WO2004002484A1 - ホスホジエステラーゼ阻害剤 - Google Patents
ホスホジエステラーゼ阻害剤 Download PDFInfo
- Publication number
- WO2004002484A1 WO2004002484A1 PCT/JP2003/008079 JP0308079W WO2004002484A1 WO 2004002484 A1 WO2004002484 A1 WO 2004002484A1 JP 0308079 W JP0308079 W JP 0308079W WO 2004002484 A1 WO2004002484 A1 WO 2004002484A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- unsubstituted
- acceptable salt
- compound
- lower alkyl
- Prior art date
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- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 title description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 80
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 78
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 26
- 239000004480 active ingredient Substances 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 20
- 229940123773 Phosphodiesterase 10A inhibitor Drugs 0.000 claims abstract description 10
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract 24
- 150000001875 compounds Chemical class 0.000 claims description 173
- -1 cyano, amino Chemical group 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 101100243082 Caenorhabditis elegans pde-1 gene Proteins 0.000 claims description 27
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- 201000010099 disease Diseases 0.000 claims description 23
- 239000003112 inhibitor Substances 0.000 claims description 22
- 208000012661 Dyskinesia Diseases 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 230000000069 prophylactic effect Effects 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
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- 230000001225 therapeutic effect Effects 0.000 claims description 8
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- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 150000001924 cycloalkanes Chemical class 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
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- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 241000270666 Testudines Species 0.000 claims description 2
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
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- 241001553014 Myrsine salicina Species 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
- C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
Definitions
- the present invention relates to phosphodiesterase 1 OA (PDE10A) inhibitory activity and various diseases derived from hyperfunction of PDE1OA (eg, Parkinson's disease, Huntington's disease, Alzheimer's disease, etc.) Quinoline useful for the treatment of neurological diseases, dyskinesia, sexual dysfunction, diabetes, ischemic heart disease, hypertension, inflammatory diseases, digestive diseases, allergic diseases, osteoporosis, pain, malignant tumors, etc.
- PDE10A inhibitor containing a derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- Cyclic nucleotides are known to mediate cellular responses to many extracellular stimuli, such as, for example, stimulation from G protein-coupled receptors (GPCRs).
- Phosphodiesterase PDE is, for example, 3 ', 5'-cyclic adenosine monophosphate
- PDE 1 OA One of the subtypes of PDE, PDE 1 OA, is used for many tissues, organs, aortic smooth muscle cells, such as the striatum, testis, kidney, thyroid, pituitary gland, thalamus, cerebellum, heart, lung, placenta, etc.
- aortic smooth muscle cells such as the striatum, testis, kidney, thyroid, pituitary gland, thalamus, cerebellum, heart, lung, placenta, etc.
- mRNA is found in cells such as aortic endothelial cells and cancer cells such as small cell lung cancer, breast cancer and colorectal cancer, and is involved in diseases involving these cells, tissues, organs, etc.
- this enzyme can be used to develop, e.g., develop Parkinson's disease, Huntington's disease, etc. -DOPA; L-3, 4-dihydroxypheny Ia anine) may be involved in dyskinesia induced by long-term administration.
- mRNA expression of PDE10A is different from that of normal mice in the striatum of a model mouse with Huntington's disease (W01 / 24781).
- PDE10A catalyzes the hydrolysis of cGMP to GMP, and since this hydrolase is present in the corpus cavernosum, PDE1OA inhibitors are useful for erectile dysfunction in men, women It is considered possible to improve the sexual dysfunction such as from (JP 2000-23682 JP) c above, PDE 1 inhibitors that have OA selectivity (PDE 1 OA inhibitor)
- OA hyperfunction Various diseases derived from OA hyperfunction (e.g., neurological diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, dyskinesia, sexual dysfunction, diabetes, ischemic heart disease, hypertension, inflammatory disease, gastrointestinal disease It is useful for the treatment and / or prevention of allergic diseases, osteoporosis, pain, malignant tumors, etc., and is expected to be a therapeutic drug with reduced side effects.
- R a represents carbonyl, etc.
- R b and R ° are the same or different and represent methyl, ethyl, hydrogen atom, fluorine atom, etc.
- R d and R e represent a hydrogen atom.
- R d and quinolinecarboxylic acid derivative R e is represented by representing) the combined such connexion sulfur atom, cancer chemotherapeutic agents (JP-a-2-233661), immunosuppressants (W0 92/00739) Is known to be useful.
- R ai represents a fluorine atom or the like
- R bi represents a methyl or the like
- R di and R ei are the same or different and represent a halogen, a hydrogen atom, or the like
- R fi is carboxy or its inorganic
- This 4-quinoline carboxylic acid derivative is, for example, a dihydroorotate dehydrogenase inhibitor [W001 / 24785, Pharmaceutical Research (Pharm. Res.), Vol. 15, p. 286 (1998), Biochemical Pharmacology (Biochem. Pharmacol.), 40 volumes, 709 pages
- An object of the present invention is to exhibit PDE 1 OA inhibitory activity and to induce various diseases caused by hyperfunction of PDE 10 A (for example, neurological diseases such as Parkinson's disease, Huntington's disease, and Alzheimer's disease, dyskinesia, sexual dysfunction) Quinoline derivatives useful for the treatment and Z or prevention of diabetes, ischemic heart disease, hypertension, inflammatory disease, gastrointestinal disease, allergic disease, osteoporosis, pain, malignant tumor, etc. or pharmacologically acceptable.
- diseases caused by hyperfunction of PDE 10 A for example, neurological diseases such as Parkinson's disease, Huntington's disease, and Alzheimer's disease, dyskinesia, sexual dysfunction
- Quinoline derivatives useful for the treatment and Z or prevention of diabetes, ischemic heart disease, hypertension, inflammatory disease, gastrointestinal disease, allergic disease, osteoporosis, pain, malignant tumor, etc. or pharmacologically acceptable.
- An object of the present invention is to provide a PDE 1 OA inhibitor containing a salt as an active ingredient. Another purpose An object of the present invention is to provide a quinoline derivative or a pharmacologically acceptable salt thereof useful for the treatment and Z or prevention of various diseases derived from PDE 1 OA hyperfunction, and the present invention provides the following (1) To (33).
- n represents an integer of 1 to 4
- R 1 is a substituted or unsubstituted lower alkyl
- R 9 (wherein Y represents an oxygen atom or a sulfur atom, and R 9 is a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted Represents aryl, substituted or unsubstituted heterocyclic group, amino, mono-lower alkylamino or di-lower alkylamino), hydroxy, halogen, cyano, amino, mono-lower alkylamino or di-lower alkylamino, R 2 Is hydrogen atom, amino, nitro, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, -S (0) m R 12 (where R 12 is substituted or unsubstituted lower alkyl or It represents a Ariru substituted or unsubstituted, m is an integer of 0 to 2), represents a mono-
- Substituted cycloalkyl, substituted or unsubstituted lower alkoxy, -S (0) ma R 12a (wherein R 12a and ma have the same meanings as R 12 and m, respectively, -C ⁇ Y 1 ) ! ⁇ (wherein, Y 1 and R 9a are the same meanings as defined above, respectively Y and), when represents a mono-lower alkylamino or di-lower alkylamino, but is an integer of 2 or more, respectively R 4 is represented by may be the same or different]
- a phosphoesterase 10A (PDE10A) inhibitor comprising, as an active ingredient, a quinoline derivative or a pharmaceutically acceptable salt thereof.
- R 3 is a general formula (A) '
- R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom, a halogen, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, an aryl, a substituted or unsubstituted lower alkyl. Or a substituted or unsubstituted heterocyclic group] or a substituted or unsubstituted lower alkyl at the 4-position or a piperazine-1-yl having a substituted or unsubstituted aryl.
- the PDE1OA inhibitor according to any one of (1) to (3).
- R 2A is carboxyethyl or methoxycarbonylethyl
- R 3A is 4- (2-fluorophenyl) phenyl or biphenyl-1-yl
- R 1A is hydroxymethyl or —C (20)
- R 9D (where R 9D represents amino or lower alkoxy) and R 2A is methyl
- R 3A is Le 4 quinoline derivative or a pharmacologically acceptable salt thereof represented by the not] in Iru.
- R 3A is substituted or unsubstituted biphenylyl or substituted or unsubstituted The quinoline derivative or the pharmaceutically acceptable salt thereof according to the above (9), which is razinyl.
- R 3A is substituted or unsubstituted biphenylyl or substituted or unsubstituted lower alkyl as a substituent at position 4 or pyrazine-1-yl having a substituted or unsubstituted aryl.
- R 3A is substituted or unsubstituted biphenylyl or substituted or unsubstituted lower alkyl as a substituent at position 4 or pyrazine-1-yl having a substituted or unsubstituted aryl.
- a PDE10A inhibitor comprising, as an active ingredient, the quinoline derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (15).
- a therapeutic and / or Z- or prophylactic agent for dyskinesia comprising as an active ingredient a compound having a PDE10A inhibitory activity or a pharmacologically acceptable salt thereof.
- a medicament comprising the quinoline derivative or the pharmaceutically acceptable salt thereof according to any of the above (9) to (15) as an active ingredient.
- a method for treating dyskinesia which comprises administering an effective amount of the quinoline derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (15).
- a method for treating a malignant tumor which comprises administering an effective amount of the quinoline derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (15).
- a method for treating dyskinesia which comprises administering an effective amount of a compound having a PDE10A inhibitory activity or a pharmacologically acceptable salt thereof.
- the lower alkyl moiety of lower alkyl, lower alkoxy, mono-lower alkylamino and di-lower alkylamino includes, for example, linear or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, isooctyl, nonyl, decyl and the like.
- the two lower alkyl moieties in the di-lower alkylamino may be the same or different.
- cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl, and the like.
- the alkylene part of (ii) hydroxy lower alkyl has the same meaning as the above lower alkyl ( ⁇ ) with one hydrogen atom removed.
- Examples of the lower alkanoyl include straight-chain or branched alkanols having 7 to 7 carbon atoms, specifically formyl, acetyl, propionyl, butyryl, isobutyryl, Valerile, isovaleryl, bivaloyl, hexanoyl, heptanyl and the like.
- aryl examples include aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl and the like.
- the heterocyclic group includes an alicyclic heterocyclic group and an aromatic heterocyclic group.
- the aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring.
- Examples of the alicyclic heterocyclic group include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 to 8 A condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a condensed bicyclic or tricyclic fused ring.
- Halogen means each atom of fluorine, chlorine, bromine and iodine.
- Examples of the condensed ring formed together with the two carbon atoms at the root include a cycloalkane condensed with a benzene ring.
- Examples of the cycloalkyne moiety of the cycloalkyne fused to the benzene ring include cycloalkanes having 5 to 8 carbon atoms, specifically, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like.
- condensed cycloalkane examples include indane, 1,2,3,4-tetrahydronaphthalene, 6,7,8,9-tetrahydro-5H-benzocycloheptene, 5,6,7 , 8, 9, 10—hexahydrobenzocyclooctene and the like.
- Substituents in substituted lower alkyl, substituted lower alkoxy, substituted cycloalkyl and substituted lower alkanoyl may be the same or different and have, for example, 1 to 3 substituents such as halogen, hydroxy, carbonyl, cyano, cycloalkyl, substituted or unsubstituted.
- halogen cycloalkyl, lower alkyl and lower alkoxy, lower alkanol, aryl and heterocyclic group shown above are the halogen (vii), cycloalkyl (ii), lower alkyl (i), lower alkyl, respectively.
- Alkanoyl cycloalkyl, lower alkyl and lower alkoxy, lower alkanol, aryl and heterocyclic group shown above are the halogen (vii), cycloalkyl (ii), lower alkyl (i), lower alkyl, respectively.
- substituent (a) in the substituted lower alkoxy, substituted lower alkyl and substituted lower alkanol shown here are the same or different and include, for example, hydroxy having 1 to 3 substituents, halogen and the like.
- substituent (b) in the substituted heterocyclic group may be the same or different, and include, for example, hydroxy, halogen, lower alkyl, lower alkoxy, lower alkanol, aryl and the like having 1 to 3 substituents.
- halogen the lower alkyl portion of the lower alkyl and the lower alkoxy, the lower alkanol and the aryl shown above are the halogen (vii) and the lower alkyl, respectively. ), Synonymous with lower alkanol (iv) and aryl (v).
- the substituents in the substituted aryl are the same or different and are, for example, 1 to 3 carboxy, hydroxy, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted And a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group and the like. Further, the substitution position is not particularly limited.
- halogen the lower alkyl portion of the lower alkyl and the lower alkoxy, the lower alkanol, the aryl and the heterocyclic group represented by the above-mentioned halogen (vii), lower alkyl (i), lower alkanol ( ⁇ ), aryl (V) And synonymous with heterocyclic group (vi).
- substituent (c) in the substituted aryl shown here in addition to the groups mentioned in the definition of the substituent (ix) in the above-mentioned substituted lower alkyl, substituted or unsubstituted lower alkyl [the lower alkyl is And the substituent in the substituted lower alkyl has the same meaning as the group (ix) in the definition of the substituent in the substituted lower alkyl]. Further, the substituent in the substituted lower alkyl, the substituted lower alkoxy and the lower alkanol shown herein has the same meaning as the substituent (a) in the substituted lower alkoxy and the like, and the substituent in the substituted heterocyclic group is the same as the substituted aryl. Has the same meaning as the substituent (G) in
- substitution position is not particularly limited.
- the halogen, the lower alkyl moiety of the lower alkyl and the lower alkoxy, the lower alkanol, and the aryl represented by the heterocyclic group represented by the halogen (vii), has the same meaning as lower alkyl (i), lower alkanol (iv;), aryl (V) and heterocyclic group (vi).
- the substituents in the substituted lower alkyl, substituted lower alkoxy and substituted lower alcohol shown here are the same as those defined in the definition of the substituent such as the substituted lower alkyl.
- Pharmaceutically acceptable salts of compound (I) or compound (IA) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. .
- Pharmaceutically acceptable acid addition salts of compound (I) or compound (IA) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, and the like.
- Organic salts such as benzenesulfonate, benzoate, citrate, fumarate, gluconate, lactate, maleate, malate, oxalate, methanesulfonate, tartrate, etc.
- pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like.
- pharmacologically acceptable ammonium salts include salts of ammonium, tetramethylammonium, and the like.
- Examples of the pharmacologically acceptable salts of organic amines include morpholine and pyriamide.
- Such addition salts mentioned et al are of the emissions, as the pharmacologically acceptable amino acid addition salts, glycine, phenylene Ruaranin, lysine, Asuparagin acid addition salts glutamic and the like.
- a method for producing compound (I) and compound (IA) will be described.
- the defined groups change under the reaction conditions or are not suitable for carrying out the method, methods commonly used in organic synthetic chemistry, such as protection and deprotection of functional groups, are used. Protection [e.g., Protective Group's 'in' organic ⁇ Protective Groups in Organic Synthesis (third edition), written by TWGreene, John 'Wiley' and John Wiley & Sons Inc. (1999)]
- the production can be easily carried out by applying the means.
- the order of reaction steps such as introduction of a substituent can be changed as necessary.
- Compound (I) can be produced, for example, by the following steps.
- R 1 is carboxy
- R 3 is R 3a , wherein R 3a is a substituted or unsubstituted aryl which is the same as the aryl (V),
- R 3a is a substituted or unsubstituted aryl which is the same as the aryl (V)
- the substituent in the substituted aryl has the same meaning as the substituent (X) in the substituted aryl).]
- Z is a substituted or unsubstituted monohalogenated aryl (the monohalogenated aryl)
- the halogen part of the reel means each atom of chlorine, bromine or iodine
- the aryl part of the monohalogenated aryl has the same meaning as the aryl (V)
- the substitution in the substituted monohalogenated aryl The group has the same meaning as the substituent (X) in the above substituted aryl (excluding halogen)) or a substituted or unsubstituted trifluoromethanesulfonyloxyaryl (an aryl of the trifluoromethanesulfonyloxyaryl)
- the substituent is the same as the aryl (V), and the substituent in the substituted trifluoromethanesulfonyloxyaryl is the same as the substituent (X) in the substituted aryl (excluding the halogen);
- R 8 is a substituted or unsubstitute
- Step 1 Compound (a) is a compound (a-1) Reaction with 1-2 equivalents of the compound (a-2) [Fittinger reaction (Pfitzger reaction); Journal of Organic Chemistry (J. Org. Chem.), Vol. 18, p. 1209 (1953) etc.].
- the compound (a-1) is treated with an aqueous solution of a base such as sodium hydroxide or potassium hydroxide or a solvent such as ethanol or methanol containing ammonia water or the like in an amount of 1 to 2 equivalents of the compound (a-2).
- a base such as sodium hydroxide or potassium hydroxide
- a solvent such as ethanol or methanol containing ammonia water or the like
- the compound (a) can be obtained by acidifying the reaction mixture with a mineral acid such as hydrochloric acid or an organic acid such as acetic acid.
- the compound (a-1) as a raw material can be obtained by the method described in Advanced @ heterocyclic * Chemie (Adv. Het. Chem.), Vol. 18, p. 1 (1975) or the like, or according to the method.
- Compound (a-2) is commercially available when Z is a monohalide aryl, or as a commercially available product or in the journal “Ob. Organic. Chem.”, Vol. 27, p. 70 (1962) And the like, or according to them.
- Step 2 Compound (I-a) is obtained by subjecting compound (a) obtained in Step 1 to a corresponding boronic acid reagent (compound (a-3)) in a Suzuki Ichinomiyaura reaction [Suzuki Ichinomiyaura reaction: Chemical Co., Ltd.] Review (Chem. Rev.), Vol. 95, p. 2457 (1995), etc.].
- compound (a) may be prepared by adding 1 to 2 equivalents of compound (a-3) in an inert solvent, in the presence of a palladium catalyst, and 1 to 5 equivalents of base, at 25 ° C to the boiling point of the solvent used.
- the compound (Ia) is obtained by reacting at a temperature of 5 minutes to 24 hours.
- the palladium catalyst include bis (tri-o-tolylphosphine) palladium (II) dichloride, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium and the like.
- the base examples include pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and the like.
- the inert solvent for example, methanol, ethanol, octamethylform, N, M-dimethylformamide (DMF), dioxane and the like can be mentioned.
- the raw material compound (a-3) can be used as a commercial product or as an organometallic
- Step 3 Compound (b) is a compound having the carboxyl group of compound (a) obtained in Step 1 After conversion to an ester such as methyl ester, ethyl ester or hydroxybenzotriazole ester by a well-known method in the field of synthetic organic chemistry [see Synthesis, p. 929 (1985)], a reduction reaction is performed. See Hoken Experimental Chemistry, 4th Edition, 15 (Oxidation and Reduction II), Maruzen, 158, 179 (1977).
- compound (a) is dissolved in an inert solvent such as dichloromethane, 1,2-dichloroethane, chloroform, DMF, dioxane or the like in the presence of 1 to 5 equivalents of a base, to 2 equivalents of N, N-dimethyl.
- a base such as dichloromethane, 1,2-dichloroethane, chloroform, DMF, dioxane or the like
- the corresponding N, N-dimethylacyloxymethane imidium chloride can be obtained by reacting chloromethane imidinyl chloride at a temperature between -20 ° C and the boiling point of the solvent used for 5 minutes to 24 hours.
- the body is obtained.
- the base used here include pyridine, triethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and the like.
- N, N-dimethylacyloxymethaneiminium chloride is dissolved in a solvent in the presence of 1 to 5 equivalents of a base.
- a solvent used here include dichloromethane and DMF
- examples of the base include pyridine, triethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.
- Compound (a) can be prepared by reacting compound (a) in the presence of an acid catalyst such as sulfuric acid, in a solvent free or in an inert solvent, for example, in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, DMF, dioxane, or the like.
- an acid catalyst such as sulfuric acid
- a solvent free or in an inert solvent for example, in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, DMF, dioxane, or the like.
- the corresponding ester such as methyl ester or ethyl ester
- the compound (a) is reacted with thionyl chloride in the presence or absence of a base, in a solvent or in an inert solvent such as benzene or toluene, and then reacted with a corresponding alcohol such as methanol or ethanol.
- the corresponding ester such as methyl ester or ethyl ester can be obtained.
- the base used herein includes, for example, pyridine, triethylamine, N-methylmorpholine, carbonated sodium, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide and the like.
- the above-obtained hydroxybenzotriazole ester or ester is converted into a protic polar solvent or an aprotic solvent, for example, in the presence of 2 to 5 equivalents of a reducing agent, at a temperature between 0 ° C. and the boiling point of the solvent used.
- Compound (b) is obtained by treating at a temperature for 5 minutes to 24 hours.
- Examples of the protonic polar solvent include methanol, ethanol, and isopropyl alcohol
- examples of the aprotic solvent include tetrahydrofuran (THF) and getyl ether.
- Examples of reducing agents include sodium borohydride, lithium aluminum hydride (LAH). When LAH is used, it is preferable to use an aprotic solvent.
- the raw material N, N-dimethylchloromethaneiminium dichloride should be prepared from oxalyl chloride and DMF according to the method described in, for example, Synthesis, p. 929 (1985) or a method similar thereto. Can be.
- Step 4 In the same manner as in the method described in step 2, compound (b) can be obtained from compound (b) and compound (a-3) obtained in step 3.
- Step 5 Converting the hydroxymethyl group of the compound obtained in Step 4 (trib) into a co-methyl group [Experimental Chemistry Lecture, 4th Edition 19 (Organic Synthesis I Hydrocarbons ⁇ halides), Maruzen, p. 444
- the compound (I-b) is reacted in 5-10 equivalents of thionyl chloride at a temperature between 0 ° C. and the boiling point of thionyl chloride for 5 minutes to 24 hours to convert to the corresponding methyl compound. Then, this chloromethyl compound is treated with 2 to 5 equivalents of sodium borohydride in an inert solvent at a temperature between 0 ° C and the boiling point of the solvent to be used for 5 minutes to 24 hours. The compound (lc) is obtained.
- inert solvent examples include dioxane.
- Production Method 3 Among compounds (I), a compound (Rk) wherein R 3 is hydroxy or halogen can be obtained by the method described in WO 97/00074 or a method analogous thereto.
- Production method 4 In compound (I), R 1 is methoxycarbonyl, carboxy or hydroxymethyl Wherein R 3 is a substituted or unsubstituted piperazine-11-yl (d d), compound (d e) or compound (d f) can be produced according to the following reaction steps.
- step 6 R 1 turtles Bok alkoxycarbonyl out of the compound obtained in process 3 (Bok k), R 3 Is converted to a trifluoromethanesulfonyloxy group according to the method described in WO 97/00074 or a method analogous thereto.
- the compound (d) can be obtained by reacting the obtained trifluoromethanesulfonate with the compound (d).
- a compound (I-ka) may be prepared in an inert solvent in the presence of 1 to 3 equivalents of a base, 1 to 3 equivalents of, for example, trifluoromethanesulfonic anhydride, and a solvent having a temperature between 0 ° C and the boiling point of the solvent used. By reacting at a temperature for 5 minutes to 24 hours, it can be converted to trifluoromethanesulfonate.
- a base used include pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.
- the inert solvent examples include dichloromethane, 1,2-dichloroethane, chloroform, DMF, dioxane, and acetonitrile.
- the trifluoromethanesulfonate compound is dissolved in an inert solvent in the presence of 1 to 3 equivalents of a base and 1 to 3 equivalents of the compound (d) at a temperature between 0 ° C. and the boiling point of the solvent used. The reaction is carried out for a period of minutes to 24 hours to obtain the compound (tri-d).
- the base used here includes, for example, pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.
- Step 7 Hydrolyzing the compound ( ⁇ d) [Experimental Chemistry Lecture, 4th edition 22 (Organic synthesis IV acid diamino acid 'peptide), see Maruzen, p. 7 (1992)] to give the compound ( ⁇ d) e) can be obtained.
- Step 9 The method described in JP-A-10-231289, JP-A-8-3144, W095 / 10505, etc.
- the compound (tri-h) is obtained by converting the hepoxyl group of the compound (tri-g) obtained according to them into a chloro-propyl group and treating the acid chloride with aqueous ammonia. (See JP-A-10-231289, etc.).
- a compound (lg) is prepared by adding 1 to 10 equivalents of a chlorinating agent to an inert solvent such as benzene or toluene in the presence or absence of a base and the boiling point of the solvent or chlorinating agent used at 0 ° C. By reacting at a temperature between 5 minutes and 24 hours, it can be converted to acid chloride.
- a base include pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and the like.
- the chlorinating agent include thionyl chloride, phosphoryl chloride, oxalyl chloride and the like.
- the acid chloride is treated with 1 to 5 equivalents of aqueous ammonia in an inert solvent at a temperature between 0 ° C. and the boiling point of the solvent to be used for 5 minutes to 24 hours to obtain a compound (I-h).
- the inert solvent include dichloromethane, 1,2-dichloroethane, chloroform, dimethyl ether, THF, toluene, DMF, dimethyl sulfoxide and the like.
- Step 10 The compound (tri-i) can be obtained by treating the compound (tri-h) with, for example, a chlorinating agent or the like [Journal of Ob'American ', Chemical Society (J. Am. Chem. Soc.), Vol.
- compound (I-h) for example, by treating compound (I-h) in 1 to 10 equivalents of a chlorinating agent at a temperature between 0 ° C. and the boiling point of the chlorinating agent to be used for 5 minutes to 24 hours, compound (tri i) Is obtained.
- a chlorinating agent include thionyl chloride, phosphoryl chloride, oxalyl chloride and the like.
- Step 11 1 The compound (Ij) can be obtained by treating the labamoyl group of the compound (I-h) with, for example, hypochlorite or hypobromite [Hofmann rearrangement (Hofmann rearrangement) Dislocation); Laboratory Chemistry, 4th Edition, 20 (Organic Synthesis II Alcohol'amine), Maruzen, p. 304 (1991)].
- hypochlorite or hypobromite Hofmann rearrangement (Hofmann rearrangement) Dislocation); Laboratory Chemistry, 4th Edition, 20 (Organic Synthesis II Alcohol'amine), Maruzen, p. 304 (1991)].
- compound (lh) is mixed with 1 to 5 equivalents of hypochlorite or hypobromite in a protic polar solvent at a temperature between 0 ° C. and the boiling point of the solvent to be used for 5 minutes to 24 hours.
- a compound (group j) is obtained.
- protic polar solvent examples include water, ethanol, methanol and the like.
- Production Method 6 Among the compounds (I), the compound wherein R 1 is methoxycarbonyl, hydroxymethyl or methyl is prepared by the method described in Step 3 and Step 5 of Production Method 2, respectively, or according to them. It can also be produced from the starting compound (I-g) used in Production Method 5.
- Production Method 7 Compound (I) can be produced, for example, by the following method, in addition to the methods described in Production Methods 1 to 6 above.
- compounds in which R 2 and R 3 together with the two carbon atoms at the roots together form a substituted or unsubstituted fused ring are, for example, bioorganic and medicinal chemicals.
- the compound (IA) can be produced in the same manner as in the above compound (I).
- the intermediates and target compounds in each of the above production methods are subjected to separation and purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. It can be isolated and purified. Further, the intermediate can be subjected to the next reaction without purification.
- Some of the compounds (I) or (IA) may have stereoisomers such as geometric isomers and optical isomers, and all possible isomers including these and isomers of the isomers Mixtures in any ratio can be used for the PDE 1 OA inhibitors of the present invention.
- compound (I) or (IA) when compound (I) or (IA) is obtained in the form of a salt, the compound may be purified as it is, and when compound (I) or (IA) is obtained in a free form, compound (I) or (IA) may be dissolved or suspended in an appropriate solvent, and then isolated or purified by adding an acid or a base.
- Compound (I) or (IA) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also used in the present invention. Can be used for PDE 10 inhibitors.
- Specific examples of the compound (IA) obtained by the present invention are shown in Tables 1 to 3. However, the compound of the present invention is not limited to these. Table 1 Conversion
- Test Example 1 PDE 1 OA inhibitory activity ([3 H] cAMP degradation inhibiting test) PGR was performed using each DNA having the nucleotide sequence shown in SEQ ID NO: 1 and SEQ ID NO: 2 as a primer and human kidney GDNA as type II to prepare a plasmid containing the amplified fragment.
- the plasmid was cut with restriction enzymes E ⁇ I and ⁇ ⁇ 1 to obtain a 0.7 kb Eil- ⁇ I fragment.
- the ⁇ inH I-j ⁇ nl cut surface prepared by using the obtained
- the linker was subcloned into the BamHI-NotI site of pVL1393 (PharMingen, San Diego, CA, USA) to obtain a plasmid for producing a baculovirus.
- the plasmid includes methionine, FLAG tag and PDE1OA [GenBank, ACCESSION NP_006652: Gene, 234, 109 pages (1999), Journal of Biological Chemistry (J. Biol). Chem.), Vol. 274, p.
- PDE1OA protein deficiency virus
- Sf9 cells Asahi Technoglass, Tokyo
- PDE1OA expression window prepared according to this manual The supernatant containing the virus (co-transfection sup) was infected to Sf9 cells and cultured at 27 ° C for 4 days. The cells were collected, washed with phosphate buffered saline (PBS), and extracted [20 ol / L Tris-acetate (pH 7.5), 2 fractions ol / L] MgGI 2 ,
- the PDE activity was measured according to the method described in Methods Enzymol., Vol. 159, p. 457 (1988).
- a hydrobromide (8 ug) was infused into the medial forebrain bundle over 3 minutes to destroy the unilateral nigrostriatal nerve.
- desipramine hydrochloride 25 mg / kg was intraperitoneally administered 30 minutes before the operation.
- a rat with a dopamine agonist, apomorphine 0.1 mg / kg was subcutaneously administered to rats and the rats with rotational behavior were successfully destroyed.
- the rats were orally administered 100 mg / kg of L-DOPA and 25 mg / kg of L-DOPA, respectively, to the rats to induce hyperkinesia.
- the number of rotations was measured for 60 minutes immediately after administration, and based on the results of the number of rotations, the number of cases in each group was 8 so that there was no statistically significant difference in the average number of rotations between groups Rats were assigned to groups A and B as described.
- L-DOP A 3 Omg / kg and benserazide 7.5 mg Z kg were orally administered.
- the rotation number was measured every 5 minutes for 60 minutes.
- the total number of revolutions for 60 minutes was 1298 ⁇ 193.
- the number of rotations was 48 ⁇ 20.
- a statistical comparison of the total number of rotations between the vehicle-administered group and the test compound-administered group using the student's t test revealed that this difference was significant at a risk rate of less than 0.1%. From the above results, it was revealed that administration of compound (I) suppressed hyperkinesia in 6-OHDA-treated rats.
- C Test example 3 Cell proliferation inhibitory activity In vitro cell proliferation assay ⁇ 3- (4,5-dimethylthiazole- 2-yl) -2,5-diphenyltetrazolium bromide [3- (4,5-dimethythythiazolI-2-yI) -2,5-diphenyltetrazolium bromide (MTT)]-colorimetric Using Atsushi [Leukemia, Vol. 7, p. 1637, (1993)], the inhibitory effect of compound 12 on the cell proliferation of MDA-MB-231 (human breast cancer cells; manufactured by American Type Culture Co., Ltd.) was investigated. investigated.
- MDA-B-231 (2.5 x 10 4 cells / m and 270 iL) was seeded on a 48-well plate and cultured for 1 hour.
- Leibovitz's L-15 (Gibco) containing 10% fetal serum (Hyclone), 0.05 units / mL penicillin (Gibco) and 0.05 jUg / mL streptomycin (Gibco) was used as a medium.
- Compound 1230 / L dissolved in the same medium containing 0.1% dimethyl sulfoxide (DMS0; Wako Pure Chemical Industries) was added to each medium. Was added.
- the cell proliferation inhibition rate (3 ⁇ 4) was determined by setting the fluorescence intensity (OD 5go — 630 ) of the group to which compound 12 (medium containing compound 12 and 0.1% DMS0) was added to 0D (sample), and the group to which no compound was added (0.1%). % Of the medium containing only DMS0 ) (0D 59M3Q )
- compound (I) or (IA) or a pharmacologically acceptable salt thereof has a PDE 1 OA inhibitory effect, and various diseases derived from PDE 1 OA function enhancement [eg, Parkinson's] Disease, tremor, dyskinesia (L-DOPA-induced dyskinesia; tardive dyskinesia, myoclonus, tics, turret syndrome), Huntington's disease, dystonia, anxiety disorder (panic attack and panic disorder, phobia, obsessive-compulsive disorder) , Post-traumatic stress disorder, acute stress disorder, general anxiety disorder, physical or substance anxiety), mood disorder (depression, dysthymia disorder, bipolar disorder, mood circulation disorder) , Cognitive impairment (aphasia, apraxia, agnosia, delirium, dementia, amnesia), emotional disorders associated with drug abuse and discontinuation, schizophrenia and related disorders (short term Degenerative disorders, schizophrenia-like disorders, schizoaffective disorders, delus
- the pharmaceutical preparations are intended for use in animals or humans.
- the pharmaceutical preparations according to the present invention may be compounds (I) or (IA) as active ingredients or pharmacology thereof.
- the pharmaceutical preparations can contain a pharmaceutically acceptable salt alone or as a mixture with any other active ingredient for treatment.
- the pharmaceutical preparations contain one or more pharmaceutically acceptable active ingredients. It is mixed with a further carrier and prepared by any of the methods well-known in the art of pharmacy, preferably using the most effective route for treatment, orally or For example, parenteral administration, such as intravenous administration, etc. Examples of the administration form include tablets, capsules, injections, etc.
- Examples of the pharmaceutical carrier used include, for example, Examples include toose, mannitol, glucose, hydroxypropylcellulose, starch, magnesium stearate, sorbitan fatty acid ester, glyceric acid ester, polyvinyl alcohol, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, and ethanol. Further, the pharmaceutical preparation according to the present invention may contain various other excipients, lubricants, binders, disintegrants, isotonic agents, emulsifiers, etc. Compound (I) or compound When (IA) or a pharmacologically acceptable salt thereof is used for the above purpose, it is usually administered systemically or locally, orally or parenterally. Is done.
- the dosage and frequency of administration will vary depending on the form of administration, the age and weight of the patient, the nature or severity of the condition to be treated, etc., but is usually ⁇ 900 mg, preferably 1-200 mg per adult per day. It is preferable to administer in 3 to 4 divided doses. However, these dosages and the number of administrations vary depending on the various conditions described above.
- BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to examples and reference examples. However, the scope of the present invention is not limited to these examples. In the proton nuclear magnetic resonance spectrum (H- ⁇ R) used in the reference examples and the examples, the notation of signal multiplicity is usually used, but br is a signal that is apparently wider. Indicates that there is.
- Reference Example 1 2- (4-bromophenyl) 1-fluoro-3-methylquinoline-4-carboxylic acid (Compound A)
- Example 12 6-Fluoro-4-hydroxymethyl-13-methyl-2- (2′-morpholinomethylbiphenyl-14-yl) quinoline dihydrochloride (Compound 12) Reference Examples 10 and To the free base of compound 12 obtained in the same manner, 338 ⁇ _ (1.35 mmol) of 4 mol / L hydrochloric acid / ethyl acetate solution was added, and the solvent was distilled off. The residue was recrystallized from ethanol. As a result, 91 mg (0.176 mmol) of the title compound (compound 12) was obtained as pale brown crystals (yield: 65%).
- Example 14 6-Fluoro-2- ⁇ 2 '— [(2-hydroxyethyl) amino] methylbiphenyl-1-yl ⁇ —4-hydroxymethyl-13-methylquinoline Dihydrochloride (Compound 14)
- Compound 14 was obtained by subjecting the free base of compound 14 obtained in the same manner as in Reference Example 10 to the same operation as in Example 12. Yield: 37% (recrystallized from ethanol; white powder)
- Example 15 6-Fluoro-3-methyl-1-([1,1 ′ : 2 ', 1''-terphenyl] -4-yl) quinoline-1.4-methyl ribonate (compound 15)
- Compound 420 mg (0.97 mmol) of compound C obtained in Reference Example 1 was ice-cooled and chlorided. The mixture was added slowly to thionyl 6 and stirred at room temperature for 2 hours. After completion of the reaction, thionyl chloride was distilled off, 50 mL of toluene was added, and the solvent was distilled off again.
- Example 16 4-acetyl-16-fluoro-3- Methyl-1-([1,1 ': 2'.1''-terphenyl] -4-1yl) quinoline (compound 16)
- Compound 136 mg (compound 16) obtained in Example 15 under an argon stream 0.304 g) was dissolved in 10 mL of THF, cooled to ⁇ 78 ° C., and 0.89 mL (0.91 mmol) of a 1.03 mol / L methyllithium solution in getyl ether was slowly added.
- Example 17 6-Fluoro-3-methyl-2-([1, 1 ': 2 ',' —terphenyl] —4-yl) quinoline-4 liponitrotriene (compound 17)
- phosphoryl chloride 300 mg (0.65 country ol) of the compound O obtained in Reference Example 13 Addition Then, the mixture was heated under reflux for 2 hours. After completion of the reaction, phosphoryl chloride was distilled off, 50 niL of toluene was added, and the solvent was distilled off again.
- Example 1 8 3, 4-dimethyl-one 6- Furuoro 2- ([1, 1 ': 2 ', 1''-terphenyl] -4-yl) quinoline (compound 18) 250 mg (0.60 traiol) of compound 1 obtained in Example 1 was added to 10 mL of ice-cooled thionyl chloride by adding ⁇ The mixture was stirred at room temperature for 2 hours. After completion of the reaction, thionyl chloride was distilled off, 50 mL of toluene was added, and the solvent was distilled off again.
- Example 21 2- (4-bromophenyl) -1-6-fluoro-4-hydroxymethyl-3-methylquinoline (compound 21)
- a mixture of 5 tnL of DN1F and 9 nl of dichloromethane was added at -20 ° C under an argon stream. Then, a solution of 1.92 mL (20.73 ol) of oxalyl chloride in 6 mL of dichloromethane was added to the dropping funnel. Used and added slowly.
- a tablet having the following composition is prepared by a conventional method.
- Formulation Compound 1 2 20 mg lactose 143.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6 mg 200 mg
- Formulation Example 2 Capsules Prepare capsules of the following composition by the usual method ⁇ Formulation Compound 1 20 mg Avicel 99.5 mg Magnesium stearate 0.5 mg
- Formulation Example 3 Injection Injection having the following composition is prepared by the usual method, Formulation Compound 19 2 mg Purified soybean oil 200 mg Purified egg yolk lecithin 24 mg Glycerin for injection 50 mg Distilled water for injection 1.72 mL
- various diseases having PDE 1 OA inhibitory activity and resulting from hyperactivity of PDE 10 A eg, Parkinson's disease, Huntington's disease, Alzheimer's disease, etc.
- Disease eg, dyskinesia, sexual dysfunction, diabetes, ischemic heart disease, hypertension, inflammatory disease, gastrointestinal disease, allergic disease, osteoporosis, pain, malignant tumor, etc.
- quinoline derivatives useful for Z or prevention
- a PDE 1 OA inhibitor containing a pharmacologically acceptable salt thereof as an active ingredient is provided.
- PDE 1 OA features A quinoline derivative or a pharmacologically acceptable salt thereof useful for treatment and Z or prevention of various diseases caused by hypertension is provided.
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Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU2003244080A AU2003244080A1 (en) | 2002-06-26 | 2003-06-26 | Phosphodiesterase inhibitor |
JP2004517283A JPWO2004002484A1 (ja) | 2002-06-26 | 2003-06-26 | ホスホジエステラーゼ阻害剤 |
EP03761814A EP1541149A1 (en) | 2002-06-26 | 2003-06-26 | Phosphodiesterase inhibitor |
US10/519,197 US20060111368A1 (en) | 2002-06-26 | 2003-06-26 | Phosphodiesterase inhibitor |
CA002493854A CA2493854A1 (en) | 2002-06-26 | 2003-06-26 | Phosphodiesterase inhibitor |
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JP2002-185707 | 2002-06-26 | ||
JP2002185707 | 2002-06-26 |
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WO2004002484A1 true WO2004002484A1 (ja) | 2004-01-08 |
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US (1) | US20060111368A1 (ja) |
EP (1) | EP1541149A1 (ja) |
JP (1) | JPWO2004002484A1 (ja) |
AU (1) | AU2003244080A1 (ja) |
CA (1) | CA2493854A1 (ja) |
WO (1) | WO2004002484A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012112946A1 (en) | 2011-02-18 | 2012-08-23 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
WO2014071044A1 (en) | 2012-11-01 | 2014-05-08 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
WO2014142322A1 (ja) | 2013-03-15 | 2014-09-18 | 第一三共株式会社 | ベンゾチオフェン誘導体 |
US9200016B2 (en) | 2013-12-05 | 2015-12-01 | Allergan, Inc. | Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1841757T3 (pl) * | 2005-01-07 | 2010-10-29 | Pfizer Prod Inc | Heteroaromatyczne związki chinoliny i ich zastosowanie jako inhibitorów PDE10 |
AU2009262150A1 (en) * | 2008-06-25 | 2009-12-30 | Envivo Pharmaceuticals, Inc. | Di-substituted phenyl compounds as phosphodiesterase 10 inhibitors |
KR20110031355A (ko) | 2008-06-25 | 2011-03-25 | 엔비보 파마슈티칼즈, 인코퍼레이티드 | 1,2―이치환된 헤테로사이클릭 화합물 |
WO2010128995A1 (en) | 2009-05-07 | 2010-11-11 | Envivo Pharmaceuticals, Inc. | Phenoxymethyl heterocyclic compounds |
EP4045485A1 (en) | 2019-10-18 | 2022-08-24 | The Regents Of The University Of California | 3-phenylsulphonyl-quinoline derivatives as agents for treating pathogenic blood vessels disorders |
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-
2003
- 2003-06-26 CA CA002493854A patent/CA2493854A1/en not_active Abandoned
- 2003-06-26 EP EP03761814A patent/EP1541149A1/en not_active Withdrawn
- 2003-06-26 US US10/519,197 patent/US20060111368A1/en not_active Abandoned
- 2003-06-26 AU AU2003244080A patent/AU2003244080A1/en not_active Abandoned
- 2003-06-26 WO PCT/JP2003/008079 patent/WO2004002484A1/ja active Application Filing
- 2003-06-26 JP JP2004517283A patent/JPWO2004002484A1/ja not_active Abandoned
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012112946A1 (en) | 2011-02-18 | 2012-08-23 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
US8772316B2 (en) | 2011-02-18 | 2014-07-08 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A) |
US9670181B2 (en) | 2011-02-18 | 2017-06-06 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
WO2014071044A1 (en) | 2012-11-01 | 2014-05-08 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
WO2014142322A1 (ja) | 2013-03-15 | 2014-09-18 | 第一三共株式会社 | ベンゾチオフェン誘導体 |
US9464076B2 (en) | 2013-03-15 | 2016-10-11 | Daiichi Sankyo Company, Limited | Benzothiophene derivative |
US9200016B2 (en) | 2013-12-05 | 2015-12-01 | Allergan, Inc. | Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
US9902710B2 (en) | 2013-12-05 | 2018-02-27 | Exonhit Therapeutics, Sa | Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
Also Published As
Publication number | Publication date |
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AU2003244080A1 (en) | 2004-01-19 |
EP1541149A1 (en) | 2005-06-15 |
US20060111368A1 (en) | 2006-05-25 |
JPWO2004002484A1 (ja) | 2005-10-27 |
CA2493854A1 (en) | 2004-01-08 |
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