ZA200306601B - New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors. - Google Patents
New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors. Download PDFInfo
- Publication number
- ZA200306601B ZA200306601B ZA200306601A ZA200306601A ZA200306601B ZA 200306601 B ZA200306601 B ZA 200306601B ZA 200306601 A ZA200306601 A ZA 200306601A ZA 200306601 A ZA200306601 A ZA 200306601A ZA 200306601 B ZA200306601 B ZA 200306601B
- Authority
- ZA
- South Africa
- Prior art keywords
- dihydro
- quinazolin
- lower alkyl
- cyclohexane
- chloro
- Prior art date
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- 239000002606 phosphodiesterase VII inhibitor Substances 0.000 title description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 250
- 125000000217 alkyl group Chemical group 0.000 claims description 234
- 229910052739 hydrogen Inorganic materials 0.000 claims description 166
- 125000005842 heteroatom Chemical group 0.000 claims description 165
- 239000001257 hydrogen Substances 0.000 claims description 164
- 229910052760 oxygen Inorganic materials 0.000 claims description 160
- 229910052757 nitrogen Inorganic materials 0.000 claims description 131
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 90
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 55
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 229910052799 carbon Inorganic materials 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 125000003003 spiro group Chemical group 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 229910006069 SO3H Inorganic materials 0.000 claims description 20
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 239000003112 inhibitor Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 208000030507 AIDS Diseases 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
- 125000004450 alkenylene group Chemical group 0.000 claims description 5
- 125000004419 alkynylene group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- -1 C(=0)-NH-S0 Chemical group 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 230000007815 allergy Effects 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 101100154785 Mus musculus Tulp2 gene Proteins 0.000 claims description 2
- 238000009396 hybridization Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims 3
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims 1
- MIXPUXLJXCDOBL-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]quinazoline Chemical compound C1=CC=C2N3C=NN=C3N=CC2=C1 MIXPUXLJXCDOBL-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 150000003997 cyclic ketones Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 230000002829 reductive effect Effects 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 150000003672 ureas Chemical class 0.000 claims 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 16
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 9
- 229940123304 Phosphodiesterase 7 inhibitor Drugs 0.000 description 7
- 102000010984 Type 7 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 6
- 108010037622 Type 7 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 6
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101100243082 Caenorhabditis elegans pde-1 gene Proteins 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 1
- 101100135868 Dictyostelium discoideum pde3 gene Proteins 0.000 description 1
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000037189 immune system physiology Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002379 progesterone receptor modulator Substances 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CZPRKINNVBONSF-UHFFFAOYSA-M zinc;dioxido(oxo)phosphanium Chemical compound [Zn+2].[O-][P+]([O-])=O CZPRKINNVBONSF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P35/04—Antineoplastic agents specific for metastasis
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- A61P37/02—Immunomodulators
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Virology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2001/003355 WO2002076953A1 (fr) | 2001-03-21 | 2001-03-21 | Nouveaux derives spirotricycliques et utilisation de ces derives en tant qu'inhibiteurs de la phosphodiesterase-7 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200306601B true ZA200306601B (en) | 2004-08-25 |
Family
ID=8164349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200306601A ZA200306601B (en) | 2001-03-21 | 2003-08-25 | New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors. |
Country Status (47)
Families Citing this family (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1400244A1 (fr) | 2002-09-17 | 2004-03-24 | Warner-Lambert Company LLC | Nouveaux quinazolinones spirocondensés et leur utilisation comme inhibiteurs de la phosphodiesterase |
| GB0230195D0 (en) * | 2002-12-24 | 2003-02-05 | Biofocus Plc | Compound Libraries |
| EP2617419A1 (fr) | 2003-04-24 | 2013-07-24 | Incyte Corporation | Dérivés d'aza-spiro-alcanes utilisés comme inhibiteurs de métalloprotéases |
| JP2006219373A (ja) | 2003-06-13 | 2006-08-24 | Daiichi Asubio Pharma Co Ltd | Ｐｄｅ７阻害作用を有するピリジニルピラゾロピリミジノン誘導体 |
| JP2006219374A (ja) | 2003-06-13 | 2006-08-24 | Daiichi Asubio Pharma Co Ltd | Ｐｄｅ７阻害作用を有するイミダゾトリアジノン誘導体 |
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