NZ575389A - Dibenzofuran derivatives as inhibitors of pde-4 and pde-10 - Google Patents

Info

Publication number

NZ575389A

NZ575389A NZ575389A NZ57538907A NZ575389A NZ 575389 A NZ575389 A NZ 575389A NZ 575389 A NZ575389 A NZ 575389A NZ 57538907 A NZ57538907 A NZ 57538907A NZ 575389 A NZ575389 A NZ 575389A

Authority

NZ

New Zealand

Prior art keywords

compound according

methoxydibenzo

furan

compound

formula

Prior art date

2006-09-11

Links

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• 239000003112 inhibitor Substances 0.000 title claims description 24
• 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 title 1
• 150000004826 dibenzofurans Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 167
• -1 Ethyl { [6-cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]oxy} acetate Chemical class 0.000 claims abstract description 74
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• 208000006673 asthma Diseases 0.000 claims abstract description 23
• 238000000034 method Methods 0.000 claims abstract description 23
• 208000035475 disorder Diseases 0.000 claims abstract description 20
• 230000004968 inflammatory condition Effects 0.000 claims abstract description 17
• 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 12
• 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 12
• 210000003169 central nervous system Anatomy 0.000 claims abstract description 12
• 208000011231 Crohn disease Diseases 0.000 claims abstract description 11
• 239000012453 solvate Substances 0.000 claims abstract description 11
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 10
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims abstract description 10
• 206010069698 Langerhans' cell histiocytosis Diseases 0.000 claims abstract description 10
• 201000004681 Psoriasis Diseases 0.000 claims abstract description 10
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims abstract description 10
• 206010040070 Septic Shock Diseases 0.000 claims abstract description 10
• 208000002205 allergic conjunctivitis Diseases 0.000 claims abstract description 10
• 208000024998 atopic conjunctivitis Diseases 0.000 claims abstract description 10
• 208000003401 eosinophilic granuloma Diseases 0.000 claims abstract description 10
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• 150000001204 N-oxides Chemical class 0.000 claims abstract description 9
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• 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 8
• 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 8
• 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 8
• 230000000172 allergic effect Effects 0.000 claims abstract description 8
• 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 8
• 206010006451 bronchitis Diseases 0.000 claims abstract description 8
• 208000007451 chronic bronchitis Diseases 0.000 claims abstract description 8
• 208000037976 chronic inflammation Diseases 0.000 claims abstract description 8
• 230000006020 chronic inflammation Effects 0.000 claims abstract description 8
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 8
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• 208000011580 syndromic disease Diseases 0.000 claims abstract description 8
• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims abstract description 7
• 238000002360 preparation method Methods 0.000 claims abstract description 7
• 208000010668 atopic eczema Diseases 0.000 claims abstract description 4
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims abstract description 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
• 238000006243 chemical reaction Methods 0.000 claims description 43
• 229920006395 saturated elastomer Polymers 0.000 claims description 38
• 125000000217 alkyl group Chemical group 0.000 claims description 36
• 239000000243 solution Substances 0.000 claims description 33
• 239000001257 hydrogen Substances 0.000 claims description 31
• 229910052739 hydrogen Inorganic materials 0.000 claims description 31
• 239000000203 mixture Substances 0.000 claims description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
• 125000005842 heteroatom Chemical group 0.000 claims description 23
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 22
• 101150041968 CDC13 gene Proteins 0.000 claims description 21
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 claims description 21
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 208000027866 inflammatory disease Diseases 0.000 claims description 19
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 18
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 18
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims description 16
• 239000012044 organic layer Substances 0.000 claims description 15
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 229910052938 sodium sulfate Inorganic materials 0.000 claims description 11
• 235000011152 sodium sulphate Nutrition 0.000 claims description 11
• 125000003107 substituted aryl group Chemical group 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 125000005843 halogen group Chemical group 0.000 claims description 10
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 239000003085 diluting agent Substances 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 8
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• 125000002723 alicyclic group Chemical group 0.000 claims description 8
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• 125000003367 polycyclic group Chemical group 0.000 claims description 7
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• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 239000000725 suspension Substances 0.000 claims description 6
• MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 claims description 5
• 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 5
• 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 125000001188 haloalkyl group Chemical group 0.000 claims description 5
• 239000010410 layer Substances 0.000 claims description 5
• 210000004072 lung Anatomy 0.000 claims description 5
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• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
• 239000002253 acid Substances 0.000 claims description 4
• 239000004480 active ingredient Substances 0.000 claims description 4
• 239000000443 aerosol Substances 0.000 claims description 4
• 239000002775 capsule Substances 0.000 claims description 4
• 210000002216 heart Anatomy 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
• 150000002923 oximes Chemical class 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 230000009467 reduction Effects 0.000 claims description 4
• 208000018737 Parkinson disease Diseases 0.000 claims description 3
• 125000003282 alkyl amino group Chemical group 0.000 claims description 3
• 125000003368 amide group Chemical group 0.000 claims description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
• 238000007333 cyanation reaction Methods 0.000 claims description 3
• GRTGGSXWHGKRSB-UHFFFAOYSA-N dichloromethyl methyl ether Chemical compound COC(Cl)Cl GRTGGSXWHGKRSB-UHFFFAOYSA-N 0.000 claims description 3
• 150000002148 esters Chemical class 0.000 claims description 3
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
• 239000007921 spray Substances 0.000 claims description 3
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
• 208000024827 Alzheimer disease Diseases 0.000 claims description 2
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• 208000031091 Amnestic disease Diseases 0.000 claims description 2
• 206010012289 Dementia Diseases 0.000 claims description 2
• 206010019280 Heart failures Diseases 0.000 claims description 2
• 125000005250 alkyl acrylate group Chemical group 0.000 claims description 2
• 239000002168 alkylating agent Substances 0.000 claims description 2
• 229940100198 alkylating agent Drugs 0.000 claims description 2
• 230000006986 amnesia Effects 0.000 claims description 2
• 208000026106 cerebrovascular disease Diseases 0.000 claims description 2
• 238000005660 chlorination reaction Methods 0.000 claims description 2
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• 238000006170 formylation reaction Methods 0.000 claims description 2
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• HIGCNPFUSCKGDA-UHFFFAOYSA-N methyl 5-cyano-5-(4-methoxydibenzofuran-1-yl)-2-oxocyclohexane-1-carboxylate Chemical compound C1CC(=O)C(C(=O)OC)CC1(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 HIGCNPFUSCKGDA-UHFFFAOYSA-N 0.000 claims description 2
• WZUXAFMNSHCLIL-UHFFFAOYSA-N n-[4-cyano-4-(4-methoxydibenzofuran-1-yl)cyclohexyl]methanesulfonamide Chemical compound C1=2C3=CC=CC=C3OC=2C(OC)=CC=C1C1(C#N)CCC(NS(C)(=O)=O)CC1 WZUXAFMNSHCLIL-UHFFFAOYSA-N 0.000 claims description 2
• 230000035939 shock Effects 0.000 claims description 2
• 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
• ZFVYYLHRPOSPAG-FYWRMAATSA-N (3e)-3-(dimethylaminomethylidene)-1-(4-methoxydibenzofuran-1-yl)-4-oxocyclohexane-1-carbonitrile Chemical compound C1=2C3=CC=CC=C3OC=2C(OC)=CC=C1C1(C#N)CCC(=O)\C(=C\N(C)C)C1 ZFVYYLHRPOSPAG-FYWRMAATSA-N 0.000 claims 1
• VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims 1
• KEOIXQQDQABMPL-UHFFFAOYSA-N 2-[6-cyano-6-(4-methoxydibenzofuran-1-yl)-4-oxo-7,8-dihydro-5h-quinazolin-3-yl]acetic acid Chemical compound N1=CN(CC(O)=O)C(=O)C(C2)=C1CCC2(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 KEOIXQQDQABMPL-UHFFFAOYSA-N 0.000 claims 1
• FDJDWXHNIUYDQQ-UHFFFAOYSA-N 2-[[6-cyano-6-(4-methoxydibenzofuran-1-yl)-7,8-dihydro-5h-quinazolin-2-yl]amino]acetic acid Chemical compound C1CC2=NC(NCC(O)=O)=NC=C2CC1(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 FDJDWXHNIUYDQQ-UHFFFAOYSA-N 0.000 claims 1
• NMBMYZIIGIVTTK-UHFFFAOYSA-N 2-amino-6-(4-methoxydibenzofuran-1-yl)-4-oxo-1,5,7,8-tetrahydroquinazoline-6-carbonitrile Chemical compound N1=C(N)NC(=O)C(C2)=C1CCC2(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 NMBMYZIIGIVTTK-UHFFFAOYSA-N 0.000 claims 1
• VXLSJDHGLZNWCZ-UHFFFAOYSA-N 2-amino-6-(4-methoxydibenzofuran-1-yl)-7,8-dihydro-5h-quinazoline-6-carbonitrile Chemical compound C1CC2=NC(N)=NC=C2CC1(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 VXLSJDHGLZNWCZ-UHFFFAOYSA-N 0.000 claims 1
• SZBXZDLWKDKXRL-UHFFFAOYSA-N 4-cyano-4-(4-methoxydibenzofuran-1-yl)cyclohexane-1-carboxylic acid Chemical compound C1=2C3=CC=CC=C3OC=2C(OC)=CC=C1C1(C#N)CCC(C(O)=O)CC1 SZBXZDLWKDKXRL-UHFFFAOYSA-N 0.000 claims 1
• JAARYBGJMQKFRG-UHFFFAOYSA-N 5-(4-methoxydibenzofuran-1-yl)-1,4,6,7-tetrahydroindazole-5-carbonitrile Chemical compound C1CC2=NNC=C2CC1(C#N)C1=CC=C(OC)C2=C1C1=CC=CC=C1O2 JAARYBGJMQKFRG-UHFFFAOYSA-N 0.000 claims 1
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