JP2009504761A - 睡眠剤と置換ビスアリール及びヘテロアリール化合物の組み合わせ物及び治療でのその使用 - Google Patents

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Publication number

JP2009504761A

JP2009504761A JP2008527115A JP2008527115A JP2009504761A JP 2009504761 A JP2009504761 A JP 2009504761A JP 2008527115 A JP2008527115 A JP 2008527115A JP 2008527115 A JP2008527115 A JP 2008527115A JP 2009504761 A JP2009504761 A JP 2009504761A

Authority

JP

Japan

Prior art keywords

alkyl

sleep

compound

formula

fluoro

Prior art date

2005-08-19

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 125000001072 heteroaryl group Chemical group 0.000 title claims description 43
• 230000000147 hypnotic effect Effects 0.000 title description 9
• 239000003326 hypnotic agent Substances 0.000 title description 7
• 238000002560 therapeutic procedure Methods 0.000 title description 2
• 230000007958 sleep Effects 0.000 claims abstract description 227
• 208000019116 sleep disease Diseases 0.000 claims abstract description 43
• 239000000126 substance Substances 0.000 claims abstract description 23
• 150000001875 compounds Chemical class 0.000 claims description 171
• 125000000217 alkyl group Chemical group 0.000 claims description 133
• 239000003795 chemical substances by application Substances 0.000 claims description 113
• 239000000203 mixture Substances 0.000 claims description 107
• 239000003826 tablet Substances 0.000 claims description 82
• 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 75
• 239000008188 pellet Substances 0.000 claims description 69
• 238000000034 method Methods 0.000 claims description 54
• 125000003118 aryl group Chemical group 0.000 claims description 45
• 125000000623 heterocyclic group Chemical group 0.000 claims description 43
• 229910052757 nitrogen Inorganic materials 0.000 claims description 43
• ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 claims description 41
• 229960001475 zolpidem Drugs 0.000 claims description 41
• 239000010410 layer Substances 0.000 claims description 38
• 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
• 206010022437 insomnia Diseases 0.000 claims description 35
• 150000003839 salts Chemical class 0.000 claims description 32
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 230000003111 delayed effect Effects 0.000 claims description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
• 239000002775 capsule Substances 0.000 claims description 28
• 239000003814 drug Substances 0.000 claims description 27
• 208000035475 disorder Diseases 0.000 claims description 26
• 229910052717 sulfur Inorganic materials 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 20
• 229910052739 hydrogen Inorganic materials 0.000 claims description 20
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 208000020685 sleep-wake disease Diseases 0.000 claims description 16
• 125000003282 alkyl amino group Chemical group 0.000 claims description 14
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• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 150000002367 halogens Chemical class 0.000 claims description 12
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 10
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 10
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• 239000012453 solvate Substances 0.000 claims description 9
• GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 claims description 7
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 7
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• GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 claims description 7
• DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical class COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
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• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
• 125000002619 bicyclic group Chemical group 0.000 claims description 6
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• UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 claims description 5
• 102000004300 GABA-A Receptors Human genes 0.000 claims description 5
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• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 5
• 229960003051 brotizolam Drugs 0.000 claims description 5
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 5
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• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 claims description 5
• 229960003386 triazolam Drugs 0.000 claims description 5
• HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 claims description 5
• 229960004010 zaleplon Drugs 0.000 claims description 5
• VMZUTJCNQWMAGF-UHFFFAOYSA-N Etizolam Chemical compound S1C(CC)=CC2=C1N1C(C)=NN=C1CN=C2C1=CC=CC=C1Cl VMZUTJCNQWMAGF-UHFFFAOYSA-N 0.000 claims description 4
• CBIAWPMZSFFRGN-UHFFFAOYSA-N Indiplon Chemical compound CC(=O)N(C)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C(=O)C=2SC=CC=2)=C1 CBIAWPMZSFFRGN-UHFFFAOYSA-N 0.000 claims description 4
• YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 4
• YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 claims description 4
• 229960004404 etizolam Drugs 0.000 claims description 4
• 229950003867 indiplon Drugs 0.000 claims description 4
• 229960003987 melatonin Drugs 0.000 claims description 4
• 229960001150 ramelteon Drugs 0.000 claims description 4
• 239000002974 melatonin derivative Substances 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
• 150000002431 hydrogen Chemical class 0.000 claims 3
• SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims 2
• 102000001419 Melatonin receptor Human genes 0.000 claims 2
• 108050009605 Melatonin receptor Proteins 0.000 claims 2
• 239000000556 agonist Substances 0.000 claims 2
• 229940075993 receptor modulator Drugs 0.000 claims 2
• 239000000969 carrier Substances 0.000 claims 1
• -1 heteroaryl compound Chemical class 0.000 description 245
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 29
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• 239000002904 solvent Substances 0.000 description 25
• 238000006243 chemical reaction Methods 0.000 description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• 239000000243 solution Substances 0.000 description 22
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
• 229940079593 drug Drugs 0.000 description 21
• 125000001544 thienyl group Chemical group 0.000 description 21
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
• 239000002585 base Substances 0.000 description 20
• 230000002829 reductive effect Effects 0.000 description 20
• 239000004480 active ingredient Substances 0.000 description 19
• 125000002541 furyl group Chemical group 0.000 description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
• 239000002245 particle Substances 0.000 description 19
• 125000004076 pyridyl group Chemical group 0.000 description 19
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• 238000002360 preparation method Methods 0.000 description 18
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• 125000001207 fluorophenyl group Chemical group 0.000 description 17
• 230000014509 gene expression Effects 0.000 description 17
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
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• 230000000694 effects Effects 0.000 description 14
• 150000001412 amines Chemical class 0.000 description 13
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
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