EP1917244A2 - Composes guanidine a substitution hetaryl et utilisation en tant que partenaires de liaison pour des recepteurs de 5-ht5 - Google Patents

Composes guanidine a substitution hetaryl et utilisation en tant que partenaires de liaison pour des recepteurs de 5-ht5

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Publication number
EP1917244A2
EP1917244A2 EP06791627A EP06791627A EP1917244A2 EP 1917244 A2 EP1917244 A2 EP 1917244A2 EP 06791627 A EP06791627 A EP 06791627A EP 06791627 A EP06791627 A EP 06791627A EP 1917244 A2 EP1917244 A2 EP 1917244A2
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EP
European Patent Office
Prior art keywords
alkyl
aryl
alkylene
hetaryl
group
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.)
Withdrawn
Application number
EP06791627A
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German (de)
English (en)
Inventor
Wilhelm Amberg
Astrid Netz
Andreas Kling
Michael Ochse
Udo Lange
Charles W. Hutchins
Francisco Javier Garcia-Ladona
Wolfgang Wernet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Deutschland GmbH and Co KG
Original Assignee
Abbott GmbH and Co KG
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Publication date
Application filed by Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Publication of EP1917244A2 publication Critical patent/EP1917244A2/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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 to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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 to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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 to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel hetaryl-substituted guanidine compounds and to the use of hetaryl-substituted guanidine compounds as binding partners for 5-HT 5 receptors for the treatment and / or prophylaxis of diseases which are modulated by 5-HT 5 receptor activity, in particular for treatment and / or prophylaxis of neurodegenerative and neuropsychiatric disorders and the associated signs, symptoms and dysfunctions.
  • At least seven different receptor classes mediate the physiological activities attributed to the involvement of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT for short). They are designated according to an internationally recognized classification with 5-HTi, 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 . Most of these classes also include other distinct receptor subtypes, such as the 5-HT 1 -KIaSSe receptors, which in turn can be divided into at least five subclasses, and as 5-HT 1 A, 5-HT 1B , 5-HT 1 C. , 5-HT 1D and 5-HT 1 E (Boess, Martin; Neuropharmacology 33: 275-317 (1994).
  • 5-HT 5A and 5-HT 5B receptors differ in that 5-HT 5A and 5-HT 5B receptors (Erlander et al., Proc Natl Acad, See, USA 90: 3452-3456 (1993).) Although only small sequence homologies exist between 5-HT 5 and other 5 -HT receptors, the pharmacological profile of these receptors is significantly different.
  • 5-HT 5 receptors could be localized to the olfactory bulb, hippocampus, cortex, cerebral ventricles, corpus callosum, and cerebellum using molecular biology techniques. It has been shown by immunohistochemical methods that 5-HT 5 receptors of neurons are expressed in different brain regions (Oliver et al., Brain Res 2000, 867, 131-142, Pasqualetti et al., Mol Brain Res 1998, 56, 1-8 )) These 5-HT 5 receptors may, on the one hand, directly or indirectly modulate important functions of the brain, but on the other hand also be involved in mechanisms involved in neuropathological, neurodegenerative and neuropsychiatric disorders.
  • 5-HT 5 receptors have also been localized in astrocytes (Carson et al., GLIA 17: 317-326 (1996).) Astrocytes are directly adjacent to the basal membrane of brain capillaries of the blood-brain barrier, and an abnormal astrocyte endothelium structure is involved The exact meaning of astrocytes is unclear, they seem to have transport tasks and connective functions Reactive astrocytes have been reported to be associated with reactive gliosis in a variety of pathological brain disorders and neuropsychiatric disorders are receptor-mediated responses of this, on the one hand believed that 5-HT 5 receptor in recovery processes of the brain involved after disturbances - protein expression pattern changes and growth factors are produced in vitro studies on cultured astrocytes showed 5-HT 5.. but then again It can not be ruled out that they contribute to the development of damage or even to an increase in damage.
  • Neuropathological conditions such as cerebral ischemia, stroke, epilepsy and seizures in general, chronic schizophrenia, other psychotic disorders, depression, anxiety, bipolar disorder, dementia, especially Alzheimer's dementia, demyelinating diseases, especially multiple sclerosis, and brain tumors lead to damage to the brain and to the associated neuronal deficits.
  • Therapeutic treatments of the described neurodegenerative and neuropsychiatric disorders have so far been directed to various membrane receptors with the aim of compensating for deficits in neurotransmission processes.
  • neuroprotective effects have been achieved with various serotonergic compounds in animal models of neuropathological conditions such as ischemia, stroke and excitotoxicity; In some cases, beneficial effects on mood disorders such as depression or anxiety were also observed.
  • Examples include 5-HTi A agonists such as buspirone, or the compound 5-HTYA receptor ligand characterized as 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT).
  • 5-HTi A agonists such as buspirone
  • these active ingredients only reduce the described neurological deficits to a limited extent, and there is currently no effective therapy for these diseases.
  • Migraine is most often characterized by recurrent headaches, of which an estimated 8 million, i. 3-5% of all children, 7% of all men and 14% of all women are affected. Although a genetic predisposition is propagated, the causes seem to be complex (Diener HC et al., Arzneiffentherapy 15: 387-394 (1997).) Two hypotheses dominate: The well-known vascular theory suggests a dilatation process of the The neurogenic theory relies on a release of vasoactive neurotransmitters, primarily neuropeptides, such as substance P and neurokinin, from axons of the vasculature due to stimulation of certain
  • migraine-specific drugs such as Sanmigran R , Nocerton R , Desernil R and Vidora R , but also commonly used for other indications agents such as beta-blockers, antiemetic agents such as Sibelium R , antidepressants such as Laroxyl R , or antiepileptic agents such as Depakin R , administered.
  • analgesics such as aspirin R , acetaminophen or Optalidon R , non-steroidal
  • Antiinflammatics such as Cebutid R , Voltaren R , B-40 R , Ponstyl R , Profenid R , Apranx R and Naprosin R for the pain and inflammation
  • ergot alkaloids such as ergotamine, dihydroergotamine, which can cause vasoconstriction
  • substances of the triptan family such as Sumatriptan, Naramig R, and R AscoTop with high affinity for 5-HT 1D receptors. The latter substances act as agonists and block vasodilation.
  • Nonopioid analgesics often have side effects.
  • the complex mechanism of action of ergot alkaloids due to the strong peripheral vasoconstriction leads to side effects such as hypertension and gangrene.
  • compounds belonging to the triptan family are not entirely satisfactory (Pfaffenrath V. Münch, Med. Wschr., 625-626 (1998).
  • 5-HT5 receptors show a high affinity for various antidepressants and antipsychotics. Previous studies indicate a role of 5-HT5 receptors in the following conditions:
  • 5-HT5 receptor ligands generally for the treatment of migraine and other cerebrovascular diseases is described in WO 00/041472, for the treatment of neurodegenerative and neuropsychiatric disorders in WO 00/041696.
  • 5-HTs receptor ligands generally for the treatment of migraine and other cerebrovascular disorders is described in WO00041472, for the treatment of neurodegenerative and neuropsychiatric disorders in WO00041696 and WO04096771.
  • WO2002018327A2 describes the synthesis of guanidinobenzamides as melanocortin-4 receptor antagonists (MC-4R), which find their use for the treatment of diseases such as obesity and type II diabetes.
  • WO9426715A1 describes the preparation of ⁇ / -pyridyl- / V-arylguanidines and analogs such as pyrimidines and pyrazines as gastric acid secretion inhibitors.
  • WO2004037166A2 generally describes the synthesis of guanidinoazines as antivirals, with a focus on the 4,6-dimethyl-, 4,6-dimethoxy- and 4-methoxy-6-methyl-substituted / V- (pyrimidin-2-yl) - / V- (2-phenylethyl) guanidines and / V- [2- (1H-indol-3-yl) ethyl] guanidines.
  • WO2000004014A1 the synthesis of pyrimidine derivatives is described as antitumor therapeutics, with a focus on the ⁇ / - [5- (hetaryloxymethyl) pyrimidin-4-yl] guanidines or ⁇ / - ⁇ 5 - [(hetarylthio) methyl] pyrimidine -4-yl ⁇ guanidine stand.
  • WO9202513A1 describes the synthesis of diphenylazines and their use as antithrombotic vasodilators, as hypotensives and as anti-inflammatory agents.
  • WO9736861A1 entitled "mete-substituted phenylene sulfone amide derivatives"
  • the focus is on the amides and ureas in focus.
  • the guanidine compounds containing in the general formula carry a benzyl radical in the mete position to an optionally substituted ⁇ / - ⁇ 3 - [(3-oxopropyl) sulfonyl] phenyl ⁇ - sulfonamide or ⁇ / - ⁇ 3 - [(3-oxopropyl) sulfonyl] phenyl ⁇ amide radical.
  • JP0830184A1 describes "squalene epoxidase activity inhibitors" wherein the 2-pyridylguanidine compounds are substituted with a phenyl side chain only in the meta and para positions to the point of attachment.
  • WO9506034A1 describes compounds such as substituted N- (Z-phenylethyl) - / V -pyridin-2-yl ureas and a few guanidines, and methods for inhibiting HIV and other related viruses.
  • WO2003011872A1 describes "platelet ADP receptor inhibitors" in which the N-hetarly residue linked to guanidine is reacted with an amide, alkoxy radical or even more complex radicals, for example from the group of isoquinolines-1,3-2H, 4H-dione-2-yl , 3,4-Dihydroisoquinoline-1 (2H) -one-2-yl, 1,4-dihydroisoquinoline-3 (2H) -one-2-yl, 1H-1,4-benzodiazepine-3,5 (2H, 4H
  • the exemplary embodiments relate predominantly to substituted N- (anilinocarbonyl) thiophene-2-sulfonamides, ⁇ / - [anilino (imino) methyl] thiophene-1-dion-4-yl and 1H-inden-1-one-2-yl.
  • methylene urea derivatives are described as RAF kinase inhibitors.
  • the embodiments relate exclusively to ⁇ / -aryl / hetaryl- ⁇ / '- methylenearyl / hetaryl-substituted urea derivatives, which in particular with respect to the urea in the ⁇ /' - methylene-aryl / hetaryl unit by the special substitution pattern as meta- or para-substituted oxy-bridged aryl / hetaryl substituents are characterized.
  • EP1270551A1 describes urea derivatives with antiproteolytic activity for the treatment and prophylaxis of thromboembolic disorders and restenoses.
  • the structures subject to this application consist of respectively para-substituted amidine units and also of the cyclic variant as 3- ⁇ 2 / - / - [1, 2,4] oxadiazol-5-one ⁇ .
  • the exemplary embodiments relate in particular to 4,5-biaryl or 4-hetaryl-5-aryl-substituted pyrimidines, which in turn in the 2-position by 2,6-dichlorobenzyl, 2- (2-chlorophenyl) ethylamino, 2- (4 Fluorophenyl) ethylamino, 3-phenylpropylamino, 3-imidazolylpropylamino, piperazinyl or other nitrogen-containing radicals.
  • Patents US 5,942,544 A, US 6,187,797 B1 and US 6,020,357 A describe novel alpha-branched anilines, toluenes and analogs, phenylisoxazoles and nitrogen-containing heteroaromatics as factor XA inhibitors.
  • US Pat. No. 5,741,661 also describes neurotransmitter release modulators 1 which consist of substituted guanidines, ⁇ T-aminoguanidines and N, N ', N ", N" -tetrasubstituted hydrazinedicarboximiamides.
  • the applications are named nerve cell death, Alzheimer's and Huntington's disease, anxiety, dementia and arteriosclerosis.
  • thiourea derivatives which contain as recurring structural element a (N'-substituted (2E) - ⁇ / ⁇ 1 - [(aminocarbonothioyl) amino] -2,2,2-trichloroethyl ⁇ -3-phenylacrylamide or ⁇ / via the thiourea - ⁇ 1 - [(aminocarbonothioyl) amino] -2,2,2-trichloroethyl ⁇ -2,2-alkylamide unit show.
  • WO0230881A1 describes the synthesis of (hetero) arylsulfonylguanidines which are used for the treatment of pain, epilepsy, migraine and other diseases.
  • Diazine-de ⁇ ved guanidines, isothioureas, and isoureas Synthesis and attempts of configurational assignment described in G. Heinisch, J. Het. Chem. 2002, 39 (4), 695-702, a new synthetic approach and spectroscopic structure elucidation to the ⁇ / '- pyrimid-2-yl, ⁇ /' - pyrazin-2-yl and ⁇ / '- pyridazine 3-yl substituted ⁇ / -tert-butyl-guanidines, 1-terf-butyl-isothioureas and 1-tert-butylisoureas.
  • the different reactivity of the aryl and alkyl biguanides with benzoylacetone is compared, which in the first case to the 6-arylamino-4-amino-2-phenyl-2- (6 1 -arylamino-4'-amino-2'- methyl-i ' ⁇ ' - dihydro-s-triazinyl ⁇ '- methyO-i ⁇ -dihydro-s-triazines and in the second case lead to the corresponding 6-methyl-4-phenyl-2-alkylguanidinopyrimidinen.
  • Cyanoguanidines are also described as cell proliferation inhibitors in WO9854146A1.
  • cyanoguanidines in particular substituted ⁇ / - ⁇ 1 - [(carboxy) methyl] -pyridinium- ⁇ / -cyano-guanidine derivatives, which are suitable as prodrugs for human and veterinary therapy of proliferative diseases such as cancer.
  • WO200061561A1 and WO200061559A1 describe novel substituted cyanoguanidine derivatives for treatment as antitumor agents or for the treatment of tumors, for example in leukemia, melanoma or lung, colon, ovarian, cervical, renal, prostate or breast cancer or Cancer of the Central Nervous System.
  • WO9520579A1 describes the synthesis of pyridinyl cyanoguanidines, WO9404500A1 that of pyridyl cyanoguanidines, US5567722A of N- (3-pyridyl) -N "-cyanoguanidinen, WO9404499A1 of ⁇ / -phenyl (cyclo) alkyl- ⁇ / '- 3-pyridylcyano guanidinen and each their use as potassium channel blocker.
  • Cyanoguanidines are also described in US Pat. No. 5,6681, 57 A as potassium channel blockers, their use for the treatment of cardiovascular diseases and as diuretics and their syntheses.
  • cyanoguanidines are described and in patent WO9429280A1 pyrimidine cyanoguanidines are also described as potassium channel blockers.
  • - DE2557438A1 describes ⁇ / -substituted ⁇ / "- cyano- ⁇ / '- pyridylguanidine derivative and DE3233380A1 substituted pyridyl-cyanoguanidine compounds whose activity has been demonstrated as antihypertensive agents.
  • WO0216318A1 claims various hetaryl-substituted thioureas, ureas and cyanoguanidines, the focus being on the novel thiourea derivatives and the pharmaceutical compositions thereof.
  • WO8906530A1 entitled “New, Contemporary Syntheses for the Treatment of Hair Loss", describes variously linked pyridyl cyanoguanidines.
  • EP0022958A1 urea derivatives for the use of fat metabolism disorder are described, wherein instead of the thioureas and ureas and the cyanamide analogues are claimed.
  • WO0076508A1 describes IL-8 receptor antagonists which are used for the treatment of diseases caused by chemokines.
  • WO0178717A1 describes ⁇ / -hydroxyguanidines for pharmacotherapy for vascular dysfunction, which is associated with insufficient nitric oxide bioactivity.
  • ⁇ / amino acid ⁇ / ', ⁇ / - disubstituted guanidine derivatives, thiourea and also amidine derivatives are disclosed in WO9500505A1 in the general formula, wherein the embodiments relate to ⁇ / amino acid-substituted thioureas, which as NO synthase inhibitors are used.
  • WO2002088323A2 describes hydrazinecarboximidamides which activate gene transfer.
  • WO 2005/095345 (PCT / US2005 / 009710) describes 2-pyridyl and 2-pyrimidylguanidine derivatives and their use as inhibitors of viral replication.
  • WO 2002/24681 (PCT / US01 / 29175) describes 1,4-pyrazine-guanidine derivatives and their use as inhibitors of tyrosine kinase activity, wherein the pyrazine ring is substituted by a heteroaryl or biheteroaryl group.
  • WO 2006/007532 (PCT / US2005 / 023346) describes 2-substituted heteroaryl compounds and their use as interleukin IL-12 modulators.
  • WO 2005/086754 (PCT / US2005 / 007316) describes dicationic compounds for the treatment of trichomoniasis infections.
  • WO 2004/058709 (PCT / US2003 / 041360) describes guanidine derivatives as chemokine receptor (CCR8) inhibitors.
  • WO 2006/021805 (PCT / GB2005 / 003352) describes diarylsulphones as 5-HT2A antagonists.
  • WO 93/12788 (PCT / US92 / 10254) describes pyridylguanidine compounds for the treatment of erectile dysfunction.
  • the EP 0401 010 B1 describes pyranyl-Cyano 'guanidine derivatives and their use as cardiovascular agents.
  • the object was to provide compounds which allow the treatment and / or prophylaxis of neuropathological, neuropsychiatric and neurodegenerative disorders with sufficient efficacy and low side effects.
  • the aim was to provide compounds which modulate 5-HT 5A receptor activity for the treatment and / or prophylaxis of diseases treatable by modulation of 5-HT 5A receptor activity.
  • substances of the general Formula I act as ligands of the 5-HT 5 receptor and therefore a treatment of the associated disease states described above and the associated symptoms and dysfunction is enabled.
  • R 1 , R 2 are each independently of one another:
  • Hydrogen OH 1 CN, or in each case optionally substituted C 1 -C 6 -alkyl, O-C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O-C 6 -alkyl, C 3 -C 7 -cycloalkyl, O-C 3 -C 7 -cycloalkyl , aryl, hetaryl, C r C 4 -alkylene-aryl, C 1 -C 4 alkylene-hetaryl, O-aryl, OC r C 4 -
  • Rz 1 ⁇ Rz 2 , Rz 3 , Rz 4 are each independently of one another: hydrogen, halogen, OH, or in each case optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -CE-alkynyl, C 1 -C 4 Alkylene-C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, hetaryl or C 1 -C 4 -alkylene-hetaryl or in each case independently of one another two radicals R z 1 and R z 2 or R z 3 and
  • Rz 4 together with the C-atom to which they are attached form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo or heterocycle which has one, two or three identical or different heteroatoms selected from the group consisting of O , N and / or S may contain;
  • Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 12 -alkynyl, CO-C 1 -C 6 -alkyl, CO-O-CrC 6 -
  • Alkyl SO 2 -C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, CO-
  • Rz 6 , Rz 7 are each independently and independently of their occurrence:
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 - alkynyl, C 3 -C 7 cycloalkyl, d ⁇ alkylene-C ß T -C cycloalkyl, C 1 - C 4 -alkylene-heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, heterocycloalkyl, or R A 1 , O-RA 1 , CO-R A 1 , SR A 1 , SO-R A 1 , CO-O-RA 1 , NR A 4 -CO-OR A 1 , O-
  • R A 1 independently of each occurrence, is: optionally substituted Ci-C 6 alkyl, Ci-C 6 -alkylene-O-Ci- Ce-alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 3 -C 7 -cycloalkyl, C r C 4 -alkylene
  • RA 2 represents, independently of each occurrence: hydrogen, OH, CN, or optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 - alkinyl, Ci-C 4 -alkylene-C C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 4 -alkylene-O-C 6 -alkyl, CO -C 1 -C 6 -alkyl, CO-aryl, CO-hetaryl, CO-C 1 -C 4 -alkylene-aryl, CO-C 1 -C 4 -alkylene
  • RA 3 independently of its occurrence, in each case represents optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl , Aryl, hetaryl, heterocycloalkyl, C 1 -
  • radicals RA 2 and RA 3 together with the nitrogen atom to which they are attached form a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle which contains one, two or three further different or identical heteroatoms selected from the group may contain O, N and S, wherein optionally substituted on this heterocycle radicals together with the ring atom to which they are attached, a 3- to 7-membered, optionally substituted, fused, saturated, unsaturated or aromatic carbocycle or heterocycle wherein the heterocycle may contain one, two or three different or identical heteroatoms selected from the group consisting of O, N and S, which may be optionally substituted;
  • RA 4 represents independently of each occurrence hydrogen, or optionally substituted 6 -alkyl, dC 6 alkylene-OD- -alkyl, C 2 -C 6 alkenyl, C 2 -C 12 alkynyl, CO-dC 6 alkyl, CO-O-Ci-C 6 - alkyl, SO 2 -dC 6 alkyl, C 3 -C 7 cycloalkyl, aryl, dC 4 alkylene-aryl, CO-
  • Hydrogen or in each case optionally substituted aryl or hetaryl, or independently of radical A has the same meanings as defined for radical A,
  • Radicals together with the ring atom to which they are attached can form a further 3- to 7-membered, optionally substituted fused, saturated, unsaturated or aromatic carbocycle or heterocycle, where the heterocycle has one, two or three different or identical heteroatoms selected from the group consisting of O, N and S may contain and wherein the thus formed cycle may optionally be substituted, means;
  • Rw 1 , Rw 2 , Rw 3 are each independently:
  • radical D is, independently of the radical A, a radical which has the same meanings as defined for radical A;
  • radical A is hydrogen or, independently of radical A, a radical which has the same meanings as defined for radical A;
  • X 1 C or N
  • X 2 C or N
  • X 3 C or N
  • X 4 C or N
  • X 5 C or N
  • one, two or three radicals selected from the group consisting of the radicals X 1 , X 2 , X 3 , X 4 and X 5 are simultaneously N and the associated binding partner is selected from the group consisting of R 4 , R 5 , R 6 , R 7 and R 8 should then stand for a free electron pair.
  • R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a radical selected from the same or different of the following groups 1), 2), 3), 4), 5), 6 ) and 7.), in which the groups 1) to 7) have the meanings mentioned below:
  • RQ 5 0-CH 2 -COO-RQ 5 , NR Q 7 -CO-RQ 5 , SO 2 -RQ 5 , NR Q 7 -SO 2 -RQ 5 , SO 2 NH 2 , CONH 2 , SO 2 -NRQ 6 RQ 7 or CO-NRQ 6 RQ 7 ; wherein RQ 4 , RQ 5 , RQ 6 and RQ 7 are independently and independently of their occurrence as defined below;
  • OCH 2 F COOH, 0-CH 2 -COOH, SH, halogen, or optionally substituted aryl, hetaryl, heterocycloalkyl, -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 4 - alkylene-C 3 -C 7 cycloalkyl, Ci-C4-alkylene-heterocycloalkyl, dC 4 - alkylene-aryl or Ci-C4-alkylene-hetaryl, or in each case optionally substituted
  • the cycle thus formed be optionally substituted, and / or at this cycle another, 3 to 7-membered, optionally substituted cycle may be fused; in which independently of each occurrence are each hydrogen or optionally substituted Ci-C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 1 -C 4 -alkylene-heterocycloalkyl, heterocycloalkyl, aryl or hetaryl; means
  • Ci-C ⁇ alkyl independently of each occurrence are each hydrogen or optionally substituted Ci-C ⁇ alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -
  • Cycloalkyl d-d-alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl or d-Ce-alkylene-O-d-Ce-alkyl;
  • C 6 alkyl independently of each occurrence is hydrogen or in each case optionally substituted C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, Ci-C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl,
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N, and S may contain, and optionally form two substituted on this heterocycle radicals together with the atom to which they are respectively bonded can form a 3- to 7-membered, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle may contain one, two or up to three different or identical heteroatoms selected from the group consisting of O, N, and S, and the cycle thus formed may optionally be substituted and / or at this cycle another, 3- to 7-membered, optionally substituted cycle may be fused;
  • each optionally substituted C 5 -Ci ⁇ - bi- or tricyclic, saturated hydrocarbon radical 6.) in each case optionally substituted C 1 -C 8 -alkyl-NH 2 , C 1 -C 8 -alkyl-NRQ 6 RQ 7 , C 1 -C 8 -alkyl-CO-NRQ 6 RQ 7 , C 1 -C 8 -alkyl-SO 2 NRQ 6 R Q 7 , Ci- C 8 -alkyl-CO-NH 21 C 1 -C 8 -alkyl-SO 2 NH 2 ;
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • R 1 , R 2 are each independently of one another:
  • R 3 is hydrogen or in each case optionally substituted C 1 -C 6 -alkyl, O-C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O-C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, hetaryl, C r C 4 alkylene-aryl, -alkylene-dC 4 hetaryl, O-aryl, 0-C 1 -C 4 -
  • Ci-C4-alkylene-hetaryl S ⁇ 2 -C-C ⁇ -alkyl, SO 2 -aryl, SO 2 hetaryl or SO 2 -C r C 4 alkylene-aryl,
  • heterocycle may contain one, two or three different or identical heteroatoms selected from the group consisting of O, N and S and wherein the cycle formed optionally substituted and / or may be fused to this cycle another, 3- to 7-membered, optionally substituted cycle;
  • Z is a radical of the general formula Z1
  • Rz 1 , Rz 2 , Rz 3 , Rz 4 are each independently:
  • Rz 4 together with the C-atom to which they are attached form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle containing one, two or three identical or different heteroatoms selected from the group may contain O, N and / or S;
  • Rz 5, 5 * Rz are each independently, and independently of their respective occurrence represent hydrogen, or optionally substituted Ci-C 6 alkyl, -C 4 alkylene-O-Cr C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 2 alkynyl, CO-Ci-C 6 alkyl, CO-O--C 6 - alkyl, SO 2 -CRC 6 alkyl, C 3 -C 7 cycloalkyl, aryl, -C 4 alkylene Aryl, CO-O-C 1 -C 4 -alkylene-aryl, CO-C 1 -C 4 -alkylene-aryl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 -CrC 4 -alkylene-aryl;
  • Rz 6, 7 Rz are each independently, and independently of their respective occurrence mean: hydrogen, OH, or optionally substituted Ci-C 6 alkyl, Ci-C 6 alkoxy, C 2 -C 6 -
  • RA 1, independently of its occurrence, in each case represents optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O-C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 - C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl,
  • RA 2 represents, independently of each occurrence: hydrogen, OH 1 CN, or optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 - alkinyl, Ci-C 4 -alkylene-C C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 6 -alkylene-O-C 6 -alkyl, CO- C 1 -C 6 -alkyl, CO-aryl, CO-hetaryl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, CO-OdC 6 -alkyl, CO-OdC 6 -alkyl
  • R A 3 is: optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 - alkynyl, -C 4 -alkylene-C 3 -C 7 cycloalkyl, dC 4- alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl,
  • C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 2 alkynyl, CO-d-Ce-alkyl, CO-O--C 6 - alkyl, SO 2 -C-C 6 alkyl, C 3 -C 7 -cycloalkyl, aryl, C 1-4 -alkylene-aryl, CO-O-arylalkyl, CO-C 1 -C 4 -alkylene-aryl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 - C 1 -C 4 alkylene aryl;
  • Hydrogen or in each case optionally substituted aryl or hetaryl, or independently of radical A has the same meanings as defined for radical A,
  • Rw 1 , Rw 2 , Rw 3 are each independently:
  • radical D is, independently of the radical A, a radical which has the same meanings as defined for radical A;
  • E is hydrogen or, independently of residue A, a residue that is the same
  • residue A means; an at least 6-membered hetaryl radical of the general formula Q.
  • X 3 C or N
  • X 4 C or N
  • X 5 C or N, where one, two or three radicals selected from the group consisting of the radicals X 1 , X 2 , X 3 , X 4 and X 5 are simultaneously N and the associated binding partner is selected from the group consisting of R 4 , R 5 , R 6 , R 7 and R 8 should then stand for a free electron pair.
  • R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a radical selected from the same or different of the following groups 1), 2), 3), 4), 5), 6 ) and 7.) in which the groups 1) to 7) have the following meanings:
  • RQ 5 0-CH 2 -COO-RQ 5 , NR Q 7 -CO-R Q 5 , SO 2 -RQ 5 , NR Q 7 -SO 2 -RQ 5 , SO 2 NH 2 , CONH 2 , SO 2 - NR 0 6 RQ 7 or CO-NRQ 6 RQ 7 ; wherein R 0 4 , RQ 5 , RQ 6 and RQ 7 are independently and independently of their occurrence as defined below;
  • a naphthyl which may be substituted by one, two or three radicals selected from the group consisting of the radicals RQ 1 , RQ 2 and RQ 3 , wherein
  • RQ 1 , RQ 2 and RQ 3 each independently represent an identical or different substituent selected from the following group:
  • RQ 2 and RQ 3 together with the C-atom to which they are attached, a 3- to 7-membered, optionally substituted, saturated, unsaturated carbocycle or a 3- to 7-membered, optionally substituted, saturated, unsaturated aromatic heterocycle, which may contain up to three further different or identical heteroatoms selected from the group consisting of O, N, and S form, where appropriate, two substituted on this carbocyclic or heterocycle radicals together with the ring atom to which they are attached, may form a 3- to 7-membered, optionally substituted fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle has one, two or up to three different or identical heteroatoms selected from the group consisting of O, N, and S may contain, and the cycle thus formed may be optionally substituted, and / or may be fused to this cycle another, 3 to 7-membered, optionally substituted cycle; in which
  • RQ 4 independently of each occurrence are each hydrogen or optionally substituted Ci-C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, Ci-C 4 -alkylene-C 3 -C 7 cycloalkyl C 1 -C 4 -alkylene-heterocycloalkyl, heterocycloalkyl, aryl or hetaryl; means
  • RQ 5 independently of each occurrence are each hydrogen or optionally substituted Ci-C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C r C 4 alkylene C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl,
  • Ci-C 6 alkyl C 2 -C 6 -
  • RQ 7 independently of each occurrence is hydrogen or optionally substituted Ci-C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, -C 4 -alkylene-C 3 -C 7 -
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N, and S may contain, and optionally two substituted on this heterocycle radicals together with the ring atom to which they are attached can form a 3- to 7-membered, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle may contain one, two or up to three different or identical heteroatoms selected from the group consisting of O, N, and S, and the thus formed
  • Cyclus may optionally be substituted and / or at this cycle another, 3- to 7-membered, optionally substituted cycle may be fused; 3.) a 5- or 6-membered, unsubstituted or optionally mono- or disubstituted by identical or different substituents hetaryl radical selected from the group consisting of:
  • N, and S may contain and wherein the thus formed carbocycle or heterocycle may optionally be substituted;
  • Ci-C 8 alkyl-NH 2 in each case optionally substituted Ci-C 8 alkyl-NH 2, C r C 8 alkyl NRQ RQ 6 7, C 1 -C 8 -alkyl-SO 2 N RQ RQ 6 7 C r C 8 -alkyl-CO-NH2, Ci-C 8 -alkyl-SO 2 NH 2;
  • a 4- to 7-membered mono- or bicyclic saturated or unsaturated heterocycle which may contain one or up to two different or identical heteroatoms selected from the group consisting of O, N and / or S, this cycle also 1 -, 2-, 3-, 4- or up to 5-fold may be substituted for the
  • this nitrogen atom may be substituted with a radical R 8 Q, wherein R Q 8 may be independent of RQ 6 assume a meaning as defined for RQ 6;
  • R 3 REST and R 4 REST are independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, sugars, steriodes and in the case of the free acid all pharmaceutically acceptable salts thereof and R 1 REST selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and aryl optionally substituted by one or more substituents selected from the group consisting of halogen, haloalkyl,
  • R w 1 , R w 2 and R w 3 are not simultaneously selected from the group consisting of Radicals C 3 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, hetaryl with the definition of a stable 5- to 7-membered monocyclic aromatic ring which contains 1 to 3, preferably 1 to 2, Heteroatoms selected from N, O and S, wherein the remaining ring atoms are carbon, or a stable bicyclic or tricyclic system having at least one 5- to 7-membered aromatic ring, which 1 to 3, preferably 1 to 2 heteroatoms selected from N, O and S, wherein the other ring atoms are carbon; and a carbocyclic group having the definition of optionally substituted 3- to 8-membered saturated, partially unsaturated or aromatic
  • provisos independently selected from the group consisting of the following provisos (viii) to (xiii):
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs (" prodrugs ") thereof, wherein the radicals R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, Z, A, B, c, R z 1, R z 2, R z 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A 1 , R A 2 , R A 3 , RA 4 , B, R W 1 , RW 2 , RW 3 , D,
  • E, Q, X 1 , X 2 , X 3 , X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 have the same meanings as defined above, with the proviso of one, several or all of the provisos (viii) to (xiii) provided.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, R A ⁇ RA 2 , RA 3 , RA, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ, R
  • Hydrogen, OH, CN in each case optionally substituted C 1 -C 4 - alkyl, OCRC 4 alkyl, Ci-C4-alkylene-O-Ci-C 4 alkyl, aryl, benzyl, CO- C 1 -C 4 - AIkYl, CO-aryl, CO-C 1 -C 4 -alkylene-aryl, OCO-C 1 -C 4 -alkyl, OCO-aryl, or OCO-d-Oj-alkylene-hetaryl; and
  • R 3 is hydrogen, optionally substituted C 1 -C 4 -alkyl, OC 1 -C 4 - alkyl, C r C 4 -alkylene-OC r C 4 alkyl, aryl, benzyl, CO-C 1 -C 4 -alkyl , CO-aryl, CO-C 1 -C 4 -alkylene-aryl, OCO-C r C 4 -alkyl, OCO-aryl, or OCO-C 1 -C 4 -alkylene-hetaryl; provided
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • At least one guanidine compound of general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutical acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c , R 2 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, R A ⁇ RA 2 , RA 3 , RA , B, Rw, Rw, Rw, D, e, Q, X, X, X, X, X, RQ, RQ, R Q, R Q, R
  • R 3 hydrogen
  • R 1 , R 2 each independently of one another:
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V z , W, W 1 , W 2 , W 3 , A, R A 1 , RA 2 , RA 3 , RA, B, R w, R w, R w, D , E, Q, X, X, X, X, X, RQ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "prodrugs") thereof, wherein the radicals R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, Z, A, B, c, R 2 1, Rz 2, Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A ⁇ R A 2 , RA 3 , RA 4 , B, R W ⁇ R W 2 , RW 3 , D, E, Q, X 1 , X 2 , X 3 , X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 ,
  • W a radical of the general formula W1a
  • R A 1 independently of its respective occurrence: in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, aryl or hetaryl;
  • R A 2 independently of each occurrence hydrogen, or optionally substituted Ci-C 6 alkyl, phenyl, benzyl, phenethyl, CO-C r C 6 alkyl, CO-aryl, SO 2 -C 1 -C 6 -Aikyl, SO 2 -aryl, SO 2 -
  • R A 3 independently of its respective occurrence: in each case optionally substituted C 1 -C 6 -alkyl, phenyl, benzyl, phenethyl, CO-C 1 -C 6 -alkyl, CO-aryl, SO 2 -C 1 -C 6 - AIKyI, SO 2 -aryl, SO 2 -
  • Hydrogen, or optionally substituted C 1 -C 6 alkyl means;
  • Hetaryl, or independently of radical A is a radical selected from the radicals as defined for radical A; Rw:
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4, Rz 5, Rz 5 * rz 6, Rz 7, V z, W, W1, W2, W3, A, R A ⁇ R A 2, R A 3, R A, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ 7 and RQ 8 ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA, RA i RA i B, Rw, Rw ⁇ Rw. D, E, Q, Xi, X2, X3 >
  • X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 have the same meanings as defined above and the radicals mentioned below have the following meanings:
  • Z a radical of the general formula Z1
  • Rz 1 , Rz 2 , Rz 3 , Rz 4 independently of each other: Is hydrogen, halogen, OH or optionally substituted C 1 -C 6 -alkyl,
  • V 2 is -CO-, -CO-NR 2 5 -, or -NR Z 5 -CO-;
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA.
  • RA. RA i B Rw »Rw, Rw. DE Q, Xi, X2. X3.
  • X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 have the same meanings as defined above and the radicals mentioned below have the following meanings:
  • Q denotes a radical according to one of the general formulas Q1, Q2, Q3, Q4 or Q5:
  • R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a radical selected from the same or different of the following groups 1), 2), 3), 4), 5), 6.) and 7.) can be:
  • Ci-Cio-alkyl C 2 -C 10 alkenyl, C 2 -Cio-alkynyl, C 3 -C 7 cycloalkyl, -C 6 -alkylene-C 3 -C 7 - Cycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 6 -alkylene-O-C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O-aryl, COO-C C 1 -C 4 -alkyl, C 1 -C 4 -alkylene-COO-C 1 -C 4 -
  • Alkyl or in each case optionally substituted O-RQ 4 , S-RQ 4 , NRQ 6 R 0 7 , CO-ORQ 5 , NR Q 7 -CO-O-RQ 5 , 0-CH 2 -COO-RQ 5 , NR Q 7 -CO-RQ 5 , SO 2 -RQ 5 , NR Q 7 -SO 2 -RQ 5 , SO 2 NH 2 , CONH 2 , SO 2 - NRQ 6 RQ 7 or CO-NRQ 6 R 0 7 ; wherein R 0 4 , RQ 5 , RQ 6 and R 0 7 independently and independently of their respective
  • Naphthyl each of which may be substituted with one, two or three groups selected from the group consisting of RQ 1 , RQ 2 and RQ 3 , wherein
  • RQ 1 I RQ 2 and RQ 3 each independently represents an identical or different substituent selected from the following group:
  • RQ 2 and RQ 3 together with the atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated, unsaturated carbocycle or a 3- to 7-membered, optionally substituted, saturated, unsaturated aromatic heterocycle, which may form two or up to three further different or identical heteroatoms selected from the group consisting of O, N and S;
  • R 4 independently of its occurrence: in each case optionally substituted C 1 -C 4 -alkylene C 3 -C 7 -cycloalkyl,
  • C 1 -C 6 -alkyl which is optionally substituted by one, two, three or more identical or different substituents each independently selected from the group consisting of halogen, NO 2 , NH 2 , OH, CN, CF 3 , CHF 2 , OCF 3, OCHF 2, optionally substituted NH- (CrC 6 - alkyl) and optionally substituted N (dC 6 alkyl) 2;
  • RQ 5 independently of each occurrence: each optionally substituted C 6 alkyl, C 2 -CE Al -alkenyl, C 2 - Ce alkynyl, C 3 -C 7 cycloalkyl, Ci-C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl or C 1 -C 6 -alkylene-O-C 1 -C 6 -alkyl;
  • RQ 6 regardless of its occurrence: hydrogen, OH or CN or in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 6 - alkylene O-C 6 alkyl, CO-Ci-C 6 alkyl, Ci-C4-alkylene-aryl, C 1 -C4- alkylene-hetaryl, CO-aryl, CO-hetaryl, CO-Ci C 4 alkylene aryl,
  • C 1 -C 4 -alkylene-hetaryl C 0 -C -alkyl, CO-O-aryl, CO-O-C 1 -C 4 -alkylene-aryl, CO-O-hetaryl, CO-O-CrC 4- alkylene-hetaryl, CO-O-CrC 4 -alkylene-aryl, SO 2 -Ci-C 6 -alkyl, SO 2 -aryl, SO 2 -hetaryl, SO 2 -C r C 4 -alkylene-aryl or SO r C 2 -C 4 alkylene means hetaryl;
  • RQ 7 regardless of its occurrence: hydrogen or optionally substituted Ci-C 6 alkyl
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N and S may contain form;
  • two adjacent radicals selected from the group consisting of the radicals R 4 , R 5 , R 6 , R 7 and R 8 as follows: for the case (1) R 4 and R 5 in Q3, Q4 or Q5, for the case (2) R 5 and R 6 in Q1, Q4 or Q5, in the case (3) R 6 and R 7 in Q1, Q2 or Q5, and the case (4) R 7 and R 8 in Q1, Q2 or Q3, and the radicals selected according to said cases (1) to (4) together with the ring atom to which they are attached have a 4- to
  • Ci-C 8 -AIKyI-SO 2 NH 2 wherein R 0 6 and RQ 7 independently of one another and regardless of their occurrence can assume a meaning as defined above;
  • N atom may be substituted with an RQ 8 radical, wherein RQ 8 independently of RQ 6 may have a meaning as defined for RQ 6 ; provided.
  • At least one guanidine compound of the general formula I is as above and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A ⁇ R A 2 , R A 3 ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, R A , R A , R A , R A , B, Rw, Rw > Rw.
  • R 3 hydrogen
  • R 1 , R 2 independently of one another:
  • Hydrogen, OH, CN each optionally substituted C1-C4 alkyl, Ci-C 4 -alkylene-OC 1 -C 4 alkyl, aryl, benzyl, CO-C 1 -C 4 alkyl, CO-aryl, CO- C 1 -C 4 -alkylene-aryl, OCO-C 1 -C 4 -alkyl, OCO-aryl, or
  • W a radical of the general formula W1a
  • RA 1 independently of its respective occurrence: in each case optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, aryl or hetaryl;
  • RA 2 independently of its occurrence: hydrogen, or in each case optionally substituted C 1 -C 6 -alkyl, phenyl, benzyl, phenethyl, CO-C 1 -C 6 -alkyl, CO-aryl, SO 2 -CrC 6 -alkyl, SO 2 -aryl , SO 2 - hetaryl, or SO 2 -Ci-C 4 alkylene-aryl;
  • R A 3 regardless of its occurrence: in each case optionally substituted C 1 -C 6 -alkyl, phenyl, benzyl, phenethyl, C 1 -C 6 -alkyl, CO-aryl, SO 2 -C 1 -C 6 -alkyl, SO 2 -aryl, SO 2 -hetaryl, or SO 2 -CrC 4 alkylene-aryl; or the radicals RA 2 and RA 3 together with the nitrogen atom to which they are attached form an optionally substituted 5- or
  • 6-membered saturated or unsaturated ring which may contain one or up to two identical or different heteroatoms selected from the group consisting of O and N, where appropriate two radicals substituted on this heterocycle together with the ring atom to which they are attached are 3- to form 7-membered, optionally substituted, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle may contain one, two or up to three different or identical heteroatoms selected from the group consisting of O, N and S, wherein the cycle thus formed may optionally be substituted;
  • Hydrogen, or optionally substituted C 1 -C 6 -alkyl means;
  • Hydrogen or in each case optionally substituted aryl or hetaryl, or, independently of radical A, a radical selected from the radicals as defined for radical A;
  • Z a radical of the general formula Z1
  • Rz 1 , Rz 2 , Rz 3 , Rz 4 independently of each other:
  • V 2 is -CO-, -CO-NR 2 5 -, or -NR Z 5 -CO-; Rz 5 regardless of its occurrence:
  • Q denotes a radical according to one of the general formulas Q1, Q2, Q3, Q4 or Q5:
  • R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a radical selected from the same or different of the following groups 1), 2), 3), 4), 5), 6.) and 7.) can be:
  • NR 0 6 RQ 7 or CO-NRQ 6 RQ 7 wherein R 0 4 , R 0 5 , RQ 6 and R 0 7 are independently and independently of their occurrence as defined below;
  • Naphthyl each of which may be substituted with one, two or three groups selected from the group consisting of RQ 1 , RQ 2 and RQ 3 , wherein
  • RQ 1 , RQ 2 and RQ 3 each independently represent an identical or different substituent selected from the following group:
  • Ring atom to which they are attached a 3- to 7-membered, optionally substituted, saturated, unsaturated carbocycle or a 3- to 7-membered, optionally substituted, saturated, unsaturated aromatic heterocycle, which may contain one, two or up to three further different or identical heteroatoms selected from the group consisting of O, N and S may form;
  • R 4 independently of its respective occurrence: in each case optionally substituted C 1 -C 4 -alkylene C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene heterocycloalkyl, heterocycloalkyl, aryl, hetaryl, or C 1 -C 6 -alkyl, optionally substituted with one
  • Substituents selected from the group consisting of halogen, NO 2 , NH 2 , OH 1 CN 1 CF 3 , CHF 2 , OCF 3 , OCHF 2 , NH- (Ci-C 6 alkyl), or N (dC 6 alkyl ) 2 means;
  • RQ 5 independently of each occurrence: in each case optionally substituted C ⁇ -alkyl, C 2 -C 6 alkenyl, C 2 - Ce alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 4 -alkylene-C C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl or C 1 -C 6 -alkylene-O-C 1 -C 6 -alkyl;
  • RQ 6 regardless of its occurrence: hydrogen, OH, CN or in each case optionally substituted Ci-C ⁇ -alkyl, C 3 -C 7 - cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, Ci-C 4- alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 6 -alkylene
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N and S may contain form;
  • Ci-C 8 alkyl-NH 2 Ci-C ⁇ alkyl NRQ RQ 6 7, Ci-C 8 alkyl-CO-NR 6 R Q Q 7, d-C ⁇ -alkyl-Soan RQ 6 RQ 7 , or Ci-C8-alkyl-SO 2 NH 2 , wherein RQ 6 and R Q 7 independently of one another and regardless of their occurrence can assume a meaning as defined above; 7.) a 5 to 6-membered monocyclic fully or partially saturated, optionally substituted heterocycle selected from the following group:
  • this N atom may be substituted by a radical RQ 8 , wherein RQ 8 independently of RQ 6 may assume a meaning as defined for RQ 6 ; provided.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA, RA > RA > B, Rw, Rw, Rw »D, E, Q, Xi, X2, X31
  • R 1 , R 2 , R 3 are each hydrogen; provided.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W 1 W 1 , W 2 , W 3 , A, R A 1 , R A 2 , R A 3 , RA, B, Rw, Rw, Rw , D, E, Q, X, X, X, X, X, RQ, RQ, R
  • RQ 7 and RQ 8 have the same meanings as defined above, with the proviso of one, several or all of the provisos (i) to (i) (xiii), more preferably with the proviso of one, several or all of the provisos (viii) to (xiii) provided.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA » R A , R A i B, Rw, Rw, Rw, D, E, Q, Xi, X2, X3.
  • X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 have the same meanings as defined above and the radicals mentioned below have the following meanings:
  • W a radical of the general formula W1a means:
  • RA 1 independently of its occurrence: each optionally substituted C 1 -C 4 alkyl
  • RA 2 independently of its occurrence: hydrogen, or in each case optionally substituted C 1 -C 4 -alkyl, SO 2 -aryl, or SO 2 - hetaryl;
  • RA 3 independently of its respective occurrence: in each case optionally substituted C 1 -C 4 -alkyl, SO 2 -aryl, or SO 2 -
  • radical B is hydrogen, optionally substituted phenyl or, independently of radical A, has a meaning as defined for radical A,
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is as above and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W1, W2, W3, A, R A 1 , R A 2 , RA 3 ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, A, RA 1 , RA 2 , RA 3 , RA 4 , B, R W ⁇ RW 2 , RW 3 , D, E, Q, X 1 , X 2 , X 3 , X 4 , X 5 , RQ 1 , RQ 2 , RQ 3 , RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 , unless otherwise stated below, have the same meanings as defined above, and the radicals R 1 , R 2 ,
  • Z a radical of the general formula Z1
  • Rz 1 , Rz 2 independently of each other:
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • At least one guanidine compound of general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutical acceptable salts thereof and / or the corresponding prodrugs thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA > RA.
  • Q is a radical of the general formula Q1, Q2 or Q3
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently a radical selected from the same or different of the following groups 1), 2), 3), 4), 5. ), 6.) and 7.) mean with:
  • RQ 1 , RQ 2 and RQ 3 each independently represent an identical or different substituent selected from the following group:
  • radicals selected from the group consisting of RQ 1 , RQ 2 and RQ 3 together with the C-atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated, unsaturated carbocycle or a 3- to 7- halogenated, optionally substituted, saturated, unsaturated aromatic heterocycle, which may contain one, two or up to three further different or identical heteroatoms selected from the group consisting of O, N and S form;
  • R 4 independently of its respective occurrence: in each case optionally substituted aryl or hetaryl, or C 1 -C 6 -alkyl which may optionally be monosubstituted or polysubstituted or differently substituted by one, two or three identical or different substituents selected from among
  • R 5 independently of its respective occurrence: in each case optionally substituted C 1 -C 6 -alkyl, aryl or hetaryl;
  • RQ 6 regardless of its occurrence: hydrogen, or in each case optionally substituted C 1 -C 6 -alkyl, aryl, hetaryl,
  • RQ 7 regardless of its occurrence: hydrogen or optionally substituted Ci-C ⁇ -alkyl
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N and S may contain form;
  • Pyrimidyl wherein the substituents preferably from the group consisting of hydrogen, halogen, CN, CF 3 , OCF 3 , C r C 6 alkyl, O-Ci-C 6 alkyl, NH- (dC 6 alkyl), N (Ci-C 6 alkyl) 2 , NHCO-C ⁇ alkyl, NHSO 2 -CrC 4 alkyl and SO 2 -Ci-C 4 alkyl are selected;
  • two adjacent radicals selected from the group consisting of the radicals R 4 , R 5 , R 6 , R 7 and R 8 in the cases (1) to (4), that is, in case (1) R 4 and R 5 in Q3; in the case (2) R s and R 6 in Q1; for the case (3) R 6 and R 7 in Q1 or Q2; and in the case (4) R 7 and R 8 in Q1, Q2 or Q3, each together with the ring atom to which they are attached, are an optionally substituted 6-membered aromatic radicals R 4 , R 5 , R 6 , R 7 and R 8 in the cases (1) to (4), that is, in case (1) R 4 and R 5 in Q3; in the case (2) R s and R 6 in Q1; for the case (3) R 6 and R 7 in Q1 or Q2; and in the case (4) R 7 and R 8 in Q1, Q2 or Q3, each together with the ring atom to which they are attached, are an optionally substituted 6-membered aromatic radicals R 4 , R 5 ,
  • Cyclus preferably each form an optionally substituted quinolinyl or Isochinolinyl- cycle, which may optionally be monosubstituted or disubstituted by identical or different substituents;
  • this N atom may be substituted by a radical RQ 8 , wherein RQ 8 independently of RQ 6 may assume a meaning as defined for R 0 6 ; provided.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V z , W, W 1 , W 2 , W 3 , A, R A 1 ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • R 1 , R 2 , R 3 each is hydrogen.
  • W a radical of the general formula W1a
  • RA 1 independently of its occurrence: each optionally substituted C 1 -C 4 alkyl;
  • RA 3 independently of its respective occurrence: in each case optionally substituted C 1 -C 4 -alkyl, SO 2 -aryl, or SO 2 -
  • radical B Is hydrogen, optionally substituted phenyl or, independently of radical A, a meaning selected from the radicals as defined for radical A,
  • Z a radical of the general formula Z1
  • Rz 1 , Rz 2 independently of each other:
  • Q is a radical of the general formula Q1, Q2 or Q3
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently a radical selected from the same or different of the following groups 1), 2), 3), 4), 5. ), 6.) and 7.) mean with
  • phenyl, 1-naphthyl or 2-naphthyl which may be substituted with one, two or three identical or different radicals independently of one another selected from the group consisting of RQ 1 , RQ 2 and RQ 3 , where
  • RQ 1 , RQ 2 and RQ 3 each independently represent an identical or different substituent from the following group: Hydrogen, CN, CF 3 , CHF 2 , OCF 3 , OCHF 2 , 0-CH 2 -COOH, halogen, or in each case optionally substituted aryl, hetaryl, heterocycloalkyl, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, OR Q 4 , NRQ 6 RQ 7 , NR Q 7 -CO-RQ 5 ,
  • N and S may contain form
  • RQ 4 regardless of its occurrence: each optionally substituted aryl or hetaryl, or Ci-C ⁇ -alkyl which is optionally mono- or polysubstituted or differently substituted with one substituent selected from the group consisting of halogen, CN, CF 3 , CHF 2 , OCF 3 , OCHF 2 , optionally substituted NH- (C 1 -C 6 -alkyl) and optionally substituted N (C 1 -C 6 -alkyl) 2 ;
  • R 5 independently of its respective occurrence: in each case optionally substituted C 1 -C 6 -alkyl, aryl or hetaryl;
  • RQ 6 regardless of its occurrence: hydrogen, or in each case optionally substituted C 1 -C 6 -alkyl, aryl, hetaryl,
  • Nitrogen atom to which they are attached form a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle which may contain one, two or three further different or identical heteroatoms selected from the group consisting of O, N and S;
  • Substituents preferably from the group consisting of hydrogen, halogen, CN, CF 3 , OCF 3 , or in each case optionally substituted d-C ⁇ -alkyl, O-Ci-C 6 alkyl, NH- (Ci-C 6 -
  • N (C 1 -C 6 alkyl) 2 N (C 1 -C 6 alkyl) 2 , NHCO-C 1 -C 4 alkyl, NHSO 2 C 1 -C 4 alkyl and SO 2 -Ci -C 4 alkyl;
  • two adjacent radicals selected from the group consisting of the radicals R 4 , R 5 , R 6 , R 7 and R 8 in the cases (1) to (4), that is for the case (1) R 4 and R 5 in Q3; for the case (2) R 5 and R 6 in Q1; for the case (3) R 6 and R 7 in Q1 or Q2; and in the case (4) R 7 and R 8 in Q1, Q2 or Q3, each together with the ring atom to which they are attached, are an optionally substituted 6-membered aromatic radicals R 4 , R 5 , R 6 , R 7 and R 8 in the cases (1) to (4), that is for the case (1) R 4 and R 5 in Q3; for the case (2) R 5 and R 6 in Q1; for the case (3) R 6 and R 7 in Q1 or Q2; and in the case (4) R 7 and R 8 in Q1, Q2 or Q3, each together with the ring atom to which they are attached, are an optionally substituted 6-membered aromatic radicals R 4 , R 5 , R 6
  • Cyclus preferably each form an optionally substituted quinolinyl or Isochinolinyl- cycle, which may optionally be monosubstituted or disubstituted by identical or different substituents; 5.) optionally substituted adamantyl;
  • Ci-C 4 -AIKyI-SO 2 NH 2 wherein RQ 6 and R Q 7 independently of one another and regardless of their occurrence can assume a meaning as defined above;
  • Heterocycle selected from the following group:
  • N atom may be substituted with an RQ 8 radical, wherein RQ 8 independently of RQ 6 may have a meaning as defined for RQ 6 ; provided.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding active substance precursors (US Pat.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R 1 R 1 R 1 R, W, A, RA, RA > RA i RA > B, Rw, Rw > Rw> D, e, Q, Xt, X2, X3, X4, X5, RQ 1, RQ 2, RQ 3, RQ 4, RQ 5, RQ 6, RQ 7 and RQ 8, insofar as nothing else denominated described, have the same meanings as defined above, and the radicals mentioned below have the following meanings:
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, R A ⁇ RA 2 , RA 3 , RA, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ, R
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA. R A , RA » B, Rw, Rw > Rw.
  • R 1 , R 2 , R 3 are each hydrogen; provided.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , R 2 5 , Rz 5 * , Rz 6 , Rz 7 , V z , W, W 1 , W 2 , W 3 , A, R A 1 , R A 2 , R A 3 , RA, B, Rw, Rw, Rw, D 1 E, Q 1 X, X, X, X, X, RQ, RQ, R
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, R A , RA, RA.
  • R 5 , R 6 , R 7 and R 8 are each, independently of one another, each of the abovementioned meanings, or one of them, should possess.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This applies in particular for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, R A 1 , R A 2 , R A 3 ,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, R A , RA i R A , RA, B, Rw, Rw, Rw i D, e, Q, Xi, X2, X31 X 4, X 5, RQ 1, RQ 2, RQ 3, RQ 4, RQ 5, RQ 6, RQ 7 and RQ 8, insofar as nothing else denominated described is, have the same meanings as defined above in each case and the radicals mentioned below have the following meanings:
  • Q is a radical Q1
  • radicals R 5 , R 6 , R 7 are selected independently of one another from the group consisting of H, CN 1 CH 3 , halogen or in each case optionally substituted C 1 -C 6 -alkyl, O-C 1 -C 6 -alkyl, aryl,
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • Z is -CH 2 -; provided.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c,
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • KA, D, Kw, Kw, Kw, U, b, U, ⁇ , ⁇ , A, ⁇ , ⁇ , KQ, KQ, KQ, KQ, KQ, KQ, RQ 7 and RQ 8 have the same meanings as defined above, with the proviso of one, several or all of the provisos (i) to (xiii), particularly preferably with the proviso of a , several or all of the provisos (viii) to (xiii) provided.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ( "Prodrugs") thereof, characterized in that the radicals R 1 , R 2 , R 3 , R 4 , R, R, R, R, W, A, RA, RA RA, RA » B, Rw, Rw. Rw.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • At least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • At least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs
  • a pharmaceutical composition containing at least one guanidine compound according to general formula I as above each and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof and / or the pharmaceutically acceptable salts thereof and or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 8 , Rz 7 , V Z
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , R 2 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A,
  • a disease that is treatable and / or prophylactically preventable by modulating 5-HT 5 receptor activity in a patient in need of such treatment and / or prophylaxis provided.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 ,
  • HT 5A receptor of less than or equal to 10 ⁇ M (Ki) 1 preferably less than or equal to 300 nM (Ki), more preferably less than or equal to 100 nM, wherein the Ki value is determined in each case according to a suitable test system, in a patient requires such treatment and / or prophylaxis, treatable and / or preventable prophylactic; provided.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, RA, RA, RA, B, R w, R w, R w, D E 1 Q, X, X, X, X, X, X, RQ, RQ 2 , RQ 3 , RQ 4 ,
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , R z 2 , R 2 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W3, A, RA 1, RA 2, RA 3, RA 4, B, R W 1, RW 2, RW 3, D, E, Q, X 1, X 2, X 3, X 4, X 5, RQ 1 , RQ 2 , RQ 3 , RQ 4
  • Prophylaxis of migraine and brain damage in a patient in need of such treatment and / or prophylaxis provided.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 ,
  • Depression bipolar and / or unipolar depression, anxiety, dementia, senile dementia, Alzheimer's disease, demyelinating disorders, multiple sclerosis and brain tumors, in a patient in need of such treatment and / or prophylaxis; provided.
  • the use of at least one guanidine compound according to the general formula I is as in each case above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding pro-drug prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R z 1 , Rz 2 , Rz 3 , Rz 4 . Rz 5 , Rz 5 * , R 2 6 , Rz 7 , V Zl W, W1, W2,
  • guanidine compound of general formula (i) as above the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , R z 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V z , W, W 1 , W 2 , W 3 , A, R A 1 , R A 2 , R A 3 , RA 4 , B, Rw , Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ,
  • the modulation of the 5-HT 5A receptor activity is preferably based on an antagonization of the 5-HT 5A receptor by substances selected from the Group consisting of antagonists, partial antagonists and inverse agonists, each based on the activity of the 5-HT 5A receptor.
  • guanidine compound of general formula (i) as above the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , R 2 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A 1 , R A 2 , RA 3 , RA 4 , B,
  • Kw, Kw, Kw, U, b, U, ⁇ , ⁇ , ⁇ , ⁇ , KQ, KQ, KQ, KQ, KQ and RQ 8 unless otherwise described below, the same meanings as each defined above, characterized in that the treatment and / or prophylaxis based on a binding affinity for 5-HT 5A receptor of less than or equal to 10 uM (Ki), determined according to a suitable test model.
  • guanidine compound of general formula (i) as above the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R z 1 , R 2 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A 1 , R A 2 , R A 3 , R A 4 , B, Rw , Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ, RQ, RQ, RQ, RQ, RQ
  • the use of at least one guanidine compound of the general formula (i) is as above the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , Vz, W, W1, W2, W3, A, R A 1 , R A 2 , RA 3 , RA 4 , B, R W ⁇ RW 2 , RW 3 , D, E, Q, X 1 , X 2 , X 3 , X 4 , X 5 , RQ 1 , RQ
  • R 1 , R 2 are each independently of one another: hydrogen, OH, CN, or in each case optionally substituted C 1 -C 6 -alkyl, O-C 1 -C 6 -alkyl, C 1 -C 6 -
  • form, preferably i optionally two substituted on this heterocycle radicals together with the ring atom to which they are attached can form a 3- to 7-membered, optionally substituted fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle one, two or three different or may contain identical heteroatoms selected from the group consisting of O, N and S and wherein the cycle formed optionally may be substituted and / or fused to this cycle another, 3- to 7-membered, optionally substituted cycle;
  • Z is a radical of the general formula Z1
  • Rz 1, Rz 2, Rz 3 Rz 4 each independently represent hydrogen, halogen, OH, or optionally substituted CrC 6 alkyl, C2-C6-alkenyl, C2-C 6 - alkinyl, Ci-C 4 -alkylene- C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, hetaryl or C 1 -C 4 -alkylene-hetaryl or in each case independently of one another two radicals R z 1 and R z 2 or R z 3 and
  • -C 4 alkylene-O-Ci- C 6 alkyl, C 2 -C hydrogen, or in each case optionally substituted C 6 alkyl 6 alkenyl, Rz 5, 5 * Rz are each independently, and independently of their respective occurrence mean C 2 -C 2 alkynyl, CO-Ci-C 6 alkyl, CO-OC 1 -C 6 - alkyl, SO 2 -C-C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, -C 4 - Alkylene-aryl, CO-O-CrC 4 -alkylene-aryl, CO-Ci-C 4 -alkylene-aryl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 -Ci-C 4 -alkylene aryl;
  • R z 6, Rz 7 each, independently of one another and independently of their respective occurrence: hydrogen, OH, or optionally substituted Ci-C 6 alkyl, Ci-C 6 -alkoxy, C 2 -C 6 - alkenyl, C 2 - C 6 -alkenyl, C 1 -C 4 -alkylene-C 1 -C -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, hetaryl or C 1 -C 4 -alkylene-hetaryl;
  • RA 1, independently of its occurrence, in each case represents optionally substituted C 1 -Ce-AIKyI, C 1 -C 6 -alkyl-OC 1 - C 6 -alkyl, C 2 -C 6 -alkyl-, C 2 -C 6 -alkyl , C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkyl-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl,
  • NRA 2 RA 3 or CrC 6 -alkylene-O-RA 2 ;
  • R A 2 regardless of its occurrence, means:
  • RA 3 is: optionally substituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 - alkinyl, Ci-C 4 -alkylene-C 3 -C 7 cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 4 -alkylene-C 1 -C 6 -alkyl, CO-C 1 -C 6 -alkyl,
  • R A 2 and R A 3 together with the nitrogen atom to which they are attached form a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle which has one, two or three further different or identical heteroatoms selected from among May contain group consisting of O, N and S, wherein optionally substituted on this heterocycle radicals together with the ring atom to which they are attached can form a 3- to 7-membered, optionally substituted fused, saturated, unsaturated or aromatic carbocycle or heterocycle wherein the heterocycle may contain one, two or three different or identical heteroatoms selected from the group consisting of O, N and S, wherein the cycle thus formed may be optionally substituted;
  • Hydrogen or in each case optionally substituted aryl or hetaryl, or independently of radical A has the same meanings of the radicals as defined for radical A,
  • radicals selected from among A, B 1 R w Rw 2 and R w 3 together with the C atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated, unsaturated radical or aromatic carbocycle or a 3- to 7-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which may contain one, two or three further different or identical heteroatoms selected from the group consisting of O, N and S; it being possible for two radicals substituted on this carbo- or heterocycle together with the ring atom to which they are attached to be able to form a further 3- to 7-membered, optionally substituted, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, the heterocycle including may contain two or three different or identical heteroatoms selected from the group consisting of O 1 N and S, and wherein the thus formed
  • Cyclus may optionally be substituted, means
  • Rw 1 , Rw 2 , Rw 3 are each independently of one another: hydrogen, NO 2 , NH 2 , OH 1 CN, CF 3 , OCF 3 , CHF 2 , CH 2 F, OCHF 2 ,
  • radical D is, independently of the radical A, a radical which has the same meanings as defined for radical A;
  • radical A is hydrogen or, independently of radical A, a radical which has the same meanings as defined for radical A;
  • X 1 C or N
  • X 2 C or N
  • X 3 C or N
  • X 4 C or N
  • X 5 C or N
  • one, two or three radicals selected from the group consisting of the radicals X 1 , X 2 , X 3 , X 4 and X 5 should simultaneously be N and the associated binding partner selected from the group consisting of R 4 , R 5 , R 6 , R 7 and R 8 should then stand for a free electron pair.
  • R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a radical selected from the same or different of the following groups 1), 2), 3), 4), 5), 6 .) and 7.) mean:
  • phenyl, 1-naphthyl or 2-naphthyl which may be substituted by one, two or three radicals independently of one another from the group consisting of RQ 1 , RQ 2 and RQ 3 , where RQ 1 , RQ 2 and RQ 3 each independently represent a substituent from the following group:
  • RQ 2 and RQ 3 together with the atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated, unsaturated carbocycle or a 3- to 7-membered, optionally substituted, saturated, unsaturated aromatic heterocycle, which form two or up to three further different or identical heteroatoms selected from the group consisting of O, N, and S, where optionally two radicals substituted on this carbo- or heterocycle together with the ring atom to which they are attached form a to form 7-membered, optionally substituted, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle may contain one, two or up to three different or identical heteroatoms selected from the group consisting of O, N, and S, and the cycle thus formed may be optionally substituted, or at this cycle another, 3- to 7-membered ger, optionally substituted cycle may be fused; in which mean: regardless of its occurrence: each
  • Ci-C 6 - alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, dC 4 -alkylene-C 3 -C 7 - cycloalkyl, dd-alkylene-heterocycloalkyl, heterocycloalkyl,
  • Aryl or hetaryl means
  • Ci-C ⁇ alkyl independently of each occurrence: hydrogen, OH, CN, or optionally substituted Ci-C ⁇ alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, dC 4 alkylene -C 3 -C 7 - cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, -C 6 alkylene-O-Ci-C 6 alkyl, CO-dC 6 alkyl, -C 4 alkylene -Aryl, C 1 -C 4 -alkylene-hetaryl, CO-aryl, CO-
  • radicals RQ 6 and RQ 7 together with the nitrogen atom to which they are attached are a 3- to 7-membered, optionally substituted, saturated or aromatic heterocycle having one, two or three further different or identical heteroatoms selected from the group consisting of O, N, and S may contain, and optionally two substituted on this heterocycle radicals together with the ring atom to which they are attached can form a 3- to 7-membered, fused, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle may contain one, two or up to three different or identical heteroatoms selected from the group consisting of O, N 1 and S, and the cycle thus formed may optionally be substituted and / or at this cycle another, 3- to 7 -membered, optionally substituted cycle may be fused;
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound of the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V z , W, W 1, W 2 , W 3 , A, R A ⁇ RA 2 , RA 3 , RA 4 , B 1 R W ⁇ Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ, R
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ, RQ, RQ and RQ 8 have the same meanings as in each case defined above and the radicals mentioned below have the following meanings:
  • W a radical of the general formula W1a means:
  • A, B and R w 1 are as defined above or in any of claims 1 to 16 and 29, respectively.
  • Z a radical of the general formula Z1 means:
  • Rz 1 , Rz 2 , Rz 3 , Rz 4 independently of each other:
  • V z -CO-, -CO-NR 2 5 -, -NR Z 5 -CO-, -S-; or -O- means;
  • Rz 5 independently:
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This applies in particular for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula (I) is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A,
  • RA, RA, RA, RA. B Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ, RQ 4 , RQ 5 , RQ 6 , RQ 7 and RQ 8 , unless otherwise specified below is, have the same meanings as defined above, characterized in that it is in the CNS disease or CNS related disease selected from the disease
  • Group consisting of neuropathological, neuropsychiatric and neurodegenerative disorders; neuropathological, neuropsychiatric and neurodegenerative symptoms; and neuropathological, neuropsychiatric and neurodegenerative disorders.
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula (I) is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , R 2 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, RA, RA, RA, RA, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ 4 I RQ 5
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, where the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, R 2 1 , R z 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A,
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, RA, RA, RA, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, X, RQ, RQ, RQ 4 , RQ 5
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as in each case above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , Rz 2 , Rz 3 , Rz 4 , Rz 5 , Rz 5 * , Rz 6 , Rz 7 , V 2 , W, W 1 , W 2 , W 3 , A, RA, RA, RA, RA, B, Rw, Rw, Rw, D, E, Q, X, X, X, X, X, RQ, RQ, RQ 4 , RQ 5
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding
  • each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding prodrugs ("Prodrugs") thereof, wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, a, b, c, Rz 1 , R 2 2 , Rz 3, Rz 4, Rz 5, R 2 5 * Rz 6, Rz 7, V 2, W, W1, W2, W3, A, RA, RA, RA, RA, B, Rw, Rw, Rw, D , E,
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • the use of at least one guanidine compound according to the general formula I is carried out as described above, and / or the corresponding enantiomeric, diastereomeric and / or tautomeric forms thereof, and / or the pharmaceutically acceptable salts thereof and / or the corresponding
  • Each of these definitions of a variable above may be associated with any of the definitions of the remaining variables above. This is especially true for the combination of preferred definitions of a variable with any or preferred definitions of the remaining variables.
  • agonist mean a substance which causes an effect similar to the physiological ligand at the receptor (here: 5-HT5 receptor), "antagonist” a substance which reduces or abolishes the biological action of an agonist, " partial agonist "means a substance that produces a submaximal effect on the receptor, in the absence of an agonist the partial agonist may be agonistic and in the presence of an agonist the partial agonist may be antagonistic, and” inverse agonist "may be a substance which causes a negative effect," competitive antagonism.a substance with affinity for the receptor, reversible binding to the receptor (competition with the agonist) and no intrinsic activity at the receptor (relative potency: ability of a substance to cause an effect on the same receptor population), and “non-competitive antagonist” a substance with allosteric binding to the receptor and influencing the potency (and optionally agonist binding) by conformational change of the receptor.
  • the term “additional binding affinity to the 5-HT 5A receptor” is to be understood as meaning that according to the inventive use of at least one compound of the general formula I 1 as described above, the activity of one, two or more
  • modulation or “modulate” in the sense of the use according to the invention, for example, the action of an antagonist, partial antagonist, partial agonist and / or agonist, each independently with respect to one, two or more.
  • 5 -HT5 receptors modulated -HT5 receptors mean, and at the same time or in addition to the
  • Modulation of one, two or more 5-HT5 receptors can be a binding affinity to the 5-HT 5A receptor.
  • brain damage and / or disorders include cerebral ischemia, stroke, epilepsy and seizures in general, psychosis, schizophrenia, Autism, OCD syndrome, cognitive disorders, attention deficit disorders, depression, bipolar and / or unipolar depression, anxiety, dementia, senile dementia, Alzheimer's disease, demyelinating disorders, multiple sclerosis and brain tumors.
  • cerebrovascular disorders pain, pain-related disorders, addiction, drug-related disorders, amnesia, alcohol abuse, substance abuse, circadian rhythm disorders, and Cushing's syndrome.
  • radicals of the formulas I have the following meanings:
  • Alkyl is an unsubstituted or optionally substituted straight-chain or branched saturated hydrocarbon chain with the number of carbon atoms given in each case, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, particularly preferably 1, 2, 3, 4, 5 or 6, more preferably 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1, 1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,3- Dimethylbutyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,
  • alkyl is also meant to include halogen substituted alkyl ("haloalkyl").
  • C5-C18-alkyl or C1-C8-alkyl is an unsubstituted or optionally substituted straight-chain or branched saturated hydrocarbon chain with the number of carbon atoms given in each case, ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms or 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms.
  • Alkylene is an unsubstituted or optionally substituted straight-chain or branched alkyl group, which is as defined above, in which
  • Hydrogen atom is replaced by a bond.
  • Cycloalkyl is an unsubstituted or optionally substituted branched or unbranched saturated hydrocarbon ring having 3, 4, 5, 6 or 7, preferably 3, 4, 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • cycloalkyl is also meant to include halogen substituted cycloalkyl ("halocycloalkyl").
  • Alkylene-O-alkyl is unsubstituted or optionally substituted in the alkylene and / or alkyl straight-chain or branched saturated alkyl ether chain containing a total of 2 to 12 carbon atoms and one oxygen atom, wherein both the alkylene radical and the alkyl independently of one another 1, 2, 3 , 4, 5 or 6, more preferably 1, 2, 3 or 4, most preferably 1 or 2 carbon atoms, both of which are as defined above.
  • Preferred examples of alkylene-O-alkyl include methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.
  • alkylene-O-alkyl is also meant to include halogen-substituted alkylene-O-alkyl in the sense of "haloalkylene-O-alkyl” or “alkylene-O-haloalkyl” or haloalkylene-O-haloalkyl ".
  • Thioalkyl is an unsubstituted or optionally substituted straight or branched alkylene sulfanyl chain containing 1, 2, 3, 4, 5 or 6 carbon atoms and one sulfur atom.
  • the alkylene radical contains 1, 2, 3 or 4, more preferably 1 or 2 carbon atoms, wherein alkylene is as defined above.
  • Examples of thioalkyl include thiomethyl or thio-tert-butyl.
  • thioalkyl is also meant to include halogen substituted thioalkyl ("halothioalkyl").
  • Alkenyl is an unsubstituted or optionally substituted branched or unbranched hydrocarbon chain containing at least one double bond, with 2, 3, 4, 5 or 6, preferably 2, 3 or 4 carbon atoms.
  • alkenyl contains one or two double bonds, most preferably one double bond.
  • alkenyl groups are those as mentioned above for alkyl, which groups contain one or two double bonds, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl 2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2 Methyl 3-butenyl, 3-methyl-3-butenyl, 1, 1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4 Methyl
  • Alkynyl is an unsubstituted or optionally substituted branched or unbranched hydrocarbon chain containing at least one triple bond with 2, 3, 4, 5 or 6, preferably 2, 3 or 4 carbon atoms.
  • alkynyl contains one or two triple bonds, most preferably one Triple bond.
  • alkynyl groups are those as mentioned above for alkyl, which groups contain one or two triple bonds, such as ethynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl 3-butynyl, 1-methyl-2-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl 2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4 pentynyl, 4-methyl-2-pentynyl, 1, 1-dimethyl-2-butynyl, 1, 1-dimethyl-3-buty
  • Heterocycloalkyl is an unsubstituted or optionally substituted saturated alkyl ring or an alkyl ring to which a further unsubstituted or optionally substituted saturated alkyl ring is fused, preferably having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms in total, more preferably 3, 4, 5 or 6 ring atoms, most preferably 5 or 6 ring atoms, this heterocycloalkyl containing at least one heteroatom, preferably 1, 2 or three identical or different heteroatoms selected from the group consisting of O, N and S, and 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3, 4 or 5 carbon atoms.
  • heterocycloalkyl contains 1 or 2 identical or different heteroatoms, which are preferably selected from the group consisting of N and O.
  • heterocycloalkyl group include, for example, N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, wherein containing at heterocycles containing amino groups such as N-piperazinyl, these amino groups continuous radicals such as methyl, benzyl, Boc (tert-butoxycarbonyl), benzyloxycarbonyl, tosyl (p-toluenesulfonyl), -SO 2 -C-C 4 Alkyl, -SO 2 -phenyl or -S ⁇ 2 -benzyl may be replaced.
  • heterocycloalkyl is also meant to include halogen substituted heterocycloalkyl ("haloheterocycloalkyl").
  • Aryl is an unsubstituted or optionally substituted aromatic mono-, bi- or polycyclic radical having preferably 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, nor more preferably 6, 7, 8, 9 or 10 carbon atoms Substituons and is preferably selected from phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl and phenanthrenyl, more preferably from phenyl and naphthyl, such as 1-naphthyl or 2-naphthyl. Most preferred is phenyl.
  • Alkylenearyl is an aryl which is bonded via CrC ⁇ -, more preferably C 1 -C 4 -alkylene and is optionally substituted in the aryl and / or alkylene radical, where alkylene and aryl are each as defined above.
  • Alkylenearyl is in particular in the aryl radical optionally substituted benzyl or phenethyl.
  • alkenylaryl is also meant to include halogen substituted alkenylaryl ("haloalkenylaryl").
  • Aryloxy or -O-aryl is an oxygen-bonded unsubstituted or optionally substituted aryl, which is as defined above, in particular -O-phenyl.
  • Hetaryl is an unsubstituted or optionally substituted mono-, bi- or tricyclic aromatic ring containing at least one heteroatom, preferably 1, 2 or 3 identical or different heteroatoms, more preferably 1 or 2 identical or different heteroatoms selected from A group consisting of O, N and S and preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the aromatic ring is preferably 5- or 6-membered.
  • Hetaryl also includes the aryl-fused derivatives thereof, namely an aromatic radical preferably having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, even more preferably 6, 7, 8, 9 or 10 carbon atoms, most preferably phenyl, which is fused to this aromatic ring containing at least one heteroatom.
  • Hetaryl may also be selected from an aromatic radical preferably having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, more preferably e, 7, 8, 9 or 10 carbon atoms, most preferably phenyl, having a heterocycloalkyl group fused thereto.
  • the heterocycloalkyl group is as defined above.
  • Hetaryl is preferably selected from 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5 Thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4- Pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isothiazolyl
  • pyridyl and pyridinyl in the context of the present invention mean one and the same radical. The same applies to “pyrimidyl” and “pyrimidinyl”.
  • Alkylenethyharyl is a hetaryl bonded via C 1 -C 6 -, more preferably C 1 -C 4 -alkylene and optionally substituted in the alkenyl and / or hetaryl radical, where alkylene and hetaryl are as defined herein.
  • Alkylenhetaryl is preferably optionally substituted -CH 2 -2-pyridyl, -CH 2 -3-pyridyl, -CH 2 ⁇ -pyridyl, -CH 2 -2-thienyl, - CH 2 -3-thienyl, -CH 2 -2- Thiazolyl, -CH 2 -4-thiazolyl, CH 2 -5-thiazolyl, -CH 2 -CH 2 - 2-pyridyl, -CH 2 -CH 2 -3-pyridyl, -CH 2 -CH 2 -4-pyridyl, -CH 2 -CH 2 -2-thienyl, -CH 2 - CH 2 -3-thienyl, -CH 2 -CH 2 -2-thiazolyl, -CH 2 -CH 2 -CH 2 - ⁇ - ThJaZoIyI or -CH 2 -CH 2 -5-thiazolyl
  • a bicyclic or tricyclic saturated hydrocarbon radical is an unsubstituted or optionally substituted bicycloalkyl or tricycloalkyl radical and has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • Bicycloalkyl radical preferably contains the ring system 5, 6, 7, 8, 9, 10, 11 or 12, more preferably e, 7, 8, 9 or 10 carbon atoms.
  • the ring system preferably contains 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15 or 16, more preferably e, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • Examples of a bicycloalkyl group include indanyl, camphyl and norbornyl.
  • Examples of a tricycloalkyl radical include adamantyl.
  • Halogen is a halogen atom selected from fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine, most preferably fluorine.
  • Halogen-substituted alkyl denotes an alkyl radical, as defined above, which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine, eg CH 2 F, CHF 2 , CF 3 , CH 2 Cl , 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl.
  • haloalkylene haloalkenyl
  • haloalkynyl haloalkenylaryl
  • haloalkenylhetaryl haloalkylene-o-ring
  • Alkyl or alkylene-O-haloalkyl
  • haloalkylene-O-haloalkyl halothioalkyl
  • halocycloalkyl halocycloalkyl
  • radicals and groups may preferably be mono-, di-, tri-, tetra-, penta-, or polyhydric, more preferably mono-, di- or tri-fold, most preferably one or two times be substituted.
  • the expression "in each case optionally substituted” is intended to make clear that not only the directly following radical but also all radicals mentioned in the respective group may be substituted identically or differently.
  • substituents of the terms “optionally substituted” include or “optionally substituted”: halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2, NO 2, NH 2, OH, COOH, in each case branched or unbranched, optionally substituted C 6 alkyl, C 3 -C ⁇ cycloalkyl, dC 6 alkylene-O-Ci-C ⁇ alkyl or C r C 6 thioalkyl, O-Ci-C 6 alkyl, N (C 1 -C 6 alkyl) (C 1 -C 6 alkyl), NH (C 1 -C 6 - alkyl), aryl, -O-aryl, C r C 6 -alkylene-O-aryl, NHCO-dC ⁇ alkyl, NH -SO 2 -C 1 -C 4 alkyl, CO-d-Ce-alkyl, SO 2 -Ci -C 6 alkyl, in the
  • Preferred substituents are F, Cl, CF 3 , OCF 3 , NH 2 , NO 2 , OH, COOH, C 1 -C 4 -alkyl, methoxy, acetyl, NH-acetyl and SO 2 NH 2 .
  • C 6 means that the radical mentioned below, such as, for example, the radical "alkyl” in “C 1 -C 6 -alkyl", has one, two, three, four, five or six carbon atoms. may have atoms.
  • C 3 -C 7 (3, 4, 5, 6 or 7 carbon atoms)
  • C 1 -C 4" (1 , 2, 3 or 4 carbon atoms
  • C 2 -C 6 (2, 3, 4, 5 or 6 carbon atoms) etc.
  • 3- to 7-membered carbocycle, heterocycle or ring refers to the total number of ring members, that is to say a ring with a total of 3, 4, 5, 6 or 7 ring members in the case of fused ring systems with fused one both adjacent (vicinal) and geminal (ie, spin-bridged ring systems), the term “3- to 7-membered” means the total number of ring members including the ring members that are part of the adjacent fused ring system.
  • the compounds of the general formula I or their salts according to the invention may have at least one asymmetric center and may be present as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention encompasses all of these stereoisomeric forms of the compounds of general formula I according to the invention.
  • the compounds of the general formula I according to the invention can be split into their individual stereoisomers by conventional methods, for example by fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof or by chiral chromatography using an optically active stationary phase.
  • Absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or crystalline intermediates which, if necessary, are derivatized with a reagent containing an asymmetric center of known absolute configuration.
  • any stereoisomer of a compound of general formula I according to the invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration or by asymmetric synthetic methods.
  • the compounds of the general formula I according to the invention can also be present as different tautomers, it being the case for the
  • salts refers to salts prepared from pharmaceutically acceptable physiologically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, ⁇ /, ⁇ / '- dibenzylethylenediamine, diethylamine, 2-diethylaminomethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-
  • salts may be prepared from pharmaceutically acceptable physiologically acceptable acids, including inorganic and organic acids.
  • acids include, but are not limited to, acetic acid (acetate), benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, malonic acid, nitric acid, Pantothenic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid and the like.
  • Particularly preferred are acetic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and
  • the invention also provides the use of the compounds of the general formula according to the invention for the treatment of:
  • - depression and / or bipolar disorders such as dysthemic disorders, seasonal disorders and / or psychotic disorders.
  • anxiety and / or stress-related disorders such as general anxiety disorders, panic disorders, obsessive-compulsive disorder, post-traumatic
  • disorder in the sense of the invention refers to anomalies that are usually regarded as pathological conditions and can be identified in the form of certain signs, symptoms and / or malfunctions.
  • the treatment may be directed to individual disorders, ie anomalies or pathological conditions, but it is also possible for a number of possibly causally linked anomalies to be patterned, i. Syndromes summarized that can be treated according to the invention. This condition may be temporary, progressive or permanent.
  • the compounds of the invention may be used for the treatment or prevention of various diseases involved in the formation and / or course of 5-HT5 receptors, i. Diseases modulated by 5-HT5 receptor activity, such as mental disorders.
  • mental disorders are according to the American Psychiatric Association DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., 1994: attention disorders and socially disruptive behavior; Learning disorders, DeNr, dementia and amnestic and other cognitive disorders; Disorders associated with various substances, such as disorders related to alcohol consumption and alcohol-induced disorders, withdrawal symptoms; Schizophrenia and other psychotic disorders, such as schizophrenia disorder, schizo-affective disorder, and delusional disorder; Substance-induced psychosis; paranoid disorders; Neuroleptic-induced disorders; mood disorders, such as depressive disorders (major depression, dysthemic disorder, seasonal disorder, unspecified depressive disorder), bipolar disorder (bipolar I disorder, bipolar disorder, cyclothymic disorder, unspecified bipolar disorder, substance (amphetamine or amp
  • Agoraphobia panic disorder with agoraphobia, agoraphobia without panic disorder in the History, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, substance-induced anxiety disorder; somatoform disorders such as somatization disorder, unspecified somatoform disorder, conversion disorder, pain disorder; Eating disorder; Sleep disorders such as primary sleep disorders (dyssomnia, parasomnia), sleep disorders associated with another mental disorder.
  • the invention also relates in particular to the use of the compounds of the general formula I according to the invention for the treatment of neuropathological, neuropsychiatric and neurodegenerative disorders.
  • Neuropathological disorders are disorders accompanied by neurological deficits, d. H. a condition characterized by neurological deficits.
  • neurodegenerative and / or neuropsychiatric disorders are preferred. These disorders occur particularly in neuropathological disorders usually causing brain damage, for example cerebral ischaemia, stroke, epilepsy and seizures in general, chronic schizophrenia, other psychotic disorders, depression, anxiety, bipolar disorders, dementia, in particular Alzheimer's dementia, demyelinating diseases, in particular multiple sclerosis, brain tumors and general inflammatory processes.
  • neuropathological disorder is migraine, and the associated signs, symptoms and dysfunctions.
  • neuropathological disorders associated with a glial response are treated.
  • the use according to the invention relates in particular to the modulation of a glial reaction.
  • a beneficial effect of the binding partners can be seen in the preventive or acute treatment of neurological deficits observed in patients suffering from psychiatric disorders, such as epilepsy, psychosis, eg psychosis of the acute exogenous type of reaction or accompanying psychiatric disorders.
  • psychosis of organic or exogenous cause eg after trauma, especially brain lesions and diffuse brain damage, in metabolic disorders, infections, and endocrinopathies; endogenous psychoses such as schizophrenia and schizotypal and delusional disorders; mood disorders, such as depression, mania or manic-depressive states; as well as mixed forms of the previously described psychoses; senile dementia and senile dementia of the Alzheimer type, as well as in the treatment or prevention of demyelinization processes.
  • the compounds of the invention are particularly effective with regard to the treatment of ischemic damage, e.g. as a result of brain and spinal cord trauma as well as vascular occlusion or heart failure.
  • ischemic damage e.g. as a result of brain and spinal cord trauma as well as vascular occlusion or heart failure.
  • the stroke sekunder (synonym: Apoplexia cerebri, cerebral or apoplectic insult, cerebral stroke).
  • Treatable according to the invention are transient ischemic attacks, reversible ischemic neurological deficits, prolonged reversible ischemic neurological deficits, partially reversible ischemic neurological symptoms and also persistent complete brain infarcts.
  • the treatment of acute forms is particularly advantageous according to the invention.
  • neuropathological disorders which are preferably treated according to the invention are based on one or more of the following enumerations of nerve tissues: degeneration or death of neurons, in particular ganglion cells, eg. Tigrolysis, nuclear membrane blurring, cell shrinkage, cytoplasmic maculolization and enucleation, parenchymal necrosis of the brain, cerebral edema, neuronal degeneration caused by oxygen deficiency, atrophy, morphological alterations such as demyelination, in particular marrow deletion, perivascular infiltrates, gliotic proliferation and / or glial scars; Degeneration of the substantia nigra.
  • ganglion cells eg. Tigrolysis, nuclear membrane blurring, cell shrinkage, cytoplasmic maculolization and enucleation, parenchymal necrosis of the brain, cerebral edema, neuronal degeneration caused by oxygen deficiency, atrophy, morphological alterations such as demyelination
  • the indication to be treated according to the invention is often characterized by a progressive development, i. the states described above change over time, the severity usually increases and, if necessary, states can merge into one another or further states can be added to existing states.
  • Treatment of neuropathological, neuropsychiatric or neurodegenerative Disorders or their underlying conditions can treat a number of other signs, symptoms and / or dysfunctions that are related to these disorders, ie in particular accompany the disease states described above.
  • these disorders include, for example, shock lung; Cranial nerve failures, eg retrobulbar neuritis, eye muscle paralysis, chanting speech, spasticity, cerebellar symptoms, sensory, bladder and rectal disorders, euphoria, dementia; Hypo- and akinesia, lack of co-movement, pacing, flexion of the trunk and limbs, pro-, retro- and lateropulsion, tremor, facial expressions, monotonous speech, depression, apathy, labile or rigid affectivity, aggravated spontaneity and determination, slowed down thinking, impoverished association ability; Muscle atrophy.
  • shock lung Cranial nerve failures, eg retrobulbar neuritis, eye muscle paralysis, chanting speech, spasticity, cerebellar symptoms,
  • a treatment according to the invention includes not only the treatment of acute or chronic signs, symptoms and / or dysfunctions but also a preventive treatment (prophylaxis), in particular as a recurrence or phase prophylaxis.
  • the treatment may be symptomatic, for example as symptom suppression. It may be short-term, medium-term, or long-term, for example in the context of maintenance therapy.
  • binding partner for 5-HT 5 receptors describes substances which bind to 5-HT 5 receptors and therefore can also be referred to as 5-HT 5 receptor ligands.
  • Binding means any molecular interaction between the binding partner and the receptor, especially under physiological conditions. These are typically classical interactions that include electrostatic attraction, hydrogen bonding, hydrophobic bonds, van der Waals forces, or metal complex-like coordinative bonds. In addition to the aforementioned reversible molecular interactions, irreversible interactions between binding partner and receptor may also be considered, such as covalent bonds.
  • the compounds of the general formula I according to the invention can competitively inhibit the binding of comparison binding partners such as 5-HT (5-hydroxytryptamine) or 5-CT (5-carboxamidotryptamine) to 5-HT 5 receptors.
  • Competitive inhibition is understood to mean that the compounds of the general formula I according to the invention compete with a comparison binding partner, in the present case for example 5-HT or 5-CT, for binding to the receptor.
  • the compounds of the general formula I according to the invention inhibit the binding of comparison binding partners such as 5-HT (5-hydroxytryptamine) or 5-CT (5-carboxamidotryptamine) to 5-HT 5 receptors non-competitively.
  • comparison binding partners such as 5-HT (5-hydroxytryptamine) or 5-CT (5-carboxamidotryptamine)
  • 5-HT 5-hydroxytryptamine or 5-CT (5-carboxamidotryptamine
  • the principle is that the displacement of one binding partner by another increases with decreasing binding affinity of one or increasing binding affinity of the other with respect to the receptor.
  • the compounds of general formula I according to the invention have a high binding affinity for 5-HT 5 receptors.
  • Such a binding affinity allows on the one hand an effective displacement of naturally occurring binding partners for 5-HT 5 receptors, such as serotonin (5-hydroxytryptamine, 5-HT) itself, the required concentration of inventive compound of general formula I for binding a certain amount of this Binding partner to 5-HT 5 receptors decreases with increasing binding affinity.
  • Guanidine compounds of general formula I whose binding affinity is so great that they can be administered as active ingredient in an acceptable amount in the context of effective medical treatment are therefore preferred with regard to medical application.
  • Useful binding partners may bind to 5-HT 5 at a lower, substantially similar, or higher affinity than to a particular receptor other than 5-HT 5 .
  • binding partners for 5-HT 5 receptors with respect to the use according to the invention include those whose binding affinity for 5-HT 5 receptors is so high compared to the affinity for 5-HT receptors that they are suitable for use according to the invention in are advantageously suitable. This does not necessarily imply a comparatively more selective binding to 5-HT 5 receptors, although selective binding partners for 5-HT 5 receptors are a particular embodiment of the present invention.
  • binding partners that are highly affine to both 5-HT 5 and other 5-HT receptors.
  • High affinity in this context means Kj values generally in the range of 1-10 "10 M to 1-10 " 6 M.
  • the guanidine compounds according to the invention have a binding profile in the high affinity region to 5-HT receptors a binding affinity to 5-HT 5 is characterized, which is substantially the same or only slightly lower compared to other binding affinities of this range. Factors of 10 or less may be beneficial.
  • the guanidine compounds according to the invention preferably have binding affinities for 5-HT 5 receptors which are greater than for one or more 5-HT 5 different 5-HT receptors, ie in particular the abovementioned 5-HT receptor classes 5-HTi, 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 6 and 5-HT 7 receptors. If the binding affinity for 5-HT 5 receptors of a binding partner is greater than that of a 5-HT 5 different 5-HT receptor, one speaks of a 5-HT 5 different 5-HT receptor selective binding this binding partner to 5-HT 5 receptors. Special binding partners are those whose binding affinity for 5-HT 5 receptors is greater than for at least one 5-HT receptor. Guanidine compounds whose binding affinity for 5-HT 5 receptors is greater than for all 5-HT 5 different 5-HT receptors, preferably represent another particular class of guanidine compounds according to the invention.
  • Selectivity refers to the property of a binding partner, preferably to bind to 5-HT 5 receptors.
  • the binding affinities for 5-HT receptors, 5 on the one hand and for one or more of 5-HT 5 different 5-HT receptors on the other hand be sufficiently distinguished.
  • Affinity differences are preferred according to which binding affinity ratios of at least 2, more preferably of at least 5, particularly advantageously of at least 10, preferably of at least 20, particularly preferably of at least 50 and in particular of at least 100 are present.
  • guanidine compounds with respect to one or more of 5-HT5 various 5HT receptors, preferably selectively to 5-HT receptors 5 with the above-described advantageous binding affinities.
  • guanidine compounds of the invention preferably bind selectively to 5-HT 5 receptors with respect to all 5-HT 5 different 5-HT receptors, with the advantageous binding affinities described above.
  • Particularly advantageous are guanidine compounds of general formula I which bind with the above-described affinities and selectivities to 5-HT 5 receptors which are expressed by glial cells and in particular by astrocytes.
  • the human receptor variant is a preferred target for the guanidine compounds according to the invention.
  • binding of guanidine compounds of general formula I according to the invention to 5-HT 5 receptors is coupled to an effector function.
  • Binding partners can be agonistic or antagonistic as well as partially agonistic and / or partially antagonistic.
  • agonists are compounds which completely or partially mimic the activity of 5-HT at 5-HT 5 receptors.
  • Antagonists are guanidine compounds according to the invention which can block the agonistic activity of 5-HT at 5-HT 5 receptors.
  • guanidine compounds of the general formula I are used whose binding at least to 5-HT 5 receptors of h5-HT 5 -transfected CHO or HEK 293 or SHSY-5Y cells causes a change in the agonist-induced stimulation GTP binding to membrane-bound G proteins, a change in intracellular calcium levels, a change in agonist-induced induction of
  • guanidine compounds of the general formula I which cause an increase in intracellular calcium levels
  • Guanidine compounds which are known in animal models for this embodiment also belong to this embodiment neurodegenerative and neuropsychiatric processes are effective.
  • guanidine compounds of the general formula I which are also selective for 5-HT 5 receptors in terms of their effector function in the sense described above.
  • the guanidine compounds of the invention are useful as active ingredients for therapeutic purposes.
  • the guanidine compounds according to the invention are preferably brought into a suitable dosage form before administration.
  • a further subject of the present invention are therefore also compositions, in particular pharmaceutical compositions, containing at least one guanidine compound according to the invention and optionally a pharmaceutically acceptable carrier and / or diluent.
  • Pharmaceutically acceptable carriers or excipients known to be useful in the pharmaceutical and related fields in particular those in relevant pharmacopoeias (eg DAB (German Pharmacopoeia), Ph. Eur. (Pharmacopoeia Europaea), BP (Baccalaureus Pharmaciae), NF (National Formulary) , USP (United States Pharmacopoeia), as well as other carriers whose properties do not preclude physiological application.
  • relevant pharmacopoeias eg DAB (German Pharmacopoeia), Ph. Eur. (Pharmacopoeia Europaea), BP (Baccalaureus Pharmaciae), NF (National Formulary) , USP (United States Pharmacopoeia), as well as other carriers whose properties do not preclude physiological application.
  • Suitable carriers and adjuvants may be: wetting agent; emulsifying and suspending agents; conserving agents; antioxidants; Antiirritatives; Chelating agent; coating aids; Emulsion stabilizers; film formers; gelling agents; Odor masking agents, flavoring agents; resins; Hydrocolloids; Solvents; Solubilizing agents; Neutralizing agents; permeation; pigments; quaternary ammonium compounds; Refatting and superfatting agents; Ointment, cream or oil bases; Silicone derivatives; spreading aids; stabilizers; Sterilanzien; suppository bases; Tablet excipients such as binders, fillers, lubricants, disintegrants or coatings; Propellant; Desiccant; Opacifiers; Thickener; waxes; plasticizers; White oils.
  • a related embodiment is based on expert knowledge, as for example in Fiedler, HP, Lexicon of excipients for pharmacy, cosmetics and related fields, 4th edition, Aulendorf: ECV Editio Kantor Verlag, 1996, is shown.
  • suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the guanidine compounds of the invention may be formulated to assure immediate or delayed release of the drug to the patient.
  • suitable pharmaceutical compositions are solid dosage forms, such as powders, powders, granules, tablets, in particular film-coated tablets, lozenges, sachets, cachets, dragees, capsules, such as hard and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms, such as ointments, creams, hydrogels, Pastes or patches, and liquid dosage forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops. Implanted delivery devices may also be used to administer the guanidine compounds of the present invention. Furthermore, liposomes or microspheres may also be used.
  • compositions according to the invention can be administered by conventional means, for example.
  • compositions according to the invention When preparing compositions according to the invention, the active ingredients are usually mixed or diluted with a suitable adjuvant, in this case also referred to as excipient. Excipients may be solid, semi-solid or liquid materials which serve as a vehicle, carrier or medium for the active ingredient. If necessary, the addition of further auxiliaries takes place in a manner known per se. Shaping steps, optionally in conjunction with blending operations, may be performed, eg granulation, compression and the like.
  • the use according to the invention of the active compounds according to the invention includes a method within the scope of the treatment.
  • the subject to be treated preferably a mammal, especially a human, and also a non-human mammal, such as a farm or pet, an effective amount of at least one guanidine compound of the formula I, usually formulated according to pharmaceutical practice administered ,
  • the invention also relates to the preparation of agents for treating an individual, preferably a mammal, in particular a human, animal or pet.
  • guanidine compounds of the formula I or the corresponding pharmaceutical composition according to the invention can be administered orally, rectally, topically, parenterally, including subcutaneously, intravenously and intramuscularly, ocularly, pulmonarily or nasally. Preferred is oral administration.
  • An effective dosage of the active ingredient may depend on the nature of the guanidine compound of the formula I 1, the mode of administration, the condition to be treated and the severity of the disease to be treated. Such an effective dosage of the active ingredient can be determined by one skilled in the art without difficulty.
  • the dosage depends on the age, condition and weight of the patient and on the mode of administration.
  • the daily dose of active ingredient is between about 0.5 and 100 mg / kg body weight when given orally and between about 0.1 and 10 mg / kg body weight when given parenterally.
  • guanine compounds according to the invention can be prepared analogously to methods known from the literature, as are known to the person skilled in the art.
  • the synthesis of guanidines is generally described in J. Org. Chem. 1997, 9, 1053; Tetrahedron 1999, 55 (10), 713; Tetrahedron Letters 1999, 40, 53; J. Org. Chem. 2000, 65, 8080 and the references cited therein.
  • guanidine compounds according to the invention can be carried out according to Scheme 1 under customary reaction conditions, as described, for example, in Journal of Medicinal Chemistry 1997, 40, 2462-2465; Journal of Medicinal Chemistry 1999, 42, 2920-2926; Bioorganic & Medicinal Chemistry Letters 2001, 11, 523-528; Journal of Medicinal Chemistry 2000, 43, 3315-3321; Journal of Organic Chemistry 1991, 56, 2139-2143 or Bioorganic and Medicinal Chemistry 2003, 11, 1319-1341.
  • Hetarylamines II are commercially available or by literature methods (eg Houben-Weyl, Methods of Organic Chemistry, Volume E8b and E8c,
  • radical Q can also be substituted by the radicals R 4 , R 5 , R 6 , R 7 and R 8 analogously to the general formula Q
  • the functionalization to Q already at an early stage of hetarylamines by using the methods known to those skilled in the art for the preparation of functionalized hetarylamines (eg Houben-Weyl, Methods of Organic Chemistry, Extension and Follow-up to the 4th edition, Bd. E7b, Hetarene, Thieme-Verlag, Stuttgart Houben-Weyl, Methods of Organic Chemistry, Additional and Supplementary Volumes to the 4th Edition, Vol.
  • the requisite reagents and starting materials are either commercially available (eg, boronic acid derivatives, organometallics, nucleophiles, etc.) or can be prepared by methods known to those skilled in the art (eg, G. Hall, Boronic Acids, Wiley-VCH, Weinheim, 2005, M. Schlosser (Editor), Organometallics in Synthesis, A Manual, Wiley & Sons, Chichester 2002; M. Beller, C. BoIm (Editors), Transition Metals for Organic Synthesis, Wiley-VCH, Weinheim, 2003; T. Eicher, S.
  • guanidine compounds of the general formula I according to the invention can be recovered in a conventional manner and, if necessary, purified, for example by recrystallization from conventional organic solvents, preferably a short-chain alcohol such as methanol or ethanol, but also in acetonitrile, water, acetoacetic ester or in volatile solvents such as diethyl ether, pentane or dichloromethane or by chromatographic techniques.
  • conventional organic solvents preferably a short-chain alcohol such as methanol or ethanol, but also in acetonitrile, water, acetoacetic ester or in volatile solvents such as diethyl ether, pentane or dichloromethane or by chromatographic techniques.
  • the guanidine compounds of the formula I according to the invention are obtained in free form or already as acid addition salts. Both the compounds in free form and salts of these compounds resulting in the process can be converted in a manner known per se into desired acid addition salts or into the free form.
  • Example 3 ⁇ / - (2,6-Dimethoxybenzyl) - ⁇ T- (5-iodopyridin-2-yl) guanidine 2.019 g (7.233 mmol) of ⁇ / - (5-iodopyridin-2-yl) thiourea were dissolved in 50 ml of methanol dissolved, 0.60 mL (9,553 mmol) of methyl iodide were added dropwise in 2 mL of methanol and heated 2.7 hours at 75 0 C (oil bath temperature). The solvent was i. Vak. removed and the intermediate again dissolved in 50 mL of ethanol.
  • the methylated intermediate methyl ⁇ / - (6-methylpyridin-2-yl) imidothiocarbamate was obtained analogously to the previously described procedure of Example 6 from the N- (G-methylpyridin-2-yl) thiourea.
  • 0.300 g (1.660 mmol) of methyl ⁇ / - (6-methylpyridin-2-yl) imidothiocarbamate were treated with 0.332 g (1.99 mmol) 2,6-dimethoxybenzylamine in the CEM microwave 30 minutes at 90 0 C (100 watts) reacted.
  • the product was obtained directly as a crystallizate from the ethanolic solution, which was filtered off with suction.
  • the methylated intermediate methyl ⁇ / - [3-chloro-5- (trifluoromethyl) pyridin-2-yl] imidothiocarbamate was prepared analogously to the previously described procedure of Example 6 from the ⁇ / - [3-chloro-5- (trifluoromethyl) pyridine-2-one. yl] thiourea recovered.
  • 0.270 g (1000 mmol) of methyl ⁇ / - [3-chloro-5- (trifluoromethyl) pyridin-2-yl] imidothiocarbamate were mixed with 0.218 g (1300 mmol) of 2,6-dichloromethane.
  • methylated intermediate methyl ⁇ / - (3-methylpyridin-2-yl) imidothiocarbamate was obtained analogously to the previously described method of Example 6 from the ⁇ / - (3-methylpyridin-2-yl) thiourea.
  • the methylated intermediate methyl ⁇ / - (3-methylpyridin-2-yl) imidothiocarbamate was obtained analogously to the previously described method of Example 6 from the ⁇ / - (3-methylpyridin-2-yl) thiourea.
  • Example 15 ⁇ / - (2,6-dimethoxybenzyl) - ⁇ T- [4- (2-thienyl) pyrimidin-2-yl] guanidine acetate
  • the methylated intermediate methyl ⁇ / - [4- (2-thienyl) pyrimidine-2 -yl] imidothiocarbamate was obtained analogously to the previously described procedure of Example 6 from the ⁇ / - [4- (2-thienyl) pyrimidin-2-yl] thiourea.
  • the methylated intermediate methyl ⁇ / -quinoline-3-yl-idothiocarbamate was obtained analogously to the previously described procedure of Example 6 from the ⁇ / -quinoline-3-ylthiourea.
  • 0.250 g (1.15 mmol) of methyl ⁇ / -quinoline-3-ylidothiocarbamate was mixed with 0.205 g (1.50 mmol) 2-methoxybenzylamine with ethanol as solvent in the CEM microwave for 45 minutes at 90 ° C. (100 watts ) reacted.
  • Example 17 ⁇ / - (2,6-dimethoxybenzyl) - ⁇ -quinolin-3-ylguanidine acetate
  • the methylated intermediate methyl ⁇ / -quinoline-3-ylidothiocarbamate was prepared analogously to the previously described procedure of Example 6 from the ⁇ / -quinoline 3-ylthiourea recovered.
  • For the subsequent reaction were respectively 0.500 g (2.30 mmol) of methyl ⁇ / -quinoline-3-ylimidothiocarbamat with 0.500 g (2.99 mmol) of 2,6-dimethoxybenzylamine with ethanol as a solvent in the CEM microwave for 45 minutes at 90 0 C ( 100 watts) reacted.
  • Example 20 ⁇ / - (2-Fluoro-6-methoxybenzyl) - ⁇ / '- (5-methylpyridin-2-yl) guanidine acetate
  • Example 23 ⁇ / - (2-Isopropoxybenzyl) - ⁇ T- (5-methylpyridin-2-yl) guanidine acetate
  • Example 26 W- [2- (Difluoromethoxy) benzyl] -TH- (5-methylpyridin-2-yl) guanidine Analogously, 0.350 g (1130 mmol) of methyl ⁇ / - (5-methylpyridin-2-yl) imidothiocarbamate Hydroiodide with 0.240 g (1.360 mmol) of 2-difluoromethoxybenzylamine and additions of 0.39 mL (2.26 mmol) of diisopropylethylamine and acetonitrile as a solvent in the CEM microwave for 40 minutes at 90-100 0 C (150 watts) reacted, after working up and Purification 0.321 g of pure ⁇ / - [2- (difluoromethoxy) benzyl] - ⁇ (5-methylpyridin-2-yl) guanidine were obtained which as the acetate salt (base / acetate in the ratio 1: 0.3) was present.
  • Example 29 ⁇ / - (2-Methoxybenzyl) - ⁇ f- (4-methylpyridin-2-yl) guanidine acetate
  • the methylated intermediate methyl ⁇ / - (4-methylpyridin-2-yl) imidothiocarbamate hydroiodide was prepared analogously to the procedure described previously Example 18 from the ⁇ / - (4-methylpyridin-2-yl) thiourea by stirring at room temperature after 12 hours in methanol.
  • Example 30 ⁇ / - (2,6-Dimethoxybenzyl) - ⁇ T- (4-methylpyridin-2-yl) guanidine acetate
  • the methylated intermediate methyl ⁇ / - (4-methylpyridin-2-yl) imidothiocarbamate hydroiodide was prepared analogously to that described above Prescription of Example 18 from the ⁇ / - (4-methylpyridin-2-yl) thiourea by stirring at room temperature after 12 hours in methanol.
  • Example 31 A / - (2-Chloro-6-methoxybenzyl) -AT- (3-methylpyridin-2-yl) guanidine 31.1 Methyl N- (3-methylpyridin-2-yl) imidothiocarbamate
  • Example 32 W- (2-Fluoro-6-methoxybenzyl) -W- (3-methylpyridin-2-yl) guanidine
  • Example 34 ⁇ / - (2-methoxybenzyl) - / V -pyridin-3-ylguanidine acetate
  • Example 35 3 - ( ⁇ imino [(2-methoxybenzyl) amino] methyl ⁇ amino) -1-methylpyridinium acetate

Abstract

L'invention concerne des composés guanidine à substitution hetaryl représentés par la formule (I), les énantiomères, diastéréomères et/ou tautomères de ces composés, ainsi que leurs sels pharmaceutiquement acceptables et promédicaments, L'invention concerne également l'utilisation desdits composés guanidine à substitution hetaryl en tant partenaires de liaison pour des récepteurs de 5-HT5 pour le traitement et/ou la prophylaxie de maladies modulées par une activité du récepteur de 5-HT5, notamment pour le traitement et/ou la prophylaxie de troubles neurodégénératifs et neuropsychiatriques et de signes, symptomes et dysfonctionnements associés à ces troubles.
EP06791627A 2005-08-24 2006-08-23 Composes guanidine a substitution hetaryl et utilisation en tant que partenaires de liaison pour des recepteurs de 5-ht5 Withdrawn EP1917244A2 (fr)

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US20150250786A1 (en) * 2012-10-12 2015-09-10 The Trustees Of The University Of Pennsylvania Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
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