WO2013000994A1 - Novel inhibitor compounds of phosphodiesterase type 10a - Google Patents
Novel inhibitor compounds of phosphodiesterase type 10a Download PDFInfo
- Publication number
- WO2013000994A1 WO2013000994A1 PCT/EP2012/062544 EP2012062544W WO2013000994A1 WO 2013000994 A1 WO2013000994 A1 WO 2013000994A1 EP 2012062544 W EP2012062544 W EP 2012062544W WO 2013000994 A1 WO2013000994 A1 WO 2013000994A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- dihydro
- pyridin
- isoindol
- quinolin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 447
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title claims description 15
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title claims description 15
- 239000003112 inhibitor Substances 0.000 title description 15
- -1 carboxamide compounds Chemical class 0.000 claims abstract description 769
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 60
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 12
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 12
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 4
- 150000003254 radicals Chemical class 0.000 claims description 165
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 124
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 84
- 125000005842 heteroatom Chemical group 0.000 claims description 84
- 229910052757 nitrogen Inorganic materials 0.000 claims description 83
- 229920006395 saturated elastomer Polymers 0.000 claims description 83
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 82
- 229910052717 sulfur Inorganic materials 0.000 claims description 80
- 229910052731 fluorine Inorganic materials 0.000 claims description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims description 78
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 76
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 76
- 239000011737 fluorine Substances 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 71
- 229910052760 oxygen Inorganic materials 0.000 claims description 71
- 239000000126 substance Substances 0.000 claims description 60
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 55
- 150000002431 hydrogen Chemical class 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical compound C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 42
- 239000000460 chlorine Substances 0.000 claims description 38
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 37
- 239000000651 prodrug Substances 0.000 claims description 37
- 229940002612 prodrug Drugs 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 34
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 29
- 150000004677 hydrates Chemical class 0.000 claims description 29
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 28
- 150000001204 N-oxides Chemical class 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 230000005764 inhibitory process Effects 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 201000000980 schizophrenia Diseases 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 13
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 208000019901 Anxiety disease Diseases 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 230000000926 neurological effect Effects 0.000 claims description 10
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 9
- 230000036506 anxiety Effects 0.000 claims description 9
- 208000010877 cognitive disease Diseases 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- NALBLJLOBICXRH-UHFFFAOYSA-N dinitrogen monohydride Chemical compound N=[N] NALBLJLOBICXRH-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 6
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 6
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 6
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 5
- 208000020925 Bipolar disease Diseases 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 5
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- IKEAEYSWAGRCKF-UHFFFAOYSA-N 2-(2,2-difluoro-2-quinolin-2-ylethyl)-7-pyridin-4-yl-3h-isoindol-1-one Chemical compound C=1C=C2C=CC=CC2=NC=1C(F)(F)CN(C(C1=2)=O)CC1=CC=CC=2C1=CC=NC=C1 IKEAEYSWAGRCKF-UHFFFAOYSA-N 0.000 claims description 4
- RSVWYWSJLYABCI-UHFFFAOYSA-N 2-[2-(2-phenylpyrimidin-4-yl)ethyl]-7-pyridin-4-yl-3h-isoindol-1-one Chemical compound C1C2=CC=CC(C=3C=CN=CC=3)=C2C(=O)N1CCC(N=1)=CC=NC=1C1=CC=CC=C1 RSVWYWSJLYABCI-UHFFFAOYSA-N 0.000 claims description 4
- OTXYKOZAQXRSPR-UHFFFAOYSA-N 3,3-difluoro-7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)isoindol-1-one Chemical compound FC1(F)N(CCC=2N=C3C=CC=CC3=CC=2)C(=O)C2=C1C=CC=C2C1=CC=NC=C1 OTXYKOZAQXRSPR-UHFFFAOYSA-N 0.000 claims description 4
- GETBNYOAHCNWMJ-UHFFFAOYSA-N 4-(1h-pyrazol-5-yl)-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound O=C1N(CCC=2N=C3C=CC=CC3=CC=2)CC2=C1C=CC=C2C=1C=CNN=1 GETBNYOAHCNWMJ-UHFFFAOYSA-N 0.000 claims description 4
- KKYGYRSDVINXQW-UHFFFAOYSA-N 4-fluoro-7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound C1=2C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)CC=2C(F)=CC=C1C1=CC=NC=C1 KKYGYRSDVINXQW-UHFFFAOYSA-N 0.000 claims description 4
- DYCPKQXCHNQDPK-UHFFFAOYSA-N 4-morpholin-4-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound O=C1N(CCC=2N=C3C=CC=CC3=CC=2)CC2=C1C=CC=C2N1CCOCC1 DYCPKQXCHNQDPK-UHFFFAOYSA-N 0.000 claims description 4
- ZHOAGHHXUHABJI-UHFFFAOYSA-N 4-morpholin-4-yl-6-(2-quinolin-2-ylethyl)-7h-pyrrolo[3,4-b]pyridin-5-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)CC2=NC=CC=1N1CCOCC1 ZHOAGHHXUHABJI-UHFFFAOYSA-N 0.000 claims description 4
- PHNVJNZMCOJVHS-UHFFFAOYSA-N 4-pyridin-3-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound O=C1N(CCC=2N=C3C=CC=CC3=CC=2)CC2=C1C=CC=C2C1=CC=CN=C1 PHNVJNZMCOJVHS-UHFFFAOYSA-N 0.000 claims description 4
- BRIHYFSPYAUCGJ-UHFFFAOYSA-N 4-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-1,2-benzoxazol-3-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)OC2=CC=CC=1C1=CC=NC=C1 BRIHYFSPYAUCGJ-UHFFFAOYSA-N 0.000 claims description 4
- FJSBVTJLTQFZAJ-UHFFFAOYSA-N 4-pyridin-4-yl-6-(2-quinolin-2-ylethyl)-7h-pyrrolo[3,4-b]pyridin-5-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)CC2=NC=CC=1C1=CC=NC=C1 FJSBVTJLTQFZAJ-UHFFFAOYSA-N 0.000 claims description 4
- RCNCAUJOTBTMRB-UHFFFAOYSA-N 5-fluoro-7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound C=1C(F)=CC=2CN(CCC=3N=C4C=CC=CC4=CC=3)C(=O)C=2C=1C1=CC=NC=C1 RCNCAUJOTBTMRB-UHFFFAOYSA-N 0.000 claims description 4
- ZQRPLDQJJVSTIU-UHFFFAOYSA-N 6-fluoro-7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound FC1=CC=C2CN(CCC=3N=C4C=CC=CC4=CC=3)C(=O)C2=C1C1=CC=NC=C1 ZQRPLDQJJVSTIU-UHFFFAOYSA-N 0.000 claims description 4
- UUVNODRQISNCGB-UHFFFAOYSA-N 7-(2-methoxypyridin-4-yl)-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound C1=NC(OC)=CC(C=2C=3C(=O)N(CCC=4N=C5C=CC=CC5=CC=4)CC=3C=CC=2)=C1 UUVNODRQISNCGB-UHFFFAOYSA-N 0.000 claims description 4
- NENJURMNDVSQSX-UHFFFAOYSA-N 7-(7-amino-3,4-dihydro-1h-isoquinolin-2-yl)-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound C1=CC=CC2=NC(CCN3CC=4C=CC=C(C=4C3=O)N3CCC4=CC=C(C=C4C3)N)=CC=C21 NENJURMNDVSQSX-UHFFFAOYSA-N 0.000 claims description 4
- HQYPNJRTOLLVEQ-UHFFFAOYSA-N 7-morpholin-4-yl-2-[2-(3-pyrimidin-2-ylphenyl)ethyl]-3h-isoindol-1-one Chemical compound C1C2=CC=CC(N3CCOCC3)=C2C(=O)N1CCC(C=1)=CC=CC=1C1=NC=CC=N1 HQYPNJRTOLLVEQ-UHFFFAOYSA-N 0.000 claims description 4
- VHHVYZTZNVZAPU-UHFFFAOYSA-N 7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-3h-isoindol-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)CC2=CC=CC=1C1=CC=NC=C1 VHHVYZTZNVZAPU-UHFFFAOYSA-N 0.000 claims description 4
- ULGMCLBYBMNJRE-UHFFFAOYSA-N 7-pyridin-4-yl-2-(2-quinolin-2-ylethyl)-3h-pyrrolo[3,4-c]pyridin-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)CC2=CN=CC=1C1=CC=NC=C1 ULGMCLBYBMNJRE-UHFFFAOYSA-N 0.000 claims description 4
- OSCMQAUHNKVTDN-UHFFFAOYSA-N 7-pyridin-4-yl-2-(2-thieno[3,2-b]pyridin-5-ylethyl)-3h-isoindol-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CSC4=CC=3)CC2=CC=CC=1C1=CC=NC=C1 OSCMQAUHNKVTDN-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 4
- LICHKWSOFAQWLZ-UHFFFAOYSA-N pyrrolo[3,4-b]pyridin-5-one Chemical compound C1=CC=C2C(=O)N=CC2=N1 LICHKWSOFAQWLZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052702 rhenium Inorganic materials 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- HKDYQVPWHSBHQG-UHFFFAOYSA-N 1-methyl-4-pyridin-4-yl-2-(2-quinolin-2-ylethyl)indazol-3-one Chemical compound C1=CC=C2N(C)N(CCC=3N=C4C=CC=CC4=CC=3)C(=O)C2=C1C1=CC=NC=C1 HKDYQVPWHSBHQG-UHFFFAOYSA-N 0.000 claims description 3
- MVTCSWVDOWITTC-UHFFFAOYSA-N 2-[2-(1-methylbenzimidazol-2-yl)ethyl]-7-morpholin-4-yl-3h-isoindol-1-one Chemical compound N=1C2=CC=CC=C2N(C)C=1CCN(C(C1=2)=O)CC1=CC=CC=2N1CCOCC1 MVTCSWVDOWITTC-UHFFFAOYSA-N 0.000 claims description 3
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- OMZVPUIJZYXIRO-UHFFFAOYSA-N 2-[2-(1-methylbenzimidazol-2-yl)ethyl]-7-pyrimidin-5-yl-3h-isoindol-1-one Chemical compound N=1C2=CC=CC=C2N(C)C=1CCN(C(C1=2)=O)CC1=CC=CC=2C1=CN=CN=C1 OMZVPUIJZYXIRO-UHFFFAOYSA-N 0.000 claims description 3
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- GZEVQFOGYHHXGH-UHFFFAOYSA-N 2-[2-(8-chloroquinolin-2-yl)ethyl]-7-morpholin-4-yl-3h-isoindol-1-one Chemical compound N1=C2C(Cl)=CC=CC2=CC=C1CCN(C(C1=2)=O)CC1=CC=CC=2N1CCOCC1 GZEVQFOGYHHXGH-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C—CHEMISTRY; METALLURGY
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- Novel inhibitor compounds of phosphodiesterase type 10A are novel inhibitor compounds of phosphodiesterase type 10A
- the present invention relates to novel compounds which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.
- Phosphodiesterase type 10A (hereinafter PDEIOA) is a dual-substrate
- PDEIOA phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP.
- PDEIOA is highly prominent in the mammalian brain. In the rat, as well as in othermammalian species, PDEIOA and the mRNA of PDEIOA are highly enriched in the GABAergic medium spiny projection neurons (MSNs) of the striatal complex (caudate nucleus, nucleus accumbens, and olfactory tubercle) where the output is regulated by the effect of PDEIOA on cAMP and cGMP signalling cascades (see e.g. C. J. Schmidt et al, The Journal of Pharmacology and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The Journal of Neuro science 2008, 28, 10450-10471).
- MSNs GABAergic medium spiny projection neurons
- MSNs express two functional classes of neurons: the Di class expressing Di dopamine receptors and the D 2 class expressing D 2 dopamine receptors.
- the Di class of neurons is part of the 'direct' striatal output pathway, which broadly functions to facilitate behavioral responses.
- the D 2 class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the 'direct' pathway.
- PDEIOA regulation of cAMP and/or cGMP signaling in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN.
- PDEIOA may be involved in the regulation of GABA release in the substantia nigra and globus pallidus (Seeger, T.F. et al. Brain Research, 2003, 985, 1 13-126). Inhibition of PDEIOA results in striatal activation and behavioral suppression such as dampened locomotion, inhibition of conditioned avoidance response (CAR), and activity in the rat auditory gating model, suggesting that inhibitors of phosphodiesterase type 10A represent a novel class of antipsychotic agents.
- CAR conditioned avoidance response
- Papaverine potentiated the cataleptic effect of the D 2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499).
- Papaverine reduced hyperactivity in rats induced by PCP, while reduction of amphetamine-induced hyperactivity was insignificant (WO 03/093499).
- PDEIOA inhibition has the classic antipsychotic potential that would be expected from theoretical considerations.
- Papaverine however has significant limitations in this regard with relatively poor potency and selectivity and a very short exposure half- life after systemic administration. It was found that inhibition of PDEIOA reverses subchronic PCP-induced deficits in attentional set-shifting in rats suggesting that PDEIOA inhibitors might alleviate cognitive deficits associated with schizophrenia. (Rodefer et al, Eur. J. Neurosci., 4 (2005) 1070-1076).
- the new class of inhibitors are exemplified by MP-10 (PF-2545920: 2- ⁇ 4-[l- methylpyridine-4-yl-l-H-pyrazol-3-31y]phenoxymethyl ⁇ -quinoline) and TP-10, i.e. 2- ⁇ 4-[pyridine-4-yl- 1 -(2,2,2-trifluoroethyl)- 1 -H-pyrazol-3-31y]phenoxymethyl ⁇ - quinoline.
- the compounds offer a therapeutic approach to the treatment of
- Positive signals in rodent models of schizophrenia include the: attenuation of conditioned avoidance response (CAR), inhibition of hyperactivity caused by amphetamine-induced dopamine release or phencyclidine (PCP) mediated NMDA receptor blockade, attenuation of pharmacologically impaired social or object recognition, and antagonism of apomorphine-induced climbing.
- CAR conditioned avoidance response
- PCP phencyclidine
- PDE10 inhibitiors may have the potential for the treatment of Huntington ' s disease (S. H. Francis et al, Physiol. Rev., 91 (2011) 651- 690) and they may be an therapeutic option for substance abuse disorders (F. Sotty et al, J. Neurochem., 109 (2009) 766-775). Furthermore, it has been suggested that PDEIOA inhibitors may be useful for treatment of obesity and non- insulin dependent diabetes (see e.g. WO 2005/120514, WO 2005/012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873).
- inhibitors of PDEIOA offer a promising therapeutic approach to the treatment or prevention of neurological and psychiatric disorders, in particular schizophrenia and related disorders, including symptoms linked to schizophrenia such as cognitive dysfunction.
- MP10 and MP10 like componds US 2007/0155779, WO 2008/001182 and WO 2008/004117; and
- metabolic stability in particular microsomal stability, e.g. measured in vitro, in liver microsomes from various species (e.g. rat or human) in human cells, such as hepatocytes;
- cytochrome P450 is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms.
- the principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.
- grapefruit juice, cimetidine, erythromycin are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced;
- the pharmacokinetics can be described by the following parameters: half- life, volume of distribution (in l-kg “1 ), plasma clearance (in l-h ⁇ -kg “1 ), AUC (area under the curve, area under the concentration-time curve (in ng-h 1 ), oral bioavailability, (the dose-normalized ratio of AUC after oral administration and AUC after intravenous administration), the so-called brain-plasma ratio
- the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al, Journal of Pharmacological and Toxico logical Methods, 50 (2004), 187-199).
- the present invention is thus based on the object of providing compounds which inhibit PDE10A at low concentrations.
- the compounds are further intended to display at least one of the properties i. to viii. mentioned above, in particular high selectivity with regard to inhibition of PDE10A, high selectivity vis-a-vis other phosphodiesterases such as , enhanced metabolic stability, in particular microsomal and/or cytosolic stability, low affinity to the HERG receptor, low inhibition of cytochrome P450 (CYP) enzymes, suitable solubility in water and suitable pharmacokinetics.
- properties i. to viii. mentioned above in particular high selectivity with regard to inhibition of PDE10A, high selectivity vis-a-vis other phosphodiesterases such as , enhanced metabolic stability, in particular microsomal and/or cytosolic stability, low affinity to the HERG receptor, low inhibition of cytochrome P450 (CYP) enzymes, suitable solubility in water and suitable pharmacokinetics.
- CYP cytochrome P450
- X is N or C-R
- phenyl which carries a monocyclic hetaryl radical having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, which in addition to monocyclic hetaryl, may carry 1, 2 or 3 identical or different substituents R x ,
- R x is selected from the group consisting of H, halogen, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -fluoroalkyl, Ci-C 4 -fluoroalkoxy, C 3 -C 6 - cycloalkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkoxy, Ci-C 4 -alkoxy-Ci-C 4 - alkyl, OH, hydroxy-Ci-C 4 -alkyl, 0-C 3 -C 6 -cycloalkyl, benzyloxy, C(0)0-(Ci-C 4 -alkyl), 0-(Ci-C 4 -alkyl)-C0 2 H, N(R xl )(R x2 ), C(0)N(R xl )(R x2 ), d-C 4 -alkyl-N(R xl )(R x2 ), -
- R xl , R x2 , R x3 and R x4 independently of each other are selected from the group consisting of hydrogen, Ci-C4-alkyl, Ci-C4-fluoroalkyl and C3-C6-cycloalkyl or R xl and R x2 form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical hetero atoms or heteroatom containing groups selected from the group of O, N, S, SO and S0 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from Ci-C4-alkyl; independently of each other, are selected from the group consisting of hydrogen, hal
- R 5a is selected from the group consisting of from Ci-C 4 -alkyl, C 1 -C 4 - alkoxy, Ci-C 4 -fluoroalkyl, Ci-C4-fluoroalkoxy, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated C3-C6- cycloalkyl, phenyl, benzyl, 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms selected from O, S and N as ring members, and 5- or 6- membered hetarylmethyl having 1 , 2 or 3 heteroatoms selected from O, S and N as ring members, where the rings in the last four mentioned radicals are unsubstituted or carry 1, 2, 3 or 4 substituents selected from fluorine, Ci-C 4 -alkyl, Ci-C 4 -fluoroalkyl, Ci-C 4 -alkoxy and Ci-C 4 -f uoro
- R 7 , R 8 , R 9 , R 10 independently of each other are selected from the group consisting of hydrogen, halogen, Ci-C 4 -alkyl, trimethylsilyl, Ci-C 4 -fluoroalkyl,
- heteroatom containing groups as ring members which are selected from O, S, SO, S0 2 and N, and where the 5- or 6-membered monocyclic hetaryl and the 8- to 10-membered bicyclic hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N,
- phenyl, naphthyl, the saturated or partially unsaturated mono- and bicarbocyclic radicals, the heteromonocyclic and heterobicyclic radicals and the mono and bicyclic hetero aromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R C1 or one radical Y * -R C2 and 0, 1, 2, 3 or 4 radicals R C1 ;
- R C1 is selected from hydrogen, halogen, OH, CN, N0 2 , Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylsulfanyl, hydroxy-Ci-C4-alkyl, C 1 -C4- alkoxy-Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkoxy, cyano-Ci-C4- alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, C 1 -C4- alkylsulfonyl, C(0)R a , Z-C(0)OR b , Z-C(0)NR c R d , S(0) 2 NR c R d and Z-NR e R f , where R a is selected from the group consisting of Ci-C4-alkyl and
- R b is selected from the group consisting of hydrogen, C 1 -C 4 - alkyl, C 2 -C 4 -alkenyl and Ci-C 4 -fluoroalkyl,
- R c , R d is selected from the group consisting of hydrogen, C 1 -C 4 - alkyl, Ci-C 4 -fluoroalkyl, Ci-C 4 -alkoxy and C 1 -C 4 - fluoroalkoxy,
- R e , R f is selected from the group consisting of hydrogen, C 1 -C 4 - alkyl, Ci-C 4 -fluoroalkyl, Ci-C 4 -alkoxy and C 1 -C 4 - fluoroalkoxy,
- Z is a covalent bond or Ci-C 4 -alkandiyl
- R C1 which are bound at adjacent carbon atoms may form a fused 5- or 6-membered carbocyclic radical or a fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N;
- radicals R C1 which are bound at the same carbon atom may form a spiro 5- or 6-membered carbocyclic radical or a spiro 5- or 6-membered heterocyclic radical having 1 or 2 heteroatoms as ring members, which are selected from O, S and N,
- R C3 is a chemical bond, CH 2 , O, 0-CH 2 , S(0) 2 , NR y ', NR y, -CH 2 or NR y '-S(0) 2 , where R y ' is selected from the group consisting of hydrogen, Ci-C 4 -alkyl, Ci-C 4 -alkylcarbonyl, C 1 -C 4 - alkylsulfonyl, Ci-C 4 -fluoroalkylsulfonyl; is a carbocyclic or heterocyclic radical selected from the group consisting of phenyl, 3- to 7-membered saturated or partially unsaturated monocarbocyclic radicals, 3- to 7-membered saturated or partially unsaturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, and 5- or 6-
- the present invention therefore relates to the compounds of the general formula I, their tautomers, the hydrates thereof, the pharmaceutically suitable salts of the compounds of formula I, the prodrugs of the compounds of formula I and the pharmaceutically suitable salts of said prodrugs, tautomers or hydrates of the compounds of formula I.
- the compounds of the formula I, their salts, their prodrugs, their hydrates and their tautomers effectively inhibit PDEIOA even at low concentrations. They are additionally distinguished by a high selectivity in relation to the inhibition of the PDEIOA vis-a-vis inhibition of other phosphodiesterease, such as PDE3 or PDE4.
- the compounds of the invention may additionally have one or more of the properties ii. to viii. mentioned above.
- the compounds of the formula I, their salts, their prodrugs, their hydrates and their tautomers are therefore particularly suitable for treating disorders and conditions in creatures, especially human creatures, which can be treated or controlled by inhibition of phosphodiesterase type 10A.
- the invention therefore also relates to the use of carboxamide compounds of the formula I, their tautomers, their hydrates and their pharmaceutically suitable salts for the manufacture of a medicament, in particular of a medicament which is suitable for the treatment of a disorder or a condition which can be treated by inhibition of phosphodiesterase type 10A.
- the invention further relates to a medicament, in particular a medicament which is suitable for the treatment of a disorder or a condition which can be treated by inhibition of phosphodiesterase type 10A.
- the medicament comprises at least one compound of the formula I, as described herein, or a tautomer, or a hydrate or a prodrug of said compound I, or a pharmaceutically suitable salt of the compound of the formula I or a pharmaceutically suitable salt of the tautomer, the hydrate or the prodrug of compound of the formula I.
- prodrugs means compounds which are metabolized in vivo to the compounds I of the invention. Typical examples of prodrugs are described in C.G.
- Suitable prodrugs in the present case may be for example derivatives of those compounds I carrying an OH or NH 2 -group, where the OH or NH 2 -group forms an ester/amide/peptide linkage, i.e. where one of the hydrogen atoms of the OH or NH 2 -group is substituted by a Ci-C4-alkylcarbonyl group, e.g.
- an amino acid e.g. glycine, alanine, serine, phenylalanine and the like, which is linked to the oxygen or nitrogen of the OH or NH 2 -group via the carbonyl group of the amino acid.
- Such carbonates and carbamates are described for example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322. These groups can then be eliminated under metabolic conditions and result in compounds I. Therefore, said prodrugs and their pharmaceutically acceptable salts are also part of the invention.
- pharmaceutically acceptable salts refers to cationic or anionic salts compounds, wherein the counter ion is derived from pharmaceutically acceptable nontoxic bases or acids including inorganic or organic bases and inorganic or organic acids.
- salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.
- Salts derived from inorganic bases include salts, wherein the counter ion is aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc ion and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium ions.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, dibenzylethylene-diamine, diethylamine, 2-diethylamino- ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins such as argin
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, trifluoro acetic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- the compounds of the invention may be in the form of a mixture of
- the compounds are preferably in the form of essentially diastereomerically pure compounds (diastereomeric excess de > 90%).
- the compounds I of the invention may furthermore be in the form of a mixture of enantiomers (for example as racemate), of a mixture of enantiomers in which one of the two enantiomers is enriched, or essentially in enantiomerically pure compounds (enantiomeric excess ee > 90%).
- the compounds of the invention are frequently prone to racemization in relation to the stereochemistry of the carbon atom which carries the radical R 1 , so that mixtures are frequently obtained in relation to this carbon atom, or compounds which exhibit a uniform stereochemistry in relation to this C atom form mixtures under physiological conditions.
- the present invention moreover relates to compounds as defined herein, wherein one or more of the atoms depicted in formula I have been replaced by its stable, preferably non-radioactive isotope (e.g., hydrogen by deuterium, 12 C by 13 C, 14 N by 15 N, 16 0 by 18 0) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.
- the compounds according to the invention contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds I.
- the compounds of the formula I and their salts in the solid form may exist in more than one crystal structure (polymorphism), and may also be in the form of hydrates or other solvates.
- the present invention includes any polymorph of the compound I or its salt as well as any hydrate or other solvate.
- alkyl "alkenyl”, “alkoxy”, “alkenyloxy”, “fluoroalkyl”, “fiuoroalkoxy”, "cycloalkyl”, “fluorinated cycloalkyl”, “alkylene”, “alkandiyl”, “hetaryl” and radicals derived therefrom, such as “alkylcarbonyl”, “alkylsulfanyl”, “alkylsulfonyl”, “fluoroalkylsulfonyl”, “hydroxylalkyl”, “cyanoalkyl", “alkoxylalkyl”, “alkoxyalkoxy”, “alkylsulfanylalkyl”, “alkylsulfanylalkoxy” and “hetarylmethyl” represent groups of individual radicals.
- C n -C m - indicates the respective number of carbons in the hydrocarbon unit. Unless indicated otherwise, fluorinated substituents preferably have one to five identical or different fluorine atoms.
- halogen designates in each case, fluorine, bromine, chlorine or iodine, specifically fluorine, chlorine or bromine.
- Fluoroalkyl and the fluoroalkyl moieties for example in fluoroalkylsulfonyl an alkyl radical having ordinarily 1 to 4 C atoms, in particular 1 or 2 C-atoms (d-C 2 - fluoroalkyl) as mentioned above, whose hydrogen atoms are partly or completely replaced by fluorine atoms such as f uoromethyl, dif uoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trif uoroethyl, pentaf uoroethyl, 2-f uoro-l- methylethyl, 2,2-difluoro-l -methylethyl, 2,2-trifluoro-l -methylethyl, 2-fluoropropyl, 3- fluoropropyl, 2,2-dif uoropropyl, 2,3-difluoropropy
- Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy or cycloalkyl- Ci-C4-alkyl monocyclic, saturated hydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6 or 7 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- Fluorinated cycloalkyl monocyclic, saturated hydrocarbon groups having three or more C atoms, e.g.
- carbon ring members such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4, 5 or 6 of the hydrogen atoms are replaced by fluorine atoms, examples including 1- fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1,2- difluorocyclopropyl, 2,3-difluorocyclopropyl, etc.
- Cycloalkoxy a cycloalkyl radical as defined above which is linked via an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
- Cycloalkylalkyl a cycloalkyl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1 -ethylene or 1,2-ethylene group, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
- an alkyl radical as defined above having preferably 1 to 4 C atoms, which is connected to the remainder of the molecule via an O atom: e.g. methoxy, ethoxy, n- propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1- dimethylethoxy.
- Fluoroalkoxy alkoxy as described above, in which the hydrogen atoms of these groups are partly or completely replaced by fluorine atoms, i.e. for example C1-C4- fluoroalkoxy, in particular Ci-C2-fluoroalkoxy, such as fluoromethoxy,
- Hydroxy alkyl an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an OH radical.
- Examples thereof are CH 2 -OH, 1- hydroxyethyl, 2-hydroxyethyl, 1 -hydro xypropyl, 2-hydroxypropyl, 1 -methyl- 1- hydroxyethyl, l-methyl-2-hydroxyethyl, 3 -hydro xypropyl, 2-hydroxybutyl, 3- hydro xybutyl, 4-hydroxybutyl, l-methyl-2-hydro xypropyl, l,l-dimethyl-2-hydroxyetyl,
- Cyanoalkyl an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by a CN radical. Examples thereof are CH 2 -CN, 1- cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, 1 -methyl- 1-cyanoethyl, 1- methyl-2-cyanoethyl, 3-cyanopropyl, 2-cyanobutyl, 3-cyanobutyl, 4-cyanobutyl, 1- methyl-2-cyanopropyl, l,l-dimethyl-2-cyanoetyl, 1 -methyl- 1-cyanopropyl etc.
- Alkoxyalkyl an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an alkoxy radical ordinarily having 1 to 4 C atoms.
- Examples thereof are CH 2 -OCH 3 , CH 2 -OC 2 H 5 , n-propoxymethyl, CH 2 -OCH(CH 3 ) 2 , n-butoxymethyl, (l-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH 2 -OC(CH 3 ) 3 ,
- Alkoxyalkoxy an alkoxyalkyl radical as defined above ordinarily having 1 to 4 C atoms both in the alkoxy and the alkyl moiety which is connected to the remainder of the molecule via an O atom: Examples thereof are OCH 2 -OCH 3 , OCH 2 -OC 2 H 5 , n- propoxymethoxy, OCH 2 -OCH(CH 3 ) 2 , n-butoxymethoxy, (l-methylpropoxy)methoxy, (2-methylpropoxy)methoxy, OCH 2 -OC(CH 3 )3, 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy, 2-(n-propoxy)ethoxy, 2-( 1 -methylethoxy)ethoxy, 2-(n-butoxy)ethoxy,
- Alkylcarbonyl alkyl as defined above preferably having 1 to 4 C atoms, which is connected via a carbonyl group to the remainder of the molecule, e.g. acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and the like.
- alkylsulfanylalkoxy alkyl as defined above preferably having 1 to 4 C atoms, which is connected via an S atom to the remainder of the molecule, e.g. methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and the like.
- Alkylsulfonyl alkyl as defined above preferably having 1 to 4 C atoms, which is connected via an SO 2 group to the remainder of the molecule, e.g. methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and the like.
- Fluoroalkylsulfanyl fluoroalkyl as defined above preferably having 1 to 4 C atoms, which is connected via an S atom to the remainder of the molecule, e.g.
- fluoromethylsulfanyl difluoromethylsulfanyl, trifluoromethylsulfanyl, 2- fluoro ethylsulfanyl, 2,2-difluoroethylsulfanyl, 2,2,2-trifluoroethylsulfanyl,
- Fluoroalkylsulfonyl fluoroalkyl as defined above preferably having 1 to 4 C atoms, which is connected via an SO 2 group to the remainder of the molecule, e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2- fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,
- Alkylsulfanylalkyl an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an alkylsulfanyl radical ordinarily having 1 to 4 C atoms. Examples thereof are CH 2 -SCH 3 , CH 2 -SC 2 H 5 , n-propylsulfanylmethyl,
- Alkylen or “Alkandiyl”: a saturated hydrocarbon chain having ordinarily from 1 to 4 carbon atoms, such as methylen (-CH 2 -), 1,2-ethylen (-CH 2 CH 2 -), 1,1-ethandiyl (-CH(CH 3 )-), 1 ,2-propandiyl, 1,3-propandiyl, 1 ,4-butandiyl, 1 ,2-butandiyl, 1,3- butandiyl, 1 -methyl- 1 ,2-propandiyl, 2-methyl- 1,3-propandiyl, 1 -methyl- 1,1-ethandiyl, 1 -methyl- 1 ,2-propandiyl etc.
- Saturated or partially unsaturated 4 to 7-membered monocarbocyclic radicals include cycloalkyl as defined above and cycloalkenyl having ordinarily from 4 to 7 carbon atoms as ring members, e.g. 1-cyclobuten-l-yl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2- cycloheptenyl, 3-cycloheptenyl.
- saturated heteromono cycles are in particular:
- Saturated heteromonocyclic radical which ordinarily has 3, 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as
- N, S or O besides carbon atoms as ring members.
- These include for example:
- hexahydropyrimidin-4-yl hexahydropyrimidin-5 -yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro- 1 ,3-oxazin- 2-yl, tetrahydro- 1, 3-o xazin-4-yl, tetrahydro- l,3-oxazin-5-yl, tetrahydro -1,3- oxazin-6-yl, tetrahydro- 1 ,3-thiazin-2-yl, tetrahydro- 1 ,3-thiazin-4-yl, tetrahydro- 1 ,3-thiazin-5-yl, tetrahydro- 1 ,3-thiazin-6-yl, tetrahydro- 1 ,4- thiazin-2-
- N-bonded, 5-membered saturated rings such as:
- Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members. These include for example:
- N-bonded, 5-membered, partially unsaturated rings such as:
- N-bonded, 6-membered, partially unsaturated rings such as:
- dihydroindolizynyl dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, chromenyl and chromanyl.
- Hetaryl a 5- or 6-membered aromatic heteromonocyclic radical (also termed 5- or
- 6-membered monocyclic hetaryl which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring members besides carbon atoms as ring members and a 8- to 10- membered aromatic heterobicyclic radical (also termed 8- to 10-membered bicyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring members besides carbon atoms as ring members: for example
- N-bonded, 5-membered hetero aromatic radicals having 1, 2, 3 or 4 nitrogen atoms as ring members such as:
- pyrrol- 1-yl pyrazol-l-yl, imidazol-l-yl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, tetrazol-l-yl.
- bicyclic hetaryl include for example quinolinyl, isoquinolinyl, cinnolinyl, indolyl, indolizynyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[l,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,l-b]-thiazol-6-yl and l,2,4-triazolo[l,5- a]pyridine-2-yl.
- Hetarylalkyl a hetaryl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1 -ethylene or 1,2-ethylene group, to the remainder of the molecule.
- the variables Het, X 1 , X 2 , X 3 , X 4 , A, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , Y, Cyc and Z preferably have the following meanings, where these represent, both considered on their own and in combination with at least one other or all, special configurations of the compounds of the formula I:
- Het is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C 4 -alkyl, Ci-C 2 -fluoroalkyl, Ci-C 4 -alkoxy, Ci-C 2 - fluoralkoxy, phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifiuoromethoxy, phenyl, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het is selected from fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member and which may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C4-alkyl, Ci-C 2 -fluoroalkyl, C 1 -C4- alkoxy, Ci-C 2 -fiuoralkoxy, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifiuoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het is selected from 6- membered monocyclic hetaryl, which may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C4-alkyl, Ci-C2-fluoroalkyl, Ci-C4-alkoxy, Ci-C 2 - fluoralkoxy, phenyl, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl or one R x may also be phenyl.
- Het radicals which have at least one imino- nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group CR 9 R 10 .
- Het radicals which have at least one imino -nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group CR 9 R 10 and which are selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C4-alkyl, Ci- C 2 -fluoroalkyl, Ci-C4-alkoxy, Ci-C 2 -fluoralkoxy, phenyl, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl,
- difluoromethyl trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het are selected from the group consisting of 2 -benzofuryl, 2-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl, l-methylbenzimidazol-2-yl, benzothiaozo-2-yl, imidazo[l,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo- [2,l-b]-thiazol-6-yl and l,2,4-triazolo[l,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals R x as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
- Het has at least one imino -nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group CR 9 R 10 and Het is selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C 4 -alkyl, Ci-C 2 -fluoroalkyl, C 1 -C 4 - alkoxy, Ci-C 2 -fluoralkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het of this embodiment are 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl, 1- methylbenzimidazol-2-yl, benzothiaozo-2-yl, imidazo[l,2-a]pyridine-2-yl, thieno[3,2- b]pyridine-5-yl, imidazo-[2,l-b]-thiazol-6-yl and l ,2,4-triazolo[l,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1 , 2 or 3 radicals R x as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
- X 1 is preferably N or CR 1 .
- X 2 is preferably CR 2 .
- X 3 is preferably CR 3 .
- X 4 is preferably CR 4 .
- radicals R 1 , R 2 , R 3 and R 4 which are different from Y-Cyc, are in particular selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C 4 -alkyl, fluorinated Ci-C 2 -alkyl, Ci-C 4 -alkoxy, fluorinated Ci- C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- X 1 is N
- X 2 is C-R 2
- X 3 is C-R 3
- X 4 is C-R 4 , where R 2 , R 3 and R 4 are as defined above.
- X is C-R
- X is C-R
- X is C-R
- X is C-R
- X is C- R 4 .
- R 1 or R 4 is a radical Y-Cyc and R 2 and R 3 , if present, have a meaning different from Y-Cyc.
- a particular embodiment relates to those compounds of the formula I, where X 4 is C-R 4 and R 4 is a radical Y-Cyc.
- another particular embodiment relates to those compounds of the formula I, where X 1 is C-R 1 and R 1 is a radical Y-Cyc.
- X 4 is C-R 4 and R 4 is a radical Y-Cyc, while X 1 is N or C-R 1 , X 2 is C-R 2 and X 3 is C-R 3 , where R 1 , if present, R 2 and R 3 have a meaning different from Y-Cyc.
- R 1 , R 2 and R 3 are as defined above and preferably selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C4-alkyl, fluorinated Ci-C2-alkyl, Ci-C4-alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- X 1 is C-R 1 and R 1 is a radical Y- Cyc
- X 4 is N or C-R 4
- X 2 is C-R 2
- X 3 is C-R 3 , where R 4 , if present, R 2 and R 3 have a meaning different from Y-Cyc.
- R 2 , R 3 and R 4 are as defined above and preferably selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C4-alkyl, fluorinated Ci-C 2 -alkyl, Ci-C4-alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- X 4 is C-R 4 and R 4 is a radical Y-Cyc
- X 4 is C-R 4 and R 4 is a radical Y- Cyc
- X 1 is C-R 1
- X 2 is C-R 2
- X 3 is C-R 3 , where R 1 , R 2 and R 3 have a meaning different from Y-Cyc.
- X 1 is C-R 1 and R 1 is a radical Y- Cyc, while X 4 is N, X 2 is C-R 2 and X 3 is C-R 3 , where R 2 and R 3 have a meaning different from Y-Cyc.
- X 1 is C-R 1 and R 1 is a radical Y- Cyc
- X 4 is C-R 4
- X 2 is C-R 2
- X 3 is C-R 3 , where R 4 , R 2 and R 3 have a meaning different from Y-Cyc.
- those R 1 , R 2 , R 3 and R 4 , if present, which are different from Y-Cyc are preferably selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C4-alkyl, fluorinated Ci-C 2 -alkyl, Ci-C4-alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- Y is preferably selected from O, NH and a chemical bond.
- Y is a chemical bond
- R CI or one radi ⁇ cal Y * -fT C2 z and 0, 1, 2, 3 or 4, i ⁇ n particular 0, 1 or 2 radicals R CI , where R cl , R C2 and Y * are as defined herein and where Y', if present, is preferably a chemical bond or O; and
- phenyl or a 5- or 6 membered hetaryl which has one heteroatom, selected from O, S and N as ring member and optionally one or two further heteroatoms as ring members, and which is in particular selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular
- radicals R where R , R" z and Y * are as defined herein and where Y', if present, is preferably a chemical bond or O.
- R C1 is preferably selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifiuoromethyl, methoxy and NH 2 , or, if Cyc is phenyl, two radicals R C1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6- benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl, 2,3- dihydrobenzofuran-6-yl, l,3-dihydroindol-2-on-5-yl, l,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-qui
- R C2 is preferably selected from the group consisting of phenyl, C 3 - C6-cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, fiuorinated C 3 -C 6 - cycloalkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, where phenyl the saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals R C3 , which are preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and N3 ⁇ 4.
- Cyc is selected from the groups of
- phenyl or a 5- or 6 membered hetaryl selected from pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
- R where R , R and Y' are as defined herein and where Y', if present, is preferably a chemical bond or O.
- R CI or one radi ⁇ cal Y * -R C"2 z and 0, 1, 2, 3 or 4, i ⁇ n particular 0, 1 or 2 radicals R CI , where R cl , R C2 and Y * are as defined herein and where Y', if present, is preferably a chemical bond or O.
- Y is preferably selected from O, NH and a chemical bond, with particular preference given to Y being a chemical bond.
- Y-Cyc is e.g. selected from the group consisting of 1-piperidinyl, 4,4-difluoro-l-piperidinyl, 4-piperidinyl, l-methyl-4- piperidinyl, 1-piperazinyl, 4-methyl-l-piperazinyl, morpholin-4-yl, 2-oxa-6-azaspiro- [3,4]octyl, 2,5-diazabicyclo[2.2. l]heptan-2-yl, 3,8-diazabicyclo[3.2.
- Cyc is phenyl or a 5- or 6 membered hetero aromatic radical, which has one heteroatom, selected from O, S and N as ring member and optionally one or two further heteroatoms as ring members, and which is in particular selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetero aromatic radical are unsubstituted or either carry, independently of each other, carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y'- fr C2 CI CI C2
- Cyc is selected from the group consisting of phenyl or a 5- or 6 membered hetaryl, selected from pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
- R where R , R and Y' are as defined herein and where Y', if present, is preferably a chemical bond or O.
- Cyc is selected from the group consisting of phenyl and 5- or 6-membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals R C1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 , or, if Cyc is phenyl, two radicals R C1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from
- Y is a chemical bond.
- Cyc is selected from the group consisting of phenyl and 5- or 6-membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals R C1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and N3 ⁇ 4.
- R C1 is preferably selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 , or, if Cyc is phenyl, two radicals R C1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from 5- or 6-indolyl, 5- or 6- benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 1 ,3-dihydroindol-2-on-5-yl, l,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or 6-isoquinoliny
- R C2 is preferably selected from the group consisting of phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, f uorinated C 3 -C 6 -cycloalkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, where phenyl the saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals R C3 , which are preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and N3 ⁇ 4.
- A is a radical CR 5 R 6 .
- R 5 and R 6 are as defined above and in particular, independently of each other, selected from the group consisting of hydrogen, fluorine and Ci-C4-alkyl, especially hydrogen, fluorine or methyl.
- A is a radical O.
- A is a radical N-R 5a .
- R 5a is as defined above and in particular selected from the group consisting of hydrogen, Ci-C4-alkyl, Ci-C 2 -fluoroalkyl, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, fluorinated cyclopropyl, phenyl and benzyl, where the rings of phenyl and benzyl are unsubstituted or carry 1 , 2 or 3 substituents selected from fluorine, methyl, Ci -fluoroalkyl, methoxy and Ci- fluoroalkoxy, especially from methyl.
- A is different from CH 2 , if X 1 is C-R 1 , X 2 is N or C-R 2 , X 3 is C-R 3 and X 4 C-R 4 .
- R 7 , R 8 are selected from hydrogen and fluorine and in particular to those compounds, where both R 7 and R 8 are hydrogen.
- R 9 , R 10 are selected from hydrogen and fluorine and in particular to those compounds, where both R 9 and R 10 are hydrogen.
- a particular preferred embodiment of the invention relates to the compounds of formula I-A, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
- R 5 and R 6 are as defined above and in particular, independently of each other, selected from the group consisting of hydrogen, fluorine and Ci-C4-alkyl, especially hydrogen, fluorine or methyl.
- the radicals R 5 and R 6 together with the carbon atom to which they are bound form a carbonyl group.
- Another particular preferred embodiment of the invention relates to the
- R 5a is in particular selected from the group consisting of hydrogen, Ci-C4-alkyl, Ci-C2-fluoroalkyl, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, fluorinated cyclopropyl, phenyl and benzyl, where the rings of phenyl and benzyl are unsubstituted or carry 1, 2 or 3 substituents selected from fluorine, methyl, Ci -fluoroalkyl, methoxy and Ci- fluoroalkoxy, especially from methyl.
- R 4 is preferably a radical Y-Cyc and X 1 is N or C- R 1 , where R 1 is as defined above and preferably has a meaning different from Y-Cyc.
- R 1 is in particular selected from the group consisting of hydrogen, fluorine, Ci-C4-alkyl, fluorinated Ci-C2-alkyl, Ci-C4-alkoxy, fluorinated Ci- C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 preferably have a meaning different from Y-Cyc.
- R 2 and R 3 are as defined above and preferably selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C4-alkyl, fluorinated Ci-C 2 -alkyl, Ci-C4-alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- R 7 , R 8 are selected from hydrogen and fluorine and in particular to those compounds, where both R 7 and R 8 are hydrogen.
- R 9 , R 10 are selected from hydrogen and fluorine and in particular to those compounds, where both R 9 and R 10 are hydrogen.
- Het is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C 4 -alkyl, Ci-C 2 -fluoroalkyl, Ci-C 4 -alkoxy, Ci-C 2 -fluoralkoxy, phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
- Het is selected from fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member and which may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, C 1 -C 4 - alkyl, Ci-C 2 -fluoroalkyl, Ci-C 4 -alkoxy, Ci-C 2 -fluoralkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl,
- difluoromethyl trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het is selected from 6-membered monocyclic hetaryl, which may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C4-alkyl, Ci-C 2 -fluoroalkyl, C 1 -C4- alkoxy, Ci-C 2 -fluoralkoxy, phenyl, C3-C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C 6 -cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl or one R x may also be phenyl.
- Het radicals which have at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group CR 9 R 10 and which are selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C 4 -alkyl, Ci-C 2 -fluoroalkyl, Ci-C 4 -alkoxy, C 1 -C 2 - fluoralkoxy, phenyl, C3-C6-cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Het are selected from the group consisting of 2-benzofuryl, 2-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl, 1- methylbenzimidazol-2-yl, imidazo[l ,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2, l-b]-thiazol-6-yl and l ,2,4-triazolo[l ,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1 , 2 or 3 radicals R x as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
- Het has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group CR 9 R 10 and Het is selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1 , 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
- R x is preferably selected from halogen, Ci-C4-alkyl, Ci-C2-fluoroalkyl, Ci-C4-alkoxy, Ci-C2-fluoralkoxy, C3-C6- cycloalkyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated C3-C6- cycloalkyl.
- R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
- Het of this embodiment are 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl, 1- methylbenzimidazol-2-yl, benzothiazol-2-yl, imidazo[l ,2-a]pyridine-2-yl, thieno[3,2- b]pyridine-5-yl, imidazo-[2, l-b]-thiazol-6-yl and l ,2,4-triazolo[l ,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1 , 2 or 3 radicals R x as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluor
- An especially preferred embodiment of the invention relates to the compounds of formulae I-Aa, I-Ab, I-Ac and I-Ad, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
- R is H, F or CH 3 and Q is S, O or in particular N-CH 3 .
- R x is selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-fluoroalkyl, C1-C4- fluoroalkoxy, cyclopropyl, which is optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 5 and R 6 are as defined above and in particular, independently of each other, selected from the group consisting of hydrogen, fluorine and Ci-C4-alkyl, especially hydrogen, fluorine or methyl.
- the radicals R 5 and R 6 together with the carbon atom to which they are bound form a carbonyl group.
- Another especially preferred embodiment of the invention relates to the compounds of formulae I-Ba, I-Bb, I-Bc and I-Bd, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
- R is H, F or CH 3 and Q is S, O or in particular N-CH 3 .
- R x is selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-fluoroalkyl, C 1 -C4- fluoroalkoxy, cyclopropyl, which is optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
- Another especially preferred embodiment of the invention relates to the compounds of formulae I-Ca, I-Cb, I-Cc and I-Cd, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
- R is H, F or CH 3 and Q is S, O or in particular N-CH 3 .
- R x is selected from the group consisting of Ci-C 4 -alkyl, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -fluoroalkyl, C 1 -C 4 - fluoroalkoxy, cyclopropyl, which is optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 5a is in particular selected from the group consisting of hydrogen, Ci-C 4 -alkyl, Ci-C 2 -fluoroalkyl, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, fluorinated cyclopropyl, phenyl and benzyl, where the rings of phenyl and benzyl are unsubstituted or carry 1, 2 or 3 substituents selected from fluorine, methyl, Ci -fluoroalkyl, methoxy and Ci- fluoroalkoxy, especially from methyl.
- the variables X 1 , R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , Y and Cyc in formulae I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I- Cb, I-Cc and I-Cd have the meanings given above, in particular the meanings given for formulae I-A, I-B and I-C and the meanings give below, where these represent, both considered on their own and in combination with at least one other or all, special configurations of the compounds of the formula I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd.
- R 4 is preferably a radical Y-Cyc and X 1 is N or C-R 1 , where R 1 is as defined above and preferably has a meaning different from Y-Cyc.
- I-Aa, I-Ab, I- Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd where X 1 is C-R 1 , , R 1 is in particular selected from the group consisting of hydrogen, fluorine, Ci-C 4 -alkyl, fluorinated Ci-C2-alkyl, Ci-C 4 -alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- a particular group of embodiments relates to compounds of formulae I-A, I-B and
- I-C and likewise to compounds of the formulae I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc, as well as to the N-oxides, the prodrugs, the tautomers and the hydrates thereof, and to the pharmaceutically acceptable salts thereof, where X 1 is N.
- variables R 2 and R 3 preferably have a meaning different from Y-Cyc.
- R 2 and R 3 are as defined above and preferably selected, independently of each other, from the group consisting of hydrogen, fluorine, Ci-C 4 -alkyl, fluorinated Ci-C 2 - alkyl, Ci-C 4 -alkoxy, fluorinated Ci-C 2 -alkoxy, cyclopropyl, optionally substituted by 1 , 2 or 3 methyl groups, and fluorinated cyclopropyl.
- R 2 and R 3 are both hydrogen.
- R 9 , R 10 are selected from hydrogen and fluorine and in particular to those compounds, where both R 9 and R 10 are hydrogen.
- Y in the moieties Y-Cyc is preferably selected from O, NH and a chemical bond.
- Cyc is preferably selected from the groups of
- phenyl or a 5- or 6 membered hetaryl which has one heteroatom, selected from O, S and N as ring member and optionally one or two further heteroatoms as ring members, and which is in particular selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular
- radicals R where R , R" z and Y * are as defined herein and where Y', if present, is preferably a chemical bond or O.
- R C1 is preferably selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 , or, if Cyc is phenyl, two radicals R C1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6- benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl, 2,3- dihydrobenzofuran-6-yl, l,3-dihydroindol-2-on-5-yl, l,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-quina
- R C2 is preferably selected from the group consisting of phenyl, C 3 -
- C6-cycloalkyl optionally substituted by 1, 2, or 3 methyl groups, fluorinated C 3 -C 6 - cycloalkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, where phenyl the saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals R C3 , which are preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and N3 ⁇ 4.
- Cyc is in particular selected from the groups of
- phenyl or a 5- or 6 membered hetaryl selected from pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
- R where R , R and Y * are as defined herein and where Y', if present, is preferably a chemical bond or O.
- R C1 unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y'-R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R C1 , where R C1 , R C2 and Y' are as defined herein and where Y', if present, is preferably a chemical bond or O.
- Y is preferably selected from O, NH and a chemical bond, with particular preference given to Y being a chemical bond.
- Y-Cyc is e.g. selected from the group consisting of 1-piperidinyl, 4,4-difluoro-l-piperidinyl, 4-piperidinyl, l-methyl-4- piperidinyl, 1-piperazinyl, 4-methyl-l-piperazinyl, morpholin-4-yl, 2-oxa-6-azaspiro- [3,4]octyl, 2,5-diazabicyclo[2.2. l]heptan-2-yl, 3,8-diazabicyclo[3.2.
- hetero aromatic radical which has one heteroatom, selected from O, S and N as ring member and optionally one or two further heteroatoms as ring members, and which is in particular selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetero aromatic radical are unsubstituted or either carry, independently of each other, carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y * -R C2
- R is preferably a chemical bond or O.
- Cyc is selected from the group consisting of phenyl or a 5- or 6 membered hetaryl, selected from yridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y * -R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R C1 ,
- Cyc is selected from the group consisting of phenyl and 5- or 6- membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals R C1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 , or, if Cyc is phenyl, two radicals R C1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6-benzotriazoly
- Y is a chemical bond.
- Cyc is selected from the group consisting of phenyl and 5- or 6-membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals R C1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 .
- R C1 is preferably selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl,
- R C2 is preferably selected from the group consisting of phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, fluorinated C 3 -C 6 -cycloalkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, where phenyl the saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals R C3 , which are preferably selected from fluorine, chlorine, CN, methyl, di
- Particular embodiment of the invention relates to the compounds of formula I, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof, where the compounds of the formula I are selected from the group consisting of:
- the compounds of the invention of the general formula I and the starting materials used to prepare them can be prepared in analogy to known processes of organic chemistry as are described in standard works of organic chemistry, e.g. Houben- Weyl, “Methoden der Organischen Chemie”, Thieme-Verlag, Stuttgart, Jerry March “Advanced Organic Chemistry", 5 th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2 nd edition, Weinheim, 1999 and the literature cited therein.
- the compounds of the invention of the general formula I are advantageously prepared by the methods described below and/or in the experimental section.
- Het, A, R 7 , R 8 , R 9 and R 10 are as defined for formulae I, I-A, I-B or I-C;
- R la , r R > 4a independently of each other, are selected from the group consisting of hydrogen, halogen, Ci-C4-alkyl, trimethylsilyl, Ci-C4-alkylsulfanyl, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, Ci-C4-alkylsulfanyl-Ci-C4-alkoxy, C2-C4-alkenyloxy, C1-C4- fluoroalkyl, Ci-C 4 -fiuoroalkoxy, CN, NR xl R x2 , NR xl R x2 -Ci-C 4 - alkoxy; R 2a , R 3a independently of each other, are selected from the group consisting of hydrogen, halogen, Ci-C 4 -alkyl, trimethylsilyl, Ci-C 4 -al
- radicals R la , R 2a , R 3a and R 4a in particular exactly one of these radicals is bromine or iodine, while the others are different from bromine or iodine;
- M is a Li, B(OR B1 )(OR B2 ) radical or an Sn(R Sn ) 3 radical, where R B1 and R B2 are, independently of each other, hydrogen or Ci-C4-alkyl or R B1 and R B2 together form a C 2 -C 6 -alkandiyl moietyl, e.g. ethan-l ,2-diyl, propan-l ,3-diyl or l , l,2,2-tetramethylethan-l ,2-diyl, and wherein R Sn is Ci-C 6 -alkyl or C 3 - C 6 -cycloalkyl or phenyl.
- reaction of the compound II with the compound III can be performed by analogy to known coupling reactions in the presence of suitable transition metal catalysts, in particular palladium catalysts.
- suitable transition metal catalysts in particular palladium catalysts.
- Typical reactions conditions are those of Stille coupling (see e.g. Stille et al. Angew. Chem. Int. Ed. Engl. 1986, 25,508;
- Het, A, R 7 , R 8 , R 9 and R 10 are as defined for formulae I, I-A, I-B or I-C;
- R lb , r R> 4b independently of each other, are selected from the group consisting of hydrogen, Ci-C4-alkyl, trimethylsilyl, Ci-C4-alkylsulfanyl, C1-C4- alkoxy-Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, Ci- C4-alkylsulfanyl-Ci-C4-alkoxy, C 2 -C4-alkenyloxy, Ci-C4-fluoroalkyl, Ci-C 4 -fiuoroalkoxy, CN, NR xl R x2 , NR xl R x2 -Ci-C 4 -alkoxy or a moiety
- R 2b R 3b independently of each other, are selected from the group consisting of hydrogen, Ci-C4-alkyl, trimethylsilyl, Ci-C4-alkoxy-Ci-C4-alkyl, Ci- C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, C 2 -C4-alkenyloxy, C1-C4- fluoroalkyl, Ci-C 4 -fluoroalkoxy, CN and NR xl R x2 , or a moiety M; provided that 1 or 2 of the radicals R lb , R 2b , R 3b and R 4b , in particular exactly one of these radicals is moiety M, while the others are different from M, where M is as defined for formual III and in particular a B(OR B1 )(OR B2 ) radical; with a compound of formula Illb,
- Hal-Y-Cyc (Illb) where Y and Cyc are as defined herein and wherein Hal is bromine or iodine.
- the reaction of the compound lla with the compound Ilia can be performed by analogy tot the reaction of compound II with compound III.
- the compounds II, Ila, III, Ilia and Illb are known or can be prepared by standard methods of organic chemistry.
- a triarylphosphine such as triphenylphosphine, tritolylphosphine or 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthalene (BINAP), tri(cyclo)alkylphosphine such as tris-n-butylphosphine, tris(tert-butyl)phosphine or tris(cyclohexylphosphine), or dicyclohexyl-(2',4',6'-tri-iso-propyl-biphenyl-2-yl)- phosphane (X-Phos).
- a base such as an alkaline alkoxide, earth alkine alkoxide, alkaline carbonate or earth alkaline carbonate such as or sodium tert-butoxide or cesium carbonate.
- X 1 , X 2 , X 3 , X 4 , X la , X 2a , X 3a , X 4a , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and Het are as defined above
- R v is Ci-C4-alkoxy, e.g. methoxy or ethoxy
- L is a suitable leaving group, e.g. chlorine, bromine, alkylsulfonyloxy such as methan- sulfonyloxy or arylsulfonyloxy such as phenylsulfonyloxy or p-tolylsulfonyloxy.
- L may also be OH or Ci-C4-alkoxy, if CR 5 R 6 represents a carbonyl group.
- X 1 , X 2 , X 3 , X 4 , X la , X 2a , X 3a , X 4a , R 7 , R 8 , R 9 , R 10 and Het are as defined above, and Hal' is a suitable leaving group, e.g. fluorine.
- the reaction of the carboxylic acid VII and Vila, respectively, with a hydroxylamine compound VI is usually carried out in the presence of an activating agent of carboxylic acids, e.g.
- carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide or triazoles such as 1 -hydro xybenzotriazole, 1 -hydro xy-7-aza-benzotriazole, benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate or benzotriazole- 1 -yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate.
- X 1 , X 2 , X 3 , X 4 , X la , X 2a , X 3a , X 4a , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 and Het are as defined above.
- Compounds of the formulae X and Xa, respectively, can be prepared in analogy to known methods, e.g. as described in J. Heterocycl. Chem.
- a suitable fluorinating agent e.g. HF or HF adduct of tetraalkyl- amonium fluoride
- the N-oxides of compound I may be prepared from the compounds of formula I according to conventional oxidation methods, for example by treating said compounds with an organic peracid; such as metachloroperbenzoic acid or 3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(1 1), 1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; such as hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7), 1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society 123(25), 5962-5973 (2001)].
- the oxidation may lead to pure mono-N-oxides or to a mixture of different N-oxides, which can be separated by conventional methods; such as chromatography.
- Compounds of the formula Ila can be prepared from compounds of the formula II by suitable metal-halogen exchange reactions.
- the reactions are usually performed in an organic solvent, including aprotic organic solvent, e.g. substituted amides, lactames and ureas; such as
- reaction mixtures are worked up in a conventional way, e.g. by mixing with water, separating the phases and, where appropriate, purifying the crude products by chromatography.
- the intermediates and final products in some cases result in the form of colorless or pale brownish, viscous oils which are freed of volatiles or purified under reduced pressure and at moderately elevated temperature. If the intermediates and final products are obtained as solids, the purification can also take place by recrystallization or digestion.
- the compounds of the formula I, their N-oxides, their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable salts thereof are particularly suitable for treating disorders or conditions, which can be treated by inhibition of phosphodiesterase type 10A.
- the terms "treating” and "treatment” in terms of the present invention have to be understood to include both curative treatment of the cause of a disease or disorder, the treatment of the symptoms associated with a disease or disorder, i.e. controlling the disease or disorder or ameliorating the conditions or symptoms associated with a disease or disorder, and prophylactic treatment, i.e. a treatment for reducing the risk of a disease or disorder.
- Neurological and psychiatric disorders or conditions which can be treated by inhibition of PDE10A, including curative treatment, control or amelioration and prophylaxis include CNS disorders, in particular schizophrenia, depression, bipolar disorders, cognitive dysfunctions associated with schizophrenia, cognitive dysfunctions associated with Alzheimer's disease, Huntington's disease (Huntington chorea), anxiety and substance-related disorders, especially substance use disorder, substance tolerance conditions associated with substance withdrawal.
- CNS disorders in particular schizophrenia, depression, bipolar disorders, cognitive dysfunctions associated with schizophrenia, cognitive dysfunctions associated with Alzheimer's disease, Huntington's disease (Huntington chorea), anxiety and substance-related disorders, especially substance use disorder, substance tolerance conditions associated with substance withdrawal.
- Disorders or conditions which can be treated by inhibition of PDE10A, including curative treatment, control or amelioration and prophylaxis also include treatment of diet induced obesity.
- the invention relates to the use of compounds of formula I, their N-oxides, their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable salts thereof, for treatment of disorders or conditions, which can be treated by inhibition of phosphodiesterase type 10A, i.e. the invention relates to the use of such compounds for curative treatment of such a disease or disorder, controlling such a disease or disorder, ameliorating the symptoms associated with such a disease or disorder and reducing the risk for such a disease or disorder.
- the present invention also relates to a method for the treatment of a medical disorder, selected from neurological and psychiatric disorders which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof, to a mammal in need thereof.
- the present invention in particular relates to :
- ⁇ a method for treating, controlling, ameliorating or reducing the risk of
- ⁇ a method for treating, controlling, ameliorating or reducing the risk of
- the subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom inhibition of PDE10A is desired.
- the terms "effective amount” and “therapeutically effective amount” mean the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention.
- treatment and “treating” refer to all processes, wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
- composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- a preferred embodiment of the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
- the present invention provides a method for treating cognitive disturbances associated with schizophrenia, comprising:
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.)
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders
- the disorder includes: paranoid, disorganized, catatonic, undifferentiated, and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, and psychotic disorder not otherwise specified.
- the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular schizophrenia, and that these systems evolve with medical scientific progress.
- the term DSM-IV Diagnostic and Statistical Manual of Mental Disorders
- schizophrenia is intended to include like disorders that are described in other diagnostic sources.
- the present invention provides a method for treating substance-related disorders, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
- the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders
- anxiety includes treatment of those anxiety disorders and related disorder as described in the DSM-IV.
- the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress.
- the term “anxiety” is intended to include like disorders that are described in other diagnostic sources.
- the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders
- Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
- depression includes treatment of those depression disorders and related disorder as described in the DSM-IV.
- the present invention provides a method for treating substance-related disorders, especially substance dependence, substance abuse, substance tolerance, and substance withdrawal, comprising: administering to a patient in need thereof an effective amount at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.)
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.)
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.)
- DSM-IV Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.)
- disorders related to taking a drug of abuse including alcohol
- Substances include alcohol, amphetamine and similarly acting sympathomimetics
- arylcyclohexylamines and sedatives, hypnotics, or anxiolytics.
- polysubstance dependence and other unknown substance-related disorders are included.
- the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular substance-related disorders, and that these systems evolve with medical scientific progress.
- the term "substance-related disorder” is intended to include like disorders that are described in other diagnostic sources.
- an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
- the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
- a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
- compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams, in the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams.
- This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
- the compounds of the present invention may be administered by conventional routes of administration, including parenteral (e.g., intramuscular, intrapentoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), oral, by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration.
- parenteral e.g., intramuscular, intrapentoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
- oral by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration.
- the compounds according to the present invention are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
- the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
- Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula I.
- a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred.
- the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules.
- the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
- the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I.
- the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
- compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
- Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
- a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
- the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
- the weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
- the present invention also relates to pharmaceutical compositions (i.e.
- medicaments which comprise at least one compound of the present invention and, where appropriate, one or more suitable excipients.
- excipients/drug carriers are chosen according to the pharmaceutical form and the desired mode of administration.
- the compounds of the present invention can be used to manufacture
- compositions for parenteral e.g., intramuscular, intrapentoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
- oral, sublingual, intratracheal, intranasal, topical, transdermal, vaginal or rectal administration e.g., intramuscular, intrapentoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
- oral, sublingual, intratracheal intranasal, topical, transdermal, vaginal or rectal administration, and be administered to animals or humans in unit dose forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above impairments or diseases.
- the at least one compound of the present invention may be formulated alone or together with further active compounds, in suitable dosage unit formulations containing conventional excipients, which generally are non-toxic and/or pharmaceutically acceptable.
- Carriers or excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound. Suitable excipients are listed in the specialist medicinal monographs.
- 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; hydro colloids; 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; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers;
- glidants such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers;
- Suitable unit dose forms include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
- the compounds of the invention can be used in creams, ointments or lotions for topical administration.
- a solid composition is prepared in the form of tablets, the main ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
- a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
- the tablets may be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a prolonged or delayed activity and in order to release a predetermined amount of the active basic ingredient continuously.
- a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
- a preparation in the form of a syrup or elixir or for administration in the form of drops may comprise active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring.
- a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring.
- the water-dispersible powders or granules may comprise the active ingredients mixed with dispersants, wetting agents or suspending agents such as
- polyvinylpyrrolidones and sweeteners or taste improvers.
- Rectal administration is achieved by the use of suppositories which are prepared with binders which melt at the rectal temperature, for example cocobutter or
- Parenteral administration is effected by using aqueous
- compositions suspensions, isotonic salt solutions or sterile and injectable solutions which comprise pharmacologically suitable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
- the active basic ingredient may also be formulated as microcapsules or liposomes/centrosomes, if suitable with one or more carriers or additives.
- compositions of the invention may comprise further active basic ingredients which may be beneficial for the treatment of the impairments or diseases indicated above.
- the present invention thus further relates to pharmaceutical compositions in which a plurality of active basic ingredients are present together, where at least one thereof is a compound of the invention.
- the compounds according to the invention are optionally mixed or diluted with one or more carriers.
- AIBN for azobisisobutyronitrile
- BINAP for 2,2'-bis (diphenylphosphino)-l,l'- binaphthyl
- BOC for tert-butyloxycarbonyl
- DCM for dichloromethane
- DEAD for diethyl azodicarboxylate
- DIAD for diisopropyl azodicarboxylate
- DIPEA N,N- diisopropylethylamine
- DMF for dimethylformamide
- DMSO for dimethyl sulfoxide
- EA or EtOAc for ethyl acetate (ethyl ethanoate); Et for ethyl; EtOH for ethanol; HO Ac or AcOH for acetic acid
- LDA for lithium diisopropylamide
- LiHMDS for lithium bis (trimethylsilyl)amide
- Me for methyl
- MeOD or MeOD-d4 for deuterated methanol
- PyBOP for benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate
- Raney-Ni for Raney nickel
- R t for retension time
- TBAI for tetrabutylammonium iodide
- TFA for trifluoro acetic acid
- THF for tetrahydroiuran
- TMSCl trimethylsilyl chloride
- X-PHOS for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Child & Adolescent Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (11)
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NZ618930A NZ618930A (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10a |
AU2012277802A AU2012277802A1 (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10A |
CN201280042318.5A CN103958504B (en) | 2011-06-30 | 2012-06-28 | 10A type phosphodiesterase inhibitor compound |
CA2839655A CA2839655A1 (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10a |
JP2014517695A JP2014518237A (en) | 2011-06-30 | 2012-06-28 | Novel phosphodiesterase type 10A inhibitor compound |
BR112013033696A BR112013033696A2 (en) | 2011-06-30 | 2012-06-28 | new phosphodiesterase type 10a inhibiting compounds |
MX2013015390A MX2013015390A (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10a. |
KR1020147002761A KR20140050028A (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10a |
RU2014102962/04A RU2014102962A (en) | 2011-06-30 | 2012-06-28 | NEW COMPOSITION INHIBITORS OF PHOSPHODIESTHERASIS TYPE 10A |
EP12731416.9A EP2726479A1 (en) | 2011-06-30 | 2012-06-28 | Novel inhibitor compounds of phosphodiesterase type 10a |
ZA2013/09561A ZA201309561B (en) | 2011-06-30 | 2013-12-18 | Novel inhibitor compounds of phosphodiestarase type 10a |
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US201161503040P | 2011-06-30 | 2011-06-30 | |
US61/503,040 | 2011-06-30 |
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US (2) | US9938269B2 (en) |
EP (1) | EP2726479A1 (en) |
JP (1) | JP2014518237A (en) |
KR (1) | KR20140050028A (en) |
CN (1) | CN103958504B (en) |
AR (1) | AR086817A1 (en) |
AU (1) | AU2012277802A1 (en) |
BR (1) | BR112013033696A2 (en) |
CA (1) | CA2839655A1 (en) |
CL (1) | CL2013003731A1 (en) |
CO (1) | CO6870032A2 (en) |
CR (1) | CR20140023A (en) |
DO (1) | DOP2013000315A (en) |
EC (1) | ECSP14013188A (en) |
GT (1) | GT201300324A (en) |
MX (1) | MX2013015390A (en) |
NZ (1) | NZ618930A (en) |
PE (1) | PE20141308A1 (en) |
RU (1) | RU2014102962A (en) |
SG (1) | SG10201605196PA (en) |
TW (1) | TW201311662A (en) |
UY (1) | UY34177A (en) |
WO (1) | WO2013000994A1 (en) |
ZA (1) | ZA201309561B (en) |
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2012
- 2012-06-27 US US13/534,127 patent/US9938269B2/en active Active
- 2012-06-28 CA CA2839655A patent/CA2839655A1/en not_active Abandoned
- 2012-06-28 WO PCT/EP2012/062544 patent/WO2013000994A1/en active Application Filing
- 2012-06-28 AU AU2012277802A patent/AU2012277802A1/en not_active Abandoned
- 2012-06-28 MX MX2013015390A patent/MX2013015390A/en unknown
- 2012-06-28 NZ NZ618930A patent/NZ618930A/en not_active IP Right Cessation
- 2012-06-28 EP EP12731416.9A patent/EP2726479A1/en active Pending
- 2012-06-28 CN CN201280042318.5A patent/CN103958504B/en not_active Expired - Fee Related
- 2012-06-28 BR BR112013033696A patent/BR112013033696A2/en not_active IP Right Cessation
- 2012-06-28 JP JP2014517695A patent/JP2014518237A/en active Pending
- 2012-06-28 PE PE2013002907A patent/PE20141308A1/en not_active Application Discontinuation
- 2012-06-28 KR KR1020147002761A patent/KR20140050028A/en not_active Application Discontinuation
- 2012-06-28 RU RU2014102962/04A patent/RU2014102962A/en not_active Application Discontinuation
- 2012-06-28 SG SG10201605196PA patent/SG10201605196PA/en unknown
- 2012-06-29 UY UY0001034177A patent/UY34177A/en not_active Application Discontinuation
- 2012-06-29 TW TW101123611A patent/TW201311662A/en unknown
- 2012-06-29 AR ARP120102358A patent/AR086817A1/en unknown
-
2013
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- 2013-12-26 GT GT201300324A patent/GT201300324A/en unknown
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2014
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TW201311662A (en) | 2013-03-16 |
DOP2013000315A (en) | 2014-04-15 |
SG10201605196PA (en) | 2016-08-30 |
US20180222905A1 (en) | 2018-08-09 |
JP2014518237A (en) | 2014-07-28 |
ECSP14013188A (en) | 2014-12-30 |
CA2839655A1 (en) | 2013-01-03 |
CR20140023A (en) | 2014-08-21 |
EP2726479A1 (en) | 2014-05-07 |
KR20140050028A (en) | 2014-04-28 |
CO6870032A2 (en) | 2014-02-20 |
CN103958504B (en) | 2016-10-12 |
AR086817A1 (en) | 2014-01-22 |
ZA201309561B (en) | 2014-08-27 |
GT201300324A (en) | 2014-09-26 |
RU2014102962A (en) | 2015-08-10 |
CL2013003731A1 (en) | 2014-10-10 |
BR112013033696A2 (en) | 2016-08-30 |
MX2013015390A (en) | 2014-07-14 |
AU2012277802A8 (en) | 2014-03-06 |
UY34177A (en) | 2013-01-31 |
US20130005705A1 (en) | 2013-01-03 |
NZ618930A (en) | 2015-05-29 |
PE20141308A1 (en) | 2014-10-26 |
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CN103958504A (en) | 2014-07-30 |
US9938269B2 (en) | 2018-04-10 |
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