WO2007118900A1 - Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor - Google Patents
Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor Download PDFInfo
- Publication number
- WO2007118900A1 WO2007118900A1 PCT/EP2007/053808 EP2007053808W WO2007118900A1 WO 2007118900 A1 WO2007118900 A1 WO 2007118900A1 EP 2007053808 W EP2007053808 W EP 2007053808W WO 2007118900 A1 WO2007118900 A1 WO 2007118900A1
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- WO
- WIPO (PCT)
- Prior art keywords
- crc
- alkyl
- fluorinated
- phenyl
- alkoxy
- Prior art date
Links
- 108091005435 5-HT6 receptors Proteins 0.000 title abstract description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 17
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 5
- 229940076279 serotonin Drugs 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 174
- 239000003446 ligand Substances 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 8
- -1 cyclic radical Chemical class 0.000 claims description 1043
- 102000005962 receptors Human genes 0.000 claims description 109
- 108020003175 receptors Proteins 0.000 claims description 109
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 82
- 229910052736 halogen Inorganic materials 0.000 claims description 70
- 150000002367 halogens Chemical class 0.000 claims description 69
- 150000003254 radicals Chemical class 0.000 claims description 67
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- 229960003638 dopamine Drugs 0.000 claims description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 208000035475 disorder Diseases 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 27
- 239000011737 fluorine Substances 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 238000009739 binding Methods 0.000 claims description 23
- 230000027455 binding Effects 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 239000000126 substance Substances 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 16
- 208000010877 cognitive disease Diseases 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 201000000980 schizophrenia Diseases 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- 102000015554 Dopamine receptor Human genes 0.000 claims description 9
- 108050004812 Dopamine receptor Proteins 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 208000015114 central nervous system disease Diseases 0.000 claims description 6
- 229910052804 chromium Inorganic materials 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 5
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims description 3
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 3
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 3
- 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 3
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 claims 1
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000003838 furazanyl group Chemical group 0.000 claims 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical class [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 21
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
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- UIYOVVYZPVVUMJ-UHFFFAOYSA-N tert-butyl carbamoyl carbonate Chemical compound CC(C)(C)OC(=O)OC(N)=O UIYOVVYZPVVUMJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
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- 208000016686 tic disease Diseases 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to novel heterocyclic compounds.
- the compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the serotonine 5-HT6 receptor.
- Serotonin (5-hydroxytryptamine, 5HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5HT is implicated in a vast array of physiological and pathophysiological path- ways. In the periphery, it contracts a number of smooth muscles and induces endothe- lium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
- 5HT 1 (with subtypes 5HT 1A , 5HT 16 , 5HT 1D , 5HT 1E and 5HT I F ), 5HT 2 (with subtypes 5HT 2A , 5HT 2B and 5HT 10 ), 5HT 3 , 5HT 4 , 5HT 5 (with subtypes 5HT 1A and 5HT 1B ), 5HT 6 and 5HT 7 ).
- Most of these receptors are coupled to G- proteins that affect the activities of either adenylate cyclase or phospholipase C ⁇ .
- the human 5HT 6 receptors are positively coupled to adenylyl cyclase. They are distributed throughout the limbic, striatal and cortical regions of the brain and show a high affinity to antipsychotics.
- the modulation of the 5HT 6 receptor by suitable substances is expected to improve certain disorders including cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syn- drome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowl Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, drug addiction and obesity.
- cognitive dysfunctions such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syn- drome, personality disorders, such as schizophrenia,
- Parkinson's disease Another neurotransmitter with implications on the CNS is dopamine.
- disorders in the dopaminergic transmitter system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.
- the dopamine receptors are divided into two families. On the one hand, there is the D 2 group, consisting of D 2 , D 3 and D 4 receptors, and, on the other hand, the D 1 group, consisting of D 1 and D 5 receptors. Whereas D 1 and D 2 receptors are widely distributed, D 3 receptors appear to be expressed regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala.
- D 3 receptors are regarded as being a target having few side-effects and it is assumed that while a selective D 3 ligand would have the properties of known antipsychotics, it would not have their dopamine D 2 receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D 3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1 ), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D 3 ) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
- Compounds having an affinity for both receptors are expected to be suitable for treating disorders related to or affected by both the 5HT 6 receptor and the D 3 receptor, thus allowing the treatment of more than one aspect of the respective disorder.
- the compounds should also have good pharmacological profile, e.g. a good brain plasma ratio, a good bioavailability, good metabolic stability, or a decreased inhibition of the mitochondrial respiration.
- the invention is based on the object of providing compounds which act as 5HT 6 receptor ligands. This object is surprisingly achieved by means of compounds of the formula I
- D is a group of the formula B or C
- n O, 1 or 2;
- G is CH 2 or CHR 3 ;
- R 1 is H, d-Ce-alkyl, C r C 6 -alkyl substituted by C 3 -C 6 -cycloalkyl, C r C 6 -hydroxyalkyl, fluorinated CrC 6 -alkyl, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 3 -C 6 - alkenyl, fluorinated C 3 -C 6 -alkenyl, formyl, acetyl, propionyl or benzyl;
- R 2 , R 2 , R 3 , R 4 and R 4 are, independently of each other, H, methyl, fluoromethyl, di- fluoromethyl, or trifluoromethyl;
- A is 2,4-pyridylene, 3,5-pyridylene or 2,6-pyridylene, which is optionally substituted by one, two or three substituents selected from halogen, d-C 4 -alkyl, CrC 4 - alkoxy, fluorinated Ci-C 4 -alkyl and fluorinated Ci-C 4 -alkoxy;
- E is NR 5 or CH 2 , wherein R 5 is H or C r C 3 -alkyl;
- Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6- membered heteroaromatic radical comprising as ring members 1 , 2 or 3 heteroa- toms selected from N, O and S and a phenyl ring fused to a saturated or unsatu- rated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1 , 2 or 3 heteroatoms selected from N, O and S and/or 1 , 2 or 3 heteroatom-containing groups each independently selected from NR 8 , where R 8 is H, C r C 4 -alkyl, fluorinated C r C 4 -alkyl, C r C 4 -alkylcarbonyl or fluorinated Ci-C 4 -alkylcarbonyl, and where the cyclic radical Ar may carry 1 , 2 or 3 substituents R a ;
- each R a is independently halogen, hydroxyl, CrC ⁇ -alky!, fluorinated Ci-C ⁇ -alkyl, CrC 6 - hydroxyalkyl, Ci-C 6 -alkoxy-CrC 6 -alkyl, C 2 -C 6 -alkenyl, fluorinated C 2 -C 6 -alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, CrC ⁇ -alkoxy, CrC6-hydroxyalkoxy, Ci-C ⁇ -alkoxy-Ci-C ⁇ -alkoxy, fluorinated CrC 6 -alkoxy, CrC 6 -alkylthio, fluorinated
- R 6 is as defined above and R 10 is Ci-C 4 -alkyl or phenyl, where the phenyl radical may be unsubstituted or may carry 1 to 3 substituents selected from CrC 4 -alkyl, fluorinated Ci-C 4 -alkyl and halogen, CH 2 -pyridyl, where the pyridyl radical may be unsubstituted or may carry 1 to 3 substituents selected from Ci-C 4 -alkyl, fluori- nated CrC 4 -alkyl and halogen, or is a saturated or unsaturated aromatic or non- aromatic 3- to 7-membered heterocyclic ring comprising as ring members 1 , 2, 3 or 4 heteroatoms selected from N, O and S and/or 1 , 2 or 3 heteroatom- containing groups selected from NR 9 , where R 9 has one of the meanings given for R 8 , SO, SO 2 and CO, and where the heterocyclic ring may carry 1 , 2 or 3
- the present invention therefore relates to compounds of the general formula I and to their physiologically tolerated acid addition salts.
- R 1 is H, Ci-C 6 -alkyl, C r C 6 -alkyl substituted by C 3 -C 6 -cycloalkyl, C r C 6 -hydroxyalkyl, fluorinated CrC 6 -alkyl, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 3 -C 6 - alkenyl, fluorinated C 3 -C 6 -alkenyl, formyl, acetyl or propionyl; and
- R a is halogen, Ci-C ⁇ -alkyl, fluorinated Ci-C ⁇ -alkyl, Ci-C 6 -hydroxyalkyl, Ci-C 6 -alkoxy- Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, fluorinated C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, fluorinated
- the present invention also relates to a method for treating disorders which respond to influencing by 5HT 6 receptor antagonists or 5HT 6 agonists, said method comprising administering an effective amount of at least one compound of the formula I and/or at least one physiologically tolerated acid addition salt of I to a subject in need thereof.
- the present invention further relates to the use of a compound of the formula I and/or physiologically tolerated acid addition salts thereof, for preparing a medicament for the treatment of a medical disorder susceptible to treatment with a 5-HT 6 receptor ligand.
- the diseases which respond to the influence of 5HT 6 receptor antagonists or agonists include, in particular, disorders and diseases of the central nervous system, in particular cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophre- nia, affective disorders such as depression, bipolar disorder, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowl Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, drug addiction and obesity.
- cognitive dysfunctions such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and
- At least one compound of the general formula I having the meanings mentioned at the outset is used for treating the above mentioned indications.
- the compounds of the formula I of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formula I and/or of their salts.
- the carbon atom of the nitrogen-containing ring D carrying the group A may have (S) or (R) configuration.
- the (S) configuration is preferred.
- the radical A may be in a cis or trans position to either of the substituents R , R R 33 oorr R R 4 (if at least one of those is not hydrogen). However, the cis position is pre- ferred.
- physiologically tolerated salts of the compounds of the formula I especially acid addition salts with physiologically tolerated acids.
- suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, Ci-C 4 -alkylsulfonic acids, such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and tolue- nesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid.
- Other utilizable acids are described in Fort Whitneye der Arzneimit- tel Kausch [Advances in drug research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966.
- the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
- the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
- halogen denotes in each case fluorine, bromine, chlorine or iodine, in particu- lar fluorine, chlorine or bromine.
- CrC 4 Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso- butyl or terf-butyl.
- CrC 2 Alkyl is methyl or ethyl
- CrC 3 alkyl is additionally n-propyl or isopropyl.
- CrC ⁇ Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include CrC 4 alkyl as mentioned above and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 ,1- dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 ,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylprop
- Branched C3-C6 alkyl is alkyl having 3 to 6 carbon atoms at least one being a secondary or tertiary carbon atom. Examples are isopropyl, tert. -butyl, 2- butyl, isobutyl, 2- pentyl, 2-hexyl, 3-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1-methyl-1- ethylpropyl.
- Fluorinated branched C 3 -C 6 alkyl is alkyl having 3 to 6 carbon atoms at least one being a secondary or tertiary carbon atom wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atom.
- Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, 2-butoxy, iso-butoxy, tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3- methylbutoxy, 2,2-dimethylpropoxy, 1 -ethyl propoxy, hexyloxy, 1 ,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1 ,1-dimethylbutyloxy, 1 ,2-dimethylbutyloxy, 1 ,3-dimethylbutyloxy, 2,2-dimethylbutyloxy,
- Ci-C 6 -Alkoxy-Ci-C 6 -alkyl is a straight-chain or branched alkyl group having from 1 to 6, especially 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms, wherein one of the hydrogen atoms is replaced by a CrC ⁇ -alkoxy group, such as in methoxymethyl, 2- methoxyethyl, ethoxymethyl, 3-methoxypropyl, 3-ethoxy propyl and the like.
- Ci-C ⁇ -Alkoxy-Ci-C ⁇ -alkoxy is a straight-chain or branched alkyl group having from 1 to 6, especially 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms, wherein one of the hydrogen atoms is replaced by a CrC ⁇ -alkoxy group, such as in 2-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy and the like.
- CrC 6 -Alkylcarbonyl is a straight-chain or branched alkyl group having from 1 to 6, especially 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms, wherein one of the hy- drogen atoms is replaced by a carbonyl group (CO), such as in acetyl and propionyl.
- CO carbonyl group
- CO-NH- carbonylamino group
- C 1 -C6 Alkylthio also termed as CrC6-alkylsulfanyl
- Ci-C ⁇ -alkylsulfinyl or C 1 -C6- alkylsulfonyl refer to straight-chain or branched alkyl groups having 1 to 6 carbon atoms, e.g. 1 to 4 carbon atoms, which are bound to the remainder of the molecule via a sulfur atom (or S(O)O in case of alkylsulfinyl or S(O) 2 O in case of alkylsul- fonyl, respectively), at any bond in the alkyl group.
- Ci-C 4 -alkylthio examples include methylthio, ethylthio, propylthio, isopropylthio, and n-butylthio.
- Examples for CrC 4 - alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, and n- butylsulfinyl.
- Ci-C 4 -alkylsulfonyl examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and n-butylsulfonyl.
- Fluorinated CrC 6 alkylthio (also termed fluorinated CrC 6 -alkylsulfanyl) is a straight- chain or branched alkylthio group having from 1 to 6, in particular 1 to 4 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms.
- Fluorinated CrC 6 alkylsulfinyl is a straight-chain or branched alkylsulfinyl group having from 1 to 6, in particular 1 to 4 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms.
- Ci-C ⁇ alkylsulfonyl is a straight-chain or branched alkylsulfonyl group having from 1 to 6, in particular 1 to 4 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms.
- Cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclo- propyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the cycloalkyl radical may be unsubsti- tuted or may carry 1 , 2, 3 or 4 CrC 4 alkyl radicals, preferably a methyl radical.
- One alkyl radical is preferably located in the 1 -position of the cycloalkyl radical, such as in 1- methylcyclopropyl or 1-methylcyclobutyl.
- Fluorinated C 3 -C 6 cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein at least one, e.g.
- 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in 1- fluorocyclopropyl, 2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl, 1 ,2- difluorocyclopropyl, 2,3-difluorocyclopropyl, pentafluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 1 ,2- difluorocyclobutyl, 1 ,3-difluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, or 1 ,2,2-trifluorocyclobutyl.
- a fluorine atoms such as in
- C 2 -C 6 -Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C- atoms, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2- methylprop-2-en-1-yl) and the like.
- C 3 -C 6 -Alkenyl is, in particular, allyl, 1-methylprop-2- en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1- yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.
- Fluorinated C 2 -C 6 -alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C-atoms, I, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by a fluorine atoms such as in 1-fluorovinyl, 2-fluorovinyl, 2,2-fluorovinyl, 3,3,3-fluoropropenyl, 1 ,1-difluoro-2-propenyl 1-fluoro-2-propenyl and the like.
- CrC 6 -Alkylene is a hydrocarbon bridging group having 1 , 2, 3, 4, 5 or 6 carbon atoms, like methylene, ethylene, 1 ,2- and 1 ,3-propylene, 1 ,4-butylene and the like.
- Examples of 5- or 6-membered heteroaromatic radicals comprise 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, pyrazinyl, 3- or 4-pyridazinyl, 2- or 3-thienyl, 2-or 3-furyl, 2- or 3- pyrrolyl, 2-, 3- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 5-thiazolyl, 3-, 4- or 5- isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 2- or 5-[1 ,3,4]oxadiazolyl, 4- or 5-[1 ,2,3]oxadiazolyl, 3- or 5-[1 ,2,4]oxadiazolyl, 2- or 5-[1 ,3,4]thiadiazolyl, 2- or 5- [1 ,3,4]thiadiazolyl, 4- or 5-[1 ,2,3]thiadiazolyl, 3- or 5-[1 ,2,4
- Examples of a phenyl ring fused to a saturated or unsaturated 5- or 6-membered car- bocyclic or heterocyclic ring comprise indenyl, indanyl, naphthyl, 1 ,2- or 2,3- dihydronaphthyl, tetralin, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, ben- zoxazinyl, dihydrobenzoxazinyl, chinolinyl, isochinolinyl, tetrahydroisochinolinyl, chromenyl, chromanyl and the like, which may be unsubstituted or which may carry 1 , 2 or 3 of the aforementioned radicals R a .
- This fused system may be bonded to the remainder of the molecule (more precisely to the sulfonyl group) via carbon atoms of the phenyl moiety or via ring atoms (C- or N-atoms) of the ring fused to phenyl.
- Examples for saturated or unsaturated 3- to 7-membered heterocyclic rings comprise saturated or unsaturated, aromatic or non-aromatic heterocyclic rings.
- examples for this type of radical comprise, apart from the above-defined 5- or 6-membered heteroaromatic radicals containig at least one N atom as ring member, azetidinyl, azetinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl and the like.
- n preferably is 0 or 1 ; i.e. the nitrogen-containing ring B is an azetidinyl group or a pyrrolidinyl group; and particularly, n is 1 , which means that in a particularly preferred embodiment, the nitrogen-containing ring B is a pyrrolidinyl ring.
- the radical R 1 is selected from H, Ci-C 4 -alkyl, Ci-C 4 -alkyl which is substituted by C 3 -C 6 -cycloalkyl or hydroxy, fluorinated CrC 4 -alkyl and C 2 -C 4 -alkenyl. More preference is given to H, propyl, cyclopropylmethylene, fluorinated ethyl, e.g. 2- fluoroethyl, fluorinated propyl, e.g. 3-fluoropropyl, hydroxypropyl, e.g. 3-hydroxypropyl, propionyl and allyl.
- R 1 is selected from H, propyl, ethyl, methyl, cyclopropylmethylene, 2-fluoroethyl, 3-fluoropropyl, 3-hydroxypropyl, and allyl. Even more preferably, R 1 is selected from H, propyl, cyclopropylmethylene, 2-fluoroethyl, 3- fluoropropyl, 3-hydroxypropyl, and allyl. In a particularly preferred embodiment, R 1 is H, n-propyl or allyl, in particular H or n-propyl and especially H.
- R 2 , R 2 , R 3 , R 4 and R 4 are H.
- D is a group of the formula B.
- D is a group of the formula C.
- preferred substituents are selected from halogen, in particular fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy. More preferred substituents are selected from halogen, in particular fluorine, methyl and methoxy. Specifically, the substituent is methoxy.
- Examples include 2-methoxy-3,5-pyridylene, 4-methoxy-3,5-pyridylene, 3-methoxy-2,4-pyridylene, 5-methoxy-2,4-pyridylene, 6-methoxy-2,4-pyridylene, 3-methoxy-2,6-pyridylene, 4- methoxy-2,6-pyridylene, 2-fluoro-3,5-pyridylene, 4-fluoro-3,5-pyridylene, 3-fluoro-2,4- pyridylene, 5-fluoro-2,4-pyridylene, 6-fluoro-2,4-pyridylene, 3-fluoro-2,6-pyridylene, 4- fluoro-2,6-pyridylene, 2-methyl-3,5-pyridylene, 4-methyl-3,5-pyridylene, 3-methyl-2,4- pyridylene, 5-methyl-2,4-pyridylene, 6-methyl-2,4-
- A is 2,4-pyridylene 3,5-pyridylene or 2,6-pyridylene, relating to the 1 -position of the nitrogen atom. This corresponds to following binding positions:
- A is 2,4-pyridylene (preferably (a)) or 3,5-pyridylene, which is optionally substituted by one or more substituents selected from halogen, Ci-C 4 -alkyl, CrC 4 - alkoxy, fluorinated CrC 4 -alkyl and fluorinated CrC 4 -alkoxy.
- the substituents are selected from halogen, in particular fluorine, methyl, difluoromethyl, trifluoro- methyl, methoxy, difluoromethoxy and trifluoromethoxy. More preferred substituents are selected from halogen, in particular fluorine, methyl and methoxy.
- A is 2,4-pyridylene (preferably (a)) or 3,5-pyridylene, which is optionally substituted by one ore more substituents selected from halogen, d-C 4 -alkyl, CrC 4 -alkoxy, fluorinated CrC 4 -alkyl and fluorinated CrC 4 -alkoxy.
- the substituents are selected from halogen, in particular fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy. More preferred substituents are selected from halogen, in particular fluorine, methyl and methoxy.
- A is 2,4- or 3,5- pyridylene, which is unsubstituted or substituted by one methoxy group.
- A is 3,5-pyridylene which is unsubstituted or substituted by methoxy.
- the group E is preferably NR 5 , more preferably NH or NCH 3 and in particular NH.
- Preferred cyclic radicals of the group Ar are phenyl, 2- or 3-thienyl, in particular 2- thienyl, imidazolyl, in particular 4-imidazolyl, isoxazolyl, in particular 4-isoxazolyl, thia- zolyl, in particular 2-thiazolyl, triazolyl, in particular 3-[1 , 2, 4]triazolyl, thiadiazolyl, in particular 3- and 5-[1 ,2,4]thiadiazolyl and 2-[1 ,3,4]thiadiazolyl, 2-, 3- or 4-pyridyl, 2- and 5- pyrimidinl, 1-, 2-, 3-, 4- or 5-indanyl, 2-, 3-, 4- or 5-benzofuranyl, quinolinyl, in particular 8-quinolinyl, isoquinolinyl, in particular 5-isoquinolinyl, 1
- the numbers indicate the position at which Ar is bound to the sulfonyl group.
- More preferred radicals Ar are phenyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-indanyl, 2-benzofuranyl, 2-benzothienyl and 2,3- dihydrobenzofuran-2-yl.
- Even more preferred radicals Ar are phenyl, thienyl, in particular 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-indanyl, benzofuran-2-yl, 2-benzothienyl and 2,3-dihydrobenzofuran-2-yl.
- Ar are phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, in particular 2-thienyl, and 2-benzothienyl and in particular phenyl, thienyl, in particular 2-thienyl, and 2-benzothienyl.
- Ar is phenyl or thienyl, in particular 2-thienyl, and more specifically phenyl.
- the cyclic radical Ar is unsubstituted or substituted by 1 , 2 or 3 substituents R a selected from the group consisting of halogen, d-C 6 -alkyl, CrC 6 - hydroxyalkyl, fluorinated CrC 4 -alkyl, CrC 4 -alkoxy, fluorinated Ci-C 4 -alkoxy, CrC 4 - alkoxy-CrC 4 -alkoxy, C 2 -C 4 -alkenyl, fluorinated C 2 -C 4 -alkenyl, NR 6 R 7 , ONR 6 R 7 , C r C 6 - alkylene-NR 6 R 7 , where R 6 and R 7 are independently of each other H, Ci-C 4 -alkyl or or CrC 4 -alkoxy, ureido (NHCONH 2 ) C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -
- R a is selected from the group consisting of halogen, CrC 6 -alkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, OCF 3 , OCHF 2 , OCH 2 F, C 2 -C 4 -alkenyl, C 3 -C 6 - cycloalkyl, fluorinated C 3 -C 6 - cycloalkyl, ureido, acetyl, carboxyl, hydroxy, cyano, benzoxy, trifluoromethylsulfanyl, methylsulfonyl, azetidin-1-yl, 2,2-difluoroazetidin-1-yl, pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2- oxo-pyrrolidin-1-yl, 2-oxo-oxazolidin-1-yl, piperidin-1-y
- Examples for such 5- or 6-membered heteroaromatic rings are pyrrolyl, such as pyrrol- 1-yl, pyrrol-2-yl, or pyrrol-3-yl, furanyl, such as 2-furanyl, or furan-3-yl, thienyl, such as thien-2-yl, thien-3-yl, or 5-propylthien-2-yl, pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-4-yl, 1-ethylpyrazol-4-yl, or 4-fluoropyrazol- 1-yl, imidazolyl, such as imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl, oxa- zolyl, such as oxazol-2-yl, oxa
- R a is selected from the group consisting of halogen, d-Ce-alkyl, fluorinated C r C 4 -alkyl, C r C 4 -alkoxy, OCF 3 , OCHF 2 , OCH 2 F, C 2 -C 4 - alkenyl, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 - cycloalkyl, ureido, acetyl, carboxyl, hydroxy, benzoxy, trifluoromethylsulfanyl, azetidin-1-yl, 2,2-difluoroazetidin-1-yl, pyr- rolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-fluoropiperidin-1-yl, 2,2- difluoropiperidin-1-yl, morpholin-4-y
- R a in this case is in particular selected from halogen, Cr Ce-alkyl, fluorinated C r C 4 -alkyl, C r C 4 -alkoxy, OCF 3 , OCHF 2 , OCH 2 F, C 2 -C 4 -alkenyl, phenyl, phenylsulfonyl, pyridylsulfonyl, pyridylmethyl, where the pyridyl radical in the two last-mentioned radicals may be substituted as defined above, aminomethyl, ace- tylaminomethyl, benzoylaminomethyl, where the benzene ring in the last-mentioned radical may be substituted as defined above, and a 5- or 6-membered heteroaromatic ring which may be substituted as defined above for R a being a 3- to 7-membered heterocyclic ring.
- R a in this case is in particular selected from halogen, d-Ce-alkyl, fluorinated C r C 4 -alkyl, C r C 4 -alkoxy, OCF 3 , OCHF 2 , OCH 2 F and a 5- or 6- membered heteroaromatic ring which may be substituted as defined above.
- Preferred 5- or 6-membered heteroaromatic rings R a are selected from pyrrolyl, such as pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl, furanyl, such as furan-2-yl, or furan-3-yl, thienyl, such as thien-2-yl, or thien-3-yl, pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, imidazolyl, such as imidazol-1-yl, imidazol-2-yl, imidazol-4- yl, or imidazol-5-yl, oxazolyl, such as oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl, isoxazolyl, such as isoxazol-3-yl, isoxazol-4
- the 5- or 6-membered heteroaromatic rings R a contain one N atom as ring member (in 5-membered rings possibly also in the form of a group NR 9 ) and optionally one or two further heteroatoms as ring members selected from O, N and S, such as pyrrolyl, such as pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl, pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, imidazolyl, such as imidazol-1-yl, imidazol-2- yl, imidazol-4-yl, or imidazol-5-yl, oxazolyl, such as oxazol-2-yl, oxazol-4-yl, or oxazol- 5-yl, isoxazolyl, such as isoxazol-3-yl, iso
- the heteroaromatc ring R a is 5-membered.
- Preferred 5-membered heteroaromatc rings contain one N atom as ring member (possibly also in the form of a group NR 9 ) and optionally one or two further heteroatoms as ring members selected from O, N and S, e.g.
- pyrrolyl such as pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl
- pyrazolyl such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl
- imidazolyl such as imi- dazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl
- oxazolyl such as oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl
- isoxazolyl such as isoxazol-3-yl, isoxazol-4-yl, or isoxazol- 5-yl
- thiazolyl such as thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl
- isothiazolyl such as isothiazol-3-
- the 5- or 6-membered heteroaromatic ring R a is unsubstituted or carries one, two or three, preferably one, substituents selected from halogen, Ci-C 4 -alkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, fluorinated CrC 4 -alkoxy, Ci-C 4 -thioalkyl, fluori- nated CrC 4 -thioalkyl, and amino-C-i-C 2 -alkylene.
- substituents selected from halogen, Ci-C 4 -alkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, fluorinated CrC 4 -alkoxy, Ci-C 4 -thioalkyl, fluori- nated CrC 4 -thioalkyl, and amino-C-i-C 2 -alkylene.
- Ar is a fused system, it is preferentially not substituted or is substituted by one or two substituents which are preferably selected from halogen, d-C 4 -alkyl and fluorinated Ci-C 4 -alkyl.
- Ar is a phenyl ring fused to a heteroaromatic ring, it is preferably bound via a carbon atom of the heteroaromatic ring to the SO 2 group.
- Ar preferably is unsubstituted or carries one radical R a in the 5-position (related to the 2-position of the SO 2 - radical) and optionally one or two further radicals selected from halogen, in particular fluorine or chlorine.
- Phenyl and the aforementioned 6-membered heteroaromatic radicals Ar preferably carry one radical R a in the 2-, 3- or 4-position, preferably 3- or 4- (related to the 1- position of the S ⁇ 2 -radical) and optionally one or two further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated C 1 -C 4 - alkoxy, in particular OCHF 2 or OCF 3 .
- halogen in particular fluorine, CrC 4 -alkyl, in particular methyl
- Ci-C 4 -alkoxy in particular methoxy
- fluorinated CrC 4 -alkyl in particular CHF 2 or CF 3
- fluorinated C 1 -C 4 - alkoxy in particular OCHF 2 or OCF 3 .
- D is a group C
- A is unsubstituted 2,4-, 2,6- or 3,5-pyridylene and Ar is phenyl or one of the aforementioned 6-membered heteroaromatic radicals
- Ar carries one radical R a in the 3- or in the 4-position, more preferably in the 3-position (related to the 1 -position of the SO 2 -radical) and optionally one or two further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, C 1 -C 4 - alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated CrC 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- Ar carries one radical R a in the 3- or in the 4-position, more preferably in the 3-position (related to the 1 -position of the SO 2 -radical) and optionally one or two further radicals selected from halogen, in par- ticular fluorine, CrC 4 -alkyl, in particular methyl, d-C 4 -alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated CrC 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- Ar is phenyl that carries one radical R a in the 4-position of the phenyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, Ci-C 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular methoxy, fluorinated Ci-C 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated CrC 4 - alkoxy, in particular OCHF 2 or OCF 3 . If in this case, A is furthermore unsubstituted un- substituted 2,4-, 2,6- or 3,5-pyridylene, it is preferred that D is not a group C.
- Ar is phenyl that carries one radical R a in the 3-position of the phenyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, CrC 4 - alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated Ci-C 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- halogen in particular fluorine, CrC 4 -alkyl, in particular methyl, CrC 4 - alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3
- Ci-C 4 -alkoxy in particular OCHF 2 or OCF 3 .
- Ar is 2-pyridyl (related to the 1 -position of the nitrogen atom of pyridyl) that carries one radical R a in the 4- or 6- position of the pyridyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated CrC 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- halogen in particular fluorine, CrC 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated CrC 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- Ar is 2-pyridyl (related to the 1 -position of the nitrogen atom of pyridyl) that carries one radical R a in the 5- position of the pyridyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular methoxy, fluorinated CrC 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated Ci-C 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- halogen in particular fluorine, CrC 4 -alkyl, in particular methyl
- Ci-C 4 -alkoxy in particular methoxy
- fluorinated CrC 4 -alkyl in particular CHF 2 or CF 3
- fluorinated Ci-C 4 -alkoxy in particular OCHF 2 or OCF 3 .
- A is furthermore unsubstituted unsubstituted 2,4-, 2,6- or 3,5-pyridylene, it is preferred that D is not a group C.
- Ar is 3-pyridyl (related to the 1 -position of the nitrogen atom of pyridyl) that carries one radical R a in the 5- position of the pyridyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, d-C 4 -alkoxy, in particular meth- oxy, fluorinated Ci-C 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated Ci-C 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- Ar is 3-pyridyl (related to the 1 -position of the nitrogen atom of pyridyl) that carries one radical R a in the 6- position of the pyridyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, Ci-C 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular meth- oxy, fluorinated Ci-C 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated Ci-C 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- A is furthermore unsubstituted unsubstituted 2,4-, 2,6- or 3,5-pyridylene, it is preferred that D is not a group C.
- Ar is 4-pyridyl (related to the 1 -position of the nitrogen atom of pyridyl) that carries one radical R a in the 2- position of the pyridyl ring and optionally 1 or 2 further radicals selected from halogen, in particular fluorine, CrC 4 -alkyl, in particular methyl, Ci-C 4 -alkoxy, in particular meth- oxy, fluorinated Ci-C 4 -alkyl, in particular CHF 2 or CF 3 , and fluorinated Ci-C 4 -alkoxy, in particular OCHF 2 or OCF 3 .
- halogen in particular fluorine, CrC 4 -alkyl, in particular methyl
- Ci-C 4 -alkoxy in particular meth- oxy
- fluorinated Ci-C 4 -alkyl in particular CHF 2 or CF 3
- fluorinated Ci-C 4 -alkoxy in particular OCHF 2 or OCF 3 .
- Ar is 2- or 3- thienyl, preferably 2-thienyl (related to the 1 -position of the sulfur atom of thienyl) that is unsub- stituted or carries 1 , 2 or 3 substituents R a .
- Preferred meaning of Ra are defined above for Ar being a heteroaromatic ring. If the thienyl ring Ar carries one substituent R a , this is preferably bound at the 5-position.
- R a is selected from the group consisting of halogen, Ci-C ⁇ -alkyl, fluorinated Ci-C 6 -alkyl, C r C 6 -hydroxyalkyl, Ci-C 6 -alkoxy-Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 6 - cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, CrC 6 -alkoxy, Ci-C ⁇ -alkoxy-Ci-C ⁇ -alkoxy, fluorinated CrC ⁇ -alkoxy, fluorinated Ci-C ⁇ -alkylthio, Ci-C6-alkylsulfonyl, phenylsulfonyl, benzyloxy, phenoxy, CN, nitro, acetyl, trifluoroacetyl, acetamido, carboxy, NH-C(O)- NH 2
- the saturated or unsaturated 3- to 7-membered heterocyclic ring R a is se- lected from azetidin-1-yl, 2-methylazetidinyl, 3-methoxyazetidinyl, 3-hydroxyazetidinyl, 3-fluoroazetidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2- and 3- fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-y 3,3-difluoropyrrolidin-1-yl, 2- and 3- methylpyrrolidin-1-yl, 1 -methylpyrrolidin-2-yl, 2,2-dimethylpyrrolidin-1-yl, 3,3- dimethylpyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2- and 3-trifluoromethylpyrrolidin-1-yl, 2- oxo-
- the saturated or unsaturated 3- to 7-membered heterocyclic ring R a is selected from nitrogen containing rings such as azetidin-1-yl, 2-methylazetidinyl, 3- methoxyazetidinyl, 3-hydroxyazetidinyl, 3-fluoroazetidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2- and 3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-y 3,3- difluoropyrrolidin-1-yl, 2- and 3-methylpyrrolidin-1-yl, 1 -methylpyrrolidin-2-yl, 2,2- dimethylpyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2- and 3- trifluoromethylpyrrolidin-1-yl, 2-oxo-o-o-
- the saturated or unsaturated 3- to 7-membered heterocyclic ring R a is selected from nitrogen containing rings which are bound to the phenyl or pyridyl ring of the group Ar via their nitrogen atom, such as azetidin-1-yl, 2-methylazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, 3-fluoroazetidin-1-yl, pyrrolidin-1-yl, 2- and 3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-y 3,3-difluoropyrrolidin-1-yl, 2- and 3- methylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 2-oxo- pyrrolidin-1-yl, 2- and 3-trifluoromethylpyrrolidin-1-y
- the saturated or unsaturated 3- to 7- membered heterocyclic ring R a is a 5- or 6-membered heteroaromatic ring, where the 5- or 6-membered heteroaromatic ring is preferably selected from pyrrolyl, such as pyr- rol-1-yl, pyrrol-2-yl, or pyrrol-3-yl, furanyl, such as furan-2-yl, or furan-3-yl, thienyl, such as thien-2-yl, or thien-3-yl, pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, imidazolyl, such as imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol- 5-yl, oxazolyl, such as oxazol-2-yl, o
- pyridyl such as pyridin-2-yl, pyridin-3-yl, pyridin-3-yl
- pyrimidinyl such as pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazinyl and pyridaz- inyl.
- the 5- or 6-membered heteroaromatic rings R a contain one N atom as ring member (in 5-membered rings possibly also in the form of a group NR 9 ) and optionally one or two further heteroatoms as ring members selected from O, N and S, such as pyrrolyl, such as pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl, pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, imidazolyl, such as imidazol-1-yl, imidazol-2- yl, imidazol-4-yl, or imidazol-5-yl, oxazolyl, such as oxazol-2-yl, oxazol-4-yl, or oxazol- 5-yl, isoxazolyl, such as isoxazol-3-yl, iso
- the heteroaromatc ring R a is 5-membered.
- Preferred 5-membered heteroaromatc rings contain one N atom as ring member (possibly also in the form of a group NR 9 ) and optionally one or two further heteroatoms as ring members selected from O, N and S, e.g.
- pyrrolyl such as pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl
- pyrazolyl such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl
- imidazolyl such as imi- dazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl
- oxazolyl such as oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl
- isoxazolyl such as isoxazol-3-yl, isoxazol-4-yl, or isoxazol- 5-yl
- thiazolyl such as thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl
- isothiazolyl such as isothiazol-3-
- the 5- or 6-membered heteroaromatic ring R a is unsubstituted or carries one, two or three, preferably one, substituents selected from halogen, Ci-C 4 -alkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, fluorinated CrC 4 -alkoxy, Ci-C 4 -thioalkyl, fluori- nated CrC 4 -thioalkyl, and amino-C- ⁇ -C 2 -alkylene.
- substituents selected from halogen, Ci-C 4 -alkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, fluorinated CrC 4 -alkoxy, Ci-C 4 -thioalkyl, fluori- nated CrC 4 -thioalkyl, and amino-C- ⁇ -C 2 -alkylene.
- R a is selected from the group consisting of halogen, C 1 -C6- alkyl, Ci-C6-hydroxyalkyl, fluorinated CrC 4 -alkyl, Ci-C 4 -alkoxy, fluorinated C 1 -C 4 - alkoxy, C 2 -C 4 -alkenyl, fluorinated C 2 -C 4 -alkenyl, NR 6 R 7 , ONR 6 R 7 , C r C 6 -alkylene-NR 6 R 7 , where R 6 and R 7 are independently of each other H, C r C 4 -alkyl or or C r C 4 -alkoxy, ureido (NHCONH 2 ) C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 - cycloalkyl , acetyl, carboxyl, hydroxy, cyano, nitro, benzoxy, methylsulfanyl
- R a is selected from the group consisting of halogen, d-Ce-alkyl, fluorinated C r C 4 -alkyl, C r C 4 -alkoxy, OCF 3 , OCHF 2 , OCH 2 F, 2- fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy,
- R a has the formula R a
- Y is N, CH or CF
- R a1 and R a2 are independently of each other selected from Ci-C 2 -alkyl, in particular methyl, fluorinated CrC 2 -alkyl, in particular fluoromethyl, difluoromethyl or trifluoromethyl, provided for Y being CH or CF one of the radicals R a1 or R a2 may also be hydrogen or fluorine, or
- R a1 and R a2 form a radical (CH 2 ) m wherein 1 or 2 of the hydrogen atoms may be re- placed by fluorine and wherein m is 2, 3 or 4, in particular CH 2 -CH 2 , CHF-CH 2
- the radical of the aforementioned formula Ra may have either (R)- or (S)-configuration with regard to the Y-moiety.
- Examples for preferred radicals of the formula R a comprise isopropyl, (R)-i-fluoroethyl, (S)-i-fluoroethyl, 2-fluoroethyl, 1 ,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (R)-i-fluoropropyl, (S)-i-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1 ,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, cyclopropyl, cyclobutyl, 1- fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl and 2-fluorocyclopropyl.
- radicals of the formula R a those are preferred which carry 1 , 2, 3 or 4, in particular 1 , 2 or 3 fluorine atoms.
- Preferred examples for Ar are in particular the following: 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-sec-butylphenyl, 3-isobutylphenyl, 3-tert- butylphenyl, 3-(1 ,1-dimethylpropyl)-phenyl, 3-vinylphenyl, 3-isopropenylphenyl, 2- fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 3- (fluoromethyl)phenyl, 3-(difluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3,5- bis(trifluoromethyl)phenyl, 3-(1-fluoroethyl)-phenyl, 3-((S)-1-fluoroethyl)-phenyl, 3-((R)- 1-fluoroethy
- Particularly preferred compounds I are those of formulae l.a.1 , I. a.2, I. a.3, l.a.4, I. a.5, l.a.6, l.a.7, l.a.8, l.a.9, l.a.10, l.a.1 1 , l.a.12, l.a.13, l.a.14, l.a.15, l.a.16, l.b.1 , l.b.2, l.b.3, l.b.4, l.b.5, l.b.6, l.b.7, l.b.8, l.b.9, l.b.10, l.b.11 , l.b.12, l.b.13, l.b.14, l.b.15, l.b.16, l.c.1 , l.c.2, l.c.3, l.c.4,
- a and Ar G, n, R 2 , and R 4 are as defined above.
- D is a group of the for- mulaAorB'
- R' is either R 1 or is a precursor of R 1 .
- a suitable sulfonic acid derivative is e.g. the sulfonyl chloride Ar-SOaCI.
- the sulfonation reaction is preferably carried out in the presence of a base, according to standard procedures in the art. In the reaction depicted in the above scheme 1 , the sulfonation takes place under the reaction conditions which are customary for preparing arylsulfonamide compounds or arylsulfonic esters, respectively, and which are described, for example, in J.
- the reaction customarily takes place in an inert solvent, for example in an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, a halohydrocarbon, such as dichloro- methane, an aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and the like, or in a mixture of the abovementioned solvents.
- the reaction with Cl-S ⁇ 2 -Ar is customarily carried out in the presence of an auxiliary base.
- Suitable bases are inor- ganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogen- carbonate or potassium hydrogencarbonate, and organic bases, for example trial- kylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine and the like. The latter compounds can at the same time serve as solvents.
- the auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound (11-1 ).
- the radical NH 2 can be converted into a NR group, in which R 5 ' has the meanings different from hydrogen which are specified for R 5 (not shown in scheme 1 ). If in the resulting sulfonamide (l'-1 ) R' is not the desired radical R 1 but a precursor thereof, the compound can be modified as outlined below to obtain the desired sub- stituent R 1 .
- a precursor is a radical which can be easily removed and replaced by the desired group R 1 or which can be modified to give R 1 .
- the precursor can also be an N- protective group.
- the allyl group can be cleaved to obtain a compound wherein R' is hydrogen.
- triarylphosphines such as triphenylphosphine, trial- kylphosphines, such as tributylphosphine, and cycloalkylphosphines, such as tricyclo- hexylphosphine, and especially with phosphine chelate ligands, such as 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl or 1 ,4-bis(diphenylphosphino)butane, using methods known from the literature (with regard to eliminating N-allyl in the presence of mercaptobenzoic acid, see WO 94/24088; with regard to eliminating in the presence of 1 ,3-dimethylbarbituric acid, see J.
- phosphine chelate ligands such as 2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl or 1 ,4-bis(
- N-allyl can also be effected by reacting in the presence of rhodium compounds, such as tris(triphenylphosphine)chlororhodium(l), using methods known from the literature (see J. Chem. Soc, Perkin Transaction I: Organic and Bio-Organic Chemistry 1999 (21 ) pp. 3089-3104 and Tetrahedron Asymmetry 1997, 8(20), pp. 3387 - 3391 ).
- R' is benzyl
- this substituent may also be cleaved to obtain a compund (l'-1 ) wherein R' is H.
- the reaction conditions for the cleavage are known in the art.
- the benzyl group is removed by a hydrogenation reaction in the presence of a suitable Pd catalyst, such as Pd on carbon or palladium hydroxide.
- R' can also be a protective group.
- the protective group may be removed to yield a compund (l'-1 ) wherein R' is H.
- Suitable protective groups are known in the art and are, for example, selected from tert-butoxycarbonyl (boc), benzyloxycarbonyl (Cbz), 9- fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt) and nitrobenzenesulfenyl (Nps).
- a preferred protective group is boc.
- the protective groups can be removed by known methods, such as treatment of the protected amine with an acid, e.g halogen acid, such as HCI or HBr, or trifluoroacetic acid, or by hydrogenation, optionally in the pres- ence of a Pd catalyst.
- an acid e.g halogen acid, such as HCI or HBr, or trifluoroacetic acid
- the resulting compound, wherein R' is H can then be reacted, in a known manner, in the sense of an alkylation, with a compound R 1 -X.
- R 1 is CrC 4 -alkyl, C 3 -C 6 -cycloalkyl, CrC 4 -haloalkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl or C 3 -C 6 -cycloalkyl-Ci-C 4 - alkyl and X is a nucleophilically displaceable leaving group, e.g. halogen, trifluoroace- tate, alkylsulfonate, arylsulfonate, alkyl sulfate and the like.
- the reaction conditions which are required for the alkylation have been adequately disclosed, e.g. in Bioorganic and Medicinal Chemistry Lett. 2002, 12(7), pp. 2443-2446 and also 2002, 12(5), pp. 1917-1919.
- a borohydride such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
- the resulting sufonamide (l'-1 ) can further be reacted with an acyl halide to obtain a compound of the formula I wherein R 1 is CrC 3 -alkylcarbonyl.
- the carbonyl group in these compounds can be reduced with diborane to obtain compounds of the general formula I, wherein R 1 is C 2 -C 4 -alkyl.
- the carbonyl group can also be reacted with a fluorinating agent to obtain a compound I wherein R 1 is 1 ,1- difluoroalkyl.
- Acylation and reduction can be achieved by standard methods, which are discussed in Jerry March, Advanced Organic Chemistry, 3rd ed. J.
- the bromo substituted compound (II-2) is reacted with an appropriate sulfonamide ArSOaNHR 5 to give the sulfonamide (l'-1 ).
- the reaction is generally carried out under activating conditions, e.g. under microwave conditions.
- Pd, especially Pd(O), or Cu catalysts may also be used for coupling (see, e.g. Org. Lett. 2000, 2, 1101 ; J.
- Pd (0) catalysts are tetrakis(triphenylphosphine)- palladium(O) and Pd 2 (dba) 3 (tris(dibenzylideneacetone) -dipalladium(O)), which are customarily used in the presence of a tri(substituted)phosphine, e.g.
- triarylphosphine such as triphenylphosphine, tritolylphosphine or xantphos, tri(cyclo)alkylphosphine such as tris-n-butylphosphine, tris(tert.-butyl)phosphine or tris(cyclohexylphosphine).
- This route is especially useful in cases where the corresponding sulfonyl chloride is not available.
- the bromo substituent may be replaced by an amino substituent, e.g. by reacting with a benzophenone imine or with lithium bis(trimethylsilyl)amide in the presence of a palladium(O) compound such as tris(dibenzylideneacetone)dipalladium(0) in the presence of a tri(substituted)phosphine, e.g.
- a triarylphosphine such as triphenyl- phosphine or tritolylphosphine, tri(cyclo)alkylphosphine such as tris-n-butylphosphine, tris(tert.-butyl)phosphine or tris(cyclohexylphosphine), preferably in the presence of a base such as sodium hydride according to the method described in, e.g., J. Org. Chem., 68 (2993) pp 8274-8276, or J. Org. Chem. 2000, 65, 2612.
- the resulting amino compound may then be subjected to the sulfonation reaction of route A.
- compound (II-3) is reacted with a mercapto compound HS-Ar in the presence of a base, such as sodium hydride or sodium alkoxide or with an alkali metal salt thereof thereby yielding a thioether compound.
- a base such as sodium hydride or sodium alkoxide or with an alkali metal salt thereof thereby yielding a thioether compound.
- the thioether moiety is then oxidized to a sulfone moiety, e.g. by oxone, to yield the sulfone (l'-2).
- the substituent Ar can be varied by either using different sulfonyl chlorides or by modifying the substituents of the group Ar after the formation of the sulfonamide (l'-1 ) or the sulfone (l'-2) by known methods.
- a bromine substituent of the Ar group may be replaced by an N-bound pyrrolidinyl group according to the procedure described in Tetrahedron Asym. 1999, 10, 1831.
- This Pd-mediated coupling is generally applicable to all nitrogen-containing heterocycles such as azetidinyl, pyrazolidinyl, imi- dazolidinyl, piperidinyl, piperazinyl, morpholinyl and the like.
- the reaction is also appli- cabel to heterocyclic compounds carrying one or more substituents such as halogen, alkyl or fluorinated alkyl.
- a bromine substituent of the Ar group may further be replaced by an isopropenyl group according to a Stille coupling where the bromo compound is reacted with an alkenyl tributyl stannate in the presence of an appropriate Pd coupling catalyst, e.g. tetrakistriphenylphosphine palladium(O) (see, e.g. Tetrahedron, 2003, 59(34), 6545 and Bioorg. Med. Chem. 1999, 7(5), 665).
- the isopropenyl group may then be converted into the isopropyl group by known hydrogenation methods.
- the conversion of the acid (III) into its methyl ester (IV) is performed by standard techniques, e.g. as described in Jerry March, Advanced Organic Chemistry, John Wiley, 3 rd edition, page 348ff.
- the acid is transformed into the corresponding acid chloride, e.g by reacting it with SOCb.
- the chloride is then converted into the ester by reaction with methanol.
- step (ii) is suitably carried out under standard conditions for the conversion of carboxylic esters into alcohols.
- Appropriate reaction conditions and reducing agents are described, e.g. in Jerry March, Advanced Organic Chemistry, John Wiley, 3 rd edition, page1093ff.
- Typical reducing agents are metal hydrides and complex hy- drides.
- suitable metal hydrides include BH 3 , 9-BBN, AIH 3 and AIH(i-Bu) 2 (DIBAL-H), suitably in the presence of complexing solvents, such as tetrahydrofuran and diethylether.
- Complex hydrides are e.g.
- LiAIH 4 NaBH 4 , LiAIH 4 and LiAIH(OR) 3 , where R is Ci-C 4 -alkyl, such as methyl, ethyl, isobutyl or tert-butyl.
- a preferred reducing agent is LiAIH 4 .
- the reduction is suitably carried out in complexing solvents, such as open- chain and cyclic ethers, e.g. tetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether and methylbutyl ether.
- a preferred solvent is tetrahydrofuran.
- the alcohol functionality is converted into a better leaving group.
- the mesylation is performed under standard conditions, e.g. by reacting the alcohol with methansulfonyl chloride in the presence of a base.
- Suitable bases are, among others, alkyl amines, such as diethyl amine, triethyl amine and ethyldiisopropyl amine.
- other functionalties representing good leaving groups such as trifluoroacetate, other alkylsulfonates, arylsulfonates, e.g. tosylates, alkyl sulfates and the like tosylate, may be introduced instead of the methansulfonyl group.
- compound (Vl) or a suitable derivative thereof is reacted with a primary amine NH 2 R'.
- the primary amine is a liquid, it may also be used as solvent, no further solvent being necessary. If the amine is visquous or a solid, the reaction is advantageously carried out in a suitable solvent.
- step (v) takes place under the reaction conditions which are customary for a nitration reaction on an aromatic radical and which are described, for example, in Jerry March, Advanced Organic Chemistry, John Wiley, 3 rd edition, page 468ff, Tetrahedron 1999, 55(33), pp. 10243-10252, J. Med. Chem. 1997, 40(22), pp. 3679-3686 and Synthetic Communications, 1993, 23(5), pp. 591-599.
- compound (VII) is reacted with concentrated nitric acid or a nitrate, such as potassium or sodium nitrate, in the presence of concentrated sulfuric acid.
- the resulting product (VIII) may in the form of different regioisomers (e.g.
- step (vi) the nitro group in (VIII) is reduced to an NH 2 group. Subsequently, the NH 2 group can be converted into a -NR 5' group, in which R 5' has the meanings different from hydrogen which are specified for R 5 .
- the reaction conditions which are required for step (vi) correspond to the customary conditions for reducing aromatic nitro groups which have been described extensively in the literature (see, for example, J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New-York, 1985, p. 1 183 and the literature cited in this reference).
- the reduction is achieved, for example, by react- ing the nitro compound VII with a metal such as iron, zinc or tin under acidic reaction conditions, i.e. using nascent hydrogen, or using a complex hydride such as lithium aluminum hydride or sodium borohydride, preferably in the presence of transition metal compounds of nickel or cobalt such as NiCI 2 (P(phenyl) 3 ) 2 , or CoCI 2 , (see Ono et al. Chem. Ind. (London), 1983 p.480), or using NaBH 2 Ss (see Lalancette et al. Can. J. Chem. 49, 1971 , p.
- the reduction can be carried out with hydrogen in the presence of a transition metal catalyst, e.g. using hydrogen in the presence of catalysts based on platinum, palladium, nickel, ruthenium or rhodium.
- the catalysts can contain the transition metal in elemental form or in the form of a complex compound, of a salt or of an oxide of the transition metal, with it being possible, for the purpose of modifying the activity, to use customary coli- gands, e.g.
- organic phosphine compounds such as triphenylphosphine, tricyclohexyl- phosphine or tri-n-butylphosphines or phosphites.
- the catalyst is customarily employed in quantities of from 0.001 to 1 mol per mol of nitro compound, calculated as catalyst metal.
- the reduction is effected using tin(ll) chloride in analogy with the methods described in Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21 ), pp. 4679-4688.
- the reaction of VII with tin(ll) chloride is preferably carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, isopropanol or butanol.
- the synthesis of these compounds also belongs to standard reaction methods and can be performed by monohalogenating the methyl group of a methyl-substituted pyridyl compound.
- enantiomerically pure compounds (I) can also be obtained by applying standard resolution techniques to suitable precursors thereof.
- compound VIII see scheme 2 above
- compounds (M-2) or (M- 3) see scheme 1 above
- R' is a suitable protective group, such as benzyl
- tartric acid or a derivative thereof e.g. diethyltartrate, dipropyltar- trate, diisopropyltartrate, etc.
- Suitable bases are, e.g., alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide, alkaline earth metal hydroxides, such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates, such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates, such as magnesium carbonate and calcium carbonate, alkali metal oxides such as sodium oxide and potassium oxide, and alkaline earth metal oxides, such as magnesium oxide and calcium oxide; organice bases, such as alkoholates, e.g.
- sodium methanolate, sodium ethanolate or sodium- tert-butanolate such as dimethylamine, trimethylamine, diethylamine, triethyl- amine, dipropylamine, tripropylamine, diisopropylamine, diisopropylethylamine and the like, and nitrogen-containing basic heterocyclic compounds, such as pyridine, picoline und lutidine.
- amines such as dimethylamine, trimethylamine, diethylamine, triethyl- amine, dipropylamine, tripropylamine, diisopropylamine, diisopropylethylamine and the like
- nitrogen-containing basic heterocyclic compounds such as pyridine, picoline und lutidine.
- a and R 3 are as defined above.
- IX alkenylpyridine derivative
- the precursor of the ylid, the amine N(CH 2 R 15 KCH 2 SiMe 3 )(CH 2 OCH 3 ) (X) is commercially available or can be synthesized from NH 2 (CH 2 R b ), Me 3 SiCH 2 CI and HCHO in the presence of methanol.
- the alkenylpyridine compound (IX) can be synthesized e.g. by a Stille coupling of a halogeno pyridine, e.g. a bromo pyridine (2-, 3- or 4-bromo pyridine), with the corresponding alkenyl tributyl stannate, such as vinyl or isobutenyl tributyl stannate, in the presence of an appropriate Pd coupling catalyst, e.g. tetrakistriphenylphosphine palla- dium(O) (see, e.g. Tetrahedron, 2003, 59(34), 6545 and Bioorg. Med. Chem. 1999, 7(5), 665).
- a halogeno pyridine e.g. a bromo pyridine (2-, 3- or 4-bromo pyridine
- an appropriate Pd coupling catalyst e.g. tetrakistriphenylphosphine palla- dium(O)
- the corresponding cis- or trans alkyl pyridyl pyrrolidine can be prepared selectively.
- Conditions for the Wittig reaction are well known in the art and are, e.g. discussed in Jerry March, Advanced Organic Chemistry, John Wiley, 3 rd edition, page 845 ff.
- a 2-alkenyl pyridine is preferably substituted by X in the 4- or 6-position
- a 3-alkenyl pyridine is preferably substituted by X in the 3-position
- a 4-alkenyl pyridine is pref- erably substituted by X in the 2-position.
- the subsequent reaction steps can be carried out as outlined in route A or B.
- the A ring may be first nitrated as described in scheme 2, step (v) and then subjected to the reaction of scheme 2, step (vi) and scheme 1 , route A; or ring A may be halogenated and then subjected to the procedure of route B.
- the group CH 2 R b of the precursor amine advantageously corresponds either to the desired group R 1 of the final compound I or is alternatively a cleavable group, such as benzyl, which can be removed to give the N-unsubstituted pyrrolidine.
- the latter can subsequently be functionalized as described above (see route A).
- Pyridylpyrrolidines can also be prepared by a [3+2] dipolar cycloaddition of a non- stabilized azomethine ylid to a 1-alkynylbenzene (XII) (in analogy to, e.g., Tetrahedron 1996, 52, 59).
- XIII non- stabilized azomethine ylid to a 1-alkynylbenzene
- T 1-alkynylbenzene
- the resulting pyrroline (XIII) or the final product (T) is then hydrogenated to the corresponding pyrrolidine (Xl).
- the hydrogenation is carried out under chiral conditions, e.g. by using chiral catalysts, the enantiomerically pure pyridylpyrrolidine compounds can be obtained.
- Chiral hydrogenation catalysts are well known in the art.
- the subsequent conversion to the desired sulfonamide can be carried out as described in route A or B.
- pyridyl pyrrolidinyl compounds can be prepared from pyridyl halides which are subjected to a Pd-mediated cross coupling with an organozinc pyrrolidine compound. This process is described in further detail below in route F.
- the pyridyl halide advantageously carries a nitro group.
- the conversion to the desired sulfonamides can be carried out as described in route A.
- the pyridyl halide carries a halogen atom. In this case, the conversion to the desired sulfonamides can be achieved as described in route B.
- the pyridyl pyrrolidine may be prepared by way of a Heck reaction where a protected pyrroline is reacted with the desired pyridine (e.g. 2-iodo-4-nitropyridine 2-iodo-6- nitropyridine or 3-iodo-5-nitropyridine) under typical Heck conditions.
- a protected pyrroline is reacted with the desired pyridine (e.g. 2-iodo-4-nitropyridine 2-iodo-6- nitropyridine or 3-iodo-5-nitropyridine) under typical Heck conditions.
- Catalytic hydrogenation of the pyrroline double bond and reduction of the nitro group according to the procedure described in scheme 2 yields the desired product.
- the N-protected pyrroline can be obtained by reacting commercially available pyrroline with the desired protective group, e.g. with chloromethylfumarate, benzylchloride, Cbz- anhydride or Boc-anhydride.
- the pyrroline may be synthesized in a metathesis reaction of N-protected diallylamine in the presence of a metathesis catalyst, e.g. a Grubbs catalyst. 5.1.5
- the pyridyl pyrrolidine may further be prepared by reacting N-protected 3- oxopyrrolidine with a metallated nitropyridine, dehydrating the resulting alcohol and hydrogenating the double bond of the pyrroline ring.
- the metallated nitropyridine may be obtained by reacting a halonitropyridine, e.g. 2-bromo-4-nitropyridine or 4-bromo-2- nitropyridine or 3-bromo-5-nitropyridine, with MgBr 2 or preferably with n-butyllithium under standard conditions for Grignard reactions or lithiations.
- the N-protected 3- oxopyrrolidine can be obtained by reacting commercially available 3-oxopyrrolidine with the desired protective group, e.g. with chloromethylfumarate, benzylchloride, allyl chloride, Cbz-anhydride or Boc-anhydride.
- Ar and R 1 are as defined above.
- X and Y are, independently of each other, CH or N.
- a 2- halo-halo-ring there is also the possibility to realize the direct coupling between the aryl-azetidine halide and the appropriate sulfonamides (Org. Lett. 2000, 2, 1 101-1 104; J. Am. Chem. Soc. 2002, 124, 6043-6048; Org. Lett. 2003, 5, 4373-4376; Tetrahedron Lett. 2003, 44, 3385-3386).
- the amine may be regenerated by cleavage of the carbamate (e.g. with trifluoroacetic acid in the case of a Boc carbamate) and subsequently converted into an amide by reaction with the appropriate acyl chloride.
- the nitro group can be reduced to the amine via tin chloride or catalytic hydrogenation (e.g. Pd-C) and then converted to the desired sulfonamide by reaction with the appropriate sulfonyl chloride in the presence of a base such as pyridine. Ultimate reduction of the amide via hydroboration furnishes the final compounds.
- catalytic hydrogenation e.g. Pd-C
- reaction also applies to compounds wherein the (hetero)aromatic ring bound to the azetidine group is a 5-membered heterocyclic radical, e.g. thienyl.
- compounds I, wherein n is 2 and E is NR 5 may be prepared by starting from commercially available 3-aryl or 3-hetaryl piperidines. These starting compounds may then be converted into the amino-substituted or halogenated derivative and then be subjected to the synthetic path of route A or B.
- Piperazinyl pyridine compounds I can be prepared by Pd-mediated coupling of a N- monoprotected piperazine to a halonitropyridine, e.g. to 3-bromo-5-nitropyridine, 3- bromo-2-methoxy-5-nitropyridine, 2-bromo-4-nitropyridine, 4-bromo-2-nitropyridine, or 4-bromo-5-methoxy-2-nitropyridine, to give the corresponding piperazinyl-substituted nitropyridine, reduction of the nitro group and sulfonation according to the above scheme A.
- a halonitropyridine e.g. to 3-bromo-5-nitropyridine, 3- bromo-2-methoxy-5-nitropyridine, 2-bromo-4-nitropyridine, 4-bromo-2-nitropyridine, or 4-bromo-5-methoxy-2-nitropyridine
- Suitable N-protective groups are those mentioned above.
- N-bound radicals R a can be introduced into compounds of the formula I by reacting the corresponding halogen compound, i.e. a compound of the formula I, which instead of R a carries a halogen atom, in particular a bromine or iodine atom, with a primary or secondary amine in the presence of a base, preferably also in the presence of a palladium catalyst in terms of a Buchwald-Hartwig reaction.
- the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed.
- the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001 , 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002.
- the sulfonylchlorides CI-SO 2 -Ar are either commercially available or can be prepared according to standard synthetic methods.
- Sulfonylchlorides containing a fluorinated radical R a may be prepared by different synthetic routes, e.g. by reacting suitable hydroxy or oxo precursor (e.g.
- a compound CI-SO 2 -Ar carrying a hydroxy or oxo substituted radical
- fluorinating reagents like DAST (diethylaminosulfurtrifluoride), mor- pholine-DAST, deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride), Ishikawa's reagent (N,N-diethyl-(1 ,1 ,2,3,3,3-hexafluoropropyl)amine; Journal of Fluorine Chemistry, 1989, 43, 371-377).
- Sulfonylchlorides may also be prepared by diazotation of suitable amine precursor Ar-NH 2 with sodium nitrite under acidic conditions and reaction with sulfur dioxide in acetic acid (scheme (iii); J.
- the 4-(1 ,1-difluoropropan-2-yl)benzene-1 -sulfonyl chloride intermediate can be prepared from the commercially available 2-phenylpropanoic acid.
- the 2- phenylpropanic acid is converted to the alkyl ester by esterification with an alcohol (e.g. methanol or ethanol) under acid catalysis (e.g. HCI , SO 2 CI 2 ).
- the ester can be reduced to the corresponding 2-phenyl propanal by a reducing agent such as DIBAL (diisobutylaluminium hydride).
- the aldehyde is converted to the 1 ,1-difluoro-2-propyl derivative by reaction with a suitable fluorinating reagent like DAST (diethylaminosul- furtrifluoride), morpholine-DAST, deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride), Ishikawa's reagent (N,N-diethyl-(1 ,1 ,2,3,3,3-hexafluoropropyl)amine; Journal of Fluorine Chemistry, 1989, 43, 371-377) (step b).
- a suitable fluorinating reagent like DAST (diethylaminosul- furtrifluoride), morpholine-DAST, deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride), Ishikawa's reagent (N,N-diethyl-(1 ,1 ,2,3,3,3-he
- the thus obtained 1 ,1-difluoro- 2-phenylpropane can be converted into 4-(1 ,1-difluoro-2-propyl)benzenesulfonyl chloride by either direct chlorosulfonylation with chlorosulfonic acid (Heterocycles, 2001 , 55, 9, 1789-1803; J. Org. Chem., 2000, 65, 1399-1406) (step c) or by a two step process preparing first the sulfonic acid derivatives (step d) which are then transformed to the sulfonylchlorides (step e) by reaction with e.g. chlorosulfonic acid, phosphorous pentachloride (Eur. J. Med.
- 4-(1 , 1 ,1 -T rifluoropropan-2-yl)benzene-1 -sulfonyl chloride intermediate can be prepared from the commercially available 2,2,2-trifluoro-1-phenylethanone by a synthetic route shown in scheme 7.
- the ketone can be converted to the 3,3,3-trifluoro-2- phenylpropene by a Wittig reaction with a suitable ylide such as methylene- triphenylphosphane (prepared by reaction of methyltriphenylphosphonium halide and a suitable base such as lithium diisopropylamide or potassium tert-butoxide) or according to a Horner-Emmons reaction by reacting the ketone with a suitable phosphonate such as diethyl methylphosphonate and a suitable suitable base such as lithium diisopropylamide or potassium tert-butoxide.
- a suitable ylide such as methylene- triphenylphosphane (prepared by reaction of methyltriphenylphosphonium halide and a suitable base such as lithium diisopropylamide or potassium tert-butoxide)
- a suitable phosphonate such as diethyl methylphosphonate
- a suitable suitable base
- scheme 7 can also be performed using a chiral catalyst for the alkene hydrogenation to allow the preparation of the corresponding chiral 4-(1 ,1 ,1- triifluoropropan-2-yl)benzene-1 -sulfonyl chlorides.
- the 4-(1 ,1 ,1-trifluoropropan-2-yl)benzene-1-sulfonyl chloride can be also prepared from the commercially available 1-phenyl-ethanone by a four step procedure as shown in scheme 8.
- the ketone can be converted to the trifluoromethyl hydroxyl intermediate by reaction with trimethyl-trifluoromethyl-silane (Journal of Organic Chemistry, 2000, 65, 8848-8856; Journal of Fluorine Chemistry, 2003, 122, 243-246) which can then be converted to the trifluoromethyl bromide (Journal of the American Chemical Society, 1987, 109, 2435-4).
- Dehalogenation by catalytic hydrogenation eg Pd-C
- Pd-C catalytic hydrogenation
- solvents which can be used are ethers, such as diethyl ether, diisopropyl ether, methyl terf-butyl ether or tetrahydrofuran, aprotic polar solvent, such as dimethyl- formamide, dimethyl sulfoxide, dimethoxyethane, and acetonitrile, aromatic hydrocar- bons, such as toluene and xylene, ketones, such as acetone or methyl ethyl ketone, halohydrocarbons, such as dichloromethane, trichloromethane and dichloroethane, esters, such as ethyl acetate and methyl butyrate, carboxylic acids, such as acetic acid or propionic acid, and alcohols, such as methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, 2-butanol and tert.-butan
- Suitable bases include inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and, in addition, alkoxides, such as sodium methoxide or sodium ethoxide, alkali metal hydrides, such as sodium hydride, and also organometallic compounds, such as butyllithium compounds or alkylmagnesium compounds, or organic nitrogen bases, such as triethylamine or pyridine.
- alkoxides such as sodium methoxide or sodium ethoxide
- alkali metal hydrides such as sodium hydride
- organometallic compounds such as butyllithium compounds or alkylmagnesium compounds
- organic nitrogen bases such as triethylamine or pyridine.
- the crude product is isolated in a customary manner, for example by filtering, distilling off the solvent or extracting from the reaction mixture, etc.
- the resulting compounds can be purified in a customary manner, for example by means of recrystallizing from a solvent, by means of chromatography or by means of converting into an acid addition salt.
- the acid addition salts of compounds I are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl terf-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
- an organic solvent for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl terf-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
- the compounds according to the invention of the formula I have a surprisingly high affinity for 5HT 6 receptors.
- Compounds of formula I are furthermore highly selective dopamine 5HT 6 receptor ligands which, because of their low affinity for other receptors such as D 1 receptors, D 5 receptors, D 4 receptors, ⁇ 1 -adrenergic and/or ⁇ 2-adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors and, in particu- lar, dopamine D 2 receptors, give rise to fewer side-effects than other, less selective 5HT 6 ligands.
- Some compounds of formula I show a high affinity for 5HT 6 receptors and optionally also for dopamine D 3 receptors.
- D 1 receptors D 5 receptors, D 4 receptors, ⁇ 1 -adrenergic and/or ⁇ 2- adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors and, in particular, dopamine D 2 receptors
- D 1 receptors D 5 receptors
- D 4 receptors ⁇ 1 -adrenergic and/or ⁇ 2- adrenergic receptors
- muscarinic receptors histamine receptors
- opiate receptors opiate receptors
- dopamine D 2 receptors dopamine D 2 receptors
- the compound of the invention can be a dopamine 5HT 6 receptor agonist, including partial agonistic activity, or a dopamine 5HT 6 receptor antagonist, including inverse agonist activity.
- the high affinity of the compounds according to the invention for 5HT 6 receptors is reflected in very low in-vitro receptor binding constants (K,(5HT 6 ) values) of as a rule less than 50 nM (nmol/l), preferably of less than 10 nM and, in particular of less than 5 nM.
- K,(5HT 6 ) values very low in-vitro receptor binding constants
- the displacement of 3 H-LSD can, for example, be used in receptor binding studies for determining binding affinities to 5-HT 6 receptors and [ 125 l]-iodosulpride for determining binding affinities to dopamine D 3 receptors.
- (D 3 ) of the receptor binding constants, is as a rule at least 25, preferably at least 50, even better at least 100.
- the displacement of [ 3 H]SCH23390 or [ 125 I] spiperone can be used, for example, for carrying out receptor binding studies on D 1 , D 2 and D 4 receptors.
- the compounds can be used for treating diseases which respond to 5HT 6 receptor ligands and optionally to dopamine D 3 receptor ligands (or which are susceptible to treatment with a 5HT 6 receptor ligand, and optionally with a dopamine D 3 receptor ligand), i.e. they are effective for treating those medical disor- ders or diseases in which exerting an influence on (modulating) the 5HT 6 receptors, and optionally on (modulating) the dopamine D 3 receptors, leads to an improvement in the clinical picture or to the disease being cured.
- diseases are disorders or diseases of the central nervous system.
- disorders or diseases of the central nervous system are understood as meaning disorders which affect the spinal chord and, in particular, the brain.
- disorder denotes disturbances and/or anomalies which are as a rule regarded as being pathological conditions or functions and which can manifest themselves in the form of particular signs, symptoms and/or malfunctions.
- treatment according to the invention can be directed toward individual disorders, i.e. anomalies or pathological conditions, it is also possible for several anomalies, which may be causatively linked to each other, to be combined into patterns, i.e. syndromes, which can be treated in accordance with the invention.
- the disorders which can be treated in accordance with the invention are in particular disorders which respond to a modulation of the 5HT 6 receptor They include cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowl Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, drug addiction and obesity.
- cognitive dysfunctions such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia
- the addiction diseases include psychic disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, such as pharmaceuticals or nar- cotics, and also other addiction diseases, such as addiction to gaming (impulse control disorders not elsewhere classified).
- addictive substances are: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics and tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine- like substances such as methylphenidate and other stimulants including caffeine.
- Addictive substances which come particularly into consideration are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.
- Compounds of formula I having a high affinity for the 5HT 6 receptor as well as for the dopamine D 3 receptor can be advantageously used for treating disorders, in particular CNS disorders, having both a dopaminergic and a serotoninergic impact. While the 5HT 6 receptor is more related to cognitive functions, the dopamine D 3 receptor is associated with positive symptoms, such as delusion, hallucination, disorganized thinking, disorganized speaking, disorganized, agitated or catatonic behaviour, and negative symptoms, such as depletion of feelings, impairment of the language, loss of motivation, loss of vitality, attention deficits and social retreat.
- positive symptoms such as delusion, hallucination, disorganized thinking, disorganized speaking, disorganized, agitated or catatonic behaviour
- negative symptoms such as depletion of feelings, impairment of the language, loss of motivation, loss of vitality, attention deficits and social retreat.
- compounds of formula I having a high affinity for the 5HT 6 receptor as well as for the dopamine D 3 receptor can be advantageously used for treating disorders, such as Alzheimer's disease and in particular schizophrenia, which are characterized by cognitive dysfunctions as well as by positive and negative symptoms.
- the compounds according to the invention are suitable for treating disorders whose causes can at least partially be attributed to an anomalous activity of 5HT 6 receptors.
- the treatment is directed, in par- ticular, toward those disorders which can be influenced, within the sense of an expedient medicinal treatment, by the binding of preferably exogeneously administered binding partners (ligands) to 5HT 6 receptors.
- ligands binding partners
- the diseases which can be treated with the compounds according to the invention are frequently characterized by progressive development, i.e. the above-described conditions change over the course of time; as a rule, the severity increases and conditions may possibly merge into each other or other conditions may appear in addition to those which already exist.
- the compounds according to the invention can be used to treat a large number of signs, symptoms and/or malfunctions which are connected with the disorders of the central nervous system and, in particular, the abovementioned conditions.
- signs, symptoms and/or malfunctions include, for example, a disturbed relationship to reality, lack of insight and ability to meet customary social norms or the demands made by life, changes in temperament, changes in individual drives, such as hunger, sleep, thirst, etc., and in mood, disturbances in the ability to observe and combine, changes in personality, in particular emotional lability, hallucinations, ego-disturbances, distracted- ness, ambivalence, autism, depersonalization and false perceptions, delusional ideas, chanting speech, lack of synkinesia, short-step gait, flexed posture of trunk and limbs, tremor, poverty of facial expression, monotonous speech, depressions, apathy, impeded spontaneity and decisiveness, impoverished association ability, anxiety, nervous agitation, stammering, social phobia, panic disturbances, withdrawal symptoms in association with dependency, maniform syndromes, states of excitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g.
- Huntington's chorea and Gilles- de-la-Tourette's syndrome vertigo syndromes, e.g. peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria and the like.
- a treatment also includes a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
- the treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.
- the compounds according to the invention are preferentially suitable for treating diseases of the central nervous system, more preferably for treating cognitive dysfunctions and in particular, for treating cognitive dysfunctions associated with schizophrenia or Alzheimer's disease.
- the use according to the invention of the described compounds involves a method.
- an effective quantity of one or more compounds is administered to the individual to be treated, preferably a mammal, in par- ticular a human being, productive animal or domestic animal.
- Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
- the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound-containing preparations such that a daily dose of preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case of oral administration, or of from about 0.1 to 100 mg/kg of bodyweight, in the case of parenteral administration, is supplied to an individual to be treated.
- the invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being, productive animal or domestic animal.
- the ligands are customarily administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient together with at least one compound according to the invention and, where appropriate, other active compounds.
- These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.
- suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar- coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops.
- Implanted release devices can also be used for administering inhibitors according to the invention.
- liposomes or microspheres can also be used for administering inhibitors according to the invention.
- the compounds according to the invention are optionally mixed or diluted with one or more excipients.
- Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
- the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hy- drocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; steri- lants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disinte- grants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticiz- ers and white
- a formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, HP., Lexikon der Hilfsstoffe fur Pharmazie, Kos- metik und angrenzende füre [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
- disorders having both a dopaminergic and a serotoniner- gic impact can also be treated by the combined use of a dopamine D 3 receptor ligand and a 5HT 6 receptor ligand. This combination surprisingly shows no adverse effects.
- a further aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound having an affinity for the dopamine D 3 receptor and at least one compound having an affinity for the 5HT 6 receptor and optionally at least one physiologically acceptable carrier and/or auxiliary substance.
- the invention also relates to the use of at least one compound having an affinity for the dopamine D 3 receptor together with at least one compound having an affinity for the 5HT 6 receptor or of the pharmaceutical composition as defined above for preparing a medicament for the treatment of a disease of the central nervous system.
- the compounds to be used according to the invention or in the above composition having an affinity for the dopamine D 3 receptor preferably have no or no significant activity for the 5HT 6 receptors and vice versa.
- the compound having an affinity for the dopamine D 3 receptor has a binding constant K 1 to the dopamine D 3 receptor of at most 150 nM and the compound having an affinity for the 5HT 6 receptor has a binding constant K, to the 5HT 6 receptor of at most 150 nM.
- the compound having an affinity for the dopamine D 3 receptor has a selectivity for the D 3 dopamine receptor versus the 5HT 6 receptor K,(5HT 6 )/K,(D 3 ) of at least 10, more preferably at least 25, and in particular at least 50 and the compound having an affinity for the 5HT 6 dopamine receptor has a selectivity for the 5HT 6 receptor versus the dopamine D 3 re- ceptor K
- WO 2006/058753 WO 2006/040176, WO 2006/040177, WO 2006/040178, WO 2006/040179, WO 2006/0040180, WO 2006/008592, WO 2006/015842, WO 2005/058328, WO 2004/89905, WO 2004/108706, WO 2004/080981 , WO 2004/069830, WO 01/72306, WO 00/67847, WO 00/42038, WO 99/09015, WO 99/02503, WO 97/25324, WO 96/002519, the contents of which are hereby fully incor- porated by reference.
- Preferred compounds having an affinity for the dopamine D 3 receptor are dopamine D 3 receptor antagonists.
- Preferred compounds having an affinity for the dopamine 5HT 6 receptor are dopamine 5HT 6 receptor antagonists.
- compounds having an affinity for the dopamine 5HT 6 receptor are the compounds of the formula I of the present invention. More preferred compounds are compounds I mentioned above as preferred.
- the combination of compound having an affinity for the dopamine D 3 receptor and at least one compound having an affinity for the 5HT 6 receptor does not have any adverse effects. This can be proved by the assay (microdialysis study) described in the examples. In particular, the binding affinity to the one or other receptor is not reduced.
- the compounds were either characterized via proton-NMR in d 6 -dimethylsulfoxid or d- chloroform, if not stated otherwise, on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradi- ent on C18-material (electrospray-ionisation (ESI) mode), or melting point.
- ESI electrospray-ionisation
- the magnetic nuclear resonance spectral properties refer to the chemical shifts ( ⁇ ) expressed in parts per million (ppm).
- the relative area of the shifts in the 1 H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule.
- the nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).
- This sec- ond solution was added after cooling to room temperature to the first solution.
- the mixture was heated in a microwave instrument (CEM) at 150°C for 1 h. After evaporation of the solvent under reduced pressure the mixture was diluted with 50 ml of water and was extracted with 25 ml of ethyl acetate. The combined organic layers were extracted with aqueous HCI solution. The pH of the aqueous solution was adjusted to pH 9 with aqueous NaOH. After extraction with ethyl acetate, the combined organic phases were dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The so obtained oil was purified via silica gel chromatography with cyclohex- ane/ethyl acetate (3:7) as eluent, yielding 100 mg of the product.
- Tablets of the following composition are pressed on a tablet press in the customary manner:
- the core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of 60:40 vinylpyrrolidone/vinyl acetate copolymer.
- the saccharification composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc.
- the sugar-coated tablets which had been prepared in this way are subsequently provided with a gastric juice-resistant coating.
- the substance to be tested was either dissolved in methanol/Chremophor® (BASF- AG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.
- the compounds were dissolved in a concentration of 10 "2 M or 10 "3 M in DMSO. Further dilutions were performed in incubation buffer.
- the procedure for the binding assay was based on the method of Monsma et al. (1993) MoI Pharmacol 43: 320-327.
- the binding reaction was carried out in a total volume of 0.250 ml for 60 min at 37°C.
- Membranes from HEK-293 cells stably expressing the human 5-HT6 receptor were incubated with 2 nM 3 H-LSD in the presence or absence of various concentrations of test compound for 60 min at 37 C.
- Non-specific binding was defined with 100 ⁇ M Serotonin (5-HT).
- Assays were performed in duplicate. Bound and free radioligand was separated by filtration and bound radioactivity determined by liquid scintillation counting.
- the specific ligand binding to the receptors was defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled 5-HT. The results are expressed as a percent of control specific binding obtained in the presence of compound.
- the IC 50 values concentration causing a half- maximal inhibition of control specific binding
- Hill coefficients ⁇ nH were determined by non-linear regression analysis of the competition curves using Hill equation curve fitting.
- Membranes of human HeIa cells stably expressing human 5-HT6 receptors were incubated for 20 min at 37 0 C in HBSS, 1 mM MgCI2, 1 mM CaCI2, 100 MM IBMX, pH 7.4 in the presence and absence of test compounds.
- agonistic effect compounds were incubated alone.
- antagonistic effects inhibition of 0.3 ⁇ M serotonin ( ⁇ -HT)-induced cAMP increase was determined.
- the assay mixture (0.250 ml) was composed of membranes derived from ⁇ 10 6 HEK-293 cells possessing stably expressed human dopamine D 3 receptors, 0.1 nM [ 125 l]-iodosulpride and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 ⁇ M spiperone (nonspecific binding). Each assay mixture was run in triplicate.
- the incubation buffer contained 50 mM tris, 120 mM NaCI, 5 mM KCI, 2 mM CaCI 2 ,
- the assay mixture (1 ml) was composed of membranes from ⁇ 10 6 HEK-293 cells possessing stably expressed human dopamine D 2L receptors (long isoform) and 0.01 nM [ 125 I] iodospiperone and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 ⁇ M haloperidol (nonspecific binding). Each assay mixture was run in triplicate.
- the incubation buffer contained 50 mM tris, 120 mM NaCI, 5 mM KCI, 2 mM CaCI 2 , 2 mM MgCI 2 and 0.1 % bovine serum albumin.
- the buffer was adjusted to pH 7.4 with HCI.
- the assay mixtures were filtered through a Whatman GF/B glass fiber filter under vacuum using a cell collecting device.
- the filters were transferred to scintillation viols using a filter transfer system.
- 4 ml of Ultima Gold ® (Packard) have been added, the samples were shaken for one hour and the radioactivity was then counted in a Beta-Counter (Packard, Tricarb 2000 or 2200CA).
- the cpm values were converted into dpm using a standard quench series and the program belonging to the instrument.
- the inhibition curves were analyzed by means of iterative nonlinear regression analysis using the Statistical Analysis System (SAS) which is similar to the "LIGAND” program described by Munson and Rodbard.
- SAS Statistical Analysis System
- the compounds according to the invention exhibit very good affinities for the 5HT 6 receptor ( ⁇ 50 nM, or ⁇ 10 nM, frequently ⁇ 5 nM). Some of the compounds also exhibit very good affinities for the D 3 receptor ( ⁇ 50 nM, or ⁇ 10 nM, frequently ⁇ 5 nM) and bind selectively to the D 3 receptor, as compared to the affinity for the D 2 receptor.
- ACh cortical extracellular acetylcholine
- test compound or its vehicle (2 ml/kg) was administered intraperitoneally.
- Microdi- alysate fractions (six 20-min fractions before and six fractions after compound administration) were analyzed for acetylcholine by high performance liquid chromatography in combination with electrochemical detection (for methods see Fox et al., J. Phamacol. Exp. Ther. 2005, 313, 176 to 190 and detailed description below).
- 5-HT 6 receptor ligands and selective D 3 receptor ligands increased dose-dependently extracellular ACh levels in the medial prefrontal cortex and in the hippocampus.
- mixed D 3 /5-HT 6 receptor ligands also increase microdialysate ACh levels in the medial prefrontal cortex and in the hippocampus. Based on dose comparisons, compounds combining D 3 /5-HT 6 within the molecule are more potent in increasing cortical cholinergic function than "pure" D 3 receptor antagonists.
- Rimadyl® (3 mg/kg, i.p.) was administered before surgery.
- the guide cannula were secured with dental cement (Technovit powder, Product No 5071 , Technovit polymerization starter fluid, Product No 2060, Kulzer GmbH, Germany) and 4 anchor screws into the skull.
- the rats were allowed to recover from surgery for 5-7 days.
- each animal was transferred into a system allow- ing for free movement (CMA/120 Axel Semrau GmbH, Germany, consisting of a plastic bowl, wire attachment, counter-balance arm, swivel assembly connecting in-/outlet of the probe with the perfusion pump).
- CMA/12 microdialysis probe (3 mm membrane length) was slowly lowered into the final position.
- the probe was perfused with Ringer solution (147 imM NaCI, 4.0 imM KCI and 2.4 imM CaCI 2 , containing 1 ⁇ M neo- stigmine), for about one hour (CMA/102 microdialysis pump, Axel Semrau GmbH,
- Flow rate was 0.14 ml/min (Rheos Flux pump, Axel Semrau GmbH, Germany), and the sample run time was less than 15 minutes.
- Acetylcholine and choline were measured via an electrochemical detector (LC-4C, BAS, U.S.A.) with a platinum working electrode set at + 500 mV versus an Ag/AgCI reference electrode.
- the system was calibrated by standard solutions (acetylcholine, choline) containing 1 pmol/10 ⁇ l injection.
- Acetylcholine was identified by its retention time and peak height with an external standard method using chromatography software (Chrom Perfect®, version 4.4.22, Justice Laboratory Software, U.S.A.).
- ANOVA analysis of variance
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CA002648892A CA2648892A1 (en) | 2006-04-19 | 2007-04-18 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor |
JP2009505888A JP2009534355A (en) | 2006-04-19 | 2007-04-18 | Heterocyclic compounds suitable for treating disorders responsive to modulation of serotonin 5HT6 receptors |
MX2008013206A MX2008013206A (en) | 2006-04-19 | 2007-04-18 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor. |
EP07728270A EP2074110A1 (en) | 2006-04-19 | 2007-04-18 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5ht6 receptor |
US12/297,328 US8497273B2 (en) | 2006-04-19 | 2007-04-18 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor |
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WO2012059432A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor |
WO2012059431A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor |
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US8642642B2 (en) * | 2006-04-19 | 2014-02-04 | Abbott Laboratories | Heterocyclic arylsulphones suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor |
WO2009109042A1 (en) * | 2008-03-06 | 2009-09-11 | Horbay Roger P | A system, method and computer program for retention and optimization of gaming revenue and amelioration of negative gaming behaviour |
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---|---|---|---|---|
WO2005113539A1 (en) * | 2004-05-21 | 2005-12-01 | Glaxo Group Limited | 3-arylsulfonyl-quinolines as 5-ht6 receptor antagonists for the treatment of cns disorders |
WO2006063718A1 (en) * | 2004-12-16 | 2006-06-22 | F.Hoffmann-La Roche Ag | Piperazinyl pyridine derivatives as anti-obesity agents |
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JP3342491B2 (en) | 1993-08-06 | 2002-11-11 | ファルマシア・アンド・アップジョン・カンパニー | 2-aminoindanes as selective dopamine D3 ligands |
ES2159017T3 (en) | 1995-02-01 | 2001-09-16 | Upjohn Co | 2-AMINOINDANS AS SELECTIVE LINKS OF DOPAMINE D3. |
DE69719186T2 (en) | 1996-05-30 | 2003-11-27 | Baker-Hughes Inc., Houston | NAPHTENIC ACID CORROSION CONTROL WITH THIOPHOSPHORIC COMPOUNDS |
DZ2376A1 (en) | 1996-12-19 | 2002-12-28 | Smithkline Beecham Plc | New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them. |
TW450954B (en) | 1998-05-14 | 2001-08-21 | Pharmacia & Amp Upjohn Company | Phenylsulfonamide-phenylethylamines useful as dopamine receptors |
WO2000005225A1 (en) | 1998-07-20 | 2000-02-03 | Merck Patent Gmbh | Biphenyl derivatives |
TW200418830A (en) * | 2003-02-14 | 2004-10-01 | Wyeth Corp | Heterocyclyl-3-sulfonylazaindole or-azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
US20040204422A1 (en) * | 2003-04-14 | 2004-10-14 | Abbott Gmbh & Co. Kg. | N-[(Piperazinyl)hetaryl]arylsulfonamide compounds |
US7320979B2 (en) * | 2003-04-14 | 2008-01-22 | Abbott Gmbh & Co. Kg. | N-[(piperazinyl)hetaryl]arylsulfonamide compounds |
GB0321473D0 (en) | 2003-09-12 | 2003-10-15 | Glaxo Group Ltd | Novel compounds |
WO2005037830A1 (en) | 2003-10-10 | 2005-04-28 | Wyeth | Piperidinylchromen-6-ylsulfonamide compounds as 5-hydroxytryptamine-6 ligands |
EP2311803A1 (en) | 2004-10-14 | 2011-04-20 | Abbott GmbH & Co. KG | Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor |
EP2013178A1 (en) * | 2006-03-31 | 2009-01-14 | Glaxo Group Limited | Piperazine derivatives as growth hormone secretagogue (ghs) receptor agonists |
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WO2005113539A1 (en) * | 2004-05-21 | 2005-12-01 | Glaxo Group Limited | 3-arylsulfonyl-quinolines as 5-ht6 receptor antagonists for the treatment of cns disorders |
WO2006063718A1 (en) * | 2004-12-16 | 2006-06-22 | F.Hoffmann-La Roche Ag | Piperazinyl pyridine derivatives as anti-obesity agents |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012059432A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor |
WO2012059431A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor |
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US20100048582A1 (en) | 2010-02-25 |
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