerlei Bioverfügbarkeit im zentralen Nervensystem. Optimierung des Tripeptides Pro-Gln-Arg-NH2 in einem kombinatorischen Ansatz führte zu Dansyl-Pro-Gln-Arg-NH2, beziehungsweise Dansyl-Pro-Ser-Arg-NH2, beide mit verbessertenThe DesaminoTyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH 2 peptide has been described as the first NPFF receptor antagonist to counteract the NPFF effects. After icv injection, this peptide attenuated the withdrawal symptoms in the case of morphine dependence (Malin et al., Peptides 1991, 12, 1011-1014). However, this peptide showed no bioavailability in the central nervous system. Optimization of the tripeptide Pro-Gln-Arg-NH 2 in a combinatorial approach led to Dansyl-Pro-Gln-Arg-NH 2 , or Dansyl-Pro-Ser-Arg-NH 2 , both with improved
Eigenschaften, die Blut-Hirn-Schranke zu passieren, was nach systemischer Verabreichung in Ratten zu verbesserter antagonistischer Wirkung der von NPFF verursachten anti- opioiden Symptome führte (Prokai et al . J. Med. Chem. 2001, 44, 1623-1626) .Properties that cross the blood-brain barrier, which after systemic administration in rats led to improved antagonistic effect of the anti-opioid symptoms caused by NPFF (Prokai et al. J. Med. Chem. 2001, 44, 1623-1626).
Das ursprünglich als NPY Yl selektiver Rezeptor Antagonist beschriebene Arg-Tyr-amide Peptoid BIBP3226 zeigte eine 10- 60 -mal höhere Affinität zum humanen- und ratten-NPFFl Rezeptor als zu den entsprechenden NPFF2 Rezeptoren (Bonini et al., J. Biol. Chem. 2000, 275 (50), 39324-31). Aus einer Serie von Verbindungen, welche vom NPY Yl selektiven Antagonisten BIP3226 abstammen, wurden selektive hNPFFl Rezeptor Antagonisten erhalten, die Affinitäten von 40-80 nM zeigten (Mollereau et al . , Europ. J. Pharmacol. 2002, 45, 245-56) .The Arg-Tyr-amide peptoid BIBP3226, originally described as an NPY Yl selective receptor antagonist, showed an affinity for the human and rat NPFF1 receptor 10-60 times higher than for the corresponding NPFF2 receptors (Bonini et al., J. Biol. Chem 2000, 275 (50), 39324-31). From a series of compounds derived from the NPY Yl selective antagonist BIP3226, selective hNPFFl receptor antagonists were obtained which showed affinities of 40-80 nM (Mollereau et al., Europ. J. Pharmacol. 2002, 45, 245-56) ,
Die beiden Neuropeptid FF Analoga 1DME ( [D-The two neuropeptide FF analogues 1DME ([D-
Tyr1, (Nme) Phe3]NPFF) und Nic-IDME (Nicotinoyl-Pro-lDme) zeigten unterschiedliche pharmakologische Eigenschaften im Mouse Tail-flick Test, obwohl beide Verbindungen mit vergleichbarer Affinität und Selektivät an NPFFl und NPFF2 binden. Sowohl 1DME als auch Nic-IDME verstärken nach i.t. und i.p. Gabe die Morphin Analgesie, Nic-IDME aber kann die Morphin induzierte Analgesie nach i.c.v. und i.p.Tyr 1 , (Nme) Phe 3 ] NPFF) and Nic-IDME (Nicotinoyl-Pro-IDme) showed different pharmacological properties in the mouse tail-flick test, although both compounds bind to NPFFl and NPFF2 with comparable affinity and selectivity. Both 1DME and Nic-IDME increase morphine analgesia after it and ip administration, but Nic-IDME can increase morphine-induced analgesia after icv and ip
Verabreichung nicht unterdrücken (Quelven et al., Europ. J. Pharmacol. 2002, 449, 91-98) .Do not suppress administration (Quelven et al., Europ. J. Pharmacol. 2002, 449, 91-98).
In WO 02/24192 AI werden synthetische NPFF Liganden peptidischer Struktur, basierend auf Arginin als zentralem Baustein, beschrieben. Die eingangs definierten Produkte sind potente und spezifische, niedermolekulare Antagonisten von Neuropeptid FFl-Rezeptoren mit nicht-peptidischen oder nicht-peptoiden Strukturen.WO 02/24192 AI describes synthetic NPFF ligands of peptide structure, based on arginine as the central building block. The products defined at the outset are potent and specific, low-molecular antagonists of neuropeptide FFl receptors with non-peptide or non-peptoid structures.
Die gängigen Behandlungsmöglichkeiten von chronischem Schmerz basieren auf NSAIDs (non-steroidal anti- inflammatory drugs) , Canabinoiden und Opioiden. So binden zum Beispiel Morphinderivate an den μ-opioiden Rezeptor und wirken dadurch schmerzlindernd. Opioidbindung an den μ- opioiden Rezeptor geht einher mit der Freisetzung von Neuropeptid FF. Basierend auf den oben aufgeführten Tierexperimenten wird vermutet, dass das freigesetzte NPFF den analgetischen Effekt der verabreichten Opioide abschwächt und zu Toleranz gegenüber Opioiden führt . Um bei längeren Behandlungen einen gleichbleibenden schmerzlindernden Effekt zu erhalten, müssen infolge dieser Toleranz zunehmend höhere Opioid-Dosen verabreicht werden, was schliesslich zu ernsthaften Nebenwirkungen führen kann. Wie eingangs schon erwähnt, sind bis heute zwei Neuropeptid FF Rezeptoren bekannt, wobei der NPFFl-Rezeptor hauptsächlich im zentralen Nervensystem und der NPFF2- Rezeptor vornehmlich im Rückenmark lokalisiert ist. Aktivieren der NPFF2-Rezeptoren zeigt eine opioid-ähnliche analgetische Wirkung. Blockieren der NPPFl Rezeptoren durch einen Antagonisten verhindert die Entwicklung von Toleranz gegenüber Opioiden und erhöht zusätzlich deren Wirkung.The common treatment options for chronic pain are based on NSAIDs (non-steroidal anti-inflammatory drugs), canabinoids and opioids. For example, morphine derivatives bind to the μ-opioid receptor and have an analgesic effect. Opioid binding to the μ-opioid receptor is accompanied by the release of neuropeptide FF. Based on the animal experiments listed above, it is assumed that the released NPFF weakens the analgesic effect of the administered opioids and leads to tolerance towards opioids. In order to obtain a constant pain-relieving effect during longer treatments, increasingly higher opioid doses have to be administered as a result of this tolerance, which can ultimately lead to serious side effects. As already mentioned at the beginning, two neuropeptide FF receptors are known to date, the NPFF1 receptor being mainly located in the central nervous system and the NPFF2 receptor predominantly in the spinal cord. Activation of the NPFF2 receptors shows an opioid-like analgesic effect. Blocking the NPPFl receptors by an antagonist prevents the development of tolerance to opioids and additionally increases their effect.
Wie eingangs erwähnt, sind die dort definierten Produkte teilweise bekannt und teilweise neu, und sie zeichnen sich durch die wertvolle pharmakologische Eigenschaft aus, die Interaktion von Neuropeptid FF mit dem Neuropeptid FF1- Rezeptor-Subtyp zu blockieren.As mentioned at the beginning, the products defined there are partly known and partly new, and are distinguished by the valuable pharmacological property of blocking the interaction of neuropeptide FF with the neuropeptide FF1 receptor subtype.
Wenn eines oder mehrere der C-Atome in der Kette A in Formel I substituiert ist/sind, dann kann eines der C-Atome einen oder zwei (also geminale) gleiche oder verschiedene Substituenten tragen; oder es können mehrere der C-Atome je einen oder zwei (also geminale) gleiche oder verschiedene Substituenten tragen.If one or more of the C atoms in chain A is / are substituted in formula I, then can one of the carbon atoms has one or two (geminal) identical or different substituents; or several of the carbon atoms can each carry one or two (geminal) identical or different substituents.
In Formel I kann A zusammen mit dem Thiazolring ein Cyclopentathiazol- , Benzothiazol- , Cycloheptathiazol- , Pyranothiazol- , Thiazolopyridin- , Thiazoloazepin- oder Thiazolooxepangerüst bilden, welches nur die beiden Doppelbindungen des Thiazolbausteins enthält, wie zum Beispiel ein 4 , 5, 6 , 7-Tetrahydrobenzothiazol- , 5,6,7,8- Tetrahydro-4H-cycloheptathiazol- , 5, 6-Dihydro-4H- cyclopentathiazol- , 6 , 7-Dihydro-4H-pyrano [4 , 3-d] thiazol- , oder 5 , 6 , 7, 8-Tetrahydro-4H-thiazolo [4 , 5-c] azepingerüst .In formula I, A together with the thiazole ring can form a cyclopentathiazole, benzothiazole, cycloheptathiazole, pyranothiazole, thiazolopyridine, thiazoloazepine or thiazolooxane skeleton which contains only the two double bonds of the thiazole building block, such as a 4, 5, 6, 7-tetrahydrobenzothiazole-, 5,6,7,8-tetrahydro-4H-cycloheptathiazole-, 5, 6-dihydro-4H-cyclopentathiazole-, 6, 7-dihydro-4H-pyrano [4, 3-d] thiazole-, or 5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-c] azepine backbone.
Eine Untergruppe der Verbindungen der Formel I kann durch die allgemeine FormelA subset of the compounds of formula I can be represented by the general formula
II wiedergegeben werden, worin Wasserstoff, Alkyl,II are reproduced in which Hydrogen, alkyl,
Alkanoyl, Alkenyl, Alkoxy, Alkoxyalkyl, Alkoxyalkanoyl , Alkoxyalkylcarbamoyl , Alkoxyalkylthiocarbamoyl , Alkoxycarbonyl , Alkoxycarbonylalkyl , Alkoxycarbonyl- alkanoyl, Alkylamido, Alkylaminocarbonyl, Alkylarylamino, Alkylcarbamoyl, Alkyl-thiocarbamoyl, Alkylcarbonyl,Alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkanoyl, alkoxyalkylcarbamoyl, alkoxyalkylthiocarbamoyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkanoyl, alkylamido, alkylaminocarbonyl, alkylarylamino, alkylcarbamoyl, alkylthiocarbamoyl, alkylcarbonyl
Alkylcarbonyloxy, Alkylendioxy, Alkylsulfinyl, Alkyl- sulfinylalkyl, Alkylsulfonyl, Alkylsulfonylalkyl, Alkylthio, Alkylsulfonamido, Alkylthioalkyl , Alkynyl, Amino, Aminoalkyl, Aminoalkanoyl , Aminoacyl, Alkylamino," Alkylaminoalkyl , Alkylaminoalkanoyl, Aminocarbonyl , Aminocarbonylalkyl, Aminocarbonylalkanoyl, Alkylaminocarbonylamino, Alkoxycarbonylamino, Aryl, Arylalkenyl, Arylalkyloxy, Arylalkyl, Arylalkylamido, Arylalkanoyl, Arylamido, Arylamino, Aryl-aminocarbonyl, Arylcarbamoyl, Arylthiocarbamoyl, Aryloxy, Aryloxyalkyl, Aryloxy-alkanoyl, Aryloxyalkylamino, Aryloxyalkylcarbamoyl, Aryloxyalkylthiocarbamoyl, Aryloxycarbonyl , Aryloxycarbonylalkyl, Aryloxycarbonylalkanoyl, Aryloxycarbonylalkylamino, Aryloxycarbonylalkylcarbamoyl, Aryloxycarbonylalkylthiocarbamoyl, Arylsulfinyl , Arylsulfinylalkyl, Arylsulfonyl, Arylsulfonylalkyl, Arylsulfonylalkanoyl, Arylsulfonamido, Arylthio, Arylthioalkyl, Arylthioalkanoyl, Carboxy, Carboxyl, Carboxyalkyl, Carboxyalkylamido, Cyano, Cyanoalkyl, Cyanoalkylamido, Cyanoalkanoyl, Cycloalkyl, Cycloalkylamido, Cycloalkanoyl, Cycloalkylamino, Cycloalkylaminocarbonyl, Cycloalkyloxycarbonyl , Cycloalkyloxycarbonylalkyl, Cycloalkyloxy- carbonylalkylamido, Cycloalkyloxycarbonylalkanoyl, Dialkylaminocarbonyl, Dialkylaminoalkyl,Alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylsulfonamido, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminoalkanoyl, aminoacyl, alkylamino, " alkylaminoalkyl, alkylaminoalkanoyyl, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonocylylamino, aminocarbonyloxyamino, aminocarbonylylamino, aminocarbonocylylamino, amine , Arylalkyloxy, arylalkyl, arylalkylamido, arylalkanoyl, arylamido, arylamino, arylaminocarbonyl, Arylcarbamoyl, arylthiocarbamoyl, aryloxy, aryloxyalkyl, aryloxy-alkanoyl Aryloxyalkylamino, Aryloxyalkylcarbamoyl, Aryloxyalkylthiocarbamoyl, aryloxycarbonyl, aryloxycarbonylalkyl, Aryloxycarbonylalkanoyl, Aryloxycarbonylalkylamino, Aryloxycarbonylalkylcarbamoyl, Aryloxycarbonylalkylthiocarbamoyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, Arylsulfonylalkanoyl, arylsulfonamido, arylthio, arylthioalkyl, Arylthioalkanoyl, carboxy, Carboxyl, carboxyalkyl, carboxyalkylamido, cyano, cyanoalkyl, cyanoalkylamido, cyanoalkanoyl, cycloalkyl, cycloalkylamido, cycloalkanoyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkyloxycarbonyl, cycloalkyloxycarbonylalkyl, cycloalkyloxycarbonylalkylamido, cycloalkyloxyylylylamino, cycloalkyloxyylylamino, cycloalkyloxyylylylamino, cycloalkyloxycarbonylalkyl,
Dialkylaminoalkylamido, Dialkylaminoalkanoyl, Diarylamino, Formyl, Formylalkyl, Halogen, Haloalkoxy, Haloalkyl, Haloalkylamido, Haloalkanoyl, Halo-alkylamino, Heteroarylamino, Heteroarylamido, Heterocyclylalkylamido, Heteroarylaminocarbonyl, Heteroaryloxycarbonylalkyl, Heteroaryloxycarbonylalkylamido, Hetero- aryloxycarbonylalkanoyl, Heterocyclyl, Heterocyclylamino, Heterocyclylamido, Heterocyclylalkyl, Heterocyclylalkanoyl, Heterocyclylalkylamino, Heterocyclylalkylamido,Dialkylaminoalkylamido, Dialkylaminoalkanoyl, diarylamino, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, Haloalkylamido, haloalkanoyl, halo-alkylamino, heteroarylamino, Heteroarylamido, Heterocyclylalkylamido, heteroarylaminocarbonyl, Heteroaryloxycarbonylalkyl, Heteroaryloxycarbonylalkylamido, hetero- aryloxycarbonylalkanoyl, heterocyclyl, heterocyclylamino, Heterocyclylamido, heterocyclylalkyl, heterocyclylalkanoyl, Heterocyclylalkylamino, heterocyclylalkylamido,
Heteroarylalkyl, Heteroarylalkanoyl , Heteroarylalkylamino, Heteroarylalkylamido, Heteroyclylalkylaminocarbonyl , Heterocyclylalkoxycarbonylalkyl, Heterocyclylalkoxy- carbonylalkanoyl, Heterocyclylalkoxycarbonylalkylamino, Heterocyclylalkoxycarbonylalkylamido, Hydroxy,Heteroarylalkyl, heteroarylalkanoyl, heteroarylalkylamino, heteroarylalkylamido, heteroyclylalkylaminocarbonyl, heterocyclylalkoxycarbonylalkyl, heterocyclylalkoxycarbonylalkanoyl, heterocyclylalkoxycarbonylalkylamino, heterocyclylalkoxy
Hydroxyalkyl, Hydroxyalkanoyl, Mercapto oder Nitro bedeuten.Hydroxyalkyl, hydroxyalkanoyl, mercapto or nitro mean.
Bevorzugte Bedeutungsmöglichkeiten für Rx sind dabei Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, tert-Butyl, 1, 1-Dimethylpropyl, oder Phenyl . Wenn R2-R6 vonPreferred meanings for R x are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1, 1-dimethylpropyl, or phenyl. If R 2 -R 6 of
Wasserstoff verschieden sind, dann bedeuten sie vorzugsweise Methyl oder einen anderen niederen Alkylrest . Eine weitere Untergruppe der Verbindungen der Formel I kann durch die allgemeine FormelHydrogen are different, then they preferably mean methyl or another lower alkyl radical. Another subgroup of the compounds of the formula I can be represented by the general formula
πi wiedergegeben werden, worin R' Alkyl, Alkanoyl, Alkenyl, Alkinyl, Alkoxycarbonylalkyl , Alkoxycarbonylaminoalkanoyl , Alkylcarbamoyl , Alkoxycarbonylalkylcarbamoyl, Alkoxycarbonylalkylthiocarbamoyl, Alkylthiocarbamoyl, mono- oder disubstituiertes Aminoalkanoyl, Aryl, Arylalkyl, Arylalkoxycarbonyl, Arylalkanoyl, Arylcarbamoyl, Alkoxyalkanoyl , Alkylsulfonyl, Arylthiocarbamoyl, Aryloxycarbonylalkyl, Aryloxycarbonylalkanoyl, Aryloxycarbonylalkylcarbamoyl , Aryloxycarbonylalkylthio- carbamoyl, Arylsulfonyl, Cycloalkyl, Cycloalkanoyl, Cycloalkylcarbamoyl , Cycloalkylthiocarbamoyl , Cycloalkylcarbonyl , Cycloalkyloxycarbonylalkyl , Cycloalkyloxycarbonylalkanoyl , Cycloalkyloxycarbonylalkylcarbamoyl, Cycloalkyloxycarbonylalkyl-thiocarbamoyl, Heteroarylalkyl, Heterocyclylalkyl , Heterocyclylalkoxycarbonylalkyl , Heterocyclylalkoxycarbonylalkanoyl, Heterocyclylalkoxycarbonylalkylcarbamoyl, Heterocyclylalkoxycarbonylalkylthiocarbamoyl, Heteroaryloxycarbonylalkyl, Hetero- aryloxycarbonylalkylcarbamoyl oder Heteroaryloxycarbonylalkylthiocarbamoyl bedeutet . are reproduced πi, where R 'is alkyl, alkanoyl, alkenyl, alkynyl, alkoxycarbonylalkyl, Alkoxycarbonylaminoalkanoyl, alkylcarbamoyl, Alkoxycarbonylalkylcarbamoyl, Alkoxycarbonylalkylthiocarbamoyl, alkylthiocarbamoyl, mono- or disubstituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, arylalkanoyl, arylcarbamoyl, alkoxyalkanoyl, alkylsulfonyl, arylthiocarbamoyl, aryloxycarbonylalkyl , Aryloxycarbonylalkanoyl, Aryloxycarbonylalkylcarbamoyl, Aryloxycarbonylalkylthio- carbamoyl, arylsulfonyl, cycloalkyl, cycloalkanoyl, cycloalkylcarbamoyl, Cycloalkylthiocarbamoyl, cycloalkylcarbonyl, Cycloalkyloxycarbonylalkyl, Cycloalkyloxycarbonylalkanoyl, Cycloalkyloxycarbonylalkylcarbamoyl, Cycloalkyloxycarbonylalkyl-thiocarbamoyl, heteroarylalkyl, heterocyclylalkyl, Heterocyclylalkoxycarbonylalkyl, Heterocyclylalkoxycarbonylalkanoyl, Heterocyclylalkoxycarbonylalkylcarbamoyl, Heterocyclylalkoxycarbonylalkylthiocarbamoyl, Heteroaryloxycarbonylalkyl, Heteroaryloxycarbonylalkyl means carbamoyl or heteroaryloxycarbonylalkylthiocarbamoyl.
Dabei bedeutet R' vorzugsweise Methyl, Ethyl, Propyl, Hexyl, 2 , 2-Dimethylpropionyl, Cyclopropylmethyl, 2-R 'is preferably methyl, ethyl, propyl, hexyl, 2, 2-dimethylpropionyl, cyclopropylmethyl, 2-
Cyclohexylethyl, Propinyl, Etyloxycarbonylethyl , Benzyl, n-Butyloxycarbonyl, tert-Butyloxycarbonyl, Benzyloxy- carbonyl, 3-Methyl-butyryl, Pentanoyl, Phenylacetyl, 2- Propyl-pentanoyl, Cyclopropan-carbonyl, Isobutyryl, But-3- enoyl, 2-Methoxy-acetyl, Propane-2-sulfonyl, Butane-1- sulfonyl, Methansulfonyl, tert-Butyloxycarbonyl- a inopropionyl oder 4-Dimethylamino-butyryl .Cyclohexylethyl, propynyl, ethyloxycarbonylethyl, benzyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 3-methylbutyryl, pentanoyl, phenylacetyl, 2-propylpentanoyl, cyclopropane-carbonyl, isobutyryl, but-3- enoyl, 2-methoxyacetyl, propane-2-sulfonyl, butane-1-sulfonyl, methanesulfonyl, tert-butyloxycarbonyl-a-inopropionyl or 4-dimethylamino-butyryl.
Bevorzugt ist die erfindungsgemässe Verwendung der folgenden Verbindungen der Formel III: 2-Guanidino-6, 7-dihydro-4Jf-thiazolo [5, 4-c] pyridin-5- carbonsäure- tert-butylester;The use of the following compounds of the formula III according to the invention is preferred: 2-guanidino-6, 7-dihydro-4Jf-thiazolo [5, 4-c] pyridine-5-carboxylic acid tert-butyl ester;
N- (5-Hexyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) - guanidin;N- (5-hexyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
N- [5- (2-Cyclohexyl-ethyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;N- [5- (2-Cyclohexyl-ethyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Ethyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) - guanidin; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure-butylester;N- (5-ethyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid butyl ester;
N- [5- (Propan-2-sulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;N- [5- (propan-2-sulfonyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Phenylacetyl-4, 5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) -guanidin;N- (5-phenylacetyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure-benzylester;2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid benzyl ester;
N- (5-Pentanoyl-4 ,5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2- yl) -guanidin; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, -c] pyridin-5- thiocarbonsäure-propylamid;N- (5-pentanoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, -c] pyridine-5-thiocarboxylic acid propylamide;
N- [5- (2-Propyl-pentanoyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;N- [5- (2-propylpentanoyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Benzyl-4 ,5,6, 7-tetrahydro-thiazolo [5, 4-c] yridin-2- yl) -guanidin;N- (5-benzyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] yridin-2-yl) guanidine;
N- (5-Prop-2-ynyl-4 ,5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin-N- (5-Prop-2-ynyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-
2-yl) -guanidin;2-yl) guanidine;
N- (5-Cyclopropancarbonyl-4 ,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) -guanidin; N- [5- (Butan-1-sulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c]pyridin-2-yl] -guanidin; N- (5-Isobutyryl-4 ,5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin- 2-yl) -guanidin;N- (5-cyclopropanecarbonyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine; N- [5- (butane-1-sulfonyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine; N- (5-isobutyryl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
N- [5- (2 , 2-Dimethyl-propionyl) -4,5,6, 7-tetrahydro- thiazolo [5 , 4-c] pyridin-2-yl] -guanidin; 2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- thiocarbonsäure-benzylamid;N- [5- (2, 2-dimethyl-propionyl) -4,5,6,7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl] guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid benzylamide;
2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure- ert-butylamid;2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid, tert-butylamide;
N- (5-But-3-enoyl-4, 5,6, 7-tetrahydro-thiazolo [5, -c] pyridin- 2-yl) -guanidin;N- (5-but-3-enoyl-4,5,6,7-tetrahydro-thiazolo [5, -c] pyridin-2-yl) guanidine;
N- (5-Benzyl-5, 6,7, 8-tetrahydro-4Jf-thiazolo [4, 5-c] azepin-2- yl) -guanidin;N- (5-benzyl-5, 6,7, 8-tetrahydro-4Jf-thiazolo [4, 5-c] azepin-2-yl) guanidine;
3- (2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5-yl) - propionsäure-ethylester; 2-Guanidino-6 , 7-dihydro-4E-thiazolo [5 , 4-c] pyridin-5- carbonsäure-pentylamid;3- (2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5-yl) ethyl propionate; 2-guanidino-6, 7-dihydro-4E-thiazolo [5, 4-c] pyridine-5-carboxylic acid pentylamide;
N- [5- (2-Methoxy-acetyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;N- [5- (2-methoxyacetyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Cyclopropylmethyl-4, 5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) -guanidin;N- (5-cyclopropylmethyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
N- (5-Methanesulfonyl-4, 5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) -guanidin;N- (5-methanesulfonyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
N- [5- (3 -Methyl-butyryl) -4,5, 6 , 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- thiocarbonsäure- (2-methoxy-l-methyl-ethyl) -amid; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure-phenylamid; [3- (2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- yl) -3-oxo-propyl] -carbaminsäure- tert-butyl ester;N- [5- (3-methylbutyryl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid (2-methoxy-l-methyl-ethyl) -amide; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid phenylamide; [3- (2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5-yl) -3-oxo-propyl] carbamic acid tert-butyl ester;
N- [5- (4-Dimethylamino-butyryl) -4 , 5, 6, 7-tetrahydro- thiazolo [5, 4-c] pyridin-2-yl] -guanidin;N- [5- (4-dimethylamino-butyryl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl] guanidine;
N- (5-Propyl-4, 5,6, 7-tetrahydro-thiazolo [5 , 4-c] yridin-2- yl) -guanidin; und 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- thiocarbonsäure-isopropylamid. Verbindungen der eingangs definierten Formel I , worin A eine Kette von 3-6 gegebenenfalls substituierten C-Atomen bedeutet, wovon eines durch -0- ersetzt sein kann, wobei das Ringgerüst nur die beiden Doppelbindungen des Thiazolbausteins enthält; pharmazeutisch verwendbare Säureadditionssalze von basischen Verbindungen, pharmazeutisch verwendbare Salze von saure Gruppen enthaltenden Verbindungen mit Basen, pharmazeutisch verwendbare Ester von Hydroxy- oderN- (5-propyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] yridin-2-yl) guanidine; and 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid isopropylamide. Compounds of the formula I defined at the outset, in which A is a chain of 3-6 optionally substituted C atoms, one of which can be replaced by -0-, the ring structure containing only the two double bonds of the thiazole component; pharmaceutically acceptable acid addition salts of basic compounds, pharmaceutically acceptable salts of acidic group-containing compounds with bases, pharmaceutically acceptable esters of hydroxy or
Carboxygruppen enthaltenden Verbindungen sowie Hydrate oder Solvate davon; mit Ausnahme vonCompounds containing carboxy groups and hydrates or solvates thereof; with the ecxeption of
N- (4 , 5, 6 , 7-Tetrahydro-benzothiazol-2-yl) -guanidin; - (2-Guanidino-4 , 5, 6 , 7-tetrahydro-benzothiazol-4-yl) - essigsäure-ethylester;N- (4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; - (2-Guanidino-4, 5, 6, 7-tetrahydro-benzothiazol-4-yl) ethyl acetate;
N- (4-Hydroxymethyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;N- (4-hydroxymethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;N- (4-tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Azidomethyl-4 ,5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;N- (4-azidomethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Aminomethyl-4 , 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; und - N- (6-Acetylaminomethyl-4, 5, 6, 7-tetrahydro- benzothiazol-2-yl) -guanidin; sind neu.N- (4-aminomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; and - N- (6-acetylaminomethyl-4, 5, 6, 7-tetrahydrobenzothiazol-2-yl) guanidine; are new.
In einem weiteren Aspekt umfasst die vorliegende Erfindung demnach diese neuen Stoffe als solche und als therapeutische Wirkstoffe; Verfahren zu deren Herstellung;In a further aspect, the present invention accordingly comprises these new substances as such and as therapeutic active substances; Processes for their manufacture;
Arzneimittel, enthaltend einen der obigen neuen Stoffe; dieMedicines containing one of the above new substances; the
Herstellung solcher Arzneimittel; sowie die Verwendung dieser neuen Stoffe als Neuropeptid FF Rezeptor- Antagonisten bzw. zur Herstellung entsprechenderManufacture of such drugs; and the use of these new substances as neuropeptide FF receptor antagonists or for the production of corresponding
Arzneimittel gemäss dem weiter oben erläuterten erstenMedicament according to the first explained above
Aspekt der vorliegenden Erfindung. In den oben definierten neuen Verbindungen der Formel I kann in der Kette A eines der C-Atome einen oder zwei (also geminale) , gleiche oder verschiedene, Substituenten tragen; oder es können mehrere der C-Atome je einen oder zwei (also geminale) , gleiche oder verschiedene, Substituenten tragen.Aspect of the present invention. In the new compounds of the formula I defined above, one of the C atoms in chain A can carry one or two (ie geminal), identical or different, substituents; or several of the C atoms can each carry one or two (ie geminal), identical or different, substituents.
Dabei kann/können der/die Substituent (en) ausgewählt sein ausThe substituent (s) can be selected from
Alkyl-, Alkenyl-, Cycloalkenyl- , Aryl-, Heteroaryl-, Aralkyl-, Alkoxycarbonyl- , Carboxamido- , Cyano- oder Cyanolakylgruppen und/oder aus mit ein und demselben C-Atom verknüpften Polymethylengruppen.Alkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, aralkyl, alkoxycarbonyl, carboxamido, cyano or cyanoolakyl groups and / or from polymethylene groups linked to one and the same carbon atom.
Insbesondere kann/können der/die Substituent (en) ausgewählt sein ausIn particular, the substituent (s) can be selected from
Methyl-, Ethyl-, n-Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, sec-Butyl-, tert-Butyl-, 1,1-Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-
Dimethylpropyl- , Allyl- und Cyclohex-1-enylgruppen; und/oderDimethylpropyl, allyl and cyclohex-1-enyl groups; and or
Phenyl-, o-Tolyl-, m-Tolyl-, p-Tolyl-, 2-Ethylphenyl- ,Phenyl, o-tolyl, m-tolyl, p-tolyl, 2-ethylphenyl,
3-Fluorphenyl- , 4-Fluorphenyl- , 4-Chlorphenyl- , 4- Cyanophenyl- , 4-Benzyloxyphenyl- , 3-Methoxyphenyl- , 4- Methoxyphenyl- , 3,4 -Dimethoxyphenyl- , 3,4- Methylendioxyphenyl- und Bis-3,5- trifluormethylphenylgruppen; und/oder Thiophen-2-yl- und Benzylgruppen; und/oder - Ethoxycarbonylgruppen; und/oder n-Propylamino- , Benzylamino- , N-Methyl-N- phenethylamino- , 3-Methylbutylamino- , Phenylamino- , N- Butyl-N-ethylamino-, Di-n-propylamino- , Allylamino-, Piperidin-1- und Morpholin-4-carbonylgruppen; und/oder - Cyano- und Cyanoethylgruppen; und/oder mit ein und demselben C-Atom verknüpften Pentamethylengruppen. Bevorzugt sind solche neuen Verbindungen, in welchen an ein und demselben C-Atom einerseits eine Phenylgruppe und anderseits eine Ethoxycarbonyl- , Cyano- oder Phenylgruppe sitzen.3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-benzyloxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl and bis -3,5-trifluoromethylphenyl groups; and / or thiophene-2-yl and benzyl groups; and / or - ethoxycarbonyl groups; and / or n-propylamino, benzylamino, N-methyl-N-phenethylamino, 3-methylbutylamino, phenylamino, N-butyl-N-ethylamino, di-n-propylamino, allylamino, piperidine-1 - and morpholine-4-carbonyl groups; and / or - cyano and cyanoethyl groups; and / or pentamethylene groups linked to one and the same carbon atom. Preferred are new compounds in which a phenyl group and an ethoxycarbonyl, cyano or phenyl group are located on one and the same carbon atom.
Ganz besonders bevorzugte neue Stoffe sind:Particularly preferred new fabrics are:
N- (5-Ethyl-5-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;N- (5-ethyl-5-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (5 , 5-Dimethyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;N- (5, 5-dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (5, 5-Dimethyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin und sein Formiat;N- (5, 5-dimethyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (4- ert-Butyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin; N- (6-Isopropyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (4- ert-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- (6-isopropyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
JW- (5, 5, 7-Trimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;JW- (5, 5, 7-trimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (6, 6-Dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (6, 6-dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (5-Butyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) - guanidin;N- (5-butyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine;
N- (4-Ethyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin; N- [6- (3 , -Dimethoxy-phenyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat;N- (4-ethyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- [6- (3, -dimethoxyphenyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] guanidine and its formate;
N- (5-Butyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;N- (5-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (6-Phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;N- (6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (5-Methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin; N- (4-Methyl-4-propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (5-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- (4-methyl-4-propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (6-Propyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;N- (6-propyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Cyclohex-l-enyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat; N- (4-sec-Butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat; undN- (4-cyclohex-1-enyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; N- (4-sec-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; and
N- (4-Isobutyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin.N- (4-isobutyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine.
Weitere besonders bevorzugte neue Stoffe sind:Other particularly preferred new fabrics are:
N- (6- ert-Butyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (6- ert-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
2-Guanidino-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-6- carbonsäure-ethylester und sein Formiat;2-guanidino-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester and its formate;
N- [6- (1, 1-Dimethyl-propyl) -4,5,6, 7-tetrahydro-benzothiazol-N- [6- (1,1-dimethyl-propyl) -4,5,6,7-tetrahydro-benzothiazole-
2-yl] -guanidin;2-yl] guanidine;
N- (7-Methyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat; N- [6- (3-Methoxy-phenyl) -4 , 5 , 6 , 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;N- (7-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; N- [6- (3-methoxyphenyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
N- (6-Thiophen-2-yl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;N- (6-thiophene-2-yl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (5,5,7, 7-Tetramethyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; \ JV- (5,5,7, 7-tetramethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; \
N- [6- (4-Fluor-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Hydrobromid;N- [6- (4-fluorophenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its hydrobromide;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- ethylester und sein Hydrobromid; N- (4,4-Dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester and its hydrobromide; N- (4,4-dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Methyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- (4-methyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (4, 5, 6, 7-Tetrahydro-benzothiazol-2-yl-4-spiro- cyclohexan) -guanidin und sein Formiat;N- (4, 5, 6, 7-tetrahydro-benzothiazol-2-yl-4-spirocyclohexane) guanidine and its formate;
N- (5, 6 , 7, 8-Tetrahydro-4H-cycloheptathiazol-2-yl) -guanidin;N- (5, 6, 7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine;
N- (4-Allyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- (4-allyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (6-Methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin; JV- [6- (3-Fluor-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;N- (6-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; JV- [6- (3-fluoro-phenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
N- (6-Cyano-6-phenyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Hydrobromid; N- (4-Phenyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat ; undN- (6-cyano-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its hydrobromide; N- (4-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; and
N- (6, 6-Diphenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat.N- (6, 6-Diphenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate.
Ebenfalls bevorzugte neue Stoffe sind:Also preferred new fabrics are:
N- [6- (4-Methoxy-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Hydrobromid;N- [6- (4-methoxyphenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its hydrobromide;
N- (5-Phenyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) - guanidin und sein Hydrobromid; N- (6 , 7-Dihydro-4H-pyrano [4 , 3-d] thiazol-2-yl) -guanidin;N- (5-phenyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine and its hydrobromide; N- (6, 7-dihydro-4H-pyrano [4, 3-d] thiazol-2-yl) guanidine;
N~ (6-Benzo [1,3] dioxol-5-yl-4 , 5,6, 7-tetrahydro-benzothiazol-N ~ (6-benzo [1,3] dioxol-5-yl-4, 5,6, 7-tetrahydro-benzothiazole-
2-yl) -guanidin und sein Formiat;2-yl) guanidine and its formate;
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure propylamid und sein Formiat; N- [6- (4-Cyano-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid propylamide and its formate; N- [6- (4-cyano-phenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
N- (4-Benzyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- (4-benzyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (5-Methyl-5-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;N- (5-methyl-5-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- [6- (3, 5-Bis-trifluoromethyl-phenyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat;N- [6- (3,5-bis-trifluoromethylphenyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] guanidine and its formate;
N- (6-o-Tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat; N- (6-m-Tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- (6-o-tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; N- (6-m-tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- [6- (2-Ethyl-phenyl) -4 , 5, 6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;N- [6- (2-ethylphenyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
N- [6- (4-Chlor-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol- -carbonsäure benzylamid und sein Formiat;N- [6- (4-chlorophenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-carboxylic acid benzylamide and its formate;
N- (5, 6-Dihydro-4ff-cyclopentathiazol-2-yl) -guanidin;N- (5, 6-dihydro-4ff-cyclopentathiazol-2-yl) guanidine;
N- [6- (4-Benzyloxy-phenyl) -4,5,6, 7-tetrahydro-benzothiazol- 2-yl] -guanidin und sein Hydrobromid;N- [6- (4-benzyloxyphenyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] guanidine and its hydrobromide;
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure methyl-phenethyl-amid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid methyl-phenethyl-amide and its formate;
N- (6-Phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl-4-spiro- cyclohexan) -guanidin und sein Hydrobromid; N- (6-p-Tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein FormiatN- (6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl-4-spirocyclohexane) guanidine and its hydrobromide; N- (6-p-Tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- (3-methyl-butyl) -amid und sein Formiat; und N- (4- tert-Butyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin.2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid- (3-methyl-butyl) -amide and its formate; and N- (4-tert-butyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine.
Weitere repräsentative Vertreter der neuen Stoffe sind: 2 -Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure phenylamid und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- butyl-ethyl-amid und sein Formiat; N- [4- (2-Cyano-ethyl) -4,5,6, 7-tetrahydro-benzothiazol-2-yl] - guanidin und sein Formiat;Other representative representatives of the new substances are: 2 -Guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid phenylamide and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid butyl ethyl amide and its formate; N- [4- (2-cyano-ethyl) -4,5,6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- ethylester und sein Hydrobromid;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester and its hydrobromide;
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol- -carbonsäure- dipropylamid und sein Formiat ;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-carboxylic acid dipropylamide and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- phenylamid und sein Formiat; 2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- allylamid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid phenylamide and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid allylamide and its formate;
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- propylamid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid propylamide and its formate;
N- [4- (Piperidin-1-carbonyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat;N- [4- (piperidine-1-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- allylamid und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- (3-methyl-butyl) -amid und sein Formiat; iV- [4- (Morpholin-4-carbonyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat; und 2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4 -carbonsäure- diisopropylamid und sein Formiat .2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid allylamide and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid- (3-methyl-butyl) -amide and its formate; iV- [4- (morpholine-4-carbonyl) -4,5,6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; and 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid diisopropylamide and its formate.
Der Begriff "Alkyl", allein oder in Kombination, bezeichnet einen unverzweigten oder verzweigten Kohlenwasserstoffrest von 1-8 C-Atomen. Repräsentative, aber nicht limitierende Beispiele für Alkyl sind Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, tert-Butyl, Isobutyl (oder 2-The term "alkyl", alone or in combination, denotes an unbranched or branched hydrocarbon radical of 1-8 C atoms. Representative but not limiting examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl (or 2-
Methylpropyl) , n-Pentyl ( oder n-Amyl) , Isopentyl (oder Isoamyl, n-Hexyl n-Heptyl, n-Octyl und dgl. Der Alkylrest kann einen oder mehrere Substituenten tragen, welche voneinander unabhängig ausgewählt sind aus Alkenyl, Alkoxy, Alkoxyalkyl , Alkoxycarbonyl , Alkoxycarbonylalkyl , Alkylcarbonyl , Alkylcarbonylalkyl, Alkylcarbonyloxy, Alkylendioxy, Alkylsulfinyl, Alkylsulfinylalkyl, Alkylsulfonyl, Alkylsulfonylalkyl, Alkylthio, Alkylthioalkyl, Alkynyl, Amino, Aminoalkyl, Aminocarbonyl, Aminocarbonylalkyl , Aryl, Arylalkenyl, Arylalkyloxy, Arylalkyl, Aryloxy, Aryloxycarbonyl, Aryloxycarbonylalkyl , Arylsulfinyl, Arylsulfinylalkyl, Arylsulfonyl,Methylpropyl), n-pentyl (or n-amyl), isopentyl (or isoamyl, n-hexyl, n-heptyl, n-octyl and the like. The alkyl radical can carry one or more substituents which are independently selected from alkenyl, alkoxy, Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkoxyoxy, arylalkyloxyylylyloxy, Arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,
Arylsulfonylalkyl, Arylthio, Arylthioalkyl, Carboxy, Carboxyalkyl , Cyano, Cyanoalkyl, Formyl, Formylalkyl, Halogen, Haloalkoxy, Haloalkyl, Heterocyclyl, Hydroxy, Hydroxyalkyl , Mercapto, Nitro und dgl., und welche mit irgendeinem C-Atom der Alkylgruppe verknüpft sein kann/ können .Arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like, and which can be linked to any C atom of the alkyl group / can .
Der Begriff "niederes Alkyl", allein oder in Kombination, bezeichnet Alkylgruppen mit 1-4 C-Atomen. Repräsentative, aber nicht limitierende Beispiele für niederes Alkyl sind Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, tert-Butyl und dgl. Der Begriff "Alkenyl", allein oder in Kombination, bezeichnet einen unverzweigten oder verzweigten Kohlenwasserstoffrest von 2-8 C-Atomen, bei dem mindestens eine Kohlenstoff-Kohlenstoff Doppelbindung (RaRbC=CRcRd) vorliegt. Ra-Rd bezeichnen Substituenten, welche voneinander unabhängig ausgewählt sind aus Wasserstoff, Alkyl, Alkoxy, Alkoxyalkyl, und dgl. Repräsentative, aber nicht limitierende Beispiele für Alkenyl sind Ethenyl, 2- Propenyl, 2 -Methyl-2-propenyl, 3-Butenyl, 4-Pentenyl, 5- Hexenyl und dgl .The term “lower alkyl”, alone or in combination, denotes alkyl groups with 1-4 C atoms. Representative but not limiting examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like. The term "alkenyl", alone or in combination, denotes an unbranched or branched hydrocarbon radical of 2-8 C atoms, in which at least one carbon-carbon double bond (R a R b C = CR c R d ) is present. R a -R d denote substituents which are independently selected from hydrogen, alkyl, alkoxy, alkoxyalkyl, and the like. Representative but not limiting examples of alkenyl are ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- Butenyl, 4-pentenyl, 5-hexenyl and the like.
Der Begriff "Alkylendioxy" , allein oder in Kombination, bezeichnet eine -O (CH2) nO-Gruppe, worin n 1 oder 2 bedeutet, wobei die O-Atome mit zwei benachbarten C-Atomen des Molekülstammgerüsts verbunden sind. Repräsentative, aber nicht limitierende Beispiele für Alkylendioxy sind Methylendioxy, Ethylendioxy und dgl.The term "alkylenedioxy", alone or in combination, denotes an -O (CH 2 ) n O group, in which n denotes 1 or 2, the O atoms being connected to two adjacent C atoms of the molecular backbone. Representative but not limiting examples of alkylenedioxy are methylenedioxy, ethylenedioxy and the like.
Der Begriff "Alkynyl", allein oder in Kombination, bezeichnet einen unverzweigten oder verzweigten Kohlenwasserstoffrest von 2-8 C-Atomen, bei dem mindestens eine Kohlenstoff- Kohlenstoff Dreifachbindung (Ra-C≡C-Rb) vorliegt. Ra und Rb bezeichnen Substituenten, welche voneinander unabhängig ausgewählt sind aus Wasserstoff,The term "alkynyl", alone or in combination, denotes an unbranched or branched hydrocarbon radical of 2-8 C atoms, in which at least one carbon-carbon triple bond (R a -C≡CR b ) is present. R a and R b denote substituents which are selected independently of one another from hydrogen,
Alkenyl, Alkoxy, Alkoxyalkyl, und dgl. Repräsentative, aber nicht limitierende Beispiele für Alkynyl sind Acetylenyl, 1-Propynyl, 2-Propynyl, 1-Butynyl, 3-Butynyl, 2-Pentynyl und dgl .Alkenyl, alkoxy, alkoxyalkyl, and the like. Representative but not limiting examples of alkynyl are acetylenyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 2-pentynyl and the like.
Der Begriff "Alkoxy", allein oder in Kombination, bezeichnet eine Alkylgruppe, die über eine Sauerstoffbrücke verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkoxy sind Methoxy, Ethoxy, Propoxy, 2- Propoxy, Butoxy, tert-Butoxy, Pentyloxy, und Hexyloxy. Der Begriff "Alkoxyalkyl", allein oder in Kombination, bezeichnet eine Alkoxygruppe, die über einen Alkylrest verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkoxyalkyl sind tert-Butoxymethyl, 2- Ethoxyethyl, 2-Methoxyethyl, und Methoxymethyl .The term "alkoxy", alone or in combination, denotes an alkyl group that is linked via an oxygen bridge. Representative but not limiting examples of alkoxy are methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkyl", alone or in combination, denotes an alkoxy group which is linked via an alkyl radical. Representative but not limiting examples of alkoxyalkyl are tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
Der Begriff "Alkoxycarbonyl" , allein oder in Kombination, bezeichnet eine Alkoxygruppe, die über eine Carbonylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkoxycarbonyl sind Methoxycarbonyl, Ethoxycarbonyl, tert-Butoxycarbonyl und dgl.The term "alkoxycarbonyl", alone or in combination, denotes an alkoxy group which is linked via a carbonyl group. Representative but not limiting examples of alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.
Der Begriff "Alkoxycarbonylalkyl" , allein oder in Kombination, bezeichnet eine Alkoxycarbonylgruppe, die über einen Alkylrest verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkoxycarbonylalkyl sind Methoxycarbonylpropyl , Ethoxycarbonylbutyl , 2-tert-The term "alkoxycarbonylalkyl", alone or in combination, denotes an alkoxycarbonyl group which is linked via an alkyl radical. Representative but not limiting examples of alkoxycarbonylalkyl are methoxycarbonylpropyl, ethoxycarbonylbutyl, 2-tert-
Butoxycarbonylethyl und dgl .Butoxycarbonylethyl and the like
Der Begriff "Alkylcarbonyl" , allein oder in Kombination, bezeichnet eine Alkylgruppe, die über eine Carbonylgruppe verknüpft ist. Repräsentative, aber nicht limitierendeThe term "alkylcarbonyl", alone or in combination, denotes an alkyl group which is linked via a carbonyl group. Representative but not limitative
Beispiele für Alkylcarbonyl sind Acetyl, 1-Oxopropyl, 2,2-Examples of alkylcarbonyl are acetyl, 1-oxopropyl, 2,2-
Dimethyl-1-oxopropyl, 1-Oxobutyl, 1-Oxopentyl und dgl.Dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl and the like
Der Begriff "Alkylcarbonylalkyl" , allein oder inThe term "alkylcarbonylalkyl", alone or in
Kombination, bezeichnet eine Alkylcarbonylgruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylcarbonylalkyl sind 2- Oxopropyl, 3 , 3-Dimethyl-2-oxopropyl, 3-Oxobutyl, 3-Combination, denotes an alkylcarbonyl group which is linked via an alkyl group. Representative but not limiting examples of alkylcarbonylalkyl are 2-oxopropyl, 3, 3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-
Oxopentyl und dgl .Oxopentyl and the like
Der Begriff "Alkylcarbonyloxy" , allein oder in Kombination, bezeichnet eine Alkylcarbonylgruppe, die über eine Sauerstoffbrücke verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylcarbonyloxy sind Acetyloxy, Ethylcarbonyloxy, tert-Butylcarbonyloxy und dgl. Der Begriff "Alkylsulfinyl" , allein oder in Kombination, bezeichnet eine Alkylgruppe, die über eine Sulfinylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylsulfinyl sind Methylsulfinyl, Ethylsulfinyl und dgl.The term "alkylcarbonyloxy", alone or in combination, denotes an alkylcarbonyl group which is linked via an oxygen bridge. Representative but not limiting examples of alkylcarbonyloxy are acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy and the like. The term "alkylsulfinyl", alone or in combination, denotes an alkyl group which is linked via a sulfinyl group. Representative but not limiting examples of alkylsulfinyl are methylsulfinyl, ethylsulfinyl and the like.
Der Begriff "Alkylsulfinylalkyl" , allein oder in Kombination, bezeichnet eine Alkylsulfinylgruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylsulfinylalkyl sind Methylsulfinylmethyl, Ethylsulfinylmethyl und dgl.The term "alkylsulfinylalkyl", alone or in combination, denotes an alkylsulfinyl group which is linked via an alkyl group. Representative but not limiting examples of alkylsulfinylalkyl are methylsulfinylmethyl, ethylsulfinylmethyl and the like.
Der Begriff "Alkylsulfonyl" , allein oder in Kombination, bezeichnet eine Alkylgruppe, die über eine Sulfonylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylsulfonyl sind Methylsulfonyl, Ethylsulfonyl und dgl.The term "alkylsulfonyl", alone or in combination, denotes an alkyl group which is linked via a sulfonyl group. Representative but not limiting examples of alkylsulfonyl are methylsulfonyl, ethylsulfonyl and the like.
Der Begriff "Alkylsulfonylalkyl" , allein oder in Kombination, bezeichnet eine Alkylsulfonylgruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylsulfonylalkyl sind Methylsulfonylmethyl, Ethylsulfonylmethyl und dgl.The term "alkylsulfonylalkyl", alone or in combination, denotes an alkylsulfonyl group which is linked via an alkyl group. Representative but not limiting examples of alkylsulfonylalkyl are methylsulfonylmethyl, ethylsulfonylmethyl and the like.
Der Begriff "Alkylthio", allein oder in Kombination, bezeichnet eine Alkylgruppe, die über eine Thiogruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Alkylthio sind Methylsulfanyl, Ethylsulfanyl, tert-Butylsulfanyl, Hexylsulfanyl und dgl.The term "alkylthio", alone or in combination, denotes an alkyl group which is linked via a thio group. Representative but not limiting examples of alkylthio are methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl and the like.
Der Begriff "Alkylthioalkyl" , allein oder in Kombination, bezeichnet eine Alkylthiogruppe, die über eine Alkylgruppe verknüpftist. Repräsentative, aber nicht limitierende Beispiele für Alkylthioalkyl sind Methylsulfanyl-methyl, 2- (Ethylsulfanyl) ethyl und dgl.The term "alkylthioalkyl", alone or in combination, denotes an alkylthio group linked through an alkyl group. Representative but not limiting examples of alkylthioalkyl are methylsulfanyl-methyl, 2- (ethylsulfanyl) ethyl and the like.
Der Begriff "Amino", allein oder in Kombination, bezeichnet eine -NReRf Gruppe, wobei Re und Rf unabhängig unabhängig voneinander ausgewählt sind aus Wasserstoff, Alkyl, Aryl, Arylalkyl, Acyl, Alkylcarbonyl, Arylcarbonyl, Carbamoyl, Ureido, Formyl, Alkylsulfonyl, Arylsulfonyl und dgl.The term "amino", alone or in combination, denotes an -NR e R f group, where R e and R f are independently selected from hydrogen, alkyl, aryl, Arylalkyl, acyl, alkylcarbonyl, arylcarbonyl, carbamoyl, ureido, formyl, alkylsulfonyl, arylsulfonyl and the like.
Der Begriff "Aminoalkyl" , allein oder in Kombination, bezeichnet eine Aminogruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Aminoalkyl sind Aminomethyl, 2-Aminoethyl, N- Benzyl-N-methyl-aminomethyl, Dimethylamino-methyl und dgl.The term "aminoalkyl", alone or in combination, denotes an amino group which is linked via an alkyl group. Representative but not limiting examples of aminoalkyl are aminomethyl, 2-aminoethyl, N-benzyl-N-methyl-aminomethyl, dimethylamino-methyl and the like.
Der Begriff "Aminocarbonyl", allein oder in Kombination, bezeichnet eine Aminogruppe, die über eine Carbonylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Aminocarbonyl sind Dimethylaminocarbonyl, Benzylaminocarbonyl, Ethylaminocarbonyl und dgl.The term "aminocarbonyl", alone or in combination, denotes an amino group which is linked via a carbonyl group. Representative but not limiting examples of aminocarbonyl are dimethylaminocarbonyl, benzylaminocarbonyl, ethylaminocarbonyl and the like.
Der Begriff "Aminocarbonylalkyl" , allein oder inThe term "aminocarbonylalkyl", alone or in
Kombination, bezeichnet eine Aminocarbonylgruppe , die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Aminocarbonylalkyl sind 2-Amino- 2-oxoethyl, 2- (Benzylamino) -2-oxoethyl, 2- (Methylamino) -2- oxoethyl, 4-Amino-4-oxobutyl, 4- (Dimethylamino) -4-oxobutyl und dgl .Combination, refers to an aminocarbonyl group that is linked via an alkyl group. Representative but not limiting examples of aminocarbonylalkyl are 2-amino-2-oxoethyl, 2- (benzylamino) -2-oxoethyl, 2- (methylamino) -2-oxoethyl, 4-amino-4-oxobutyl, 4- (dimethylamino) -4-oxobutyl and the like
Der Begriff "Aryl", allein oder in Kombination, bezeichnet eine aromatische carbocyclische Gruppe, enthaltend mindestens einen aromatischen Ring, zum Beispiel Phenyl oder Biphenyl, oder kondensierte Ringsysteme, in denen mindestens ein Ring aromatisch ist, zum Beispiel 1,2,3,4- Tetrahydronaphthyl , Naphthyl, Anthryl, Phenanthryl, Fluorenyl und dgl . Die Arylgruppe kann einen oder mehrere Substitutenten tragen, welche voneinander unabhängig ausgewählt sind aus Alkenyl, Alkoxy, Alkoxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl, Alkyl, Alkylcarbonyl, Alkylcarbonylalkyl, Alkylcarbonyloxy, Alkylendioxy, Alkylsulfinyl, Alkylsulfinylalkyl, Alkylsulfonyl,The term "aryl", alone or in combination, denotes an aromatic carbocyclic group containing at least one aromatic ring, for example phenyl or biphenyl, or fused ring systems in which at least one ring is aromatic, for example 1,2,3,4 - tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl and the like. The aryl group can carry one or more substituents which are independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,
Alkylsulfonylalkyl, Alkylthio, Alkylthioalkyl, Alkynyl, Amino, Aminoalkyl, Aminocarbonyl, Aminocarbonylalkyl, Arylalkenyl, Arylalkyloxy, Arylalkyl, Aryloxy, Aryloxycarbonyl, Aryloxycarbonylalkyl, Arylsulfinyl, Arylsulfinylalkyl, Arylsulfonyl, Arylsulfonylalkyl, Arylthio, Arylthioalkyl, Carboxy, Carboxyalkyl , Cyano, Cyanoalkyl, Formyl, Formylalkyl, Halogen, Haloalkoxy, Haloalkyl, Heterocyclyl, Hydroxy, Hydroxyalkyl, Mercapto, Nitro und dgl .Alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, Aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, nitro, hydroxy, hydroxy, hydroxy, hydroxy.
Der Begriff "Arylalkenyl" , allein oder in Kombination, bezeichnet eine Arylgruppe, die über eine Alkenylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Arylalkenyl sind 2-Phenylethenyl, 3- Phenylpropen-2-yl, 2-Naphth-2-ylethenyl und dgl.The term "arylalkenyl", alone or in combination, denotes an aryl group which is linked via an alkenyl group. Representative but not limiting examples of arylalkenyl are 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2-ylethenyl and the like.
Der Begriff "Arylalkoxy" , allein oder in Kombination, bezeichnet eine Arylgruppe, die über eine Alkoxygruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Arylalkoxy sind 2-Phenylethoxy, 5- Phenylpentyloxy, 3-Naphth-2-ylpropoxy und dgl.The term "arylalkoxy", alone or in combination, denotes an aryl group which is linked via an alkoxy group. Representative but non-limiting examples of arylalkoxy are 2-phenylethoxy, 5-phenylpentyloxy, 3-naphth-2-ylpropoxy and the like.
Der Begriff "Arylalkyl", allein oder in Kombination, bezeichnet eine Arylgruppe, die über eine Alkylgruppe verknüpft ist. Die Arylgruppe kann unsubstituiert oder substituiert sein. Repräsentative, aber nicht limitierende Beispiele für Arylalkyl sind Benzyl, 2-Phenylethyl, 3- Phenylpropyl , 2-Naphth-2-ylethyl und dgl.The term "arylalkyl", alone or in combination, denotes an aryl group which is linked via an alkyl group. The aryl group can be unsubstituted or substituted. Representative but not limiting examples of arylalkyl are benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl and the like.
Der Begriff "Aryloxy", allein oder in Kombination, bezeichnet eine Arylgruppe, die über eine Sauerstoffbrücke verknüpft ist. Die Arylgruppe kann unsubstituiert oder substituiert sein. Repräsentative, aber nicht limitierende Beispiele für Aryloxy sind Phenoxy, Naphthyloxy, 3- Bromphenoxy, 4-Chlorphenoxy, 4-Methylphenoxy, 3,4- Dimethoxyphenoxy und dgl . Die Arylgruppe kann unsubstituiert oder definitionsgemäss substituiert sein.The term "aryloxy", alone or in combination, denotes an aryl group that is linked via an oxygen bridge. The aryl group can be unsubstituted or substituted. Representative but not limiting examples of aryloxy are phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 3,4-dimethoxyphenoxy and the like. The aryl group can be unsubstituted or substituted by definition.
Der Begriff "Carbamoyl", allein oder in Kombination, bezeichnet eine -C (0) NReRf-Gruppe . Der Begriff "Thiocarbamoyl" , allein oder in Kombination, bezeichnet eine -C (S) NReRf-Gruppe .The term "carbamoyl", alone or in combination, denotes a -C (0) NR e R f group. The term "thiocarbamoyl", alone or in combination, denotes a -C (S) NR e R f group.
Der Begriff "Carbonyl" , allein oder in Kombination, bezeichnet eine -C (0) -Gruppe .The term "carbonyl", alone or in combination, denotes a -C (0) group.
Der Begriff "Carboxy", allein oder in Kombination, bezeichnet eine -C02H-Gruppe .The term "carboxy", alone or in combination, denotes a -C0 2 H group.
Der Begriff "Carboxyalkyl" , allein oder in Kombination, bezeichnet eine Carboxygruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Carboxyalkyl sind Carboxymethyl, 2- Carboxyethyl, 3-Carboxypropyl und dgl.The term "carboxyalkyl", alone or in combination, denotes a carboxy group which is linked via an alkyl group. Representative but not limiting examples of carboxyalkyl are carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and the like.
Der Begriff "Cyano", allein oder in Kombination, bezeichnet eine -C≡N-Gruppe.The term "cyano", alone or in combination, denotes a -C≡N group.
Der Begriff "Cyanoalkyl", allein oder in Kombination, bezeichnet eine Cyanogruppe, die über eine Alkylgruppe verknüpft ist . Repräsentative, aber nicht limitierende Beispiele für Cyanoalkyl sind Cyanomethyl, 2-Cyanoethyl, 3- Cyanopropyl und dgl .The term "cyanoalkyl", alone or in combination, denotes a cyano group which is linked via an alkyl group. Representative but not limiting examples of cyanoalkyl are cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and the like.
Der Begriff "Cycloalkyl" , allein oder in Kombination, bezeichnet einen gesättigten cyclischenThe term "cycloalkyl", alone or in combination, denotes a saturated cyclic
Kohlenwasserstoffrest mit 3-15 C-Atomen, der einen oder mehrere Substituenten tragen kann. Die Substituenten sind unabhängig voneinander ausgewählt aus Alkenyl, Alkoxy, Alkoxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl, Alkyl, Alkylcarbonyl, Alkylcarbonylalkyl, Alkylcarbonyloxy, Alkylendioxy, Alkylsulfinyl, Alkylsulfinylalkyl, Alkylsulfonyl, Alkylsulfonylalkyl, Alkylthio, Alkylthioalkyl, Alkynyl, Amino, Aminoalkyl, Aminocarbonyl, Aminocarbonylalkyl, Aryl, Arylalkenyl, Arylalkyloxy, Arylalkyl, Aryloxy, Aryloxycarbonyl, Aryloxycarbonylalkyl, Arylsulfinyl, Arylsulfinylalkyl, Arylsulfonyl, Arylsulfonylalkyl, Arylthio, Arylthioalkyl, Carboxy, Carboxyalkyl, Cyano, Cyanoalkyl, Formyl, Formylalkyl, Halogen, Haloalkoxy, Haloalkyl, Heterocyclyl, Hydroxy, Hydroxyalkyl, Mercapto, Nitro und dgl. Repräsentative, aber nicht limitierende Beispiele für Cycloalkyl sind Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl,Hydrocarbon residue with 3-15 C atoms, which can carry one or more substituents. The substituents are selected independently of one another from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, arylyl, arylyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocyl, aminocarbonyl , Arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, arylthio, arylthioalkyl, carboxy, Carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like. Representative but not limiting examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, Cyclooctyl. In polycyclischen Cycloalkylresten kann einer der ankondensierten Ringe aromatisch sein, wie zum Beispiel 1-Indanyl, 2-Indanyl, Tetrahydronaphthyl und dgl.Cycloheptyl, cyclooctyl. In polycyclic cycloalkyl radicals, one of the fused rings can be aromatic, such as 1-indanyl, 2-indanyl, tetrahydronaphthyl and the like.
Die Begriffe "Cycloalkenyl" und "Cycloalkinyl" bezeichnen cyclische Kohlenwasserstoffreste, welche mindestens eine Kohlenstoff-Kohlenstoff-Doppel- oder -Dreifachbindung enthalten. Diese Reste können, wie die Cycloalkylreste, einen oder mehrere Substituenten tragen.The terms "cycloalkenyl" and "cycloalkynyl" refer to cyclic hydrocarbon radicals which contain at least one carbon-carbon double or triple bond. Like the cycloalkyl radicals, these radicals can carry one or more substituents.
Der Begriff "Formyl", allein oder in Kombination, bezeichnet eine -C (O) H-Gruppe .The term "formyl", alone or in combination, denotes a -C (O) H group.
Der Begriff "Formylalkyl", allein oder in Kombination, bezeichnet eine Formylgruppe, die über eine Alkylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Formylalkyl sind Formylmethyl, 2-Formylethyl, und dgl .The term "formylalkyl", alone or in combination, denotes a formyl group which is linked via an alkyl group. Representative but not limiting examples of formylalkyl are formylmethyl, 2-formylethyl, and the like.
Der Begriff "Halo" oder "Halogen", allein oder in Kombination, bezeichnet Fluor, Brom, Chlor, und Iod.The term "halo" or "halogen", alone or in combination, denotes fluorine, bromine, chlorine and iodine.
Der Begriff "Haloalkyl", allein oder in Kombination, bezeichnet eine Alkylgruppe, in der mindestens einThe term "haloalkyl", alone or in combination, denotes an alkyl group in which at least one
Wasserstoffatom durch Halogen ersetzt ist. Repräsentative, aber nicht limitierende Beispiele für Haloalkyl sind Chlormethyl, 2-Fluorethyl, Trifluormethyl, Pentafluorethyl, 2-Chlor-3-fluorpentyl und dgl.Hydrogen atom is replaced by halogen. Representative but not limiting examples of haloalkyl are chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl and the like.
Der Begriff "Haloalkoxy", allein oder in Kombination, bezeichnet eine Alkoxygruppe, in der mindestens ein Wasserstoffatom durch Halogen ersetzt ist. Repräsentative, aber nicht limitierende Beispiele für Haloalkoxy sind Chlormethoxy, 2-Fluorethoxy, Trifluormethoxy, Pentafluorethoxy und dgl.The term "haloalkoxy", alone or in combination, denotes an alkoxy group in which at least one Hydrogen atom is replaced by halogen. Representative but not limiting examples of haloalkoxy are chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy and the like.
Der Begriff "Heterocyclyl", allein oder in Kombination, bezeichnet ein monocyclisches, bicyclisches oder polycylisches Ringsystem mit bis zu 15 Ringatomen, enthaltend mindestens ein Heteroatom unabhängig ausgewählt aus Stickstoff, Sauerstoff, oder Schwefel, wobei der/die Ring(e) gesättigt, partiell ungesättigt oder ungesättigt bzw. aromatisch sein kann/können. Repräsentative, aber nicht limitierende Beispiele für Heterocyclyl sind Furyl, Imidazolyl, Imidazolinyl, Imidazolidinyl, Isothiazolyl, Isoxazolyl, Morpholinyl, Oxadiazolyl, Oxazolyl, Oxazolinyl, Oxazolidinyl, Piperazinyl, Piperidinyl, Pyranyl, Pyrazinyl, Pyrazolyl, Pyridyl, Pyrimidinyl, Pyridazinyl, Pyrrolyl, Pyrrolinyl, Pyrrolidinyl, Tetrahydrofuranyl , Tetrahydrothienyl, Thiadiazolyl, Thiazolyl, Thiazolinyl, Thiazolidinyl, Thienyl, Thiomorpholinyl, 1,1-The term "heterocyclyl", alone or in combination, denotes a monocyclic, bicyclic or polycyclic ring system with up to 15 ring atoms, containing at least one heteroatom independently selected from nitrogen, oxygen, or sulfur, the ring (s) saturated, partially can be unsaturated or unsaturated or aromatic. Representative but non-limiting examples of heterocyclyl are furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl , Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-
Dioxothiomorpholinyl, Benzimidazolyl, Benzothiazolyl, Benzothienyl, Benzoxazolyl, Benzofuranyl, Indolyl, Indolinyl, Isobenzofuranyl, Isobenzothienyl, Isoindolyl, Isoindolinyl, Isochuinolinyl, Chinolinyl und dgl. Die Heterocylylreste können einen oder mehrere Substituenten tragen, wobei diese voneinander unabhängig ausgewählt sind aus Alkenyl, Alkoxy, Alkoxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl , Alkyl , Alkylcarbonyl , Alkylcarbonylalkyl, Alkylcarbonyloxy, Alkylendioxy, Alkylsulfinyl, Alkylsulfinylalkyl, Alkylsulfonyl,Dioxothiomorpholinyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl and the like. The heterocylyl radicals may be selected from one another, where alkenyloxy may be one or more, wherein Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,
Alkylsulfonylalkyl, Alkylthio, Alkylthioalkyl, Alkynyl, Amino, Aminoalkyl, Aminocarbonyl, Aminocarbonylalkyl, Aryl, Arylalkenyl, Arylalkyloxy, Arylalkyl, Aryloxy, Aryloxycarbonyl, Aryloxycarbonylalkyl, Arylsulfinyl, Arylsulfinylalkyl, Arylsulfonyl, Arylsul onylalkyl,Alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonyl, arylsulphonyl, arylsulphonyl
Arylthio, Arylthioalkyl , Carboxy, Carboxyalkyl, Cyano, Cyanoalkyl, Cycloalkyl, Formyl, Formylalkyl, Halogen, Haloalkoxy, Haloalkyl, Hydroxy, Hydroxyalkyl, Mercapto, Nitro und dgl .Arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, formylalkyl, halogen, Haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like.
Der Begriff "Heteroaryl" , allein oder in Kombination, ist ein Spezialfall von Heterocyclyl und bezeichnet ein monocyclisches, bicyclisches oder polycylisches Ringsystem, worin der bzw. mindestens ein Ring heteroaromatisch ist.The term "heteroaryl", alone or in combination, is a special case of heterocyclyl and denotes a monocyclic, bicyclic or polycyclic ring system, in which the or at least one ring is heteroaromatic.
Der Begriff "Heterocyclylalkenyl" , allein oder in Kombination, bezeichnet eine Heterocyclylgruppe, die über eine Alkenylgruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Heterocyclylalkenyl sind 2-Pyrid-3-ylethenyl, 3-Chinolin-3-ylpropen-2-yl, 5-Pyrid-4- ylpentylen-4-yl und dgl.The term "heterocyclylalkenyl", alone or in combination, denotes a heterocyclyl group which is linked via an alkenyl group. Representative but not limiting examples of heterocyclylalkenyl are 2-pyrid-3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, 5-pyrid-4-ylpentylen-4-yl and the like.
Der Begriff "Heterocyclylalkoxy" , allein oder inThe term "heterocyclylalkoxy", alone or in
Kombination, bezeichnet eine Heterocyclylgruppe, die über eine Alkoxygruppe verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Heterocyclylalkoxy sind 2-Pyrid- 3-ylethoxy, 3-Chinolin-3-ylpropoxy, 5-Pyrid-4-ylpentyloxy und dgl .Combination, denotes a heterocyclyl group which is linked via an alkoxy group. Representative but not limiting examples of heterocyclylalkoxy are 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy and the like.
Der Begriff "Heterocyclylalkyl" , allein oder in Kombination, bezeichnet eine Heterocyclylgruppe, die über eine definitionsgemässe Alkylgruppe verknüpft ist.The term "heterocyclylalkyl", alone or in combination, denotes a heterocyclyl group which is linked via an alkyl group by definition.
Repräsentative, aber nicht limitierende Beispiele für Heterocyclylalkyl sind 2-Pyrid-3-ylmethyl, 2-Pyrimidin-2- ylpropyl und dgl .Representative but not limiting examples of heterocyclylalkyl are 2-pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl and the like.
Der Begriff "Heterocyclyloxy" , allein oder in Kombination, bezeichnet eine Heterocyclylgruppe, über eine Sauerstoffbrücke verknüpft ist. Repräsentative, aber nicht limitierende Beispiele für Heterocyclyloxy sind Pyrid-3- yloxy, Chinolin-3-yloxy und dgl.The term "heterocyclyloxy", alone or in combination, denotes a heterocyclyl group which is linked via an oxygen bridge. Representative but not limiting examples of heterocyclyloxy are pyrid-3-yloxy, quinolin-3-yloxy and the like.
Die Begriffe "Hydroxy" oder "Hydroxyl" , allein oder in Kombination, bezeichnen eine -OH Gruppe. Der Begriff "Hydroxyalkyl", allein oder in Kombination, bezeichnet eine Alkylgruppe, in der mindestens ein Wasserstoffatom durch eine Hydroxylgruppe ersetzt ist. Repräsentative, aber nicht limitierende Beispiele für Hydroxyalkyl sind Hydroxymethyl , 2-Hydroxyethyl, 3- Hydroxypropyl, 2-Ethyl-4-hydroxyheptyl und dgl.The terms "hydroxy" or "hydroxyl", alone or in combination, denote an -OH group. The term "hydroxyalkyl", alone or in combination, denotes an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group. Representative but not limiting examples of hydroxyalkyl are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl and the like.
Der Begriff "Nitro", allein oder in Kombination, bezeichnet eine -N02-Gruppe.The term "nitro", alone or in combination, denotes a -N0 2 group.
Der Begriff "Oxo", allein oder in Kombination, bezeichnet eine =0-Gruppe .The term "oxo", alone or in combination, denotes a = 0 group.
Der Begriff "Oxy", allein oder in Kombination, bezeichnet eine -0- -Gruppe.The term "oxy", alone or in combination, denotes a -0- group.
Die Begriffe "Mercapto" und "Thiol" bezeichnet eine -SH- Gruppe .The terms "mercapto" and "thiol" designate an -SH group.
Die Begriffe "Thio" , "Sulfinyl" und "Sulfonyl" bezeichnet eine -S (0) „-Gruppe mit n= 0,1 und 2.The terms "thio", "sulfinyl" and "sulfonyl" denote an -S (0) "group with n = 0.1 and 2.
Die eingangs definierten Verbindungen der Formel I können in freier Form, als pharmazeutisch verwendbareThe compounds of the formula I defined at the outset can be in free form as pharmaceutically usable
Säureadditionssalze, als pharmazeutisch verwendbare Salze von sauren Verbindungen der Formel I mit Basen, als pharmazeutisch verwendbare Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I sowie als Hydrate oder Solvate davon vorliegen. Der BegriffAcid addition salts, as pharmaceutically usable salts of acidic compounds of formula I with bases, as pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and as hydrates or solvates thereof. The term
"pharmazeutisch verwendbare Salze" bezieht sich auf solche"Pharmaceutically usable salts" refers to such
Salze, welche die biologische Wirkung und Eigenschaften der freien Basen nicht mindern und welche nicht biologisch oder anderweitig unerwünscht sind.Salts which do not diminish the biological effects and properties of the free bases and which are not biologically or otherwise undesirable.
Die Säureadditionssalze werden aus den freien Basen mittels anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure und dgl., vorzugsweise Salzsäure oder Bromwasserstoffsäure, oder mittels organischer Säuren, wie Essigsäure, Propionsäure, Glycolsäure, Brenztraubensäure, Oxalsäure, Maleinsäure, Malonsäure, Bernsteinsäure, Weinsäure, Salicylsäure, Citronensäure, Benzoesäure, Mandelsäure, Methansulfonsäure, p-Toluolsulfonsäure und dgl. gebildet.The acid addition salts are made from the free bases by means of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. preferably hydrochloric acid or hydrobromic acid, or by means of organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Verbindungen der Formel I, die saure Gruppen enthalten, können mit anorganischen Basen oder mit organischen Basen Salze bilden. Bevorzugte Salze mit anorganischen Basen sind, aber nicht ausschliesslich, Natrium-, Kalium-, Lithium-, Ammonium-, Calcium-, Magnesiumsalze und dgl. Bevorzugte Salze mit organischen Basen sind, aber nicht ausschliesslich, Salze mit primären, sekundären und tertiären, gegebenenfalls substituierten Aminen, einschliesslich aller natürlich vorkommenden substituierten Amine, mit cyclischen Aminen und mit basischen Ionenaustauschharzen, wie Isopropylamin, Trimethylamin, Diethylamin, Triethylamin, Tripropylamin, Ethanolamin, Lysin, Arginin, N-Ethylpiperidin, Piperidin, Polyamin-Harze und dgl. Verbindungen der Formel I, die eine saure Gruppe enthalten, können auch als Zwitterionen vorliegen.Compounds of the formula I which contain acidic groups can form salts with inorganic bases or with organic bases. Preferred salts with inorganic bases are, but not exclusively, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Preferred salts with organic bases are, but not exclusively, salts with primary, secondary and tertiary, if appropriate substituted amines, including all naturally occurring substituted amines, with cyclic amines and with basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like compounds of the formula I, which contain an acidic group, can also be present as zwitterions.
Eingangs werden auch pharmazeutisch verwendbare Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I erwähnt. "Pharmazeutisch verwendbare Ester" bedeutet, dass in Verbindungen der Formel I entsprechende funktioneile Gruppen so zu Estergruppen derivatisiert sind, dass sie in vivo wieder in ihre aktive Form zurücktransformiert werden. Einerseits können COOH-Gruppen verestert sein. Beispiele geeigneter derartiger Ester sind die Alkyl- und Aralkylester . Bevorzugte derartige Ester sind die Methyl-, Ethyl-, Propyl-, Butyl- und Benzylester sowie die (R/S) -1- [ (Isopropoxycarbonyl) oxy] ethylester . Besonders bevorzugt sind die Ethylester und die isomeren Butylester. Anderseits können OH-Gruppen verestert sein. Beispiele solcher Verbindungen enthalten physiologisch akzeptable und metabolisch labile Estergruppen, wie Methoxymethylester, Methylthiomethylester, Pivaloyloxymethylester und ähnliche Estergruppen.Pharmaceutically usable esters of compounds of the formula I containing hydroxyl or carboxy groups are also mentioned at the outset. "Pharmaceutically usable esters" means that corresponding functional groups in compounds of the formula I are derivatized to ester groups in such a way that they are transformed back into their active form in vivo. On the one hand, COOH groups can be esterified. Examples of suitable such esters are the alkyl and aralkyl esters. Preferred such esters are the methyl, ethyl, propyl, butyl and benzyl esters and the (R / S) -1- [(isopropoxycarbonyl) oxy] ethyl esters. The ethyl esters and the isomeric butyl esters are particularly preferred. On the other hand, OH groups can be esterified. Examples of such compounds contain physiologically acceptable and metabolically labile ester groups, such as Methoxymethyl ester, methyl thiomethyl ester, pivaloyloxymethyl ester and similar ester groups.
Verbindungen der Formel I wurden im folgenden Test auf ihre Affinität für die NPFF Rezeptoren untersucht:Compounds of the formula I were tested in the following test for their affinity for the NPFF receptors:
Für Neuropeptid FF Rezeptor-Bindungsstudien geeignete Hamster-Zellen (Chinese Hamster Ovary cells, CHOSP10) , welche jeweils den NPFFl oder NPFF2 Rezeptor produzieren, wurden bei Standard-Zellkulturbedingungen vermehrt. DasHamster cells (Chinese Hamster Ovary cells, CHOSP10) suitable for neuropeptide FF receptor binding studies, which each produce the NPFF1 or NPFF2 receptor, were grown under standard cell culture conditions. The
Zellkultur-Medium wurde abgesaugt und 5 ml von Puffer A (5 mM Tris pH=7.4, 1 M MgCl2) pro 17cm Petrischale zugegeben. Die Zellen wurden von der Zellkulturplatte abgeschabt und in ein 50 ml Falkon-Gefäss transferiert. Danach wurden die Zellen 5 Minuten bei 450 g zentrifugiert , wiederum imCell culture medium was aspirated and 5 ml of buffer A (5 mM Tris pH = 7.4, 1 M MgCl 2 ) per 17 cm petri dish was added. The cells were scraped off the cell culture plate and transferred to a 50 ml Falkon tube. The cells were then centrifuged at 450 g for 5 minutes, again in
Puffer A resuspendiert und 30 Sekunden auf einem Polytron Vortex gemixt. Nach Zentrifugieren bei 30' 000 g während 20 Minuten wurde der Überstand verworfen und das Membran- Pellet in 500 μl Puffer C (75 mM Tris pH=7.4, 25 mM MgCl2, 250 mM Saccharose, 0.1 mM PMSF, 0.1 mM Phenanthrolin) aufgenommen. Das Membran-Puffer-Gemisch wurde danach in Aliquots aufgeteilt und tiefgefroren. Der Proteingehalt von einem Aliquot wurde nach der Methode von Lowry bestimmt.Buffer A resuspended and mixed on a Polytron Vortex for 30 seconds. After centrifugation at 30,000 g for 20 minutes, the supernatant was discarded and the membrane pellet was taken up in 500 μl buffer C (75 mM Tris pH = 7.4, 25 mM MgCl 2 , 250 mM sucrose, 0.1 mM PMSF, 0.1 mM phenanthroline) , The membrane-buffer mixture was then divided into aliquots and deep-frozen. The protein content of an aliquot was determined by the Lowry method.
Der Bindungstest wurde in einem Endvolumen von 250 μl durchgeführt. 100 μl Membran-Puffermix entsprechend 35 μgThe binding test was carried out in a final volume of 250 μl. 100 μl membrane buffer mix corresponding to 35 μg
Proteingehalt wurden mit 95 μl Bindungs-Puffer (50 mM Tris pH 7.4, 60 mM NaCl, 0.1 % Protease freies BSA, 0.01% NaN3) gemischt. Nach Zugabe von 5 μl jeweils einer Konzentration Testsubstanz pro Messpunkt, wurde 0.2 nM 125I-Tyrl-NPFF (NEN, NEX381) pro Messpunkt in 50 μl zugegeben. Nach 90 Minuten Inkubatieren bei Zimmertemperatur wurden die Proben durch ein GF/C Filter (Millipore (MAHFC1H60) ) abgesaugt und der Filter mit eiskaltem Bindungs-Puffer mit 3 mal 300 μl gewaschen (Packard Filtermate) . Nach Zugabe von 55 μlProtein contents were mixed with 95 μl binding buffer (50 mM Tris pH 7.4, 60 mM NaCl, 0.1% protease free BSA, 0.01% NaN 3 ). After adding 5 μl of a concentration of test substance per measurement point, 0.2 nM 125 I-Tyrl-NPFF (NEN, NEX381) was added per measurement point in 50 μl. After incubating for 90 minutes at room temperature, the samples were aspirated through a GF / C filter (Millipore (MAHFC1H60)) and the filter was washed with ice-cold binding buffer with 3 times 300 μl (Packard Filtermate). After adding 55 μl
Microscint 40 (Packard 6013641) Scintillationsflüssigkeit wurden die Messpunkte im Gamma-counter (Packard, Top Count NXT) quantifiziert.Microscint 40 (Packard 6013641) scintillation fluid the measuring points were quantified in the gamma counter (Packard, Top Count NXT).
Nicht spezifische Bindung wurde in Gegenwart von 1 μM unmarkiertem Neuropeptid FF ermittelt. Spezifische Bindung ist definiert als die Differenz zwischen totaler und nichtspezifischer Bindung. IC50 Werte werden definiert als diejenige Konzentration des Antagonisten, welche 50% des 12SI-markierten Neuropeptids FF verdrängt. Diese Konzentration wird durch lineare Regressions-Analyse nach logit/log-Transformation der Bindungs-Werte ermittelt.Non-specific binding was determined in the presence of 1 μM unlabeled neuropeptide FF. Specific binding is defined as the difference between total and non-specific binding. IC 50 values are defined as the concentration of the antagonist which displaces 50% of the 12S I-labeled neuropeptide FF. This concentration is determined by linear regression analysis after logit / log transformation of the binding values.
Bevorzugte erfindungsgemässe Verbindungen zeigen in der oben beschriebenen Rezeptor-Bindungsstudie IC50 Werte unter 1000 nM, besonders bevorzugte Verbindungen zeigen IC50 Preferred compounds according to the invention show IC 50 values below 1000 nM in the receptor binding study described above, particularly preferred compounds show IC 50
Werte unter 100 nM, ganz besonders bevorzugte unter 50 nM.Values below 100 nM, very particularly preferred below 50 nM.
Die Ergebnisse des im vorstehend beschriebenen biologischen Tests gemessenen repräsentativen Verbindungen der Formel I sind in der nachfolgenden Tabelle 1 zusammengestellt.The results of the representative compounds of formula I measured in the biological test described above are summarized in Table 1 below.
Tabelle 1: NPFFl-Rezeptor-BindingTable 1: NPFFl receptor binding
Binding Verbindung NPFF-1Binding connection NPFF-1
IC50 [μM]IC50 [μM]
N- (5-Ethyl-5-methyl-4,5, 6 , 7-tetrahydro-N- (5-ethyl-5-methyl-4,5,6,7-tetrahydro-
0.0002 benzothiazol-2-yl) -guanidin0.0002 benzothiazol-2-yl) guanidine
N- (5,5-Dimethyl-4, 5,6, 7-tetrahydro-N- (5,5-dimethyl-4, 5,6, 7-tetrahydro-
0 . 002 benzothiazol-2-yl) -guanidin0. 002 benzothiazol-2-yl) guanidine
N- (4- ert-Butyl-4, 5, 6, 7-tetrahydro- 0 . 002 benzothiazol-2-yl) -guanidinN- (4- ert-butyl-4, 5, 6, 7-tetrahydro-0.002 benzothiazol-2-yl) guanidine
N- (5, 5-Dimethyl-6-phenyl-4, 5, 6,7- 0 . 002 tetrahydro-benzothiazol-2-yl) -guanidinN- (5, 5-Dimethyl-6-phenyl-4,5,6,7-0,002 tetrahydro-benzothiazol-2-yl) guanidine
N- (6-Isopropyl-4, 5,6, 7-tetrahydro- ° • 004 benzothiazol-2-yl) -guanidinN- (6-isopropyl-4, 5,6, 7-tetrahydro- ° • 004 benzothiazol-2-yl) guanidine
N- (6, 6-Dimethyl-4,5, 6, 7-tetrahydro-N- (6, 6-dimethyl-4,5, 6, 7-tetrahydro-
0.004 benzothiazol-2-yl) -guanidin0.004 benzothiazol-2-yl) guanidine
N- (5,5, 7-Trimethyl-4,5, 6 , 7-tetrahydro-N- (5,5,7-trimethyl-4,5,6,7-tetrahydro-
0.004 benzothiazol-2-yl) -guanidin0.004 benzothiazol-2-yl) guanidine
N- (5-Butyl-5, 6, 7, 8-tetrahydro-4H-N- (5-butyl-5, 6, 7, 8-tetrahydro-4H-
0.005 cycloheptathiazol-2-yl) -guanidin0.005 cycloheptathiazol-2-yl) guanidine
N- (5-Butyl-4, 5, 6 , 7-tetrahydro-N- (5-butyl-4, 5, 6, 7-tetrahydro-
0.005 benzothiazol-2-yl) -guanidin0.005 benzothiazol-2-yl) guanidine
N- (4-Ethyl-4-methyl-4, 5, 6, 7-tetrahydro-N- (4-ethyl-4-methyl-4, 5, 6, 7-tetrahydro-
0.005 benzothiazol-2-yl) -guanidin0.005 benzothiazol-2-yl) guanidine
N- [6- (3,4-Dimethoxy-phenyl) -4,5,6,7-N- [6- (3,4-dimethoxyphenyl) -4,5,6,7-
0.005 tetrahydro-benzothiazol-2-yl] -guanidin0.005 tetrahydro-benzothiazol-2-yl] guanidine
N- (5-Methyl-4, 5, 6, 7-tetrahydro-N- (5-methyl-4, 5, 6, 7-tetrahydro-
0.006 benzothiazol-2-yl) -guanidin0.006 benzothiazol-2-yl) guanidine
N- (6-Phenyl-4,5, 6, 7-tetrahydro-N- (6-phenyl-4,5, 6, 7-tetrahydro-
0.006 benzothiazol-2-yl) -guanidin0.006 benzothiazol-2-yl) guanidine
N- (6-Propyl-4, 5,6, 7-tetrahydro-N- (6-propyl-4, 5,6, 7-tetrahydro-
0.007 benzothiazol-2-yl) -guanidin0.007 benzothiazol-2-yl) guanidine
N- (4-Methyl-4-propyl-4, 5,6, 7-tetrahydro-N- (4-methyl-4-propyl-4, 5,6, 7-tetrahydro-
0.007 benzothiazol-2-yl) -guanidin0.007 benzothiazol-2-yl) guanidine
N- (4-Cyclohex-l-enyl-4, 5,6, 7-tetrahydro-N- (4-cyclohex-l-enyl-4, 5,6, 7-tetrahydro-
0.008 benzothiazol-2-yl) -guanidin0.008 benzothiazol-2-yl) guanidine
N- (4-sec-Butyl-4, 5,6, 7-tetrahydro-N- (4-sec-butyl-4, 5,6, 7-tetrahydro-
0.009 benzothiazol-2-yl) -guanidin0.009 benzothiazol-2-yl) guanidine
N- (4-Isobutyl-4-methyl-4, 5, 6, 7-N- (4-isobutyl-4-methyl-4, 5, 6, 7-
0.009 tetrahydro-benzothiazol-2-yl) -guanidin0.009 tetrahydro-benzothiazol-2-yl) guanidine
N- (6-tert-Butyl-4,5,6,7-tetrahydro- 0.010 benzothiazol-2-yl) -guanidinN- (6-tert-butyl-4,5,6,7-tetrahydro-0.010 benzothiazol-2-yl) guanidine
Wie eingangs erwähnt, sind die dort definierten Stoffe aufgrund ihrer Fähigkeit, die Neuropeptid FF Rezeptoren zu blockieren, wertvoll zur Behandlung von Schmerz, von Schmerzüberempfindlichkeit (Hyperalgesie) und von chronischen, akuten, lang andauernden oder vorübergehenden Schmerzen, wobei diese Schmerzen operativen, traumatischen, oder pathologischen Ursprungs sein können. Vor allem ergänzen sie die gängigen Behandlungsmethoden von chronischen Schmerzen mit dem Vorteil, die unerwünschte Opioidtoleranz und/oder Opioidabhängigkeit zu verhindern. Zudem können die Verbindungen zur Regulierung der Insulin- Freisetzung, der Nahrungsaufnahme, von Gedächtnisfunktionen, des Blutdrucks sowie des Elektrolyt- und Energiehaushalts und zur Behandlung der Harninkontinenz eingesetzt werden.As mentioned at the beginning, the substances defined there are valuable for the treatment of pain, hypersensitivity to pain (hyperalgesia) and chronic, acute, long-lasting or temporary pain, due to their ability to block the neuropeptide FF receptors, these pains being operative, traumatic, or can be of pathological origin. Above all, they complement the common treatment methods for chronic pain with the advantage of preventing undesired opioid tolerance and / or opioid dependence. The compounds can also be used to regulate insulin release, food intake, memory functions, blood pressure and the electrolyte and energy balance and to treat urinary incontinence.
Die eingangs definierten Stoffe können nach allgemein bekannten und jedem Fachmann geläufigen Methoden in geeignete galenische Darreichungsformen gebracht werden. Solche Darreichungsformen sind beispielsweise Tabletten, Lacktabletten, Dragees, Kapseln, Injektionslösungen usw. Zur Herstellung solcher galenischer Darreichungsformen geeignete Exzipientien und Hilfsstoffe sind ebenfalls allgemein bekannt und jedem Fachmann geläufig. Ausser einer oder mehreren der eingangs definierten Stoffe können diese Darreichungsformen auch noch weitere pharmakologisch aktive Verbindungen enthalten.The substances defined at the outset can be brought into suitable pharmaceutical dosage forms by methods which are generally known and familiar to any person skilled in the art. Such dosage forms are, for example, tablets, coated tablets, dragees, capsules, injection solutions, etc. Excipients and auxiliaries suitable for producing such pharmaceutical dosage forms are also generally known and familiar to any person skilled in the art. In addition to one or more of the substances defined at the outset, these dosage forms can also contain further pharmacologically active compounds.
Die Dosierung der eingangs definierten Stoffe bzw. der sie enthaltenden Darreichungsformen ist vom behandelnden Arzt den jeweiligen Bedürfnissen des Patienten anzupassen. Im Allgemeinen dürfte eine Tagesdosis von 0.1-20 mg, bevorzugt 0.5-5 mg eines der eingangs definierten Stoffe pro kg Körpergewicht des Patienten angebracht sein. Die Guanidinderivate der allgemeinen Formel I, sowie die entsprechenden Ausgangs- und Zwischenprodukte können mittels in der organischen Synthese bekannter Methoden hergestellt und unter Verwenden bekannter Techniken wie Fällen, Chromatographieren, Kristallisieren, präperative reversed-phase HPLC, usw. isoliert und gereinigt werden.The dosage of the substances defined at the outset or of the dosage forms containing them must be adjusted by the attending physician to the respective needs of the patient. In general, a daily dose of 0.1-20 mg, preferably 0.5-5 mg of one of the substances defined at the beginning per kg of body weight of the patient should be appropriate. The guanidine derivatives of the general formula I and the corresponding starting materials and intermediates can be prepared using methods known in organic synthesis and can be isolated and purified using known techniques such as precipitation, chromatography, crystallization, preparative reversed-phase HPLC, etc.
Allfällig erhaltene Stereoisomerengemische, wie Racemate, können nach allgemein üblichen Methoden aufgetrennt werden, bevorzugt durch Chromatographieren an einer chiralen Phase .Any stereoisomer mixtures obtained, such as racemates, can be separated by generally customary methods, preferably by chromatography on a chiral phase.
Die Herstellung der Guanidinderivate der allgemeinen Formel I erfolgt gemäss dem nachstehenden Schema 1:The guanidine derivatives of the general formula I are prepared according to scheme 1 below:
Schema 1Scheme 1
Eine Verbindung der Formel 1, worin das in A allfällig vorhandene Stickstoffatom geschützt ist, wird in α-Stellung zur Carbonylgruppe halogeniert, worauf man die erhaltene Verbindung der Formel 2 mit einem Thioharnstoffderivat , wieA compound of formula 1, in which the nitrogen atom present in A is protected, is halogenated in the α-position to the carbonyl group, whereupon the compound of formula 2 obtained is obtained with a thiourea derivative, such as
2-Imino-4-thiobiuret der Formel 3, einer Cyclokondensation unterwirft, gegebenenfalls aus der erhaltenen Verbindung die an dem allfällig vorhandenen Stickstoffatom sitzende Schutzgruppe abspaltet, gegebenenfalls dieses Stickstoffatome mit einem einen Rest R' abgebenden Mittel entsprechend substituiert und gegebenenfalls eine erhaltene basische Verbindung in ein pharmazeutisch verwendbares Säureadditionssalz, bzw. eine erhaltene, eine saure Gruppe enthaltende Verbindung in ein pharmazeutisch verwendbares Salz mit einer Base, bzw. eine erhaltene Hydroxy- oder Carboxygruppe enthaltende Verbindung in einen pharmazeutisch verwendbaren Ester überführt und gegebenenfalls das erhaltene Produkt in ein Hydrat oder Solvat überführt .2-Imino-4-thiobiuret of the formula 3, is subjected to cyclocondensation, optionally splitting off the protective group attached to the nitrogen atom which may be present from the compound obtained, optionally substituting this nitrogen atom appropriately with an agent which gives off a radical R 'and optionally a basic compound obtained in a pharmaceutically usable acid addition salt, or a compound containing an acid group obtained in a pharmaceutically usable salt with a base, or a compound containing a hydroxyl or carboxy group obtained in one transferred pharmaceutically usable ester and optionally the product obtained is converted into a hydrate or solvate.
Da in den neuen Verbindungen der Formel I die Kette A kein Stickstoffatom enthalten kann, sind die vorstehenden Ausführungen über eine N-Schutzgruppe, deren Abspaltung und fakultative N-Substitution des Endproduktes für die Herstellung dieser neuen Verbindungen irrelevant . Demgemäss lassen sich die erfindungsgemässen neuen Produkte einfach dadurch herstellen, dass man eine Verbindung der obigenSince the chain A in the new compounds of the formula I cannot contain a nitrogen atom, the above statements about an N-protecting group, its elimination and optional N-substitution of the end product are irrelevant for the preparation of these new compounds. Accordingly, the new products according to the invention can be produced simply by combining the above
Formel 1 in α-Stellung zur Carbonylgruppe halogeniert, die erhaltene Verbindung der obigen Formel 2 mit 2-Imino-4- thiobiuret der obigen Formel 3 einer Cyclokondensation unterwirft und gegebenenfalls eine erhaltene basische Verbindung in ein pharmazeutisch verwendbares Säureadditionssalz, bzw. eine erhaltene, eine saure Gruppe enthaltende Verbindung in ein pharmazeutisch verwendbares Salz mit einer Base, bzw. eine erhaltene Hydroxy- oder Carboxygruppen enthaltende Verbindung in einen pharmazeutisch verwendbaren Ester überführt und gegebenenfalls das erhaltene Produkt in ein Hydrat oder Solvat überführt .Formula 1 halogenated in the α-position to the carbonyl group, the resulting compound of the above formula 2 with 2-imino-4-thiobiuret of the above formula 3 is subjected to a cyclocondensation and, if appropriate, a basic compound obtained in a pharmaceutically acceptable acid addition salt, or a obtained one acidic group-containing compound is converted into a pharmaceutically acceptable salt with a base, or a compound containing hydroxyl or carboxy groups obtained is converted into a pharmaceutically acceptable ester and, if appropriate, the product obtained is converted into a hydrate or solvate.
Typischerweise wird die Synthese sowohl derTypically, the synthesis of both
Guanidinderivate der Formel I als auch der entsprechenden Zwischenprodukte in Lösung unter Verwendung eines organischen Lösungsmittels durchgeführt. Einführen und Entfernen von Schutzgruppen erfolgen mit typischen, dem Fachmann bekannten Methoden (T.W. Greene & P.G.M. Wuts inGuanidine derivatives of the formula I and the corresponding intermediates are carried out in solution using an organic solvent. Protective groups are introduced and removed using typical methods known to those skilled in the art (T.W. Greene & P.G.M. Wuts in
Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999) . Allgemein können Cycloalkanone (1) mit bekannten Methoden in Position α zur Carbonylgruppe halogeniert werden. Die nachfolgende Cyclokondensation von α-Halo-oxoverbindungen (2) mit einem Thioharnstoffderivat, wie z. B. 2-Imino-4-thiobiuret (3) erfolgt in bekannter Art und führt zu den gewünschten Guanidinderivaten der Formel I (J. Med. Chem. 1991, 34(3), 914-918; J. Med. Chem. 1994, 37(8), 1189-1199). Generell können heterocyclische Oxoverbindungen (1) in analoger Weise zu den entsprechendenProtective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999). In general, cycloalkanones (1) can be halogenated to the carbonyl group in position α using known methods. The subsequent cyclocondensation of α-halo-oxo compounds (2) with a thiourea derivative, such as. B. 2-imino-4-thiobiuret (3) takes place in a known manner and leads to the desired guanidine derivatives of the formula I (J. Med. Chem. 1991, 34 (3), 914-918; J. Med. Chem. 1994, 37 (8), 1189-1199). In general, heterocyclic oxo compounds (1) can be used in an analogous manner to the corresponding ones
ZielVerbindungen der Formel I umgesetzt werden. Zu beachten gilt dabei, dass eine in A des Ausgangsprodukts vorhandene -NH-Gruppe (vgl. die nachstehende Formel 4) mit einer gängigen Schutzgruppe (PG) versehen werden soll, siehe das nachfolgende Schema 2 :Target compounds of Formula I are implemented. It should be noted here that an -NH group present in A of the starting product (cf. formula 4 below) should be provided with a common protective group (PG), see scheme 2 below:
Schema 2Scheme 2
m m
Die benötigten cyclischen Azaketone der Formel 4 sind teilweise literaturbekannt (Yokoo et al . , Bull. Chem. Soc . Japan 1959, 29, 631; Griss et al . , DE 2206385, publiziert 10. Februar 1972) oder können analog der Vorstufe für Beispiel N-07 hergestellt werden.The cyclic azaketones of the formula 4 required are known in some cases from the literature (Yokoo et al., Bull. Chem. Soc. Japan 1959, 29, 631; Griss et al., DE 2206385, published February 10, 1972) or can be analogous to the precursor for example N-07 can be manufactured.
Halogenieren von 5 und Cyclokondensation von 6 mit 2-Imino- 4-thiobiuret (3) zum entsprechend N-geschützten bicyclischen Guanidinothiazol 7 erfolgt unter bekanntenHalogenation of 5 and cyclocondensation of 6 with 2-imino-4-thiobiuret (3) to give the correspondingly N-protected bicyclic guanidinothiazole 7 is carried out under known methods
Bedingungen. Nach Abspalten der Schutzgruppe, was zu 8 führt, werden die eingangs definierten R' -Reste unter bekannten Bedingungen mittels den jeweils entsprechenden R' abgebenden Reagenzien, wie z.B. Alkylhalogenide, Carbonsäurehalogenide oder -anhydride, oder auch Carbonsäuren in Gegenwart von Kupplungsreagenzien und mit Base als Hilfsreagens, Chlorformiaten, Sulfonylhalogeniden, Isocyanaten, Isothiocyanaten und dgl. zur entsprechenden Verbindung der Formel III umgesetzt.Conditions. After the protective group has been split off, which leads to 8, the R 'radicals defined at the outset are known under known conditions by means of the corresponding R' releasing reagents, such as, for example, alkyl halides, carboxylic acid halides or anhydrides, or also carboxylic acids in the presence of coupling reagents and with base as Auxiliary reagent, chloroformates, sulfonyl halides, Isocyanates, isothiocyanates and the like. Reacted to the corresponding compound of formula III.
Geeignete organische Lösungsmittel sind solche, welche sich unter den gewählten Reaktionsbedingungen inert verhalten. Es sind dies bevorzugt Ether, wie Diethylether, Dioxan, Tetrahydrofuran oder Glycoldimethylether; oder Alkohole, wie zum Beispiel Methanol, Ethanol, Propanol, Isopropanol, Butanol, Isobutanol oder tert-Butanol; oder Kohlenwasserstoffe, wie Benzol, Toluol, Xylol, Hexan,Suitable organic solvents are those which are inert under the chosen reaction conditions. These are preferably ethers, such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether; or alcohols, such as, for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; or hydrocarbons, such as benzene, toluene, xylene, hexane,
Cyclohexan oder Petroleum-Fraktionen; oder halogenierte Kohlenwasserstoffe, wie Dichlormethan, Trichlormethan, Tetrachlormethan, Dichlorethylen, Trichlorethylen oder Chlorbenzol; oder auch Ethylacetat, Triethylamin, Pyridin, Dimethylsulfoxid, Dirnethylformamid, Hexamethyl- phosphoramid, Acetonitril, Aceton oder Nitromethan. Ebenfalls können Mischungen der erwähnten Lösungsmittel verwendet werden .Cyclohexane or petroleum fractions; or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene; or also ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphoramide, acetonitrile, acetone or nitromethane. Mixtures of the solvents mentioned can also be used.
Basen, welche für die beschriebenen Prozesse verwendet werden können, sind im allgemeinen anorganische oder organische Basen. Bevorzugt werden Alkalimetallhydroxide, zum Beispiel Natrium- oder Kaliumhydroxid, Erdalkalimetallhydroxide, zum Beispiel Bariumhydroxid, Alkalimetallcarbonate wie Natriumcarbonat oder Kaliumcarbonat , Erdalkalimetallcarbonate, wie Calciumcarbonat , oder Alkalimetall- oderBases that can be used for the processes described are generally inorganic or organic bases. Alkali metal hydroxides, for example sodium or potassium hydroxide, alkaline earth metal hydroxides, for example barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or
Erdalkalimetallalkoxide wie Natrium- oder Kaliummethoxid, Natrium- oder Kaliumethoxid oder Kalium- ert-butoxid, oder organische Amine, z.B Trialkyl- -amine, wie Triethylamin, oder heterocyclische Amine, wie 1,4- Diazabicyclo [2.2.2] octan (DABCO) , 1,8- Diazabicyclo [5.4.0] undec-7-en (DBU) , Pyridin, 4- Dimethylaminopyridin, N-Methyl-piperidin oder N- Methylmorpholin. Es ist auch möglich, Alkalimetalle, wie Natrium, oder deren Hydride, wie Natriumhydrid, zu verwenden. Die erwähnten Basen können, wo dienlich, als säurebindendes Hilfsmittel verwendet werden. Als Kupplungsreagenzien können dehydratisierende Reagenzien dienen, beispielsweise Carbodiimide, wieAlkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium ert-butoxide, or organic amines, for example trialkyl -amines, such as triethylamine, or heterocyclic amines, such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine , N-methyl-piperidine or N-methylmorpholine. It is also possible to use alkali metals, such as sodium, or their hydrides, such as sodium hydride. The bases mentioned can, where appropriate, be used as an acid-binding auxiliary. Dehydrating reagents can serve as coupling reagents, for example carbodiimides such as
Diisopropylcarbodiimid, Dicyclohexylcarbodiimid oder N-(3- Dimethylaminopropyl) -N' -ethylcarbodiimid-hydrochlorid, oder Carbonylverbindungen, wie Carbonyldiimidazol, oder 1,2- Oxazolium-Verbindungen, wie 2-Ethyl-5-phenyl-isoxazolium-3- sulfonat, oder auch Propanphosphonsäureanhydrid oder iso- Butylchloroformiat oder Benzotriazolyloxy-tris- (dimethylamino)phosphonium-hexafluorophosphat (BOP) oder Diphenylphosphoramidat oder Methansulfonylchlorid, wenn angebracht in Gegenwart von Basen, wie Triethylamin oder N- Ethylmorpholin oder N-Methylpiperidin oder Diisopropylethylamin .Diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride, or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-isoxazolium-3-sulfonate, or also propanephosphonic anhydride or iso-butylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) or diphenylphosphoramidate or methanesulfonyl chloride, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperethylamine or diisopropylamine.
Die nachfolgenden Beispiele sollen zur Erläuterung der vorliegenden Erfindung dienen, diese aber in keiner Weise einschränken. Die erhaltenen Produkte werden in den nachstehenden Tabellen 3 und 4 angegeben.The following examples are intended to illustrate the present invention, but in no way limit it. The products obtained are given in Tables 3 and 4 below.
Beispiel C-01 rac . N- (6-Isopropyl-4 ,5,6, 7-tetrahvdro-benzothiazol-2-yl) - guanidinExample C-01 rac. N- (6-isopropyl-4, 5,6, 7-tetrahvdro-benzothiazol-2-yl) guanidine
Zu einer Lösung von 2-Brom-4-isopropyl-cyclohexanon (5 mmol) in Ethanol (10 ml) werden unter Rühren 2-Imino-4- thiobiuret (5 mmol) gegeben und das Reaktionsgemisch anschliessend während 16 Stunden am Rückfluss gekocht . Nach Abdampfen des Lösungsmittels wird der Rückstand mit Essigester versetzt und das ausgefallene Produkt durch Abfiltrieren isoliert: tR 2.75 min (LC-1, ein Peak); ESI-MS2-Imino-4-thiobiuret (5 mmol) is added to a solution of 2-bromo-4-isopropyl-cyclohexanone (5 mmol) in ethanol (10 ml) with stirring and the reaction mixture is then refluxed for 16 hours. After the solvent has been evaporated off, ethyl acetate is added to the residue and the precipitated product is isolated by filtration: t R 2.75 min (LC-1, one peak); ESI-MS
(+/-): m/z 239.25 [M+H] + / 237.24 [M-H]".(+/-): m / z 239.25 [M + H] + / 237.24 [MH] " .
2-Brom-4-isopropyl-cyclohexanon (Ausgangsprodukt für Beispiel C-01) Zu einer Lösung von 4-Isopropyl-cyclohexanon (5 mmol) in Diethylether (10 ml) wird bei Raumtemperatur Brom (5 mmol) zugetropft. Nach beendeter Zugabe wird das Reaktionsgemisch während 30 min weitergerührt. Nach Zugabe von gesättigter wassriger Natriumsulfit-Lösung (5 ml) wird mit Diethylether extrahiert, die vereinigten organischen Phasen werden nach Trocknen über Natriumsulfat eingedampft. Das als Rohprodukt erhaltene Bromketon wird ohne weitere Reinigung direkt im nächsten Schritt mit 2-Imino-4-thiobiuret zur Reaktion gebracht .2-Bromo-4-isopropyl-cyclohexanone (starting product for Example C-01) To a solution of 4-isopropyl-cyclohexanone (5 mmol) in diethyl ether (10 ml), bromine (5 mmol) is added dropwise at room temperature. After the addition has ended, the reaction mixture is stirred for a further 30 min. After adding saturated aqueous sodium sulfite solution (5 ml) is extracted with diethyl ether, the combined organic phases are evaporated after drying over sodium sulfate. The bromoketone obtained as the crude product is reacted with 2-imino-4-thiobiuret directly in the next step without further purification.
Analog zur Herstellung von Beispiel C-01 werden ausgehend von den entsprechenden α-Brom- oder α-Chlorketonen die Verbindungen gemäss Beispielen C-02 bis C-73 in Tabelle 3 hergestellt .Analogously to the preparation of Example C-01, the compounds according to Examples C-02 to C-73 in Table 3 are prepared starting from the corresponding α-bromo or α-chloro ketones.
Die Bromierung der in den Beispielen C-02 bis C-17 verwendeten Ketone erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl-cyclohexanon beschrieben. Die α-Bromketone werden generell alsThe bromination of the ketones used in Examples C-02 to C-17 is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropylcyclohexanone. The α-bromoketones are generally called
Rohprodukte ohne weitere Charakterisierung umgesetzt .Raw products implemented without further characterization.
3 -Butylcyclohexanon (Vorprodukt für Beispiel C-05)3-butylcyclohexanone (precursor for example C-05)
Eine Lösung von Kupferiodid (6.3 mmol) in Dimethylsulfid (12 ml) wird auf 50°C gekühlt. Unter Rühren wird eineA solution of copper iodide (6.3 mmol) in dimethyl sulfide (12 ml) is cooled to 50 ° C. With stirring, a
Lösung von Butyllithium (6.2 mmol) zugetropft und während 5 bis 15 min weitergerührt . Das Reaktionsgemisch wird auf -Solution of butyllithium (6.2 mmol) was added dropwise and stirring continued for 5 to 15 min. The reaction mixture is
78°C gekühlt und nachfolgend eine auf -78°C vorgekühlte Lösung von Cyclohex-2-enon (6 mmol) , gelöst in Dimethylsulfid (1 ml), langsam zugetropft. Nach einstündigem Rühren bei -78°C wird mit gesättigter wassriger Ammoniumchlorid-Lösung gequencht . Das auf Raumtemperatur erwärmte Reaktionsgemisch wird mit Diethylether extrahiert. Die vereinigten Ether-Phasen werden mit gesättigter wassriger Ammoniumchlorid-Lösung gewaschen und über Natriumsulf t getrocknet. Nach Abdampfen des Lösungsmittels wird der erhaltene Rückstand in Hexan aufgenommen, die Lösung wird filtriert und eingedampft. Nach Chromatographieren des Rückstands an Kieselgel mit Ethylacetat/ Hexan 1:4 wird reines 3-Butylcyclohexanon erhalten (Tetrahedron 1989, 45 (2), 425-434). 2-Brom-5-butyl-cyclohexanon (Ausgangsprodukt für Beispiel C-05)Cooled 78 ° C and then a solution of cyclohex-2-enone (6 mmol), pre-cooled to -78 ° C, dissolved in dimethyl sulfide (1 ml), slowly added dropwise. After stirring for one hour at -78 ° C., the mixture is quenched with saturated aqueous ammonium chloride solution. The reaction mixture warmed to room temperature is extracted with diethyl ether. The combined ether phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is taken up in hexane, the solution is filtered and evaporated. After chromatography of the residue on silica gel with ethyl acetate / hexane 1: 4, pure 3-butylcyclohexanone is obtained (Tetrahedron 1989, 45 (2), 425-434). 2-bromo-5-butyl-cyclohexanone (starting product for example C-05)
Die Bromierung von 3-Butylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl- cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 3-butylcyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropylcyclohexanone. The title compound is implemented as a crude product without further characterization.
2- ert-Butyl-6-chlorcyclohexanon (Ausgangsprodukt für Beispiel C-07) Zu einer auf 0°C gekühlten Lösung von Diisopropylamin (5.5 mmol) in trockenem Tetrahydrofuran wird tropfenweise N- Butyllithium zugegeben. Nach vollständiger Zugabe wird auf2-Ert-butyl-6-chlorocyclohexanone (starting product for example C-07) N-butyllithium is added dropwise to a solution of diisopropylamine (5.5 mmol) in dry tetrahydrofuran which is cooled to 0 ° C. After the addition is complete
-78°C gekühlt, und eine Lösung von 2- tert-Butylcyclohexanon-78 ° C cooled, and a solution of 2-tert-butylcyclohexanone
(5 mmol) in trockenem Tetrahydrofuran (50 ml) eingetragen, gefolgt von der Zugabe von p-Toluolsulfonylchorid (5 mmol) , gelöst ebenfalls in trockenem Tetrahydrofuran (50 ml) . Das Reaktionsgemisch wird auf Raumtemperatur erwärmt und nach 30 min Rühren über Kieselgel mit Ether als Elutionsmittel filtriert. Nach Eindampfen im Vakuum wird 2- ert-Butyl-6- chlorcyclohexanon (760 mg) in 81% Ausbeute erhalten (Tet. Lett. 1999, 40(12), 2231-2234).(5 mmol) in dry tetrahydrofuran (50 ml), followed by the addition of p-toluenesulfonyl chloride (5 mmol), also dissolved in dry tetrahydrofuran (50 ml). The reaction mixture is warmed to room temperature and, after stirring for 30 min, filtered through silica gel with ether as the eluent. After evaporation in vacuo, 2-tert-butyl-6-chlorocyclohexanone (760 mg) is obtained in 81% yield (Tet. Lett. 1999, 40 (12), 2231-2234).
4 , 4-Dimethylcyclohexanon (Vorprodukt für Beispiel C-ll)4, 4-dimethylcyclohexanone (precursor for example C-II)
Eine Lösung von 4 , 4-Dimethyl-cyclohex-2-enon (3 mmol) in Ethylacetat wird über Nacht bei Raumtemperatur an Pd/CA solution of 4, 4-dimethyl-cyclohex-2-enone (3 mmol) in ethyl acetate is overnight at room temperature on Pd / C
(0.05 mmol) mit Wasserstoff unter Normaldruck hydriert.(0.05 mmol) hydrogenated with hydrogen under normal pressure.
Filtrieren über Celite und nachfolgendes Eindampfen ergibtFiltration through Celite and subsequent evaporation gives
4, 4-Dimethyl-cyclohexanon (355 mg) in 94% Ausbeute (J. Org.4, 4-Dimethyl-cyclohexanone (355 mg) in 94% yield (J. Org.
Chem. 2001, 66 (3), 733-738).Chem. 2001, 66 (3), 733-738).
2-Brom-4 , 4-dimethylcyclohexanon (Ausgangsprodukt für2-bromo-4, 4-dimethylcyclohexanone (starting product for
Beispiel C-ll)Example C-ll)
Die Bromierung von 4 , 4-Dimethylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt . 2 -sec-Butyl-6-chlor-cyclohexanon (Ausgangsprodukt fürThe bromination of 4, 4-dimethylcyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization. 2-sec-butyl-6-chloro-cyclohexanone (starting product for
Beispiel C-18)Example C-18)
Die Chlorierung von 2-sec-Butylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-tert-The chlorination of 2-sec-butylcyclohexanone is carried out in an analogous manner to that for the preparation of 2-tert-
Butyl-6-chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .Butyl-6-chloro-cyclohexanone described. The title compound is implemented as a crude product without further characterization.
3-Chlor-bicyclohexyl-l ' -en-2-on (Ausgangsprodukt für Beispiel C-19)3-chloro-bicyclohexyl-l '-en-2-one (starting product for example C-19)
Die Chlorierung von 2- (1-Cyclohexenyl) cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-tert-The chlorination of 2- (1-cyclohexenyl) cyclohexanone is carried out in an analogous manner to that for the preparation of 2-tert-
Butyl-6 -chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .Butyl-6-chloro-cyclohexanone described. The title compound is implemented as a crude product without further characterization.
2-Benzyl-6-chlor-cyclohexanon (Ausgangsprodukt für Beispiel C-20) Die Chlorierung von 2-Benzylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-tert-2-Benzyl-6-chloro-cyclohexanone (starting product for example C-20) The chlorination of 2-benzylcyclohexanone is carried out in an analogous manner to that for the preparation of 2-tert-
Butyl-6-chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .Butyl-6-chloro-cyclohexanone described. The title compound is implemented as a crude product without further characterization.
2-Allyl-6-chlor-cyclohexanon (Ausgangsprodukt für Beispiel2-Allyl-6-chloro-cyclohexanone (starting product for example
C-21)C-21)
Die Chlorierung von 2-Allylcyclohexanon erfolgt in analogerThe chlorination of 2-allylcyclohexanone takes place in an analogous manner
Weise wie oben für die Herstellung von 2- tert-Butyl-6- chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.Way as described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is implemented as a crude product without further characterization.
2-Chlor-6-phenyl-cyclohexanon (Ausgangsprodukt für Beispiel C-22) Die Chlorierung von 2 -Phenylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-tert-2-chloro-6-phenyl-cyclohexanone (starting product for example C-22) The chlorination of 2-phenylcyclohexanone is carried out in an analogous manner to that for the preparation of 2-tert-
Butyl-6-chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .Butyl-6-chloro-cyclohexanone described. The title link is implemented as a raw product without further characterization.
Ethyl (3-Chlor-2-oxo-cyclohexyl) -acetat (Ausgangsprodukt für Beispiel C-23)Ethyl (3-chloro-2-oxo-cyclohexyl) acetate (starting product for example C-23)
Die Chlorierung von Ethyl (2 -Oxo-cyclohexyl) -acetat erfolgt in analoger Weise wie oben für die Herstellung von 2- ert- Butyl-6-chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.The chlorination of ethyl (2-oxo-cyclohexyl) acetate is carried out in an analogous manner to that described above for the preparation of 2-butyl-6-chloro-cyclohexanone. The title compound is implemented as a crude product without further characterization.
3- (3-Chlor-2-oxo-cyclohexyl) -propionitril (Ausgangsprodukt für Beispiel C-24)3- (3-chloro-2-oxo-cyclohexyl) propionitrile (starting product for example C-24)
Die Chlorierung von 2-Oxo-l-cyclohexanpropionitril erfolgt in analoger Weise wie oben für die Herstellung von 2-tert-The chlorination of 2-oxo-1-cyclohexane propionitrile is carried out in an analogous manner to that for the preparation of 2-tert-
Butyl-6-chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .Butyl-6-chloro-cyclohexanone described. The title compound is implemented as a crude product without further characterization.
2 -Chlor-6-methyl-cyclohexanon (Ausgangsprodukt für Beispiel C-25)2-chloro-6-methyl-cyclohexanone (starting product for example C-25)
Die Chlorierung von 2-Methylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2- ert- Butyl- 6 -chlor-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The chlorination of 2-methylcyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is implemented as a crude product without further characterization.
2 , 2-Dimethyl-cyclohexanon (Vorprodukt für Beispiel C-26) Eine Suspension von Kaliumhydrid (5.5 mmol) und 2- Methylcyclohexanon (5 mmol) in trockenem Tetrahydrofuran2, 2-Dimethyl-cyclohexanone (precursor for example C-26) A suspension of potassium hydride (5.5 mmol) and 2-methylcyclohexanone (5 mmol) in dry tetrahydrofuran
(10 ml) wird während 30 min bei Raumtemperatur gerührt. Man tropft langsam Triethylboran (6.25 mmol) zu und rührt 16 Stunden bei Raumtemperatur. Nach Zugabe von Methyliodid wird weitere 8 Stunden gerührt, die Reaktion anschliessend mit gesättigter wassriger Ammoniumchlorid-Lösung gequencht und zweimal mit Diethylether extrahiert . Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und im Vakuum zur Trockene eingeengt und ergeben die Titelverbindung, welche ohne ohne Aufreinigung weiter umgesetzt werden kann (JACS 1985, 107, 19, 5391-5396) .(10 ml) is stirred at room temperature for 30 min. Triethylborane (6.25 mmol) is slowly added dropwise and the mixture is stirred at room temperature for 16 hours. After the addition of methyl iodide, the mixture is stirred for a further 8 hours, the reaction is then quenched with saturated aqueous ammonium chloride solution and extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate and evaporated to dryness in vacuo and give the title compound which can be reacted further without purification (JACS 1985, 107, 19, 5391-5396).
6-Brom-2 , 2-dimethyl-cyclohexanon (Ausgangsprodukt für Beispiel C-26)6-bromo-2, 2-dimethyl-cyclohexanone (starting product for example C-26)
Die Bromierung von 2 , 2 -Dimethyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 2,2-dimethyl-cyclohexanone takes place in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
2-Ethyl-2 -methyl-cyclohexanon (Vorprodukt für Beispiel C- 27) Die Alkylierung von 2-Methylcyclohexanon mit Ethyliodid erfolgt in analoger Weise wie oben für die Herstellung von 2 , 2-Dimethyl-cyclohexanon beschrieben.2-ethyl-2-methyl-cyclohexanone (precursor for example C-27) The alkylation of 2-methylcyclohexanone with ethyl iodide is carried out in an analogous manner to that described above for the preparation of 2, 2-dimethyl-cyclohexanone.
6-Brom-2-ethyl-2-methyl-cyclohexanon (Ausgangsprodukt für Beispiel C-27)6-bromo-2-ethyl-2-methyl-cyclohexanone (starting product for example C-27)
Die Bromierung von 2-Ethyl-2-methyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 2-ethyl-2-methyl-cyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
2 -Isobutyl-2-methyl-cyclohexanon (Vorprodukt für Beispiel C-28) Die Alkylierung von 2-Methylcyclohexanon mit l-Iod-2- methyl-propan erfolgt in analoger Weise wie oben für die Herstellung von 2 , 2-Dimethyl-cyclohexanon beschrieben.2-isobutyl-2-methyl-cyclohexanone (precursor for Example C-28) The alkylation of 2-methylcyclohexanone with l-iodo-2-methyl-propane is carried out in a manner analogous to that for the preparation of 2, 2-dimethyl-cyclohexanone described.
6-Brom-2-isobutyl-2 -methyl-cyclohexanon (Ausgangsprodukt für Beispiel C-28)6-bromo-2-isobutyl-2-methylcyclohexanone (starting product for example C-28)
Die Bromierung von 2-Isobutyl-2-methyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom- 4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 2-isobutyl-2-methyl-cyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title link is implemented as a raw product without further characterization.
2 -Methyl-2 -propyl-cyclohexanon (Vorprodukt für Beispiel C- 29)2-methyl-2-propyl-cyclohexanone (precursor for example C-29)
Die Alkylierung von 2-Methylcyclohexanon mit 1-Iodpropan erfolgt in analoger Weise wie oben für die Herstellung von 2 , 2 -Dimethyl-cyclohexanon beschrieben.The alkylation of 2-methylcyclohexanone with 1-iodopropane is carried out in an analogous manner to that described above for the preparation of 2, 2-dimethylcyclohexanone.
6-Brom-2 -methyl-2-propyl-cyclohexanon (Ausgangsprodukt für Beispiel C-29)6-bromo-2-methyl-2-propyl-cyclohexanone (starting product for example C-29)
Die Bromierung von 2-Methyl-2-propyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom- 4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 2-methyl-2-propyl-cyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
Beispiel C-30 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- ethylesterExample C-30 Ethyl 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylate
Analog zur Herstellung von Beispiel C-01 wird 3-Brom-2-oxo- cyclohexancarbonsäureethylester mit 2-Imino-4-thiobiuret zur Titelverbindung umgesetzt.Analogously to the preparation of Example C-01, 3-bromo-2-oxocyclohexanecarboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to give the title compound.
3 -Brom-2-oxo-cyclohexancarbonsäure-ethylester3-Bromo-2-oxo-cyclohexane carboxylic acid ethyl ester
(Ausgangsprodukt für Beispiel C-30)(Starting product for example C-30)
Die Bromierung von 2-Oxo-cyclohexancarbonsäure-ethylester erfolgt in analoger Weise wie oben für die Herstellung von 2 -Brom-4-isopropyl-cyclohexanon beschrieben. DieThe bromination of 2-oxo-cyclohexane carboxylic acid ethyl ester takes place in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The
Titelverbindung wird als Rohprodukt ohne weitereTitle compound is used as a crude product without further
Charakterisierung umgesetzt.Characterization implemented.
Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4 -carbonsäure Eine Suspension von 2-Guanidino-4 , 5, 6 , 7-tetrahydro- benzothiazol-4-carbonsäure-ethylester (5 mmol) und Natriumhydroxid (20 mmol) in Methanol/ Wasser (4:1, 10 ml) wird über Nacht bei Raumtemperatur gerührt . Man stellt durch Zugabe von 25% Chlorwasserstoffsäure auf pH 5 und filtriert das ausgefallene Produkt ab. Auf diese Weise erhält man die Titelverbindung (671 mg) in 56% Ausbeute: tR Guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid A suspension of 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester (5 mmol) and sodium hydroxide (20 mmol ) in methanol / water (4: 1, 10 ml) is stirred overnight at room temperature. One poses by adding 25% hydrochloric acid to pH 5 and filtering off the precipitated product. In this way, the title compound (671 mg) is obtained in 56% yield: t R
0.64 min (LC-1); ESI-MS (+/-): m/z 241.49 [M+H] + / 239.37 [M-HΓ .0.64 min (LC-1); ESI-MS (+/-): m / z 241.49 [M + H] + / 239.37 [M-HΓ.
Beispiel C-31Example C-31
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- benzylamid und sein Formiat 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure (0.1 mmol), Diisopropylethylamin (0.2 mmol), O- (Benzotriazol-1-yl) -N,N,N' ,N' -tetramethyluronium- hexafluorophosphat (0.1 mmol) und Benzylamin (0.2 mmol) werden in Dimethylformamid (0.5 ml) gelöst und über Nacht bei Raumtemperatur gerührt. Nach Entfernen des2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid benzylamide and its formate 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid (0.1 mmol), diisopropylethylamine ( 0.2 mmol), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.1 mmol) and benzylamine (0.2 mmol) are dissolved in dimethylformamide (0.5 ml) and overnight at room temperature touched. After removing the
Lösungsmittels im Vakuum wird der Rückstand in Essigester (1 ml) und IM wassriger Natronlauge (0.5 ml) verteilt. Man trennt die Phasen, trocknet die organische Phase über Natriumsulfat, dampft das Lösungsmittel ab und erhält die reine Titelverbindung mittels präparativer HPLC (WatersSolvent in vacuo, the residue is distributed in ethyl acetate (1 ml) and 1N aqueous sodium hydroxide solution (0.5 ml). The phases are separated, the organic phase is dried over sodium sulfate, the solvent is evaporated off and the pure title compound is obtained by means of preparative HPLC (Waters
Prep LC ausgerüstet mit einem Waters 600 Controller, Waters 2767 Sample Manager, Waters 996 Massenspektrometer und Photodioden-Array Detektor) .Prep LC equipped with a Waters 600 controller, Waters 2767 sample manager, Waters 996 mass spectrometer and photodiode array detector).
Analog zu Beispiel C-31 werden die Verbindungen der in Tabelle 3 aufgeführten Beispiele C-32 bis C-41 durch Reaktion von 2-Guanidino-4, 5 , 6 , 7-tetrahydro-benzothiazol-4- carbonsäure mit den entsprechenden Aminen in Gegenwart eines Kupplungsreagenzes wie O- (Benzotriazol-1-yl) - N,N,N' ,N' -tetramethyluronium-hexafluorophosphat hergestellt .Analogously to Example C-31, the compounds of Examples C-32 to C-41 listed in Table 3 are obtained by reacting 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid with the corresponding amines in the presence a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
Beispiel C 42Example C 42
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- ethylester2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid, ethyl ester
Analog zur Herstellung von Beispiel C-01 wird 3-Brom-4-oxo- cyclohexancarbonsäure-ethylester mit 2-Imino-4-thiobiuret zur Titelverbindung umgesetzt. 3 -Brom-4-oxo-cyclohexancarbonsäure-ethylester (Ausgangsprodukt für Beispiel C-42)Analogously to the preparation of Example C-01, 3-bromo-4-oxocyclohexanecarboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to give the title compound. 3-bromo-4-oxo-cyclohexane carboxylic acid ethyl ester (starting product for example C-42)
Die Bromierung von 4-Oxo-cyclohexancarbonsäure-ethylester erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.The bromination of 4-oxo-cyclohexane carboxylic acid ethyl ester takes place in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure Analog zur Herstellung von 2-Guanidino-4 , 5, 6 , 7-tetrahydro- benzothiazol-4-carbonsäure wird 2-Guanidino-4 , 5 , 6 , 7- tetrahydro-benzothiazol-6-carbonsäure-ethylester zur Titelverbindung verseift: tR 2.49 min (LC-1); ESI-MS (+/-): m/z 241.04 [M+H] + / 238.39 [M-2H]".2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid Analogously to the preparation of 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid, 2-guanidino-4, 5 , 6, 7-ethyl tetrahydro-benzothiazole-6-carboxylate saponified to give the title compound: t R 2.49 min (LC-1); ESI-MS (+/-): m / z 241.04 [M + H] + / 238.39 [M-2H] " .
Analog zu Beispiel C-31 werden die Verbindungen der in Tabelle 3 aufgeführten Beispiele C-43 bis C-46 durch Reaktion von 2-Guanidino-4 , 5, 6 , 7-tetrahydro-benzothiazol-4- carbonsäure mit den entsprechenden Aminen in Gegenwart eines Kupplungsreagenzes wie O- (Benzotriazol-1-yl) - N,N,N' ,N' -tetramethyluronium-hexafluorophosphat hergestellt .Analogously to Example C-31, the compounds of Examples C-43 to C-46 listed in Table 3 are reacted with 2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazole-4-carboxylic acid with the corresponding amines in the presence a coupling reagent such as O- (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate.
Beispiel C-47Example C-47
N- (Tetrahydro-benzothiazol-2-yl-4-spiro-cyclohexan) - guanidin und sein FormiatN- (tetrahydro-benzothiazol-2-yl-4-spiro-cyclohexane) guanidine and its formate
Analog zur Herstellung von Beispiel C-01 wird 2-Brom- spiro [5.5] undecan-1-on mit 2-Imino-4-thiobiuret zur Titelverbindung umgesetzt.Analogously to the preparation of Example C-01, 2-bromo-spiro [5.5] undecan-1-one is reacted with 2-imino-4-thiobiuret to give the title compound.
2-Brom-spiro [5.5] undecan-1-on (Ausgangsprodukt für Beispiel C-47)2-bromo-spiro [5.5] undecan-1-one (starting product for example C-47)
Die Bromierung von Spiro [5.5] ndecan-1-on erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt . Spiro [5.5] undecan-1-on (Vorprodukt für Beispiel C-47)The bromination of spiro [5.5] ndecan-1-one is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization. Spiro [5.5] undecan-1-one (preliminary product for example C-47)
Zu einer Lösung von Cyclohexanon (5 mmol) und Kalium- tert- butanolat (10 mmol) in Toluol (7.5 ml) wird Dibrompentan (5 mmol) gegeben und das Reaktionsgemisch während 48 Stunden am Rückfluss gekocht. Nach Abkühlen auf Raumtemperatur wird 25% Chlorwasserstoffsäure zugegeben und mit Diethylether extrahiert. Die vereinigten organischen Phasen ergeben nach Trocknen über Natriumsulfat, Entfernen des Lösungsmittels im Vakuum und Chromatographieren des Rückstandes an Kieselgel (Ethylacetat/ Heptan, 1:5) reines Spiro[5.5]undecan-l-on { Tetrahedron 1964, 20, 2553-2573): tR 1.90 min. (LC-2) ; ESI-MS (+) : m/z 161 . 21 [M+H]+.Dibromopentane (5 mmol) is added to a solution of cyclohexanone (5 mmol) and potassium tert-butoxide (10 mmol) in toluene (7.5 ml) and the reaction mixture is boiled under reflux for 48 hours. After cooling to room temperature, 25% hydrochloric acid is added and extracted with diethyl ether. After drying over sodium sulfate, removing the solvent in vacuo and chromatographing the residue on silica gel (ethyl acetate / heptane, 1: 5), the combined organic phases give pure spiro [5.5] undecan-l-one {Tetrahedron 1964, 20, 2553-2573) : t R 1.90 min. (LC-2); ESI-MS (+): m / z 161. 21 [M + H] + .
Beispiel C-48Example C-48
N- (6-Phenyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl-4-spiro- cyclohexan) -guanidin und sein Hydrobromid SalzN- (6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl-4-spirocyclohexane) guanidine and its hydrobromide salt
Die Titelverbindung wird ausgehend von 4-Phenyl- spiro [5.5] undecan-1-on an Stelle von Spiro [5.5] undecan-1-on in analoger Weise wie N- (Tetrahydro-benzothiazol-2-yl-4- spiro-cyclohexan) -guanidin hergestellt.The title compound is based on 4-phenyl-spiro [5.5] undecan-1-one instead of spiro [5.5] undecan-1-one in an analogous manner to N- (tetrahydro-benzothiazol-2-yl-4-spiro-cyclohexane ) -guanidine.
4-Phenyl-spiro [5.5] undecan-1-on (Vorprodukt für Beispiel C- 48) Die Herstellung der Titelverbindung erfolgt in analoger4-phenyl-spiro [5.5] undecan-1-one (precursor for example C-48) The title compound is prepared in an analogous manner
Weise wie oben für die Herstellung von Spiro [5.5] undecan-1- on beschrieben: tR 1.92 min (LC-2); ESI-MS(+): m/z 243.36Way as described above for the preparation of Spiro [5.5] undecan-1-one: t R 1.92 min (LC-2); ESI-MS (+): m / z 243.36
[M+H] + . 1H NMR (ppm,CDCl3) : 7.3(5H); 3.25(1H); 2.8(1H); 2.35 (1H); 2.2 (2H); 1.95(3H); 1.75(2H); 1.65(2H); 1.4 (4H); 1.15 (1H) .[M + H] + . 1 H NMR (ppm, CDCl 3 ): 7.3 (5H); 3.25 (1H); 2.8 (1H); 2.35 (1H); 2.2 (2H); 1.95 (3H); 1.75 (2H); 1.65 (2H); 1.4 (4H); 1.15 (1H).
4 , 4-Diphenylcyclohexanon (Vorprodukt für Beispiel C-49) Die Herstellung von 4 , 4-Diphenylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 4,4- dimethylcyclohexanon beschrieben: tR 3.68 min (LC-1); ESI-4,4-diphenylcyclohexanone (precursor for example C-49) 4,4-diphenylcyclohexanone is prepared in an analogous manner to that described for the preparation of 4,4-dimethylcyclohexanone: t R 3.68 min (LC-1); IT I-
MS(-): m/z 249.00 [M-H] " . 2-Brom-4 , 4-diphenylcyclohexanon (Ausgangsprodukt für Beispiel C-49)MS (-): m / z 249.00 [MH] " . 2-bromo-4,4,4-diphenylcyclohexanone (starting product for example C-49)
Die Bromierung von 4, 4-Diphenylcyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2 -Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 4,4-diphenylcyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
3 -Brom-4-oxo-1-phenyl-cyclohexancarbonsäureethylester (Ausgangsprodukt für Beispiel C-50)3-bromo-4-oxo-1-phenyl-cyclohexane carboxylic acid ethyl ester (starting product for example C-50)
Die Bromierung von 4-Oxo-l-phenyl-cyclohexancarbonsäure- ethylester erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.The bromination of 4-oxo-1-phenyl-cyclohexanecarboxylic acid ethyl ester takes place in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
3-Brom-4-oxo-l-phenyl-cyclohexancarbonitril (Ausgangsprodukt für Beispiel C-51)3-bromo-4-oxo-l-phenyl-cyclohexane carbonitrile (starting product for example C-51)
Die Bromierung von 4-Oxo-l-phenyl-cyclohexancarbonitril erfolgt in analoger Weise wie oben für die Herstellung von 2 -Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of 4-oxo-l-phenyl-cyclohexanecarbonitrile is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
3 -Brom-4-arylcyclohexanon (Ausgangsprodukte für die Beispiele C-52 bis C-66)3-bromo-4-arylcyclohexanone (starting materials for examples C-52 to C-66)
Die Bromierung der 4-Arylcyclohexanon Derivate (Vorstufen zu den Beispielen C-52 bis C-66) erfolgt in analoger Weise wie oben für die Herstellung von 2 -Brom-4 -isopropyl- cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .The bromination of the 4-arylcyclohexanone derivatives (precursors to Examples C-52 to C-66) is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropylcyclohexanone. The title compound is implemented as a crude product without further characterization.
Herstellung der 4 -Arylcyclohexanon Derivate (Vorprodukte für die Beispiele C-54 bis C-66) :Preparation of the 4-arylcyclohexanone derivatives (precursors for Examples C-54 to C-66):
1 , 4-Dioxa-spiro [4.5] dec-7-en-8-yl-trifluormethan- sulfonsäureester Zu einer auf -78°C gekühlten Lösung von Lithium-bis- (trimethylsilyl) -amid (IM in Tetrahydrofuran, 1.1 mmol) in trockenem Tetrahydrofuran werden 1, 4-Dioxa-spiro [4.5] decan- 8-on (1 mmol) , gelöst in Tetrahydrofuran (2 ml) gegeben. Man rührt 1.5 Stunden bei -78°C weiter und tropft dann eine Lösung von N-Phenyl-trifluormethansulfonimid (1.07 mmol) in Tetrahydrofuran (2 ml) zu. Anschliessend wird über Nacht bei Raumtemperatur gerührt und das Lösungsmittel anschliessend im Vakuum entfernt. Nach Trocknen des Rückstandes im Vakuum wird 1, 4-Dioxa-spiro [4.5] dec-7-en-8- yl-trifluormethan-sulfonsäureester erhalten, welcher ohne zusätzliche Aufreinigung sofort weiter umgesetzt wird { Tetrahedron 1999, 55, 14479-14490): lH NMR (ppm,CDCl3):1,4-dioxa-spiro [4.5] dec-7-en-8-yl-trifluoromethanesulfonic acid ester To a solution of lithium bis (trimethylsilyl) amide (IM in tetrahydrofuran, 1.1 mmol) in dry tetrahydrofuran, cooled to -78 ° C., 1,4-dioxa-spiro [4.5] decan-8-one (1 mmol) , dissolved in tetrahydrofuran (2 ml). The mixture is stirred for a further 1.5 hours at -78 ° C. and then a solution of N-phenyl-trifluoromethanesulfonimide (1.07 mmol) in tetrahydrofuran (2 ml) is added dropwise. The mixture is then stirred overnight at room temperature and the solvent is then removed in vacuo. After drying the residue in vacuo, 1,4-dioxa-spiro [4.5] dec-7-en-8-yl-trifluoromethane-sulfonic acid ester is obtained, which is immediately reacted further without additional purification {Tetrahedron 1999, 55, 14479-14490) : 1 H NMR (ppm, CDCl 3 ):
5.65(1H); 4 (4H) ; 2.55(2H); 2.4 (2H); 1.9(2H).5.65 (1H); 4 (4H); 2:55 (2H); 2.4 (2H); 1.9 (2H).
4- (4-Fluor-phenyl) -cyclohexanon (Vorprodukt für Beispiel C-4- (4-fluorophenyl) cyclohexanone (precursor for example C-
54) a) 8- (4-Fluor-phenyl) -1, 4-dioxa-spiro [ .5] dec-7-en:54) a) 8- (4-fluorophenyl) -1, 4-dioxa-spiro [.5] dec-7-en:
In einem mit Argon beschickten Kolben werden 2M Natriumcarbonat (4.8 mmol), 1, 2-Dimethoxyethan (8 ml), 4- Fluor-phenylboronsäure (2.8 mmol), Lithiumchlorid (6 mmol), 1, 4-Dioxa-spiro [4.5] dec-7-en-8-yl-trifluormethansulfonsäureester (2 mmol) und Tetrakis (triphenyl- phosphin) palladium (0.1 mmol) zusammengegeben und über Nacht bei 80°C gerührt. Das Reaktionsgemisch wird im Vakuum aufkonzentriert und der Rückstand in Dichlormethan/ 2M wässrige Natriumcarbonat-Lösung verteilt. Die wässrige Phase wird mit Dichlormethan extrahiert . Die vereinigten organischen Phasen werden anschliessend über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum abgedampft . Aus dem Rückstand wird nach Säulenchromatographie an Kieselgel (Ethylacetat/ Heptan 1:4) reines 8- (4-Fluor-phenyl) -1, 4- dioxa-spiro [4.5] dec-7-en isoliert (Synthesis 1993, 735-In a flask charged with argon, 2M sodium carbonate (4.8 mmol), 1, 2-dimethoxyethane (8 ml), 4-fluorophenylboronic acid (2.8 mmol), lithium chloride (6 mmol), 1, 4-dioxa-spiro [4.5] dec-7-en-8-yl-trifluoromethanesulfonic acid ester (2 mmol) and tetrakis (triphenylphosphine) palladium (0.1 mmol) were combined and stirred at 80 ° C. overnight. The reaction mixture is concentrated in vacuo and the residue is distributed in dichloromethane / 2M aqueous sodium carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are then dried over sodium sulfate and the solvent is evaporated off in vacuo. Pure 8- (4-fluorophenyl) -1, 4-dioxa-spiro [4.5] dec-7-ene is isolated from the residue after column chromatography on silica gel (ethyl acetate / heptane 1: 4) (Synthesis 1993, 735-
762): tR 3.61 min (LC-1); ESI-MS(+): m/z 235.34 [M+H] + . "Η NMR (ppm,CDCl3): 7.35 (2H); 6.95(2H); 5.9(1H); 4.05(4H); 2.65(2H); 2.45 (2H) ; 1.9(2H). b) 8- (4-Fluor-phenyl) -1, 4-dioxa-spiro [4.5] decan:762): t R 3.61 min (LC-1); ESI-MS (+): m / z 235.34 [M + H] + . "Η NMR (ppm, CDCl 3 ): 7.35 (2H); 6.95 (2H); 5.9 (1H); 4.05 (4H); 2.65 (2H); 2.45 (2H); 1.9 (2H). b) 8- (4-fluorophenyl) -1, 4-dioxa-spiro [4.5] decane:
8- (4-Fluor-phenyl) -1, -dioxa-spiro [4.5] dec-7-en wird an Pd/C mit Wasserstoff hydriert. Nach Abfiltrieren des Katalysators über Celite und Abdampfen des Lösungsmittels wird 8- (4-Fluor-phenyl) -1, 4-dioxa-spiro [4.5] decan in quantitativer Ausbeute erhalten: tR 3.65 min (LC-1); ESI-8- (4-Fluoro-phenyl) -1, -dioxa-spiro [4.5] dec-7-ene is hydrogenated on Pd / C with hydrogen. After filtering off the catalyst through Celite and evaporating the solvent, 8- (4-fluorophenyl) -1, 4-dioxa-spiro [4.5] decane is obtained in quantitative yield: t R 3.65 min (LC-1); IT I-
MS(+): m/z 237.26 [M+H] + .MS (+): m / z 237.26 [M + H] + .
c) 4- (4-Fluor-pheny1) -cyclohexanon : 8- (4-Fluor-phenyl) -1, 4-dioxa-spiro [4.5] decan (2 mmol) wird in Dioxan (6.5 ml) gelöst und mit 3 ml 50% wassriger Schwefelsäure unter Rühren bei Raumtemperatur während 5 Stunden behandelt. Nach Verdünnen mit Wasser (12 ml) wird zweimal mit Dichlormethan extrahiert. Aus den vereinigten organischen Phasen wird, nach Trocknen über Natriumsulfat und Abdampfen des. Lösungsmittel im Vakuum, die rohe Titelverbindung erhalten ( Tetrahedron 1998, 54, 15509-c) 4- (4-Fluoropheny1) cyclohexanone: 8- (4-fluorophenyl) -1, 4-dioxa-spiro [4.5] decane (2 mmol) is dissolved in dioxane (6.5 ml) and mixed with 3 ml of 50% aqueous sulfuric acid treated with stirring at room temperature for 5 hours. After dilution with water (12 ml) the mixture is extracted twice with dichloromethane. The crude title compound is obtained from the combined organic phases after drying over sodium sulfate and evaporation of the solvent in vacuo (Tetrahedron 1998, 54, 15509-
15524): tR 3.44 min (LC-1); ESI-MS (+): m/z 193.29 [M+H] + .15524): t R 3.44 min (LC-1); ESI-MS (+): m / z 193.29 [M + H] + .
Die Herstellung der Vorprodukte für die Beispiele C-55 bis C-66 erfolgt in analoger Weise wie oben für die Herstellung von 4- (4-Fluor-phenyl) -cyclohexanon beschrieben.The precursors for Examples C-55 to C-66 are prepared in an analogous manner to that described above for the preparation of 4- (4-fluorophenyl) cyclohexanone.
4 -o- oly1-cyclohexanon (Vorprodukt für Beispiel C-55) "Η NMR (ppm,CDCl3): 7.3 (2H) ; 7.1 (2H) ; 3.15 (1H) ; 2.454-o-poly1-cyclohexanone (precursor for example C-55) "Η NMR (ppm, CDCl 3 ): 7.3 (2H); 7.1 (2H); 3.15 (1H); 2.45
(4H) ; 2.35 (3H) ; 2.1 (2H) ; 1.85 (2H) ; 1.65(2H); 1.4 (4H); 1.15 (1H) .(4H); 2.35 (3H); 2.1 (2H); 1.85 (2H); 1.65 (2H); 1.4 (4H); 1.15 (1H).
4- (2-Ethyl-phenyl) -cyclohexanon (Vorprodukt für Beispiel C- 56) tR 3.62 min (LC-1); ESI-MS (+) : m/z 203.29 [M+H] + .4- (2-ethylphenyl) cyclohexanone (precursor for example C-56) t R 3.62 min (LC-1); ESI-MS (+): m / z 203.29 [M + H] + .
4- (3 , 4-Dimethoxy-phenyl) -cyclohexanon (Vorprodukt für Beispiel C-57) tR 3.43 min (LC-1); ESI-MS (+) : m/z 235.28 [M+H] + . 4- (4-Cyano-phenyl) -cyclohexanon (Vorprodukt für Beispiel C-4- (3, 4-dimethoxyphenyl) cyclohexanone (precursor for example C-57) t R 3.43 min (LC-1); ESI-MS (+): m / z 235.28 [M + H] + . 4- (4-cyano-phenyl) -cyclohexanone (precursor for example C-
58) tR 1.92 min (LC-2); ESI-MS (+) : m/z 200.33 [M+H] + .58) t R 1.92 min (LC-2); ESI-MS (+): m / z 200.33 [M + H] + .
4- (3 , 5-Bis-trifluormethyl-phenyl) -cyclohexanon (Vorprodukt für Beispiel C-59) tR 2.46 min (LC-2); ESI-MS (+) : m/z 311.29 [M+H]+.4- (3,5-bis-trifluoromethyl-phenyl) cyclohexanone (precursor for example C-59) t R 2.46 min (LC-2); ESI-MS (+): m / z 311.29 [M + H] + .
4-p-Tolyl-cyclohexanon (Vorprodukt für Beispiel C-60) tR 2.11 min (LC-2); ESI-MS (+) : m/z 189.32 [M+H]+.4-p-tolylcyclohexanone (precursor for example C-60) t R 2.11 min (LC-2); ESI-MS (+): m / z 189.32 [M + H] + .
4-m-Tolyl-cyclohexanon (Vorprodukt für Beispiel C-61) tR 2.12 min (LC-2); ESI-MS (+) : m/z 189.32 [M+H] + .4-m-tolyl-cyclohexanone (precursor for example C-61) t R 2.12 min (LC-2); ESI-MS (+): m / z 189.32 [M + H] + .
4- (3-Methoxy-phenyl) cyclohexanon (Vorprodukt für Beispiel C-62) tR 2.08 min (LC-2); ESI-MS (+) : m/z 205.35 [M+H] + .4- (3-methoxyphenyl) cyclohexanone (precursor for example C-62) t R 2.08 min (LC-2); ESI-MS (+): m / z 205.35 [M + H] + .
4- (4-Chlor-phenyl) -cyclohexanon (Vorprodukt für Beispiel C- 63) tR 2.26 min (LC-2); ESI-MS (+) : m/z 209.23 [M+H]+.4- (4-chlorophenyl) cyclohexanone (precursor for example C-63) t R 2.26 min (LC-2); ESI-MS (+): m / z 209.23 [M + H] + .
4- (3-Fluor-phenyl) -cyclohexanon (Vorprodukt für Beispiel C- 64) tR 2.11 min (LC-2); ESI-MS (+) : m/z 193.26 [M+H] + .4- (3-fluorophenyl) cyclohexanone (precursor for example C-64) t R 2.11 min (LC-2); ESI-MS (+): m / z 193.26 [M + H] + .
4-Thiophen-2-yl-cyclohexanon (Vorprodukt für Beispiel C-65) tR 2.05 min (LC-2); ESI-MS (+) : m/z 219.29 [M+H] + .4-thiophene-2-yl-cyclohexanone (precursor for example C-65) t R 2.05 min (LC-2); ESI-MS (+): m / z 219.29 [M + H] + .
4-Benzo [1,3] dioxol-5-yl-cyclohexanon (Vorprodukt für Beispiel C-66) tR 2.05 min (LC-2); ESI-MS (+) : m/z 181.23 [M+H] + .4-benzo [1,3] dioxol-5-yl-cyclohexanone (precursor for example C-66) t R 2.05 min (LC-2); ESI-MS (+): m / z 181.23 [M + H] + .
2-Brom-5 , 5-dimethyl-cyclohexanon (Ausgangsprodukt für Beispiel C-67) ; 2 -Brom-5-ethyl-5-methyl-cyclohexanon (Ausgangsprodukt für Beispiel C-68) und2-bromo-5, 5-dimethyl-cyclohexanone (starting product for example C-67); 2-bromo-5-ethyl-5-methyl-cyclohexanone (starting product for example C-68) and
2 -Brom-5-methyl-5-phenyl-cyclohexanon (Ausgangsprodukt für Beispiel C-69) Die Bromierung von 3 , 3-Dimethyl-cyclohexanon, 3-Ethyl-3- methyl-cyclohexanon, beziehungsweise 3 -Methyl-3 -phenyl- cyclohexanon (Vorstufen zu den Beispielen C-67 bis C-69) erfolgt in analoger Weise wie oben für die Herstellung von 2 -Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindungen werden als Rohprodukte ohne weitere Charakterisierung umgesetzt .2-Bromo-5-methyl-5-phenyl-cyclohexanone (starting product for example C-69) The bromination of 3, 3-dimethyl-cyclohexanone, 3-ethyl-3-methyl-cyclohexanone, or 3-methyl-3-phenyl - Cyclohexanone (precursors to Examples C-67 to C-69) is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compounds are implemented as raw products without further characterization.
2-Brom-5 , 5-dimethyl-4 -phenyl-cyclohexanon (Ausgangsprodukt für Beispiel C-70) Die Bromierung von 3 , 3-Dimethyl-4 -phenyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.2-bromo-5, 5-dimethyl-4-phenyl-cyclohexanone (starting product for example C-70) The bromination of 3, 3-dimethyl-4-phenyl-cyclohexanone is carried out in an analogous manner to that for the preparation of 2-bromo -4-isopropyl-cyclohexanone. The title compound is implemented as a crude product without further characterization.
3 , 3-Dimethyl-4-phenyl-cyclohexanon (Vorstufe für Beispiel3, 3-Dimethyl-4-phenyl-cyclohexanone (precursor for example
C-70)C-70)
Lithiumchlorid (0.6 mmol) und Kupferiodid (0.3 mmol) werden unter Argon in trockenem Tetrahydrofuran (18 ml) vorgelegt. Bei 0°C wird 3-Methyl-4-phenylcyclohex-2-enon (3 mmol) zugegeben und während 10 min bei dieser Temperatur weitergerührt. Anschliessend wird eine Lösung von Methylmagnesiumbromid (3.6 mmol) langsam zugetropft und das Reaktionsgemisch unter Rühren während 3 Stunden bei 0°C gehalten. Die Reaktion wird durch Zugabe von gesättigter wassriger Ammoniumchlorid-Lδsung gestoppt. Das Gemisch wird mit Diethylether extrahiert . Aus den vereinigten organischen Phasen wird nach Trocknen über Natriumsulfat und Abdampfen des Lösungsmittels im Vakuum die Titelverbindung erhalten (J". Organom . Chem . 1995, 502, C5-Lithium chloride (0.6 mmol) and copper iodide (0.3 mmol) are placed under argon in dry tetrahydrofuran (18 ml). 3-Methyl-4-phenylcyclohex-2-enone (3 mmol) is added at 0 ° C. and stirring is continued for 10 min at this temperature. A solution of methyl magnesium bromide (3.6 mmol) is then slowly added dropwise and the reaction mixture is kept at 0 ° C. for 3 hours with stirring. The reaction is stopped by adding saturated aqueous ammonium chloride solution. The mixture is extracted with diethyl ether. After drying over sodium sulfate and evaporating the solvent in vacuo, the title compound is obtained from the combined organic phases (J " . Organom. Chem. 1995, 502, C5-
C7) : tR 2.36 min (LC-2); ESI-MS (+) : m/z 203.35 [M+H] + . 2 -Brom-3 -methyl-cyclohexanon (Ausgangsprodukt für Beispiel C-71)C7): t R 2.36 min (LC-2); ESI-MS (+): m / z 203.35 [M + H] + . 2-bromo-3-methyl-cyclohexanone (starting product for example C-71)
Eine Lösung von N-Bromsuccinimid (0.48 mmol) und Natriumacetat (0.04 mmol) in THF/ Wasser (1:1, 5.2 ml) wird auf 0°C gekühlt und tropfenweise mit Trimethyl- (3 -methyl- cyclohex-1-enyloxy) -silan (0.4 mmol, 80% rein) versetzt. Man lässt das Reaktionsgemisch auf Raumtemperatur erwärmen und rührt über Nacht weiter. Nach Zugabe von Wasser wird mit Ethylacetat extrahiert. Aus den vereinigten organischen Phasen wird nach Trocknen über Natriumsulfat und Abdampfen des Lösungsmittel im Vakuum die Titelverbindung erhalten (JOC 1997, 62, 19, 6692-6696) .A solution of N-bromosuccinimide (0.48 mmol) and sodium acetate (0.04 mmol) in THF / water (1: 1, 5.2 ml) is cooled to 0 ° C. and added dropwise with trimethyl- (3-methylcyclohex-1-enyloxy) -silane (0.4 mmol, 80% pure) was added. The reaction mixture is allowed to warm to room temperature and is stirred further overnight. After adding water, the mixture is extracted with ethyl acetate. The title compound is obtained from the combined organic phases after drying over sodium sulfate and evaporating the solvent in vacuo (JOC 1997, 62, 19, 6692-6696).
Trimethyl- (3 -methyl-cyclohex-1-enyloxy) -silan (Vorprodukt für Beispiel C-71)Trimethyl- (3-methyl-cyclohex-1-enyloxy) -silane (precursor for example C-71)
Lithiumchlorid (2 mmol) und Kupferiodid (1 mmol) werden unter Argon in Tetrahydrofuran (5.6 ml) vorgelegt und aufLithium chloride (2 mmol) and copper iodide (1 mmol) are placed under argon in tetrahydrofuran (5.6 ml) and applied
-78°C gekühlt. Man gibt Cyclohex-2-enon (1 mmol) sowie Trimethylsilylchlorid (1.1 mmol) zu und rührt die Lösung während 10 min weiter. Anschliessend wird langsam eine Lösung von Methylmagnesiumbromid (1.2 mmol) zugetropft. Nach 3 Stunden Rühren bei -78°C wird gesättigte wässrige Ammoniumchlorid-Lösung zugegeben und mit Ether extrahiert . Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Das erhaltene Rohprodukt enthält gemäss LC-MS 80% Trimethyl- (3 -methyl-cyclohex-1-enyloxy) -silan und 20% der Ausgangsverbindung und wird ohne weitere Aufreinigung in der Folgereaktion eingesetzt (J". Organom. Chem. 1995, 502, C5-C7) : XH NMR (ppm, CDC13) : 4.75 (1H); 2.25(1H); 1.95(2H); 1.75(2H); 1.05(1H); 0.95 (3H) ; 0.2 (9H) .-78 ° C cooled. Cyclohex-2-enone (1 mmol) and trimethylsilyl chloride (1.1 mmol) are added and the solution is stirred for a further 10 min. A solution of methyl magnesium bromide (1.2 mmol) is then slowly added dropwise. After 3 hours of stirring at -78 ° C, saturated aqueous ammonium chloride solution is added and extracted with ether. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. According to LC-MS, the crude product obtained contains 80% trimethyl- (3-methyl-cyclohex-1-enyloxy) -silane and 20% of the starting compound and is used in the subsequent reaction without further purification (J " . Organom. Chem. 1995, 502 , C5-C7): X H NMR (ppm, CDC1 3 ): 4.75 (1H); 2.25 (1H); 1.95 (2H); 1.75 (2H); 1.05 (1H); 0.95 (3H); 0.2 (9H) ,
2 -Brom-6-phenyl-cycloheptanon (Ausgangsprodukt für Beispiel C-72) Die Bromierung von 3-Phenylcycloheptanon erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4- isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt .2-Bromo-6-phenyl-cycloheptanone (starting product for example C-72) The bromination of 3-phenylcycloheptanone takes place in an analogous manner to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title link is implemented as a raw product without further characterization.
2- tert-Butyl-6 -chlor-4 -phenyl-cyclohexanon (Ausgangsprodukt für Beispiel C-73)2-tert-butyl-6-chloro-4-phenyl-cyclohexanone (starting product for example C-73)
Die Chlorierung von 2- ert-Butyl-4-phenyl-cyclohexanon erfolgt in analoger Weise wie oben für die Herstellung von 2- ert-Butyl-6-chlor-cyclohexanon beschrieben. DieThe chlorination of 2-tert-butyl-4-phenyl-cyclohexanone is carried out in an analogous manner to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The
Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.Title compound is implemented as a crude product without further characterization.
2- ert-Butyl-4-phenyl-cyclohexanon (Vorstufe für Beispiel2- ert-butyl-4-phenyl-cyclohexanone (precursor for example
C-73) a) Trimethyl- (4-phenyl-cyclohex-1-enyloxy) -silan: Zu einer Lösung von 4-Phenylcyclohexanon (10 mmol) in Hexan (10 ml) gibt man bei Raumtemperatur tropfenweise in Acetonitril (12.4 ml) gelöstes Natriumiodid (12.4 mmol), gefolgt von Triethylamin (12.4 mmol) und Trimethylchlorsilan (12.4 mmol). Nach zweistündigem Rühren werden kaltes Pentan und Eiswasser zugegeben. DieC-73) a) Trimethyl- (4-phenyl-cyclohex-1-enyloxy) -silane: To a solution of 4-phenylcyclohexanone (10 mmol) in hexane (10 ml) is added dropwise at room temperature in acetonitrile (12.4 ml) dissolved sodium iodide (12.4 mmol), followed by triethylamine (12.4 mmol) and trimethylchlorosilane (12.4 mmol). After stirring for two hours, cold pentane and ice water are added. The
Wasserphase wird mit Hexan extrahiert. Die vereinigten organischen Phasen werden mit Eiswasser gewaschen, über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Trimethyl- ( -phenyl-cyclohex-1-enyloxy) -silan (1.8 g) wird rein in 73% Ausbeute erhalten ( TetrahedronWater phase is extracted with hexane. The combined organic phases are washed with ice water, dried over sodium sulfate and the solvent removed in vacuo. Trimethyl- (-phenyl-cyclohex-1-enyloxy) -silane (1.8 g) is obtained purely in 73% yield (tetrahedron
1987, 43, 9, 2075-2088): tR 2.29 min (LC-2); ESI-MS (+) : m/z 247.27 [M+H] + . b) 2- tert-Butyl-4-phenyl-cyclohexanon:1987, 43, 9, 2075-2088): t R 2.29 min (LC-2); ESI-MS (+): m / z 247.27 [M + H] + . b) 2-tert-butyl-4-phenyl-cyclohexanone:
Trimethyl- (4-phenyl-cyclohex-1-enyloxy) -silan (7.27 mmol) und tert-Butylchlorid (7.85 mmol) werden in Dichlormethan unter Stickstoff vorgelegt und auf -45 °C gekühlt. Es wird eine ebenfalls auf -45°C gekühlte Lösung von Titantetrachlorid (7.63 mmol) in Dichlormethan (3.6 ml) zugegeben und 3 Stunden bei dieser Temperatur weitergerührt. Das Reaktionsgemisch wird mit Dichlormethan verdünnt und mit Eiswasser gewaschen. Die organische Phase wird über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt . Säulenchromatographie (Ethylacetat/ Heptan 1:4) des Rückstandes liefert die Titelverbindung (250 mg) in 15% Ausbeute {Angew Chem Int Ed Engl 1978, 17, 1, 48- 49). 'H fflR (ppm,CDCl3) : 7.35(5H); 3.15 (1H); 2.55 (1H) ; 2.4 (3H) ; 2.25(1H); 2 (1H) ; 1.8(1H); 1.05(9H).Trimethyl- (4-phenyl-cyclohex-1-enyloxy) -silane (7.27 mmol) and tert-butyl chloride (7.85 mmol) are placed in dichloromethane under nitrogen and cooled to -45 ° C. A solution of titanium tetrachloride (7.63 mmol) in dichloromethane (3.6 ml), likewise cooled to -45 ° C., is added and stirring is continued for 3 hours at this temperature. The reaction mixture is diluted with dichloromethane and washed with ice water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. Column chromatography (ethyl acetate / heptane 1: 4) of the residue gives the title compound (250 mg) in 15% yield {Angew Chem Int Ed Engl 1978, 17, 1, 48-49). 'H fflR (ppm, CDCl 3 ): 7.35 (5H); 3.15 (1H); 2.55 (1H); 2.4 (3H); 2.25 (1H); 2 (1H); 1.8 (1H); 1:05 (9H).
Beispiel N-01Example N-01
2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- carbonsäure- ert-butylester2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid, tert-butyl ester
Analog zur Herstellung von Beispiel C-01 wird 3-Bromo-4- oxo-piperidin-1-carbonsäure- tert-butylester mit 2-Imino-4- thiobiuret zur Titelverbindung umgesetzt. tR 2.55 min (LC-1); ESI-MS (+) : m/z 298.25 [M+H] + .Analogously to the preparation of Example C-01, tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate is reacted with 2-imino-4-thiobiuret to give the title compound. t R 2.55 min (LC-1); ESI-MS (+): m / z 298.25 [M + H] + .
3 -Bromo-4 -oxo-piperidin-1-carbonsäure- ert-butylester3-Bromo-4-oxo-piperidine-1-carboxylic acid, er-butyl ester
(Ausgangsprodukt für Beispiel N-01)(Starting product for example N-01)
Die Bromierung von 4-Oxo-piperidin-l-carbonsäure- tert- butylester erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl-cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.The bromination of 4-oxopiperidine-1-carboxylic acid tert-butyl ester is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropylcyclohexanone. The title compound is implemented as a crude product without further characterization.
N- (4 , 5 , 6 , 7-Tetrahydro-thiazolo [5 , 4-c] pyridin-2-yl) -guanidin (Abspaltung der Schutzgruppe aus dem Produkt gemässN- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine (splitting off of the protective group from the product according to
Beispiel N-01, 2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4- c] pyridin-5-carbonsäure- ert-butylester)Example N-01, 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid, tert-butyl ester)
2-Guanidino-6 , 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure- ert-butylester (9.6 mmol) wird in einer Lösung von Ethanol (10 ml) und konzentrierter2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid, tert-butyl ester (9.6 mmol) is concentrated in a solution of ethanol (10 ml)
Chlorwasserstoffsäure (3.8 ml) suspendiert und während 3 Stunden bei Raumtemperatur gerührt . Nach Filtrieren wird durch Zugabe von Ethylacetat zur klaren Lösung das Produkt ausgefällt. Der weisse Niederschlag wird abfiltriert, mit Ethylacetat gewaschen und anschliessend im Vakuum getrocknet. Die Titelverbindung (1.63 g) wird rein als Dihydrochlorid-Salz in 62% Ausbeute erhalten: tR 0.83 min (LC-1); ESI-MS (-): /z 232.23 [M-H] " .Hydrochloric acid (3.8 ml) suspended and stirred for 3 hours at room temperature. After filtering, the product is precipitated by adding ethyl acetate to the clear solution. The white precipitate is filtered off, washed with ethyl acetate and then dried in vacuo. The title compound (1.63 g) is pure as Dihydrochloride salt obtained in 62% yield: t R 0.83 min (LC-1); ESI-MS (-): / z 232.23 [MH] " .
Beispiel N-02 N- (5-Hexyl-4 ,5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin-2-yl) - guanidinExample N-02 N- (5-Hexyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine
Zu einer Suspension von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4- c] pyridin-2-yl) -guanidin (0.1 mmol) und Cäsiumcarbonat (0.22 mmol) in Dimethylformamid (0.3 ml) wird 1-Bromhexan (0.11 mmol) zugegeben und das Reaktionsgemisch beiTo a suspension of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine (0.1 mmol) and cesium carbonate (0.22 mmol) in dimethylformamide (0.3 ml) 1-bromohexane (0.11 mmol) was added and the reaction mixture was added
Raumtemperatur über Nacht gerührt . Nach Zugabe von 2M Natronlauge (1 ml) wird das Gemisch mit Essigester extrahiert, die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und anschliessend eingedampft, wobei die Titelverbindung in reiner Form erhalten wird.Room temperature stirred overnight. After adding 2M sodium hydroxide solution (1 ml), the mixture is extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and then evaporated to give the title compound in pure form.
Analog zu Beispiel N-02 werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-03 bis N-10 durch Reaktion von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridin- 2-yl) -guanidin mit den entsprechenden Alkylhalogeniden ( "R1 -Reagenzien" ) hergestellt.Analogously to Example N-02, the compounds of Examples N-03 to N-10 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2- yl) -guanidine with the corresponding alkyl halides ("R 1 reagents").
Beispiel N-07Example N-07
N- (5-Benzyl-5 , 6 , 7 , 8-tetrahydro-4H-thiazolo [4 , 5-c] azepin- 2 - yl) -guanidinN- (5-Benzyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-c] azepin-2-yl) guanidine
Mittels einer alternativen Methode wird, analog zur Herstellung von Beispiel 1, l-Benzyl-4-brom-azepan-3-on mit 2-Imino-4-thiobiuret zur Titelverbindung umgesetzt.Using an alternative method, l-benzyl-4-bromo-azepan-3-one is reacted with 2-imino-4-thiobiuret to give the title compound, analogously to the preparation of Example 1.
l-Benzyl-azepan-3-on (Vorprodukt für Beispiel N-07) a) 5- (Benzyl-ethoxycarbonylmethyl-amino) -pentansäure : N-Benzylglycinethylester (1.87 ml) und 5-Bromvaleriansäure- ethylester (1.92 ml) werden in Dimethylformamid (100 ml) gelöst und in Gegenwart von Kaliumcarbonat (1.66 g) während 2 Tagen bei Raumtemperatur gerührt. Die Reaktion wird mit gesättigter wassriger Ammoniumchlorid-Lösung gequencht, und mit Ethylacetat extrahiert . Nach Trocknen über Natriumsulfat werden die vereinigten organischen Phasen eingedampft . Aus dem erhaltenen Rückstand wird durch Chromatographieren an Kieselgel (Ethylacetat/ Heptan 1:5) 5- (Benzyl-ethoxycarbonylmethyl-amino) -pentansäure in 30% Ausbeute isoliert. b) l-Benzyl-azepan-3-on:l-Benzyl-azepan-3-one (precursor for example N-07) a) 5- (benzyl-ethoxycarbonylmethyl-amino) -pentanoic acid: N-benzylglycine ethyl ester (1.87 ml) and 5-bromovaleric acid ethyl ester (1.92 ml) are in Dimethylformamide (100 ml) dissolved and stirred in the presence of potassium carbonate (1.66 g) for 2 days at room temperature. The reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After drying over Sodium sulfate, the combined organic phases are evaporated. 5- (Benzyl-ethoxycarbonylmethylamino-amino) pentanoic acid is isolated in 30% yield from the residue obtained by chromatography on silica gel (ethyl acetate / heptane 1: 5). b) l-benzyl-azepan-3-one:
Eine Suspension von Kalium tert-Butylat (336 mg) in ToluolA suspension of potassium tert-butoxide (336 mg) in toluene
(2.5 ml) wird während 10 min am Rückfluss gekocht. Anschliessend wird 5- (Benzyl-ethoxycarbonylmethyl-amino) - pentansäure (695 mg) in Toluol (1 ml) langsam zur(2.5 ml) is boiled under reflux for 10 min. Then 5- (benzyl-ethoxycarbonylmethylamino) pentanoic acid (695 mg) in toluene (1 ml) slowly becomes
Suspension gegeben und nach beendeter Zugabe während 1.5 Stunden weiter gekocht . Nach Abkühlen auf Raumtemperatur wird 25% Chlorwasserstoffsäure (1 ml) zugegeben. Die organische Phase wird abgetrennt und mit 25% Chlorwasserstoffsäure (4x 1 ml) gewaschen. Die vereinigten salzsauren wässrigen Phasen werden anschliessend während 5 Stunden am Rückfluss gekocht. Nach Abkühlen auf Raumtemperatur wird die Lösung mit 2N Natronlauge basisch (pH 11) gestellt und mit Ethylacetat extrahiert. Die vereinigten organischen Phasen werden nach dem Trocknen über Natriumsulfat eingedampft. Der erhaltene Rückstand ergibt nach Chromatographie an Kieselgel (Ethylacetat/ Heptane 1:5) und ergibt die gewünschte Titelverbindung (197 mg) in 45 % Ausbeute {Bull . Chem. Soc. Jpn. 1956, 29, 631- 632; DE2206385) .Suspended suspension and cooked for 1.5 hours after the addition is complete. After cooling to room temperature, 25% hydrochloric acid (1 ml) is added. The organic phase is separated off and washed with 25% hydrochloric acid (4x 1 ml). The combined hydrochloric acid aqueous phases are then refluxed for 5 hours. After cooling to room temperature, the solution is made basic (pH 11) with 2N sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases are evaporated after drying over sodium sulfate. The residue obtained after chromatography on silica gel (ethyl acetate / heptane 1: 5) and gives the desired title compound (197 mg) in 45% yield {Bull. Chem. Soc. Jpn. 1956, 29, 631-632; DE2206385).
l-Benzyl-4-brom-azepan-3-on (Ausgangsprodukt für Beispiel N-07)l-benzyl-4-bromo-azepan-3-one (starting product for example N-07)
Die Bromierung von l-Benzyl-azepan-3-on erfolgt in analoger Weise wie oben für die Herstellung von 2-Brom-4-isopropyl- cyclohexanon beschrieben. Die Titelverbindung wird als Rohprodukt ohne weitere Charakterisierung umgesetzt.The bromination of l-benzyl-azepan-3-one is carried out in an analogous manner to that described above for the preparation of 2-bromo-4-isopropylcyclohexanone. The title compound is implemented as a crude product without further characterization.
Beispiel N-ll N- (Pentanoyl-4 ,5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin-2- yl) -guanidinExample N-II N- (Pentanoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine
Zu einer gerührten Suspension von N- (4 , 5, 6 , 7-Tetrahydro- thiazolo [5, 4-c] pyridin-2-yl) -guanidin-dihydrochlorid (0.1 mmol) in Dimethylformamid (0.7 ml) werden Diisopropylethylamin (0.22 mmol) und nachfolgend Pentanoylchlorid (0.11 mmol) zugegeben und das Reaktionsgemisch während 16 Stunden bei Raumtemperatur weitergerührt. Nach Zugabe von 2M Natronlauge (1 ml) wird mit Ethylacetat extrahiert. Die vereinigten organischen Phasen ergeben nach Trocknen über Natriumsulfat und Eindampfen zur Trockene die reine Titelverbindung.To a stirred suspension of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine dihydrochloride (0.1 mmol) in dimethylformamide (0.7 ml), diisopropylethylamine (0.22 mmol) and subsequently pentanoyl chloride (0.11 mmol) are added and the reaction mixture is stirred for a further 16 hours at room temperature. After adding 2M sodium hydroxide solution (1 ml), the mixture is extracted with ethyl acetate. The combined organic phases give the pure title compound after drying over sodium sulfate and evaporation to dryness.
Analog zu Beispiel N-ll werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-13 bis N-33 durch Reaktion von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridin- 2 -yl) -guanidin mit den entsprechenden Säurechloriden ("R'- Reagenzien") hergestellt.Analogously to Example N-II, the compounds of Examples N-13 to N-33 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2 - yl) -guanidine with the corresponding acid chlorides ("R'-reagents").
Beispiel N-12Example N-12
N- (5-But-3-enoyl-4 ,5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin-N- (5-But-3-enoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-
2-yl) -guanidin2-yl) guanidine
Zu einer gerührten Suspension von N- (4 , 5 , 6 , 7-Tetrahydro- thiazolo [5, 4-c] pyridin-2-yl) -guanidin-dihydrochlorid (0.1 mmol) in Dimethylformamid (0.7 mL) werden nacheinander Diisopropylethylamin (0.22 mmol), Vinylessigsäure (0.11 mmol) und Benzotriazolyloxy-tris- (dimethylamino) phosphonium-hexafluorophosphat (0.11 mmol) zugegeben, und das Reaktionsgemisch während 16 Stunden bei Raumtemperatur gerührt. Nach Zugabe von 2M Natronlauge (1 ml) wird mit Ethylacetat extrahiert. Die vereinigten organischen Phasen ergeben nach Trocknen über Natriumsulfat und Eindampfen zur Trockene die reine Titelverbindung.To a stirred suspension of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine dihydrochloride (0.1 mmol) in dimethylformamide (0.7 mL), diisopropylethylamine ( 0.22 mmol), vinyl acetic acid (0.11 mmol) and benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (0.11 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. After adding 2M sodium hydroxide solution (1 ml), the mixture is extracted with ethyl acetate. The combined organic phases give the pure title compound after drying over sodium sulfate and evaporation to dryness.
Analog zu Beispiel N-12 werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-19 bis N-21 durch Reaktion von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, -c] pyridin- 2 -yl) -guanidin mit den entsprechenden Carbonsäuren ("R'- Reagenzien") in Gegenwart von Benzotriazolyloxy-tris- (dimethylamino) phosphonium-hexafluorophosphat als Kupplungsreagens durchgeführt . Beispiel N- 22Analogously to Example N-12, the compounds of Examples N-19 to N-21 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, -c] pyridin-2 -yl ) -guanidine with the corresponding carboxylic acids ("R'-reagents") in the presence of benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate as coupling reagent. Example N-22
2-Guanidino-6 , 7-dihydro-4ff-thiazolo [5 , 4-c] pyridin-5- carbonsäure-benzylester2-Guanidino-6, 7-dihydro-4ff-thiazolo [5, 4-c] pyridine-5-carboxylic acid benzyl ester
Zu einer gerührten Suspension von N- (4 , 5 , 6 , 7-Tetrahydro- thiazolo [5, 4-c] pyridin-2-yl) -guanidin (0.1 mmol) undTo a stirred suspension of N- (4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) guanidine (0.1 mmol) and
Diisopropylethylamin (0.22 mmol) in Dimethylformamid (0.7 ml) wird Benzylchloroformiat zugegeben und das Gemisch während 3 Stunden bei Raumtemperatur weitergerührt . Nach Zugabe von gesättigter w ssriger Natriumcarbonat-Lösung wird mit Ethylacetat extrahiert; die vereinigten organischen Phasen ergeben nach Trocknen über Natriumsulfat und vollständigem Abdampfen des Lösungsmittels die reine Titelverbindung .Diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) benzyl chloroformate is added and the mixture is stirred for a further 3 hours at room temperature. After adding saturated aqueous sodium carbonate solution, the mixture is extracted with ethyl acetate; the combined organic phases give the pure title compound after drying over sodium sulfate and complete evaporation of the solvent.
Analog zu Beispiel N-22 wird die Verbindung des in Tabelle 4 aufgeführten Beispiels N-23 durch Reaktion von N-(4, 5, 6, 7-Tetrahydro-thiazolo [5 , 4-c] pyridin-2-yl) -guanidin mit Butylchlorformiat ( "R' -Reagens" ) hergestellt.Analogously to Example N-22, the compound of Example N-23 listed in Table 4 is obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine made with butyl chloroformate ("R 'reagent").
Beispiel N-24Example N-24
N- [5- (Propan-2-sulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) ] -guanidinN- [5- (Propan-2-sulfonyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl)] guanidine
Zu einer gerührten Suspension von N- (4 , 5 , 6 , 7-Tetrahydro- thiazolo [5, 4-c] pyridin-2-yl) -guanidin (0.1 mmol) und Diisopropylethylamin (0.22 mmol) in Dimethylformamid (0.7 ml) wird Propan-2-sulfonylchlorid zugegeben und das Gemisch während 16 Stunden bei Raumtemperatur weitergerührt . Nach Zugabe von 2M Natronlauge (1 ml) wird mit Ethylacetat extrahiert; die vereinigten organischen Phasen ergeben nach Trocknen über Natriumsulfat und vollständigem Abdampfen des Lösungsmittels von der reinen Titelverbindung.To a stirred suspension of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine (0.1 mmol) and diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) propane-2-sulfonyl chloride is added and the mixture is stirred for a further 16 hours at room temperature. After adding 2M sodium hydroxide solution (1 ml), the mixture is extracted with ethyl acetate; the combined organic phases give after drying over sodium sulfate and complete evaporation of the solvent from the pure title compound.
Analog zu Beispiel N-24 werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-25 und N-26 durch Reaktion von N- (4 , 5, 6 , 7-Tetrahydro-thiazolo [5 , 4-c] pyridin- 2 -yl) -guanidin mit den entsprechenden Sulfonylchloriden ( "R1 -Reagenzien") hergestellt. Beispiel N- 27Analogously to Example N-24, the compounds of Examples N-25 and N-26 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2 - yl) -guanidine with the corresponding sulfonyl chlorides ("R 1 reagents"). Example N-27
2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] yridin-5- carbonsäure-phenylamid2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] yridine-5-carboxylic acid phenylamide
Zu einer Suspension von N- (4 , 5 , 6 , 7-Tetrahydro-thiazolo [5 , 4- c] pyridin-2-yl) -guanidin Dihydrochlorid (0.1 mmol) inTo a suspension of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine dihydrochloride (0.1 mmol) in
Dimethylformamid (0.5 ml) wird Diisopropylethylamin (0.2 mmol) und nach 5 min Phenylisocyanat (0.11 mmol) zugegeben.Dimethylformamide (0.5 ml) is added diisopropylethylamine (0.2 mmol) and after 5 min phenyl isocyanate (0.11 mmol).
Das Reaktionsgemisch wird während 3 Stunden beiThe reaction mixture is at for 3 hours
Raumtemperatur weitergerührt. Anschliessend wird gesättigte wässrige Natriumcarbonat-Lösung zugegeben und mitRoom temperature stirred further. Then saturated aqueous sodium carbonate solution is added and with
Ethylacetat extrahiert. Nach Trocknen der vereinigten organischen Phasen über Natriumsulfat und Entfernen des Lösungsmittels im Vakuum wird die reine Titelverbindung erhalten.Extracted ethyl acetate. After drying the combined organic phases over sodium sulfate and removing the solvent in vacuo, the pure title compound is obtained.
Analog zu Beispiel N-27 werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-28 und N-29 durch Reaktion von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridin- 2-yl) -guanidin Dihydrochlorid mit den "R1 -Reagenzien" tert- Butylisocyanat, beziehungsweise Pentylisocyanat hergestellt .Analogously to Example N-27, the compounds of Examples N-28 and N-29 listed in Table 4 are obtained by reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-2- yl) -guanidine dihydrochloride with the "R 1 reagents" tert-butyl isocyanate or pentyl isocyanate.
Beispiel N-30Example N-30
2-Guanidino-6 , 7-dih.ydro-4.H-thiazolo [5, 4-c] pyridin-5- thiocarbonsäure-benzylamid2-guanidino-6, 7-dih.ydro-4.H-thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid benzylamide
Benzylamin (0.1 mmol), gelöst in Dimethylformamid (0.3 ml), wird unter Argon zu einer Lösung von 1 ' -Thiocarbonyldi- imidazol (0.1 mmol) in Dimethylformamid (0.5 ml) gegeben. Nach 2.5 Stunden Rühren bei Raumtemperatur werden nacheinander eine Lösung von N- (4 , 5 , 6, 7-Tetrahydro- thiazolo [5 , 4-c] pyridin-2-yl) -guanidin Dihydrochlorid (0.1 mmol) und Diisopropylethylamin (0.2 mmol) in Dimethylformamid dem Reaktionsgemisch beigegeben. Dieses wird weitere 16 Stunden bei Raumtemperatur gerührt und anschliessend mit gesättigter wassriger Natriumcarbonat- Lösung gequencht . Man extrahiert mit Ethylacetat und trocknet die vereinigten organischen Phasen über Natriumsulfat. Nach Entfernen des Lösungmittels im Vakuum wird die reine Titelverbindung erhalten (Bioog. Med . Chem . Lett . 2002, 12, 337-340) .Benzylamine (0.1 mmol), dissolved in dimethylformamide (0.3 ml), is added under argon to a solution of 1'-thiocarbonyldiimidazole (0.1 mmol) in dimethylformamide (0.5 ml). After stirring for 2.5 hours at room temperature, a solution of N- (4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) guanidine dihydrochloride (0.1 mmol) and diisopropylethylamine (0.2 mmol ) added to the reaction mixture in dimethylformamide. This is stirred for a further 16 hours at room temperature and then quenched with saturated aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. After removing the solvent in vacuo the pure title compound is obtained (Bioog. Med. Chem. Lett. 2002, 12, 337-340).
Analog zu Beispiel N-30 werden die Verbindungen der in Tabelle 4 aufgeführten Beispiele N-31 bis N-33 durchAnalogously to Example N-30, the compounds of Examples N-31 to N-33 listed in Table 4 are passed through
Reaktion von N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridin- 2 -yl) -guanidin Dihydrochlorid mit den entsprechenden Aminen in Gegenwart von 1 ' -Thiocarbonyldiimidazol hergestellt.Reaction of N- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) -guanidine dihydrochloride with the corresponding amines in the presence of 1'-thiocarbonyldiimidazole.
Präperative LC-MSPreparative LC-MS
Präparative Trennungen von Substanzgemischen werden auf einer präperativen LC-MS Anlage (Waters Prep LC-MS ausgerüstet mit einem Waters 600 Controller, Waters 2767 Sample Manager, Waters 996 Massenspektrometer und Photodioden-Array Detektor) durchgeführt . Verwendet wird eine Xterra Prep MS C18-Säule (5 μm Teilchengrösse, Länge 50 mm, Durchmesser 19 mm) , mit einem linearen Gradienten von Wasser/0.06% Ameisensäure (A) und Acetonitril/0.06% Ameisensäure (B) und einer Flussrate von 20 ml/min.Preparative separations of substance mixtures are carried out on a preparative LC-MS system (Waters Prep LC-MS equipped with a Waters 600 controller, Waters 2767 sample manager, Waters 996 mass spectrometer and photodiode array detector). An Xterra Prep MS C18 column (5 μm particle size, length 50 mm, diameter 19 mm) with a linear gradient of water / 0.06% formic acid (A) and acetonitrile / 0.06% formic acid (B) and a flow rate of 20 is used ml / min.
Analytische MethodenAnalytical methods
Die ^-NMR-Spektren werden auf einem Varian Oxford 300The ^ NMR spectra are on a Varian Oxford 300
Spektrometer, bei 300 K gemessen; die chemischeSpectrometer, measured at 300 K; the chemical
Verschiebung δ wird in ppm Tieffeld verschoben vom Signal von Tetramethylsilan als Referenz angegeben, als interner Standard dienen die Restsignale von deuteriertemShift δ is shifted in ppm downfield from the signal from tetramethylsilane as a reference, the residual signals from deuterated serve as internal standard
Dimetylsulfoxid ( δ (H) 2.49 ppm), deuteriertem Chloroform ( δ(~Α) 7.24 ppm) und Deuteriumoxid. 62Dimethyl sulfoxide (δ (H) 2.49 ppm), deuterated chloroform (δ ( ~ Α) 7.24 ppm) and deuterium oxide. 62
Tabelle 2Table 2
Die hergestellten Verbindungen werden mittels reversed- phase HPLC analysiert, und zwar auf einem Waters Alliance The compounds produced are analyzed by means of reversed-phase HPLC on a Waters Alliance
LC, ausgerüstet mit einem UV-Detektor und einem MassLynx NT Massenspektrometer .LC, equipped with a UV detector and a MassLynx NT mass spectrometer.
LC-1: GROM-SIL 120 ODS-4 HE HPLC-Säule (Teilchengrösse 3μm, Säulenlänge 30 mm, Durchmesser 2mm) , mit einem linearen Gradienten mit Wasser/0.06% Ameisensäure (A) und Acetonitril/0.06% Ameisensäure (B) von 5% auf 95% B in 3 min. mit einer Flussrate von 0.75 ml/min.LC-1: GROM-SIL 120 ODS-4 HE HPLC column (particle size 3μm, column length 30mm, diameter 2mm), with a linear gradient with water / 0.06% formic acid (A) and acetonitrile / 0.06% formic acid (B) from 5% to 95% B in 3 min. with a flow rate of 0.75 ml / min.
LC-2 : XTerra MS C18 HPLC-Säule (Teilchengrösse 5μm, Säulenlänge 50 mm, Durchmesser 2.1 mm), mit einem linearen Gradienten mit Wasser/0.06% Ameisensäure (A) undLC-2: XTerra MS C18 HPLC column (particle size 5μm, column length 50 mm, diameter 2.1 mm), with a linear gradient with water / 0.06% formic acid (A) and
Acetonitril/0.06% Ameisensäure (B) von 5% auf 95% B in 2.5 min. mit einer Flussrate von 0.75 ml/min. Acetonitrile / 0.06% formic acid (B) from 5% to 95% B in 2.5 min. with a flow rate of 0.75 ml / min.
Tabelle 3: Analytische Daten von den Beispielen C-01 bis C-73Table 3: Analytical data from Examples C-01 to C-73
Summenformel fR [min] MS Daton mfc Molecular formula f R [min] MS Daton mfc
Beispiel Struktur Name 9. **. " Molekular- (HPLC- r produkt gewicht Meth.) [M+H] [M-H]-Example structure name 9 . ** . "Molecular (HPLC r Product weight Meth.) [M + H] [MH] -
N-(6-lsopropyl-4,5,6,7-N- (6-isopropyl-4,5,6,7-
4-isopropyl- C11H18N4S 2.754-isopropyl-C11H18N4S 2.75
C-01 tetrahydro-benzothiazol-2- 239.25/ 237.24 cyclo exaπon 238.4 (LC-1) yl)-guanidin C-01 tetrahydro-benzothiazole-2- 239.25 / 237.24 cyclo exaπon 238.4 (LC-1) yl) guanidine
C-02C-02
C-03C-03
C-04 C-04
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten mfzOutput MS data mfz
Beispiel Struktur Name Molekular(HPLC- produkt gewicht Meth.) [M+H]7 [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] 7 [M-H] -
Summenformel fR[min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]7 [M-H]- Meth.)Example structure name molecular (HPLC product weight [M + H] 7 [M-H] - meth.)
C-09 273.20/ 271.30 C-09 273.20 / 271.30
N-(6-Met y[-4,5,6,7-N- (6-Met y [-4,5,6,7-
4-Methyl- C9H14N4S 2.74-methyl- C9H14N4S 2.7
C-10 tetrahydro-benzothiazol-2- 211.24/ 209.19 cyclohexanon 210.3 (LC-1) yl)-guanidin C-10 tetrahydro-benzothiazol-2- 211.24 / 209.19 cyclohexanone 210.3 (LC-1) yl) guanidine
Ausgangs- Summenformel 'R I™"] MS Daten m/zInitial sum formula 'RI ™ "] MS data m / z
Beispiel Struktur Name , ,~ Moleku ar- (HPLC- + Example structure name,, ~ Molec ar- (HPLC- +
Produkt gewicht Meth.) [M-H]7 [M-H]" Product weight meth.) [MH] 7 [MH] "
C-13C-13
C-14C-14
N-(4,5,6,7-Tetrahydro- C8H12N4S 2.75N- (4,5,6,7-tetrahydro-C8H12N4S 2.75
C-15 Cyclohexanon 197.22/ 195.34 benzothiazol-2-yl)-guanidin 196.3 (LC-1) C-15 cyclohexanone 197.22 / 195.34 benzothiazol-2-yl) guanidine 196.3 (LC-1)
C-16C-16
Summenformel fR [min] MS Daten m/z Molecular formula f R [min] MS data m / z
Ausgangs¬Ausgangs¬
Beispiel Struktur Name Molekular- (HPLC- „. , „+, ... , ... produkt gewicht Meth.) +H] / [M-H]Example structure name molecular (HPLC- ".," + , ..., ... product weight meth.) + H] / [MH]
C-17 199.27/ 197.31C-17 199.27 / 197.31
C-18 253.28/ 251.36C-18 253.28 / 251.36
C-19 277.25/ 275.39C-19 277.25 / 275.39
C-20C-20
Summenformel fR [min] MS Daten m/z Molecular formula f R [min] MS data m / z
AusgangsMolekular- (HPLC-Starting Molecular (HPLC)
Beispiel Struktur Name produkt [M+H]7 [M-H]- gewicht Meth.)Example structure name product [M + H] 7 [M-H] - weight meth.)
C-21C-21
C-22C-22
" C13H20N4O4S 1.54 283.08 " C13H20N4O4S 1.54 283.08
C-23 328.4 (LC-2)C-23 328.4 (LC-2)
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
C-25C-25
C-26C-26
C-27C-27
C-28C-28
Summenformel fR[min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
C-31C-31
C-32C-32
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
C-33C-33
C-34C-34
C-35C-35
C16H27N503S 1.53C16H27N503S 1.53
C-36 324.15/ n.a. 369.488 (LC-2) - C-36 324.15 / na 369.488 (LC-2) -
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]+/ [M-H]" Meth.)Example structure name molecular (HPLC product weight [M + H] + / [MH] " meth.)
1.531:53
C-37 C16H27N503S 324.28/ 322.24 369.5 (LC-2) C-37 C16H27N503S 324.28 / 322.24 369.5 (LC-2)
C-38C-38
C-39C-39
C-40C-40
Summenformel f [min]Sum formula f [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular- (HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
C14H21 N504S 1.21C14H21 N504S 1.21
C-41 355.4 (LC-2) 310.20/ 308.23 - C-41 355.4 (LC-2) 310.20 / 308.23 -
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]+/ [M-H]' Meth.)Example structure name molecular (HPLC product weight [M + H] + / [MH] ' meth.)
C-45C-45
C-46C-46
C-47C-47
C-48C-48
Summenformel tR [min]Sum formula t R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]+/ [M-H]- Meth.)Example structure name molecular (HPLC product weight [M + H] + / [MH] - meth.)
N-(6,6-Diphenyl-4,5,6,7-N- (6,6-diphenyl-4,5,6,7-
4,4-Diphenyl- C21 H22N402S 3.154,4-diphenyl-C21 H22N402S 3.15
C-49 tetrahydro-benzothiazol-2- 349.24/ 347.44 cyclohexanon 394.5 (LC-1) yl)-guanidin FormiatC-49 tetrahydro-benzothiazol-2- 349.24 / 347.44 cyclohexanone 394.5 (LC-1) yl) guanidine formate
2-Guanidino-6-phenyl-2-guanidino-6-phenyl-
4-Oxo-l -phenyl- 4,5,6,7-tetrahydro- cyclohexancarb C18H22N404S 1.754-oxo-1-phenyl- 4,5,6,7-tetrahydrocyclohexane carb C18H22N404S 1.75
C-50 benzothiazol-6- 345.36 onsäure- 390.5 (LC-2) carbonsäu re-ethy lester ethylester FormiatC-50 benzothiazole-6- 345.36 onionic acid 390.5 (LC-2) carboxylic acid re-ethyl ester formate
N-(6-Cyano-6-phenyl-N- (6-cyano-6-phenyl-
4-Cyano-4- 4,5,6,7-tetrahydro- C15H16BrN5S 2.924-cyano-4- 4,5,6,7-tetrahydro-C15H16BrN5S 2.92
C-51 phenylcyclohex 298.1/ 295.97 benzothiazol-2-yl)-guanidin anon 378.3 (LC-1) HydrobromidC-51 phenylcyclohex 298.1 / 295.97 benzothiazol-2-yl) guanidine anon 378.3 (LC-1) hydrobromide
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]+/ [M-H]" Meth.)Example structure name molecular (HPLC product weight [M + H] + / [MH] " meth.)
C-53 379.26 C-53 379.26
C-54C-54
C-55C-55
C-56C-56
Summenformel fR [min] Ms Daten m/z Molecular formula f R [min] Ms data m / z
Ausgangs¬Ausgangs¬
Beispiel Struktur Name Molekular- (HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
Ausgangs- Su menformel ^ imi^ MS Daten m/z Initial summer formula ^ i mi ^ MS data m / z
Beispiel Struktur Name a a Molekular- (HPLC 'o«. M gewichrt Ϊ MSeth.) [M-HrαM-Hi-Example Structure Name aa Molecular (HPLC 'o «. M weighted Ϊ MSeth.) [M-HrαM-Hi
N-(6-m-Tolyl-4,5,6,7-N- (6-m-tolyl-4,5,6,7-
3-m-Tolyl- C16H20N4O2S 1.733m Tolyl C16H20N4O2S 1.73
C-61 tetrahydro-benzothiazol-2- 287.22 cyclohexanon 332.4 (LC-2) yl)-guanidin Formiat C-61 tetrahydro-benzothiazol-2- 287.22 cyclohexanone 332.4 (LC-2) yl) guanidine formate
C-62 C-62
C-63 352?.8 02 „ (LC∞-2) 307.15/305.13 C-63 352? .8 02 "(LC∞-2) 307.15 / 30 5.1 3
Ausgangs- Summenformel Initial sum formula
Beispiel Struktur Name PΛ* " icnT Example structure name PΛ * "icnT
N-(5,5-Dimethyl-4,5,6,7-N- (5,5-dimethyl-4,5,6,7-
3,3-Dimethyl- C11H18N402S 2.92 tetrahydro-benzothiazol-2- 225.34 cyclohexanon 270.3 (LC-2) yl)-guanidin Formiat3,3-dimethyl-C11H18N402S 2.92 tetrahydro-benzothiazol-2- 225.34 cyclohexanone 270.3 (LC-2) yl) guanidine formate
CT OHCT OH
C-68C-68
Summenformel fR [min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht [M+H]+/ [M-H]- Meth.)Example structure name molecular (HPLC product weight [M + H] + / [MH] - meth.)
N-(5-Methyl-5-phenyl-N- (5-methyl-5-phenyl-
3-Methyl-3- 4,5,6,7-tetrahydro- C16H20N4O2S 3.013-methyl-3, 4,5,6,7-tetrahydro-C16H20N4O2S 3.01
C-69 phenyl- 286.45 benzothiazol-2-yl)-guanidin 332.4 (LC-2) cyclohexanon FormiatC-69 phenyl-286.45 benzothiazol-2-yl) guanidine 332.4 (LC-2) cyclohexanone formate
, N OH, N OH
C-70C-70
C-71 211.24C-71 211.24
C-72C-72
Summenformel fR[min]Sum formula f R [min]
AusgangsMS Daten m/zOutput MS data m / z
Beispiel Struktur Name Molekular(HPLC- produkt gewicht Meth.) [M+H]+/ [M-H]-Example Structure Name Molecular (HPLC product weight meth.) [M + H] + / [MH] -
C-73C-73
Tabelle 4: Analytische Daten von den Beispielen N-01 bis N-33Table 4: Analytical data from Examples N-01 to N-33
Summenformel fR [min] MS Daten π7/z Molecular formula f R [min] MS data π7 / z
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- „. , „+, „. , ,,. gewicht Meth.) [M+H. . -H]Ex. Structure Name R'-Reagent Molecular (HPLC- ".," + , "., ,,. Weight Meth.) [M + H. , -H]
N-01 298.22/ 296.29 N-01 298.22 / 296.29
N-(5-Hexyl-4,5,6,7-N- (5-hexyl-4,5,6,7-
C13H23N5S 0.94C13H23N5S 0.94
N-02 TCO " -=NH tetrahydro-thiazolo[5,4- 1 -Bromhexan 282.18/ 280.33 281.4 (LC-1) v c]pyridin-2-yl)-guanidinN-02 TCO " - = NH tetrahydro-thiazolo [5.4-1 bromohexane 282.18 / 280.33 281.4 (LC-1) vc] pyridin-2-yl) guanidine
N-03 240.18/ 238.31 N-03 240.18 / 238.31
Summenformel fR[min] MS Daten m/z Molecular formula f R [min] MS data m / z
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- ,„ , ,,+, ... „,. gewicht Meth.) [M+H]/[M-H]Example structure name R'-reagent molecular (HPLC-, ", ,, + , ...",. Weight meth.) [M + H] / [MH]
N-06 288.22/286.16 N-06 288.22 / 286.16
00
N-07 302.12/300.02 N-07 302.12 / 300.02
N-08N-08
Summenformel fR[min] MS Datenm/z Molecular formula f R [min] MS data m / z
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- „. , ,,+f _„ , ,,. gewicht Meth.) [M+H]/[M-H]Example structure name R 'reagent molecular (HPLC- "., ,, + f _", ,,. Weight meth.) [M + H] / [MH]
N-09N-09
N-10N-10
N-11N-11
N-12N-12
S" T,n.rmel tRlminl MS Daten m/z S "T, n . Rmel tRlminl MS data m / z
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- .„,.„-, ... ur gewicht Meth.) [M+H]/[M-H]Example structure name R 'reagent molecular (HPLC-. ",." -, ... ur weight meth.) [M + H] / [MH]
268.20/ 266.32268.20 / 266.32
N-13N-13
C C
N-[5-(2,2-Dimethyl- propionyl)-4,5,6,7- 2,2-Dimethyl-_ C12H19N50S 2A7 282.18/ 31 N- [5- (2,2-Dimethyl-propionyl) -4,5,6,7-2,2-dimethyl-C12H19N50S 2A7 282 . 18/31
N-15 tetrahydro-thiazolo[5,4- propionylchlorid 281.4 (LC-1) c]pyridin-2-yl]-guanidinN-15 tetrahydro-thiazolo [5,4-propionyl chloride 281.4 (LC-1) c] pyridin-2-yl] guanidine
N-16 N-16
Summenformel f R [min]Sum formula f R [min]
MS Daten m/zMS data m / z
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- [M+H]+/ [M-H]- gewicht Meth.)Example structure name R 'reagent molecular (HPLC- [M + H] + / [MH] - weight meth.)
N-[5-(3-Methyl-butyryl)- 4,5,6,7-tetrahydro- 3-Methyl- C12H19N50S 0.83N- [5- (3-Methylbutyryl) - 4,5,6,7-tetrahydro-3-methyl-C12H19N50S 0.83
N-17 282.25/ 280.33 thiazolo[5,4-c]pyridin-2-yl]- butyrylchlorid 281.4 (LC-1) guanidinN-17 282.25 / 280.33 thiazolo [5,4-c] pyridin-2-yl] butyryl chloride 281.4 (LC-1) guanidine
N-18 316.15/ 314.25 N-18 316.15 / 314.25
0 00 0
Summenformel rR [min] MS Daten m/zMolecular formula r R [min] MS data m / z
Bsp. Struktur Name R'-Reagens Molekular(HPLC- gewicht Meth.) [M+H]+/ [M-H]-Example structure name R'-reagent molecular (HPLC weight meth.) [M + H] + / [MH] -
N-21 N-21
N-22 332,7/ 330.24 N-22 332 , 7 / 330.24
κ N,-2,3 ? 4uHG-thιazidoi,lno?[5Y,4-c"]phyyrιHdrι%n-5- RBuHty.l-c hh.loro fforma ,t C12H1 g 9N502S (L 2C.6-71 298.25/ 296.28 carbonsäure-butylester ' ~ ) κ N, -2.3? 4uH G -thιaz id o i , l n o? [5Y, 4-c " ] p h y y rιHd r ι% n-5- RBuHty.lc hh.loro fforma, t C1 2H1 g 9N50 2 S ( L 2C 6 - 7 1 298.25 / 296.28 carboxylic acid butyl ester '~)
N-24N-24
Summenformel fR[min] MS Daten m/2 Molecular formula f R [min] MS data m / 2
Bsp. Struktur Name R'-Reagens Molekular- (HPLC- ... 1J1+, ... „,. gewicht Meth.) +H]/[M-H]Example structure name R'-reagent molecular ( HPLC- ... 1J1 + , ... ",. Weight meth.) + H] / [MH]
..„.. "
N-25N-25
N-26 11/ /4._«> N-26 11 / / 4 ._ «>
N-27 317.19/315.33 N-27 317.19 / 315.33
N-28N-28
Summenformel *R _min] MS Daten m/zMolecular formula * R _min] MS data m / z
Bsp. Struktur Name R'-Reagens Molekular(HPLC- [M+H]+/ [M-H]- gewicht Meth.)Example structure name R 'reagent molecular (HPLC- [M + H] + / [MH] - weight meth.)
N-29 311.23/ 309.37N-29 311.23 / 309.37
2-Guanidino-6,7-dihydro- sA€0 AH -thiazolo[5,4-c ]pyridin-5- C15H18N6S2 2.912-Guanidino-6,7-dihydro- sA € 0 AH -thiazolo [5,4-c] pyridine-5-C15H18N6S2 2.91
N-30 Benzylamin 346.82/ 345.09 thiocarbonsäure- 346.5 (LC-1) benzylamidN-30 benzylamine 346.82 / 345.09 thiocarboxylic acid-346.5 (LC-1) benzylamide
- , , . C11 H18N6S2 2.94-,,. C11 H18N6S2 2.94
N-31 Isopropy amin _no . .. _ .. 298.86/ 296.29 v v* 298.4 (LC-1) N-31 isopropy amine _ no . .. _ .. 298.86 / 296.29 vv * 298.4 (LC-1)
.. ...... ....
N-32N-32
Summenformel fR [min] MS Daten m/zMolecular formula f R [min] MS data m / z
Bsp. Struktur Name R'-Reagens Molekular(HPLC- gewicht Meth.) [M+H]+/ [M-H]" Example structure name R 'reagent molecular (HPLC weight meth.) [M + H] + / [MH] "
2-Guanidino-6,7-dihydro- 4H -thiazolo[5,4-c ]pyridin-5-2-guanidino-6,7-dihydro-4H -thiazolo [5,4-c] pyridine-5-
2-Amino-1- C12H20N6OS2 2.722-Amino-1-C12H20N6OS2 2.72
N-33 Q thiocarbonsäure-(2- 329.38/ 326.93 methoxypropan 328.4 (LC-1) methoxy-1 -methyl-ethyl)- amidN-33 Q thiocarboxylic acid (2- 329.38 / 326.93 methoxypropane 328.4 (LC-1) methoxy-1-methyl-ethyl) amide
t t

Claims

Patentansprüche claims
1. Verwendung von Guanidinderivaten der allgemeinen Formel1. Use of guanidine derivatives of the general formula
worin A eine Kette von 3-6 gegebenenfalls substituierten C-where A is a chain of 3-6 optionally substituted C-
Atomen bedeutet, wovon eines durch -N(R')- oder -0- ersetzt sein kann; undAtoms means one of which can be replaced by -N (R ') - or -0-; and
R' Wasserstoff oder einen Substituenten bedeutet; wobei das Ringgerüst nur die beiden Doppelbindungen des Thiazolbausteins enthält; von pharmazeutisch verwendbaren Säureadditionssalzen von basischen Verbindungen der Formel I, von pharmazeutisch verwendbaren Salzen von saure Gruppen enthaltenden Verbindungen der Formel I mit Basen, von pharmazeutisch verwendbaren Estern von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I sowie von Hydraten oder Solvaten davon; als Neuropeptid FF Rezeptor-Antagonisten bzw. zur Herstellung entsprechender Arzneimittel.R 'represents hydrogen or a substituent; wherein the ring structure contains only the two double bonds of the thiazole building block; of pharmaceutically usable acid addition salts of basic compounds of formula I, of pharmaceutically usable salts of acidic group-containing compounds of formula I with bases, of pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and of hydrates or solvates thereof; as a neuropeptide FF receptor antagonist or for the production of corresponding drugs.
2. Verwendung gemäss Anspruch 1 zur Behandlung von Schmerz und Hyperalgesie, von Entzugserscheinungen bei Alkohol-, Psychopharmaka- und Nicotinabhangigkeit und zur Verbesserung oder Aufhebung dieser Abhängigkeiten, zur Regulierung der Insulin-Freisetzung, der Nahrungsaufnahme, von Gedächtnisfunktionen, des Blutdrucks, und des Elektrolyt- und Energiehaushaltes und zur Behandlung von Harninkontinenz bzw. zur Herstellung entsprechender Arzneimittel .2. Use according to claim 1 for the treatment of pain and hyperalgesia, withdrawal symptoms with alcohol, psychopharmaceutical and nicotine dependency and for improving or removing these dependencies, for regulating insulin release, food intake, memory functions, blood pressure, and the electrolyte - and energy balance and for the treatment of Urinary incontinence or for the production of appropriate medicines.
3. Verwendung gemäss Anspruch 1 oder 2 von Verbindungen der allgemeinen Formel3. Use according to claim 1 or 2 of compounds of the general formula
III worin R' Alkyl, Alkanoyl, Alkenyl, Alkinyl, Alkoxycarbonylalkyl, Alkoxycarbonylaminoalkanoyl, Alkylcarbamoyl, Alkoxycarbonylalkylcarbamoyl,III wherein R 'is alkyl, alkanoyl, alkenyl, alkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkanoyl, alkylcarbamoyl, alkoxycarbonylalkylcarbamoyl,
Alkoxycarbonylalkylthiocarbamoyl, Alkylthiocarbamoyl, mono- oder di-substituiertes Aminoalkanoyl, Aryl, Arylalkyl, Arylalkoxycarbonyl, Arylalkanoyl, Arylcarbamoyl, Alkoxyalkanoyl, Alkylsulfonyl, Arylthiocarbamoyl , Aryloxycarbonylalkyl, Aryloxycarbonylalkanoyl , Aryloxycarbonylalkylcarbamoyl,Alkoxycarbonylalkylthiocarbamoyl, alkylthiocarbamoyl, mono- or di-substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, arylalkanoyl, arylcarbamoyl, alkoxyalkanoyl, alkylsulfonyl, arylthiocarbamoyl, aryloxycarbonylalkyl, aryloxyoylyloxycarbonylalkyl, aryloxycarbonylalkyl, aryloxycarbonylalkyl, aryl
Aryloxycarbonylalkylthiocarbamoyl, Arylsulfonyl , Cycloalkyl, Cycloalkanoyl, Cycloalkylcarbamoyl, Cycloalkylthiocarbamoyl, Cycloalkylcarbonyl , Cycloalkyloxycarbonylalkyl, Cycloalkyloxycarbonylalkanoyl, Cycloalkyloxycarbonylalkylcarbamoyl,Aryloxycarbonylalkylthiocarbamoyl, arylsulfonyl, cycloalkyl, cycloalkanoyl, cycloalkylcarbamoyl, cycloalkylthiocarbamoyl, cycloalkylcarbonyl, cycloalkyloxycarbonylalkyl, cycloalkyloxycarbonylalkanoyl, cycloalkyloxycarbonylalkylcarbamoyl,
Cycloalkyloxycarbonylalkylthiocarbamoyl, Heteroarylalkyl, Heterocyclylalkyl , Heterocyclylalkoxycarbonylalkyl, Heterocyclylalkoxycarbonylalkanoyl, Heterocyclylalkoxycarbonylalkylcarbamoyl,Cycloalkyloxycarbonylalkylthiocarbamoyl, heteroarylalkyl, heterocyclylalkyl, heterocyclylalkoxycarbonylalkyl, heterocyclylalkoxycarbonylalkanoyl, heterocyclylalkoxycarbonylalkylcarbamoyl,
Heterocyclylalkoxycarbonylalkylthiocarbamoyl, Heteroaryloxycarbonylalkyl, Hetero- aryloxycarbonylalkylcarbamoyl oder Heteroaryloxycarbonylalkylthiocarbamoyl bedeutet .Heterocyclylalkoxycarbonylalkylthiocarbamoyl, heteroaryloxycarbonylalkyl, heteroaryloxycarbonylalkylcarbamoyl or heteroaryloxycarbonylalkylthiocarbamoyl means.
4. Verwendung gemäss Anspruch 3 , worin das Ringgerüst ein Thiazolopyridin- , Thiazoloazepin- oder Thiazolooxepangerüst ist, welches nur die beiden Doppelbindungen des Thiazolbausteins enthält. 4. Use according to claim 3, wherein the ring structure is a thiazolopyridine, thiazoloazepine or thiazolooxane structure which contains only the two double bonds of the thiazole building block.
5. Verwendung gemäss Anspruch 4, worin das Ringgerüst ein 5 , 6-Dihydro-4H-cyclopentathiazol- , 6 , 7-Dihydro-4H- pyrano [4 , 3-d] thiazol- , oder 5, 6, 7, 8-tetrahydro-4H- thiazolo [4, 5-c] azepingerüst ist.5. Use according to claim 4, wherein the ring structure is a 5, 6-dihydro-4H-cyclopentathiazole-, 6, 7-dihydro-4H-pyrano [4, 3-d] thiazole-, or 5, 6, 7, 8- tetrahydro-4H-thiazolo [4, 5-c] azepine backbone.
6. Verwendung gemäss einem der Ansprüche 3-5, worin R' Methyl, Ethyl, Propyl, Hexyl, 2 , 2-Dimethylpropionyl, Cyclopropylmethyl, 2-Cyclohexylethyl, Propinyl, Etyloxycarbonylethyl, Benzyl, n-Butyloxycarbonyl, tert-6. Use according to any one of claims 3-5, wherein R 'is methyl, ethyl, propyl, hexyl, 2, 2-dimethylpropionyl, cyclopropylmethyl, 2-cyclohexylethyl, propynyl, ethyloxycarbonylethyl, benzyl, n-butyloxycarbonyl, tert-
Butyloxycarbonyl, Benzyloxy-carbonyl, 3-Methyl-butyryl, Pentanoyl, Phenylacetyl, 2-Propyl-pentanoyl, Cyclopropan- carbonyl, Isobutyryl, But-3-enoyl, 2-Methoxy-acetyl, Propane-2-sulfonyl, Butane-1-sulfonyl, Methansulfonyl, tert-Butyloxycarbonyl-aminopropionyl oder 4-Dimethylamino- butyryl bedeutet .Butyloxycarbonyl, benzyloxy-carbonyl, 3-methyl-butyryl, pentanoyl, phenylacetyl, 2-propyl-pentanoyl, cyclopropane-carbonyl, isobutyryl, but-3-enoyl, 2-methoxy-acetyl, propane-2-sulfonyl, butane-1- sulfonyl, methanesulfonyl, tert-butyloxycarbonyl-aminopropionyl or 4-dimethylamino-butyryl.
7. Verwendung gemäss Anspruch 1 oder 2 von 2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- carbonsäure- tert-butylester;7. Use according to claim 1 or 2 of 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid tert-butyl ester;
N- (5-Hexyl-4, 5,6, 7-tetrahydro-thiazolo [5 , 4-c] pyridin-2-yl) - guanidin;N- (5-hexyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
N- [5- (2-Cyclohexyl-ethyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin; N- (5-Ethyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) - guanidin;N- [5- (2-Cyclohexyl-ethyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine; N- (5-ethyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- carbonsäure-butylester;2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid butyl ester;
N- [5- (Propan-2-sulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;N- [5- (propan-2-sulfonyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Phenylacetyl-4, 5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl) -guanidin;N- (5-phenylacetyl-4, 5,6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
2-Guanidino-6, 7-dihydro-4H-thiazolo [5 , -c] pyridin-5- carbonsäure-benzylester; N- (5-Pentanoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2- yl) -guanidin;2-guanidino-6, 7-dihydro-4H-thiazolo [5, -c] pyridine-5-carboxylic acid benzyl ester; N- (5-pentanoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
2-Guanidino-6, 7-dihydro-4iT-thiazolo [5, 4-c] pyridin-5- thiocarbonsäure-propylamid; N- [5- (2-Propyl-pentanoyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin;2-guanidino-6, 7-dihydro-4iT-thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid propylamide; N- [5- (2-propylpentanoyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Benzyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2- yl) -guanidin;N- (5-benzyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
N- (5-Prop-2-ynyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin- 2-yl) -guanidin;N- (5-prop-2-ynyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine;
N- (5-Cyclopropancarbonyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4- c] pyridin-2-yl) -guanidin;N- (5-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
N~ [5- (Butan-1-sulfonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin; JV- (5-Isobutyryl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-N ~ [5- (butane-1-sulfonyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine; JV- (5-isobutyryl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-
2-yl) -guanidin;2-yl) guanidine;
N- [5- (2, 2-Dimethyl-propionyl) -4,5,6, 7-tetrahydro- thiazolo [5, 4-c] pyridin-2-yl] -guanidin; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, -c] pyridin-5- thiocarbonsaure-benzylamid,• N- [5- (2, 2-dimethyl-propionyl) -4,5,6,7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl] guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, -c] pyridine-5-thiocarboxylic acid benzylamide, •
2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure- tert-butylamid;2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid tert-butylamide;
N- (5-But-3-enoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-N- (5-But-3-enoyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridine-
2-yl) -guanidin; N- (5-Benzyl-5, 6,7, 8-tetrahydro-4H-thiazolo [4, 5-c] azepin-2- yl) -guanidin;2-yl) guanidine; N- (5-benzyl-5, 6,7, 8-tetrahydro-4H-thiazolo [4, 5-c] azepin-2-yl) guanidine;
3- (2-Guanidino-6, 7-dihydro-4JJ-thiazolo [5, 4-c] pyridin-5-yl) - propionsäure-ethylester;3- (2-Guanidino-6, 7-dihydro-4JJ-thiazolo [5, 4-c] pyridin-5-yl) propionic acid ethyl ester;
2-Guanidino-6 , 7-dihydro-4H-thiazolo [5 , 4-c] pyridin-5- carbonsäure-pentylamid;2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid pentylamide;
JV- [5- (2-Methoxy-acetyl) -4,5,6, 7-tetrahydro-thiazolo [5, 4- c] pyridin-2-yl] -guanidin;JV- [5- (2-methoxyacetyl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine;
N- (5-Cyclopropylmethyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4- c] pyridin-2-yl) -guanidin; N~ (5-Methansulfonyl-4, 5, 6, 7-tetrahydro-thiazolo [5,4- c]pyridin-2-yl) -guanidin;N- (5-cyclopropylmethyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine; N ~ (5-methanesulfonyl-4, 5, 6, 7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) guanidine;
N- [5- (3 -Methyl-butyryl) -4,5,6, 7-tetrahydro-thiazolo [5,4- c] pyridin-2-yl] -guanidin; 2-Guanidino-6, 7-dihydro-4H~thiazolo [5, 4-c] pyridin-5- thiocarbonsäure- (2-methoxy-1-methyl-ethyl) -amid; 2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- carbonsäure-phenylamid; [3- (2-Guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5- yl) -3-oxo-propyl] -carbaminsäure- ert-butylester;N- [5- (3-methyl-butyryl) -4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl] guanidine; 2-guanidino-6, 7-dihydro-4H ~ thiazolo [5, 4-c] pyridine-5-thiocarboxylic acid (2-methoxy-1-methyl-ethyl) -amide; 2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid phenylamide; [3- (2-guanidino-6, 7-dihydro-4H-thiazolo [5, 4-c] pyridin-5-yl) -3-oxo-propyl] carbamic acid, tert-butyl ester;
N- [5- (4-Dimethylamino-butyryl) -4,5,6, 7-tetrahydro- thiazolo [5, 4-c] pyridin-2-yl] -guanidin;N- [5- (4-dimethylamino-butyryl) -4,5,6,7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl] guanidine;
JV- (5-Propyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2- yl) -guanidin; und 2-Guanidino-6, 7-dihydro-4fT-thiazolo [5, 4-c] yridin-5- thiocarbonsäure-isopropylamid.JV- (5-propyl-4, 5,6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) guanidine; and 2-guanidino-6, 7-dihydro-4fT-thiazolo [5, 4-c] yridine-5-thiocarboxylic acid isopropylamide.
8. Verbindungen der in Anspruch 1 definierten Formel I, worin A eine Kette von 3-6 gegebenenfalls substituierten C- Atomen bedeutet, wovon eines durch -0- ersetzt sein kann, wobei das Ringgerüst nur die beiden Doppelbindungen des8. Compounds of formula I defined in claim 1, wherein A is a chain of 3-6 optionally substituted carbon atoms, one of which can be replaced by -0-, wherein the ring structure only the two double bonds of
Thiazolbausteins enthält; pharmazeutisch verwendbare Säureadditionssalze von basischen Verbindungen, pharmazeutisch verwendbare Salze von saure Gruppen enthaltenden Verbindungen mit Basen, pharmazeutisch verwendbare Ester von Hydroxy- oderContains thiazole building block; pharmaceutically acceptable acid addition salts of basic compounds, pharmaceutically acceptable salts of acidic group-containing compounds with bases, pharmaceutically acceptable esters of hydroxy or
Carboxygruppen enthaltenden Verbindungen sowie Hydrate oderCompounds containing carboxy groups and hydrates or
Solvate davon; mit Ausnahme von - N- (4, 5, 6, 7-Tetrahydro-benzothiazol-2-yl) -guanidin;Solvate thereof; with the exception of - N- (4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
(2-Guanidino-4, 5, 6, 7-tetrahydro-benzothiazol-4-yl) - essigsaure-ethylester;(2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazol-4-yl) - ethyl acetate;
N- ( -Hydroxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; - J\T- (4-Tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; N- (4-Azidomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;N- (hydroxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; - J \ T- (4-tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- (4-azidomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Aminomethyl-4 , 5 , 6 , 7-tetrahydro-benzothiazol-2- yl) -guanidin; und - N- (6-Acetylaminomethyl-4, 5, 6, 7-tetrahydro- benzothiazol-2-yl) -guanidin.N- (4-aminomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; and - N- (6-acetylaminomethyl-4, 5, 6, 7-tetrahydrobenzothiazol-2-yl) guanidine.
9. Verbindungen gemäss Anspruch 8 , worin in der Kette A eines der C-Atome einen oder zwei, gleiche oder verschiedene, Substituenten trägt; oder mehrere der C-Atome je einen oder zwei, gleiche oder verschiedene, Substituenten tragen.9. Compounds according to claim 8, wherein in chain A one of the C atoms carries one or two, identical or different, substituents; or more of the C atoms each carry one or two, identical or different, substituents.
10. Verbindungen gemäss Anspruch 9, worin der/die Substituent (en) ausgewählt ist/sind aus Alkyl-, Alkenyl-,10. Compounds according to claim 9, wherein the substituent (s) is / are selected from alkyl, alkenyl,
Cycloalkenyl- , Aryl-, Heteroaryl-, Aralkyl-,Cycloalkenyl, aryl, heteroaryl, aralkyl,
Alkoxycarbonyl-, Carboxamido- , Cyano- oderAlkoxycarbonyl, carboxamido, cyano or
Cyanolakylgruppen und/oder aus mit ein und demselben C-Atom verknüpften Polymethylengruppen.Cyanolakylgruppen and / or from polymethylene groups linked to one and the same C atom.
11. Verbindungen gemäss Anspruch 10, worin der/die Substituent (en) ausgewählt ist/sind aus11. Compounds according to claim 10, wherein the substituent (s) is / are selected from
Methyl-, Ethyl-, n-Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, sec-Butyl-, tert-Butyl-, 1,1- Dirnethylpropyl-, Allyl- und Cyclohex-1-enylgruppen; und/oderMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dirnethylpropyl, allyl and cyclohex-1-enyl groups; and or
Phenyl-, o-Tolyl-, m-Tolyl-, p-Tolyl-, 2-Ethylphenyl- , 3-Fluorphenyl-, 4-Fluorphenyl- , 4-Chlorphenyl- , 4- Cyanophenyl- , 4-Benzyloxyphenyl- , 3 -Methoxyphenyl- , 4 - Methoxyphenyl- , 3,4-Dimethoxyphenyl- , 3,4- Methylendioxyphenyl- und Bis-3,5- trifluormethylphenylgruppen; und/oder Thiophen-2-yl- und Benzylgruppen; und/oder Ethoxycarbonylgruppen; und/oder - n-Propylamino- , Benzylamino- , N-Methyl-N- phenethylamino-, 3-Methylbutylamino- , Phenylamino- , N- Butyl-N-ethylamino- , Di-n-propylamino- , Allylamino-, Piperidin-1- und Morpholin-4-carbonylgruppen; und/oder Cyano- und Cyanoethylgruppen; und/oder mit ein und demselben C-Atom verknüpften Pentamethylengruppen.Phenyl, o-tolyl, m-tolyl, p-tolyl, 2-ethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-benzyloxyphenyl, 3 - Methoxyphenyl, 4 - methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl and bis-3,5-trifluoromethylphenyl groups; and / or thiophene-2-yl and benzyl groups; and / or ethoxycarbonyl groups; and / or - n-propylamino-, benzylamino-, N-methyl-N-phenethylamino-, 3-methylbutylamino-, phenylamino-, N- Butyl-N-ethylamino, di-n-propylamino, allylamino, piperidine-1 and morpholine-4-carbonyl groups; and / or cyano and cyanoethyl groups; and / or pentamethylene groups linked to one and the same carbon atom.
12. Verbindungen gemäss Anspruch 11, worin an ein und demselben C-Atom einerseits eine Phenylgruppe und anderseits eine Ethoxycarbonyl- , Cyano- oder Phenylgruppe sitzen.12. Compounds according to claim 11, wherein on one and the same carbon atom on the one hand a phenyl group and on the other hand an ethoxycarbonyl, cyano or phenyl group.
13 N- (5-Ethyl-5-methyl-4 ,5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin und sein Formiat;13 N- (5-ethyl-5-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (5, 5-Dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;N- (5, 5-dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (5, 5-Dimethyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin und sein Formiat;N- (5, 5-dimethyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- (4- ert-Butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin; N- (6-Isopropyl-4 , 5, 6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (4- ert-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- (6-isopropyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (5,5, 7-Trimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (5,5,7-trimethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl) guanidine;
N- ( 6 , 6-Dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (6, 6-dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (5-Butyl-5, 6, 7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) - guanidin;N- (5-butyl-5, 6, 7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine;
N- (4-Ethyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin; JV- [6- (3,4-Dimethoxy-phenyl) -4 , 5, 6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat;N- (4-ethyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; JV- [6- (3,4-dimethoxyphenyl) -4, 5, 6, 7-tetrahydrobenzothiazol-2-yl] guanidine and its formate;
N- (5-Butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;N- (5-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (6-Phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;N- (6-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (5-Methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin; JV- (4-Methyl-4-propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (5-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine; JV- (4-methyl-4-propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
JV- (6-Propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;JV- (6-propyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
JV- (4-Cyclohex-l-enyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;JV- (4-cyclohex-1-enyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (4-sec-Butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat; undJV- (4-sec-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; and
N- (4-Isobutyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin.N- (4-isobutyl-4-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine.
14. N- (6- ert-Butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;14. N- (6- ert-butyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
2-Guanidino-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-6- carbonsäure-ethylester und sein Formiat JV- [6- (1, 1-Dimethyl-propyl) -4,5,6, 7-tetrahydro-benzothiazol-Ethyl 2-guanidino-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylate and its formate JV- [6- (1, 1-dimethyl-propyl) -4,5,6,7 tetrahydro-benzothiazol
2-yl] -guanidin;2-yl] guanidine;
JV- (7-Methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;JV- (7-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
IV- [6- (3-Methoxy-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein FormiatIV- [6- (3-methoxy-phenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate
JV- (6-Thiophen-2-yl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;JV- (6-thiophene-2-yl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (5, 5, 7, 7-Tetramethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; N- [6- (4-Fluor-phenyl) -4, 5, 6 , 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Hydrobromid;JV- (5, 5, 7, 7-tetramethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; N- [6- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its hydrobromide;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- ethylester und sein Hydrobromid;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester and its hydrobromide;
N- (4, 4-Dimethyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin;N- (4,4-dimethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Methyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat .N- (4-Methyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate.
N- (4, 5, 6, 7-Tetrahydro-benzothiazol-2-yl-4-spiro- cyclohexan) -guanidin und sein Formiat . JV- (5, 6, 7, 8-Tetrahydro-4H-cycloheptathiazol-2-yl) -guanidin; JV- (4-Allyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- (4, 5, 6, 7-tetrahydro-benzothiazol-2-yl-4-spirocyclohexane) guanidine and its formate. JV- (5, 6, 7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine; JV- (4-allyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (6-Methyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin;JV- (6-methyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
JV- [6- (3-Fluor-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;JV- [6- (3-fluoro-phenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
N- (6-Cyano-6-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Hydrobromid;N- (6-cyano-6-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its hydrobromide;
JV- (4-Phenyl-4 ,5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat; und JV- (6, 6-Diphenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat .JV- (4-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate; and JV- (6, 6-diphenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate.
15. N- [6- (4-Methoxy-phenyl) -4,5, 6 , 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Hydrobromid; JV- (5-Phenyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) - guanidin und sein Hydrobromid;15. N- [6- (4-methoxyphenyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] guanidine and its hydrobromide; JV- (5-phenyl-5, 6,7, 8-tetrahydro-4H-cycloheptathiazol-2-yl) guanidine and its hydrobromide;
JV- (6, 7-Dihydro-4H-pyrano [4, 3-d] thiazol-2-yl) -guanidin;JV- (6, 7-dihydro-4H-pyrano [4, 3-d] thiazol-2-yl) guanidine;
JV- (6-Benzo [1,3] dioxol-5-yl-4, 5,6, 7-tetrahydro-benzothiazol-JV- (6-benzo [1,3] dioxol-5-yl-4, 5,6, 7-tetrahydro-benzothiazole-
2-yl) -guanidin und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- propylamid und sein Formiat; JV- [6- (4-Cyano-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;2-yl) guanidine and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid propylamide and its formate; JV- [6- (4-cyano-phenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
JV- (4-Benzyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;JV- (4-benzyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (5-Methyl-5-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) - guanidin und sein Formiat;JV- (5-methyl-5-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
N- [6- (3, 5-Bis-trifluoromethyl-phenyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat; JV- (6-o-Tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat;N- [6- (3,5-bis-trifluoromethylphenyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] guanidine and its formate; JV- (6-o-tolyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- (6-m-Tolyl-4 , 5 , 6 , 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein Formiat ;JV- (6-m-tolyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate;
JV- [6- (2-Ethyl-phenyl) -4, 5, 6 , 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat; JV- [6- ( -Chloro-phenyl) -4,5,6, 7-tetrahydro-benzothiazol-2- yl] -guanidin und sein Formiat;JV- [6- (2-ethylphenyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; JV- [6- (-Chlorophenyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol- -carbonsäure- benzylamid und sein Formiat; JV- (5, 6-Dihydro-4H-cyclopentathiazol-2-yl) -guanidin;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-carboxylic acid benzylamide and its formate; JV- (5, 6-dihydro-4H-cyclopentathiazol-2-yl) guanidine;
JV- [6- (4-Benzyloxy-phenyl) -4 , 5, 6, 7-tetrahydro-benzothiazol-JV- [6- (4-benzyloxyphenyl) -4, 5, 6, 7-tetrahydro-benzothiazole-
2-yl] -guanidin und sein Hydrobromid;2-yl] guanidine and its hydrobromide;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- methyl-phenethyl-amid und sein Formiat; JV- (6-Phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl-4-spiro- cyclohexan) -guanidin und sein Hydrobromid;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid methyl-phenethyl-amide and its formate; JV- (6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl-4-spirocyclohexane) guanidine and its hydrobromide;
N- (6-p-Tolyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -guanidin und sein FormiatN- (6-p-Tolyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine and its formate
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- (3 -methyl-butyl) -amid und sein Formiat; und2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid (3-methyl-butyl) -amide and its formate; and
N- (4- tert-Butyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2- yl) -guanidin.N- (4-tert-Butyl-6-phenyl-4, 5,6, 7-tetrahydro-benzothiazol-2-yl) guanidine.
16. 2-Guanidino- ,5,6, 7-tetrahydro-benzothiazol-6- carbonsäure-phenylamid und sein Formiat;16. 2-guanidino-, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid phenylamide and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- butyl-ethyl-amid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid butyl ethyl amide and its formate;
N- [4- (2-Cyano-ethyl) -4,5,6, 7-tetrahydro-benzothiazol-2-yl] - guanidin und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- ethylester und sein Hydrobromid;N- [4- (2-cyano-ethyl) -4,5,6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester and its hydrobromide;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- dipropylamid und sein Formiat ;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid dipropylamide and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- phenylamid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid phenylamide and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- allylamid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid allylamide and its formate;
2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- propylamid und sein Formiat; JV- [4- (Piperidin-1-carbonyl) -4,5,6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat; 2-Guanidino-4 ,5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- allylamid und sein Formiat;2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid propylamide and its formate; JV- [4- (piperidine-1-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid allylamide and its formate;
2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-6-carbonsäure- (3-methyl-butyl) -amid und sein Formiat; JV- [4- (Morpholin-4-carbonyl) -4 , 5, 6, 7-tetrahydro- benzothiazol-2-yl] -guanidin und sein Formiat; und 2-Guanidino-4, 5,6, 7-tetrahydro-benzothiazol-4-carbonsäure- diisopropylamid und sein Formiat .2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid- (3-methyl-butyl) -amide and its formate; JV- [4- (morpholine-4-carbonyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl] guanidine and its formate; and 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid diisopropylamide and its formate.
17. Verbindungen gemäss einem der Ansprüche 8-16 zur Anwendung als therapeutische Wirkstoffe.17. Compounds according to any one of claims 8-16 for use as therapeutic agents.
18. Arzneimittel, enthaltend eine Verbindung gemäss einem der Ansprüche 8-16 und einen inerten Träger.18. Medicament containing a compound according to any one of claims 8-16 and an inert carrier.
19. Verwendung von Verbindungen gemäss einem der Ansprüche 8-16 gemäss Anspruch 1 oder 2.19. Use of compounds according to any one of claims 8-16 according to claim 1 or 2.
20. Verwendung von - IV- (4, 5, 6, 7-Tetrahydro-benzothiazol-2-yl) -guanidin;20. Use of - IV- (4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
(2-Guanidino-4, 5 , 6 , 7-tetrahydro-benzothiazol-4-yl) - essigsäure-ethylester;(2-guanidino-4, 5, 6, 7-tetrahydro-benzothiazol-4-yl) - ethyl acetate;
JV- ( -Hydroxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; - JV- (4-Tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;JV- (-hydroxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine; - JV- (4-tosyloxymethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
N- (4-Azidomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin;N- (4-azidomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine;
JV- (4-Aminomethyl-4,5, 6, 7-tetrahydro-benzothiazol-2- yl) -guanidin; undJV- (4-aminomethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl) guanidine; and
IV- (6-Acetylaminomethyl-4, 5, 6, 7-tetrahydro- benzothiazol-2-yl) -guanidin gemäss Anspruch 1 oder 2.IV- (6-acetylaminomethyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) guanidine according to claim 1 or 2.
21. Verfahren zur Herstellung von Verbindungen gemäss einem der Ansprüche 8-16, dadurch gekennzeichnet, dass man eine Verbindung der nachstehenden Formel 1 21. A process for the preparation of compounds according to any one of claims 8-16, characterized in that a compound of formula 1 below
in α-Stellung zur Carbonylgruppe halogeniert, die erhaltene Verbindung der obigen Formel 2 mit 2-Imino-4-thiobiuret der obigen Formel 3 einer Cyclokondensation unterwirft und gegebenenfalls eine erhaltene basische Verbindung in ein pharmazeutisch verwendbares Säureadditionssalz bzw. eine erhaltene, eine saure Gruppe enthaltende Verbindung in ein pharmazeutisch verwendbares Salz mit einer Base bzw. eine erhaltene Hydroxy- oder Carboxygruppen enthaltende Verbindung in einen pharmazeutisch verwendbaren Ester überführt und gegebenenfalls das erhaltene Produkt in ein Hydrat oder Solvat überführt . halogenated in the α-position to the carbonyl group, subjecting the compound of the above formula 2 obtained with 2-imino-4-thiobiuret of the above formula 3 to cyclocondensation and, if appropriate, a basic compound obtained into a pharmaceutically acceptable acid addition salt or a obtained one containing an acidic group Conversion of a compound into a pharmaceutically usable salt with a base or a compound containing a hydroxyl or carboxy group obtained into a pharmaceutically usable ester and optionally converting the product obtained into a hydrate or solvate.
EP04722212A 2003-03-20 2004-03-22 Guanidine derivatives and use thereof as neuropeptide ff receptor antagonists Withdrawn EP1608662A1 (en)

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